Hanne Scholz

• Rao, Joseph Sushil; Barra, Jessie M.; Parmentier, Catherine; Chaudhry, Ahsen; Doherty, Daniel & Komatsu, Hirotake [Show all 11 contributors for this article] (2026). Advances in Beta-cell Replacement Therapy for Diabetes—Insights From the 20th International Pancreas and Islet Transplant Association (IPITA) World Congress, Pisa, 2025. Transplantation. ISSN 0041-1337. doi: 10.1097/TP.0000000000005710. Full text in Research Archive
• Niemi, Essi Maria; Nyman, Tuula Anneli; Attramadal, Håvard; Hoel, Henrik; Rosales, Antonio & Hisdal, Jonny [Show all 7 contributors for this article] (2026). Proteomic evaluation and comparison of native and decellularized human saphenous vein extracellular matrices. Frontiers in Bioengineering and Biotechnology. 14. doi: 10.3389/fbioe.2026.1773372. Full text in Research Archive
• Schöb, Franziska Jessica; Binder, Alexander; Zamarian, Valentina; Sordi, Valeria; Scholz, Hanne & Malthe-Sørenssen, Anders [Show all 7 contributors for this article] (2026). Deep learning for predicting stem cell efficiency for use in beta cell differentiation. Scientific Reports. 16(1). doi: 10.1038/s41598-026-42830-3. Full text in Research Archive Show summary

  Recent clinical trial data show curative potential of cell therapy for diabetes, however the cells required are a bottleneck. Cell differentiation exhibits substantial variability, even among clones of stem cells generated from the same patient. Human experts struggle to see the difference between highly- and lowly-efficient cell clones early. We therefore propose an image-based deep learning model to guide the selection of the most efficient clones. We apply different deep learning models to learn the morphological differences between good and bad stem cell clones and classify them based on phase-contrast imaging. To gain insight into the learned features, we use layer-wise relevance propagation, and Fourier-based frequency analysis. Using an EfficientNet-V2-S model, we obtain a novel early prediction for the outcome of the differentiation process from patient-derived stem cells to β -cells using imaging. Clone level accuracy is 96.7 % at 53 hours after start of differentiation. The analysis of learned features shows that the structure of the cell population is an important predictive feature. This study is a proof-of-concept that deep learning combined with label-free imaging can be highly predictive and guide selection of stem cell clones, thereby reducing cost of β -cell production.

• Josifovska, Natasha; Niemi, Essi Maria; Ramalingam, Murugan; Manivasagam, Geetha; Scholz, Hanne & Petrovski, Goran (2025). A pilot study for decellularizing porcine cornea for future use in corneal regeneration. PLOS ONE. 20(12). doi: 10.1371/journal.pone.0339462. Full text in Research Archive Show summary

  Porcine corneas were decellularized for future use in corneal regeneration by using various washing steps with 3-[(3-cholamidopropyl) dimethylammonio]-1-propanesulfonate (CHAPS) detergent, Benzonase, and Ethylenediaminetetraacetic acid (EDTA). The quality of the decellularized corneas was assessed by quantitative and qualitative measurement of DNA content, glycosaminoglycans (GAGs), immunofluorescent staining for Collagen (Col) I, V, Keratocan, Fibronectin, Laminin, Lumican and Decorin, and Transmission Electron Microscopy (TEM) to observe the structure of the collagen fibrils was used. The decellularization process showed 99.5% DNA content reduction in the corneas and a similar pattern was observed in the preservation of GAGs. Hematoxylin & Eosin (H&E) and immunofluorescent staining showed no presence of cell nuclei, while Alcian blue staining confirmed the presence of GAGs. Col I, V, Keratocan, Fibronectin, Laminin, Lumican and Decorin were still present in the decellularized corneas and TEM microscopy further confirmed the similar patterns of the collagen fibrils in the decellularized, compared to the native corneas. This pilot study showed our method is effective in decellularizing porcine corneas, with a very high amount of DNA being removed, while the GAGs being preserved to an acceptable extent, and the structure and pattern of the collagen fibrils maintained.

• Hrušková, Helena; Olsen, Christine; Řemínek, Roman; Wang, Chencheng; Aizenshtadt, Aleksandra & Krauss, Stefan Johannes Karl [Show all 10 contributors for this article] (2024). Preparative agarose gel electrophoresis for reducing matrix interferences of organoid cell medium prior to LC-MS analysis of insulin. Journal of Chromatography A. ISSN 0021-9673. 1717. doi: 10.1016/j.chroma.2024.464669. Full text in Research Archive Show summary

  Organoids are 3D cell cultures with microanatomies mimicking aspects of real organs, useful for e.g. animal-free studies of development, disease, and drug discovery. The cell medium of organoid models of Langerhans islets, regulating blood glucose levels by insulin secretion, can be analyzed by liquid chromatography-mass spectrometry (LC-MS). However, organoid medium complexity is a major challenge, as matrix interferences can reduce sensitivity and selectivity, even with optimized LC-MS conditions. By applying preparative agarose gel electrophoresis-electrodialysis (PGE-ED), we were able to decrease the cell medium background signal, allowing for reduced interferences affecting LC-MS analysis of human insulin.

• Aizenshtadt, Aleksandra; Wang, Chencheng; Abadpour, Shadab; Menezes, Pedro Duarte; Wilhelmsen, Ingrid & Dalmao-Fernandez, Andrea [Show all 15 contributors for this article] (2024). Pump-Less, Recirculating Organ-on-Chip (rOoC) Platform to Model the Metabolic Crosstalk between Islets and Liver. Advanced Healthcare Materials. ISSN 2192-2640. 13(13). doi: 10.1002/adhm.202303785. Full text in Research Archive Show summary

  Type 2 diabetes mellitus (T2DM), obesity, and metabolic dysfunction-associated steatotic liver disease (MASLD) are epidemiologically correlated disorders with a worldwide growing prevalence. While the mechanisms leading to the onset and development of these conditions are not fully understood, predictive tissue representations for studying the coordinated interactions between central organs that regulate energy metabolism, particularly the liver and pancreatic islets, are needed. Here, a dual pump-less recirculating organ-on-chip platform that combines human pluripotent stem cell (sc)-derived sc-liver and sc-islet organoids is presented. The platform reproduces key aspects of the metabolic cross-talk between both organs, including glucose levels and selected hormones, and supports the viability and functionality of both sc-islet and sc-liver organoids while preserving a reduced release of pro-inflammatory cytokines. In a model of metabolic disruption in response to treatment with high lipids and fructose, sc-liver organoids exhibit hallmarks of steatosis and insulin resistance, while sc-islets produce pro-inflammatory cytokines on-chip. Finally, the platform reproduces known effects of anti-diabetic drugs on-chip. Taken together, the platform provides a basis for functional studies of obesity, T2DM, and MASLD on-chip, as well as for testing potential therapeutic interventions.

• Wang, Chencheng; Abadpour, Shadab; Aizenshtadt, Aleksandra; Dalmao-Fernandez, Andrea; Høyem, Merete & Wilhelmsen, Ingrid [Show all 13 contributors for this article] (2024). Cell identity dynamics and insight into insulin secretagogues when employing stem cell-derived islets for disease modeling. Frontiers in Bioengineering and Biotechnology. 12. doi: 10.3389/fbioe.2024.1392575. Full text in Research Archive Show summary

  Stem cell-derived islets (SC-islets) are not only an unlimited source for cell-based therapy of type 1 diabetes but have also emerged as an attractive material for modeling diabetes and conducting screening for treatment options. Prior to SC-islets becoming the established standard for disease modeling and drug development, it is essential to understand their response to various nutrient sources in vitro. This study demonstrates an enhanced efficiency of pancreatic endocrine cell differentiation through the incorporation of WNT signaling inhibition following the definitive endoderm stage. We have identified a tri-hormonal cell population within SC-islets, which undergoes reduction concurrent with the emergence of elevated numbers of glucagon-positive cells during extended in vitro culture. Over a 6-week period of in vitro culture, the SC-islets consistently demonstrated robust insulin secretion in response to glucose stimulation. Moreover, they manifested diverse reactivity patterns when exposed to distinct nutrient sources and exhibited deviant glycolytic metabolic characteristics in comparison to human primary islets. Although the SC-islets demonstrated an aberrant glucose metabolism trafficking, the evaluation of a potential antidiabetic drug, pyruvate kinase agonist known as TEPP46, significantly improved in vitro insulin secretion of SC-islets. Overall, this study provided cell identity dynamics investigation of SC-islets during prolonged culturing in vitro, and insights into insulin secretagogues. Associated advantages and limitations were discussed when employing SC-islets for disease modeling.

• Mathisen, Andreas Frøslev; Legøy, Thomas Aga; Larsen, Ulrik; Unger, Lucas; Abadpour, Shadab & Paulo, Joao A. [Show all 9 contributors for this article] (2024). The age-dependent regulation of pancreatic islet landscape is fueled by a HNF1a-immune signaling loop. Mechanisms of Ageing and Development. ISSN 0047-6374. 220. doi: 10.1016/j.mad.2024.111951. Full text in Research Archive Show summary

  Animal longevity is a function of global vital organ functionality and, consequently, a complex polygenic trait. Yet, monogenic regulators controlling overall or organ-specific ageing exist, owing their conservation to their function in growth and development. Here, by using pathway analysis combined with wet-biology methods on several dynamic timelines, we identified Hnf1a as a novel master regulator of the maturation and ageing in the adult pancreatic islet during the first year of life. Conditional transgenic mice bearing suboptimal levels of this transcription factor in the pancreatic islets displayed age-dependent changes, with a profile echoing precocious maturation. Additionally, the comparative pathway analysis revealed a link between Hnf1a age-dependent regulation and immune signaling, which was confirmed in the ageing timeline of an overly immunodeficient mouse model. Last, the global proteome analysis of human islets spanning three decades of life largely backed the age-specific regulation observed in mice. Collectively, our results suggest a novel role of Hnf1a as a monogenic regulator of the maturation and ageing process in the pancreatic islet via a direct or indirect regulatory loop with immune signaling.

• Waage, Anne; Khan, Ammar; Labori, Knut Jørgen; Birkeland, Kåre Inge; Scholz, Hanne & Jenssen, Trond [Show all 9 contributors for this article] (2024). Implementation of a nationwide program for total pancreatectomy and islet autotransplantation in chronic pancreatitis: A Scandinavian single-center observational study. Scandinavian Journal of Surgery. ISSN 1457-4969. doi: 10.1177/14574969241298985. Full text in Research Archive
• Wang, Chencheng; Abadpour, Shadab; Olsen, Petter Angell; Wang, Daxin; Stokowiec, Justyna & Chera, Simona [Show all 11 contributors for this article] (2024). Glucose Concentration in Regulating Induced Pluripotent Stem Cells Differentiation Toward Insulin-Producing Cells. Transplant International. ISSN 0934-0874. 37. doi: 10.3389/ti.2024.11900. Full text in Research Archive Show summary

  The generation of insulin-producing cells from human-induced pluripotent stem cells holds great potential for diabetes modeling and treatment. However, existing protocols typically involve incubating cells with un-physiologically high concentrations of glucose, which often fail to generate fully functional IPCs. Here, we investigated the influence of high (20 mM) versus low (5.5 mM) glucose concentrations on IPCs differentiation in three hiPSC lines. In two hiPSC lines that were unable to differentiate to IPCs sufficiently, we found that high glucose during differentiation leads to a shortage of NKX6.1+ cells that have co-expression with PDX1 due to insufficient NKX6.1 gene activation, thus further reducing differentiation efficiency. Furthermore, high glucose during differentiation weakened mitochondrial respiration ability. In the third iPSC line, which is IPC differentiation amenable, glucose concentrations did not affect the PDX1/NKX6.1 expression and differentiation efficiency. In addition, glucose-stimulated insulin secretion was only seen in the differentiation under a high glucose condition. These IPCs have higher KATP channel activity and were linked to sufficient ABCC8 gene expression under a high glucose condition. These data suggest high glucose concentration during IPC differentiation is necessary to generate functional IPCs. However, in cell lines that were IPC differentiation unamenable, high glucose could worsen the situation.

• Berishvili, Ekaterine; Piemonti, Lorenzo; Koning, Eelco J. P. de; Lindstedt, Sandra; Scholz, Hanne & Scott, William E. [Show all 13 contributors for this article] (2024). ESOT Roadmap for Advanced Therapy Medicinal Products in Transplantation: Navigating Regulatory Challenges to Enhance Access and Care. Transplant International. ISSN 0934-0874. 37. doi: 10.3389/ti.2024.13485. Full text in Research Archive Show summary

  The field of organ transplantation is experiencing a transformative shift with the rise of Advanced Therapy Medicinal Products (ATMPs), which include gene therapies, somatic cell therapies, and tissue-engineered products. These therapies offer new, potentially curative treatments for longstanding medical challenges, impacting numerous patients. However, their adoption is hindered by complex regulatory frameworks, high production costs, and inconsistent access across Europe. The ESOT ATMP Task Force’s position paper analyzes these challenges from research to clinical application, advocating for a coordinated strategy to position Europe as a leader in ATMP development. It proposes specific actions such as streamlining regulatory pathways to accelerate approvals, boosting funding for ATMP research, and creating specialized facilities for development and implementation. The paper also highlights the critical roles of patient engagement and real-world evidence in optimizing clinical and regulatory practices.

• Gramignoli, Roberto; Hofmann, Nicola; Agudo-Barriuso, Marta; Antica, Mariastefania; Flores, Ana I. & Girandon, Lenart [Show all 14 contributors for this article] (2024). Expert Revision of Key Elements for Clinical-Grade Production and Qualification of Perinatal Derivatives. Stem Cells Translational Medicine. ISSN 2157-6564. 13(1), p. 14–29. doi: 10.1093/stcltm/szad068. Full text in Research Archive Show summary

  Perinatal derivatives have been proposed as adjunct therapeutic strategies or innovative treatments. Undoubtedly, perinatal derivatives can offer the opportunity and source material to isolate multipotent stem cells, but both maternal- and fetal-derived tissues can be processed and transformed into engineered tissues or advanced biomedical devices, whose potential remains to be fully elucidated. Promising preclinical and clinical results collected so far clearly foresee an escalation of such novel treatments. Market forecasts predict exponential growth in such advanced medicinal products during the next decade, with a pragmatic innovation for medicine into a more advanced biomedical version, enlarging the portfolio for treating a wide range of congenital and acute conditions. However, all these promising and fascinating therapeutic possibilities cannot gain a solid and recognized role in established medical practice without rigid and harmonized manufacturing strategies. The implementation of strategies according to guidelines and directives compiled by Regulatory Agencies, in conformity to (European) Pharmacopoeia and for Good Manufacturing Practice -conforming production of such products, represent critical steps required to translate perinatal technologies into effective therapeutic approaches. During the past 5 years, a panel of European experts and developers, gathered under the umbrella of the COST Sprint Action, supported by the European Cooperation in Science and Technology action, had the opportunity to revise and summarize experience and recommendations for a fruitful and proficient generation of perinatal biomedical products. In order to facilitate the creation and potential commercialization of perinatal bioengineered and advanced pharmaceutical products and technologies, such a collection of data and recommendations is described and discussed here.

• Piemonti, Lorenzo; Scholz, Hanne; Jongh, Dide de; Kerr-Conte, Julie; Apeldoorn, Aart van & Shaw, James A. M. [Show all 14 contributors for this article] (2023). The Relevance of Advanced Therapy Medicinal Products in the Field of Transplantation and the Need for Academic Research Access: Overcoming Bottlenecks and Claiming a New Time. Transplant International. ISSN 0934-0874. 36. doi: 10.3389/ti.2023.11633. Full text in Research Archive
• LaLone, Vernon; Aizenshtadt, Aleksandra; Goertz, John; Skottvoll, Frøydis Sved; Mota, Marco Barbero & You, Junji [Show all 15 contributors for this article] (2023). Quantitative chemometric phenotyping of three-dimensional liver organoids by Raman spectral imaging. Cell Reports Methods. 3(4). doi: 10.1016/j.crmeth.2023.100440. Full text in Research Archive Show summary

  Confocal Raman spectral imaging (RSI) enables high-content, label-free visualization of a wide range of molecules in biological specimens without sample preparation. However, reliable quantification of the deconvoluted spectra is needed. Here we develop an integrated bioanalytical methodology, qRamanomics, to qualify RSI as a tissue phantom calibrated tool for quantitative spatial chemotyping of major classes of biomolecules. Next, we apply qRamanomics to fixed 3D liver organoids generated from stem-cell-derived or primary hepatocytes to assess specimen variation and maturity. We then demonstrate the utility of qRamanomics for identifying biomolecular response signatures from a panel of liver-altering drugs, probing drug-induced compositional changes in 3D organoids followed by in situ monitoring of drug metabolism and accumulation. Quantitative chemometric phenotyping constitutes an important step in developing quantitative label-free interrogation of 3D biological specimens.

• Mathisen, Andreas Frøslev; Abadpour, Shadab; Legøy, Thomas Aga; Paulo, Joao A.; Ghila, Luiza Mihaela & Scholz, Hanne [Show all 7 contributors for this article] (2023). Global proteomics reveals insulin abundance as a marker of human islet homeostasis alterations. Acta Physiologica. ISSN 1748-1708. 239(2). doi: 10.1111/apha.14037. Full text in Research Archive Show summary

  Abstract Aim The variation in quality between the human islet samples represents a major problem for research, especially when used as control material. The assays assessing the quality of human islets used in research are non‐standardized and limited, with many important parameters not being consistently assessed. High‐throughput studies aimed at characterizing the diversity and segregation markers among apparently functionally healthy islet preps are thus a requirement. Here, we designed a pilot study to comprehensively identify the diversity of global proteome signatures and the deviation from normal homeostasis in randomly selected human‐isolated islet samples. Methods By using Tandem Mass Tag 16‐plex proteomics, we focused on the recurrently observed disparity in the detected insulin abundance between the samples, used it as a segregating parameter, and analyzed the correlated changes in the proteome signature and homeostasis by pathway analysis. Results In this pilot study, we showed that insulin protein abundance is a predictor of human islet homeostasis and quality. This parameter is independent of other quality predictors within their acceptable range, thus being able to further stratify islets samples of apparent good quality. Human islets with low amounts of insulin displayed changes in their metabolic and signaling profile, especially in regard to energy homeostasis and cell identity maintenance. We further showed that xenotransplantation into diabetic hosts is not expected to improve the pre‐transplantation signature, as it has a negative effect on energy balance, antioxidant activity, and islet cell identity. Conclusions Insulin protein abundance predicts significant changes in human islet homeostasis among random samples of apparently good quality.

• Olsen, Christine; Wang, Chencheng; Aizenshtadt, Aleksandra; Abadpour, Shadab; Lundanes, Elsa & Skottvoll, Frøydis Sved [Show all 11 contributors for this article] (2023). Simultaneous LC–MS determination of glucose regulatory peptides secreted by stem cell–derived islet organoids. Electrophoresis. ISSN 0173-0835. 44(21-22), p. 1682–1697. doi: 10.1002/elps.202300095. Full text in Research Archive Show summary

  Abstract For studying stem cell–derived islet organoids (SC‐islets) in an organ‐on‐chip (OoC) platform, we have developed a reversed‐phase liquid chromatography–tandem mass spectrometry (RPLC–MS/MS) method allowing for simultaneous determination of insulin, somatostatin‐14, and glucagon, with improved matrix robustness compared to earlier methodology. Combining phenyl/hexyl‐C18 separations using 2.1 mm inner diameter LC columns and triple quadrupole mass spectrometry, identification and quantification were secured with negligible variance in retention time and quantifier/qualifier ratios, negligible levels of carryover (<2%), and sufficient precision (±10% RSD) and accuracy (±15% relative error) with and without use of an internal standard. The obtained lower limits of quantification were 0.2 µg/L for human insulin, 0.1 µg/L for somatostatin‐14, and 0.05 µg/L for glucagon. The here‐developed RPLC–MS/MS method showed that the SC‐islets have an insulin response dependent on glucose concentration, and the SC‐islets produce and release somatostatin‐14 and glucagon. The RPLC–MS/MS method for these peptide hormones was compatible with an unfiltered offline sample collection from SC‐islets cultivated on a pumpless, recirculating OoC (rOoC) platform. The SC‐islets background secretion of insulin was not significantly different on the rOoC device compared to a standard cell culture well‐plate. Taken together, RPLC–MS/MS method is well suited for multi‐hormone measurements of SC‐islets on an OoC platform.

• Lemonche, Gerard Boix; Nagymihaly, Richard; Niemi, Essi Maria; Josifovska, Natasha; Johansen, Stian & Moe, Morten Carsten [Show all 8 contributors for this article] (2023). Intracorneal Implantation of 3D Bioprinted Scaffolds Containing Mesenchymal Stromal Cells Using Femtosecond-Laser-Assisted Intrastromal Keratoplasty. Macromolecular Bioscience. ISSN 1616-5187. 23. doi: 10.1002/mabi.202200422. Full text in Research Archive Show summary

  Abstract Injury of the cornea is a complex biological process. Regeneration of the corneal stroma can be facilitated by the presence of mesenchymal stromal cells (MSCs) and application of tissue equivalents. A new tissue‐engineering strategy for corneal stroma regeneration is presented using cellularized 3D bioprinted hydrogel constructs implanted into organ cultured porcine corneas using femtosecond laser‐assisted intrastromal keratoplasty. The ex vivo cultured, MSC‐loaded 3D bioprinted structures remain intact, support cell survival, and contain de novo synthesized extracellular matrix components and migrating cells throughout the observation period. At day 14 postimplantation, the cellularized tissue equivalents contain few or no cells, as demonstrated by optical coherence tomography imaging and immunofluorescent staining. This study successfully combines a laboratory‐based method with modern, patient‐care practice to produce a cell‐laden tissue equivalent for corneal implantation. Optimal bioink composition and cellularization of tissue equivalents are essential in fine‐tuning a method to promote the current technique as a future treatment modality.

• Oskarsdotter, Kristin; Säljö, Karin; Sämfors, Sanna; Niemi, Essi Maria; Li, Susann & Simonsson, Stina [Show all 10 contributors for this article] (2023). Autologous endothelialisation by the stromal vascular fraction on laminin-bioconjugated nanocellulose-alginate scaffolds. Biomedical Materials. ISSN 1748-6041. 18(4). doi: 10.1088/1748-605X/acdebb. Full text in Research Archive Show summary

  Abstract Establishing a vascular network in biofabricated tissue grafts is essential for ensuring graft survival. Such networks are dependent on the ability of the scaffold material to facilitate endothelial cell adhesion; however, the clinical translation potential of tissue-engineered scaffolds is hindered by the lack of available autologous sources of vascular cells. Here, we present a novel approach to achieving autologous endothelialisation in nanocellulose-based scaffolds by using adipose tissue-derived vascular cells on nanocellulose-based scaffolds. We used sodium periodate-mediated bioconjugation to covalently bind laminin to the scaffold surface and isolated the stromal vascular fraction and endothelial progenitor cells (EPCs; CD31 + CD45 − ) from human lipoaspirate. Additionally, we assessed the adhesive capacity of scaffold bioconjugation in vitro using both adipose tissue-derived cell populations and human umbilical vein endothelial cells. The results showed that the bioconjugated scaffold exhibited remarkably higher cell viability and scaffold surface coverage by adhesion regardless of cell type, whereas control groups comprising cells on non-bioconjugated scaffolds exhibited minimal cell adhesion across all cell types. Furthermore, on culture day 3, EPCs seeded on laminin-bioconjugated scaffolds showed positive immunofluorescence staining for the endothelial markers CD31 and CD34, suggesting that the scaffolds promoted progenitor differentiation into mature endothelial cells. These findings present a possible strategy for generating autologous vasculature and thereby increase the clinical relevance of 3D-bioprinted nanocellulose-based constructs.

• Abadpour, Shadab; Niemi, Essi Maria; Orrhult, Linnea Strid; Hermanns, Carolin; Vries, Rick de & Nogueira, Liebert Parreiras [Show all 12 contributors for this article] (2023). Adipose-Derived Stromal Cells Preserve Pancreatic Islet Function in a Transplantable 3D Bioprinted Scaffold. Advanced Healthcare Materials. ISSN 2192-2640. 12(32). doi: 10.1002/adhm.202300640. Full text in Research Archive Show summary

  Intra-portal islet transplantation is currently the only clinically approved beta cell replacement therapy, but its outcome is hindered by limited cell survival due to a multifactorial reaction against the allogeneic tissue in liver. Adipose-derived stromal cells (ASCs) can potentially improve the islet micro-environment by their immunomodulatory action. The challenge is to combine both islets and ASCs in a relatively easy and consistent long-term manner in a deliverable scaffold. W e report on manufacturing the Three-dimensional (3D) bioprinted double-layered scaffolds with primary islets and ASCs using a mix of alginate/nano-fibrillated cellulose (NFC) bioink. W e demonstrate the diffusion properties of the bioink and the supportive effect of human ASCs on islet viability, glucose sensing, insulin secretion and reducing the secretion of pro-inflammatory cytokines. Diabetic mice transplanted with islet-ASC scaffolds reached normoglycemia 7 days post transplantation with no significant difference between this group and the group received islets under the kidney capsules. In addition, animals transplanted with islet-ASC scaffolds stayed normoglycemic and showed elevated levels of C-peptide compared to mice transplanted with islet-only scaffolds. Our data presents a functional 3D bioprinted scaffold for islets and ASCs transplanted to the extrahepatic site and suggest a possible role of ASCs on improving the islet micro-environment.

• Brinch, Shoshy Alam; Amundsen-Isaksen, Enya; Espada, Sandra; Hammarström, Clara Louise; Aizenshtadt, Aleksandra & Olsen, Petter Angell [Show all 18 contributors for this article] (2022). The Tankyrase Inhibitor OM-153 Demonstrates Antitumor Efficacy and a Therapeutic Window in Mouse Models. Cancer Research Communications. 2(4), p. 233–245. doi: 10.1158/2767-9764.CRC-22-0027. Full text in Research Archive
• Olsen, Christine; Wiborg, Elisa; Lundanes, Elsa; Abadpour, Shadab; Scholz, Hanne & Wilson, Steven Ray Haakon (2022). On-line reduction of insulin disulfide bonds with photoinduced radical reactions, upstream to nano liquid chromatography-mass spectrometry. Separation Science Plus (SSC plus). 5(6), p. 220–227. doi: 10.1002/sscp.202200022. Full text in Research Archive
• Sämfors, Sanna; Niemi, Essi Maria; Oskarsdotter, Kristin; Egea, Claudia Villar; Mark, Andreas & Scholz, Hanne [Show all 7 contributors for this article] (2022). Design and biofabrication of a leaf-inspired vascularized cell-delivery device. Bioprinting. doi: 10.1016/j.bprint.2022.e00199. Full text in Research Archive Show summary

  We designed and biofabricated a channeled construct as a possible cell-delivery device that can be endothelialized to overcome size limitations due to oxygen diffusion. The channeled device mimicking a leaf was designed using computer-aided design software, with fluid flow through the channels visualized using simulation studies. The device was fabricated either by form casting using a custom 3D-printed plastic mold or by 3D-bioprinting using Pluronic F-127 as sacrificial ink to print the channels. The actual leaf was cast or bioprinted using hydrogel made from a mixture of tunicate cellulose nanofibers and alginate that was cross-linked in calcium chloride solution to allow a stable device. The resulting device was a 20 × 8 × 3 mm or 35 × 18 × 3 mm (length × width × height) leaf with one main channel connected to several side channels. Surface modification using periodate oxidation, followed by laminin bioconjugation, was performed to enhance endothelial cell adhesion in the channels. We subsequently used human umbilical vein endothelial cells to demonstrate the efficacy of the device for promoting endothelialization. These results indicated that the biofabricated device has great potential for use in tissue-engineering for various applications associated with the need of perfusable vasculature.

• Kwak, Dongho; Combriat, Thomas Michel Daniel; Wang, Chencheng; Scholz, Hanne; Danielsen, Anne & Jensenius, Alexander Refsum (2022). Music for Cells? A Systematic Review of Studies Investigating the Effects of Audible Sound Played Through Speaker-Based Systems on Cell Cultures. Music & Science. 5. doi: 10.1177/20592043221080965. Full text in Research Archive Show summary

  There have been several studies investigating whether musical sound can be used as cell stimuli in recent years. We systematically searched publications to get an overview of studies that have used audible sound played through speaker-based systems to induce mechanical perturbation in cell cultures. A total of 12 studies were identified. We focused on the experimental setups, the sounds that were used as stimuli, and relevant biological outcomes. The studies are categorized into simple and complex sounds depending on the type of sound employed. Some of the promising effects reported were enhanced cell migration, proliferation, colony formation, and differentiation ability. However, there are significant differences in methodologies and cell type-specific outcomes, which made it difficult to find a systematic pattern in the results. We suggest that future experiments should consider using: (1) a more controlled acoustic environment, (2) standardized sound and noise measurement methods, and (3) a more comprehensive range of controlled sound parameters as cellular stimuli.

• Olsen, Christine; Wang, Chencheng; Abadpour, Shadab; Lundanes, Elsa; Hansen, Audun Skau & Skottvoll, Frøydis Sved [Show all 8 contributors for this article] (2022). Determination of insulin secretion from stem cell-derived islet organoids with liquid chromatography-tandem mass spectrometry. Journal of chromatography. B. ISSN 1570-0232. 1215. doi: 10.1016/j.jchromb.2022.123577. Full text in Research Archive Show summary

  Organoids are laboratory-grown 3D organ models, mimicking human organs for e.g. drug development and personalized therapy. Islet organoids (typically 100–200 µm), which can be grown from the patient́s own cells, are emerging as prototypes for transplantation-based therapy of diabetes. Selective methods for quantifying insulin production from islet organoids are needed, but sensitivity and carry-over have been major bottlenecks in previous efforts. We have developed a reverse phase liquid chromatography-tandem mass spectrometry (RPLC-MS/MS) method for studying the insulin secretion of islet organoids. In contrast to our previous attempts using nano-scale LC columns, conventional 2.1 mm inner diameter LC column (combined with triple quadrupole mass spectrometry) was well suited for sensitive and selective measurements of insulin secreted from islet organoids with low microliter-scale samples. Insulin is highly prone to carry-over, so standard tubings and injector parts were replaced with shielded fused silica connectors. As samples were expected to be very limited, an extended Box-Behnken experimental design for the MS settings was conducted to maximize performance. The finale method has excellent sensitivity, accuracy and precision (limit of detection: ≤0.2 pg/µL, relative error: ≤±10%, relative standard deviation: <10%), and was well suited for measuring 20 µL amounts of Krebs buffer containing insulin secreted from islet organoids.

• Ward, Casey; Odorico, Jon S.; Rickels, Michael R.; Berney, Thierry; Burke, George W. & Kay, Thomas W.H. [Show all 14 contributors for this article] (2022). International Survey of Clinical Monitoring Practices in Pancreas and Islet Transplantation. Transplantation. ISSN 0041-1337. 106(8), p. 1647–1655. doi: 10.1097/TP.0000000000004058. Full text in Research Archive
• Fernandez, Manuel Carrasco; Wang, Chencheng; Søviknes, Anne Mette; Bjørlykke, Yngvild; Abadpour, Shadab & Paulo, Joao A. [Show all 16 contributors for this article] (2022). Spatial Environment Affects HNF4A Mutation-Specific Proteome Signatures and Cellular Morphology in hiPSC-Derived β-Like Cells. Diabetes. ISSN 0012-1797. 71(4), p. 862–869. doi: 10.2337/db20-1279. Full text in Research Archive Show summary

  Studies of monogenic diabetes are particularly useful because we can gain insight into the molecular events of pancreatic β-cell failure. Maturity-onset diabetes of the young 1 (MODY1) is a form of monogenic diabetes caused by a mutation in the HNF4A gene. Human-induced pluripotent stem cells (hiPSCs) provide an excellent tool for disease modeling by subsequently directing differentiation toward desired pancreatic islet cells, but cellular phenotypes in terminally differentiated cells are notoriously difficult to detect. Re-creating a spatial (three-dimensional [3D]) environment may facilitate phenotype detection. We studied MODY1 by using hiPSC-derived pancreatic β-like patient and isogenic control cell lines in two different 3D contexts. Using size-adjusted cell aggregates and alginate capsules, we show that the 3D context is critical to facilitating the detection of mutation-specific phenotypes. In 3D cell aggregates, we identified irregular cell clusters and lower levels of structural proteins by proteome analysis, whereas in 3D alginate capsules, we identified altered levels of glycolytic proteins in the glucose sensing apparatus by proteome analysis. Our study provides novel knowledge on normal and abnormal function of HNF4A, paving the way for translational studies of new drug targets that can be used in precision diabetes medicine in MODY.

• Kogler, Stian; Aizenshtadt, Aleksandra; Harrison, Sean; Skottvoll, Frøydis Sved; Berg, Henriette Engen & Abadpour, Shadab [Show all 14 contributors for this article] (2022). "Organ-in-a-Column" Coupled On-line with Liquid Chromatography-Mass Spectrometry. Analytical Chemistry. ISSN 0003-2700. 94(50), p. 17677–17684. doi: 10.1021/acs.analchem.2c04530. Full text in Research Archive Show summary

  Organoids, i.e., laboratory-grown organ models developed from stem cells, are emerging tools for studying organ physiology, disease modeling, and drug development. On-line analysis of organoids with mass spectrometry would provide analytical versatility and automation. To achieve these features with robust hardware, we have loaded liquid chromatography column housings with induced pluripotent stem cell (iPSC) derived liver organoids and coupled the “organ-in-a-column” units on-line with liquid chromatography-mass spectrometry (LC-MS). Liver organoids were coloaded with glass beads to achieve an even distribution of organoids throughout the column while preventing clogging. The liver organoids were interrogated “on column” with heroin, followed by on-line monitoring of the drug’s phase 1 metabolism. Enzymatic metabolism of heroin produced in the “organ-in-a-column” units was detected and monitored using a triple quadrupole MS instrument, serving as a proof-of-concept for on-line coupling of liver organoids and mass spectrometry. Taken together, the technology allows direct integration of liver organoids with LC-MS, allowing selective and automated tracking of drug metabolism over time.

• Berney, Thierry; Andres, Axel; Bellin, Melena D.; Koning, Eelco J. P. de; Johnson, Paul R. V. & Kay, Thomas W. H. [Show all 11 contributors for this article] (2022). A Worldwide Survey of Activities and Practices in Clinical Islet of Langerhans Transplantation. Transplant International. ISSN 0934-0874. 35. doi: 10.3389/ti.2022.10507. Full text in Research Archive
• Berishvili, Ekaterine; Casiraghi, Federica; Cristiano, Amarelli; Scholz, Hanne; Piemonti, Lorenzo & Berney, Thierry [Show all 7 contributors for this article] (2021). Mini-organs forum: how to advance organoid technology to organ transplant community. Transplant International. ISSN 0934-0874. 34(9), p. 1588–1593. doi: 10.1111/tri.13988. Full text in Research Archive
• Piemonti, Lorenzo; Andres, Axel; Casey, John; Koning, Eelco de; Engelse, Marten & Hilbrands, Robert [Show all 19 contributors for this article] (2021). US food and drug administration (FDA) panel endorses islet cell treatment for type 1 diabetes: A pyrrhic victory? Transplant International. ISSN 0934-0874. p. 1182–1186. doi: 10.1111/tri.13930. Full text in Research Archive
• Ghila, Luiza; Legøy, Thomas Aga; Mathisen, Andreas Frøslev; Abadpour, Shadab; Paulo, Joao A. & Scholz, Hanne Bjørnson [Show all 8 contributors for this article] (2021). Chronically elevated exogenous glucose elicits antipodal effects on the proteome signature of differentiating human ipsc-derived pancreatic progenitors. International Journal of Molecular Sciences. ISSN 1661-6596. 22(7). doi: 10.3390/ijms22073698. Full text in Research Archive Show summary

  The past decade revealed that cell identity changes, such as dedifferentiation or transdifferentiation, accompany the insulin-producing β-cell decay in most diabetes conditions. Mapping and controlling the mechanisms governing these processes is, thus, extremely valuable for managing the disease progression. Extracellular glucose is known to influence cell identity by impacting the redox balance. Here, we use global proteomics and pathway analysis to map the response of differentiating human pancreatic progenitors to chronically increased in vitro glucose levels. We show that exogenous high glucose levels impact different protein subsets in a concentration-dependent manner. In contrast, regardless of concentration, glucose elicits an antipodal effect on the proteome landscape, inducing both beneficial and detrimental changes in regard to achieving the desired islet cell fingerprint. Furthermore, we identified that only a subgroup of these effects and pathways are regulated by changes in redox balance. Our study highlights a complex effect of exogenous glucose on differentiating pancreas progenitors characterized by a distinct proteome signature.

• Zhou, Alex-Xianghua; Mondal, Tanmoy; Tabish, Ali Mustafa; Abadpour, Shadab; Ericson, Elke & Smith, David M. [Show all 11 contributors for this article] (2021). The long noncoding RNA TUNAR modulates Wnt signaling and regulates human β-cell proliferation. American Journal of Physiology. Heart and Circulatory Physiology. ISSN 0363-6135. 320(4), p. E846–E857. doi: 10.1152/AJPENDO.00335.2020. Full text in Research Archive
• Nordheim, Espen; Lindahl, Jørn Petter Hanto; Carlsen, Rasmus Kirkeskov; Åsberg, Anders; Birkeland, Kåre I. & Horneland, Rune [Show all 9 contributors for this article] (2021). Patient selection for islet or solid organ pancreas transplantation: experiences from a multidisciplinary outpatient-clinic approach. Endocrine Connections. 10(2), p. 230–239. doi: 10.1530/EC-20-0519. Full text in Research Archive Show summary

  Objective - β-cell replacement therapy (βCRT), including pancreas transplantation alone (PTA) and islet transplantation (ITX), is a treatment option for selected type 1 diabetes patients. All potential candidates for βCRT in Norway are referred to one national transplant centre for evaluation before any pre-transplant workup is started. This evaluation was performed by a transplant nephrologist alone prior to 2015 and by a multidisciplinary team (MDT) from 2015. We have reviewed the allocation of patients to treatment modality and the 1-year clinical outcome for the patients after transplantation.<p> <p>Research design and methods - Medical charts of all patients evaluated for βCRT between 2010 and 2020 in Norway were retrospectively analysed and the outcome of patients receiving βCRT were studied.<p> <p>Results - One hundred and forty-four patients were assessed for βCRT eligibility between 2010 and 2020. After MDT evaluation was introduced for βCRT eligibility in 2015, the percentage of referred patients accepted for the transplant waiting list fell from 84% to 40% (P < 0.005). One year after transplantation, 73% of the PTA and none of the ITX patients were independent of exogenous insulin, 8% of the PTA and 90% of the ITX patients had partial graft function while 19% of the PTA and 10% of the ITX patients suffered from graft loss.<p> <p>Conclusion - The acceptance rate for βCRT was significantly reduced during a 10-year observation period and 81% of the PTA and 90% of the ITX patients had partial or normal graft function 1 year post-transplant.

• Abadpour, Shadab; Wang, Chencheng; Niemi, Essi Maria & Scholz, Hanne (2021). Tissue Engineering Strategies for Improving Beta Cell Transplantation Outcome. Current Transplantation Reports. 8(3), p. 205–219. doi: 10.1007/s40472-021-00333-2. Full text in Research Archive Show summary

  Abstract Purpose of Review Beta cell replacement therapy as a form of islet transplantation is a promising alternative therapy with the possibility to make selected patients with type 1 diabetes (T1D) insulin independent. However, this technique faces challenges such as extensive activation of the host immune system post-transplantation, lifelong need for immunosuppression, and the scarcity of islet donor pancreas. Advancement in tissue engineering strategies can improve these challenges and allow for a more widespread application of this therapy. This review will discuss the recent development and clinical translation of tissue engineering strategies in beta cell replacement therapy. Recent Findings Tissue engineering offers innovative solutions for producing unlimited glucose responsive cells and fabrication of appropriate devices/scaffolds for transplantation applications. Generation of pancreatic organoids with supporting cells in biocompatible biomaterials is a powerful technique to improve the function of insulin-producing cell clusters. Fabrication of physical barriers such as encapsulation strategies can protect the cells from the host immune system and allow for graft retrieval, although this strategy still faces major challenges to fully restore physiological glucose regulation. Summary The three main components of tissue engineering strategies including the generation of stem cell-derived insulin-producing cells and organoids and the possibilities for therapeutic delivery of cell-seeded devices to extra-hepatic sites need to come together in order to provide safe and functional insulin-producing devices for clinical beta cell replacement therapy.

• Abadpour, Shadab; Tyrberg, Björn; Schive, Simen Walberg; Huldt, Charlotte; Gennemark, P & Ryberg, Erik [Show all 12 contributors for this article] (2020). Inhibition of the Prostaglandin D(2)-Gpr44/Dp2 Axis Improves Human Islet Survival and Function. Diabetologia. ISSN 0012-186X. 63(7), p. 1355–1367. doi: 10.1007/s00125-020-05138-z. Full text in Research Archive Show summary

  Aims/hypothesis Inflammatory signals and increased prostaglandin synthesis play a role during the development of diabetes. The prostaglandin D2 (PGD2) receptor, GPR44/DP2, is highly expressed in human islets and activation of the pathway results in impaired insulin secretion. The role of GPR44 activation on islet function and survival rate during chronic hyperglycaemic conditions is not known. In this study, we investigate GPR44 inhibition by using a selective GPR44 antagonist (AZ8154) in human islets both in vitro and in vivo in diabetic mice transplanted with human islets. Methods Human islets were exposed to PGD2 or proinflammatory cytokines in vitro to investigate the effect of GPR44 inhibition on islet survival rate. In addition, the molecular mechanisms of GPR44 inhibition were investigated in human islets exposed to high concentrations of glucose (HG) and to IL-1β. For the in vivo part of the study, human islets were transplanted under the kidney capsule of immunodeficient diabetic mice and treated with 6, 60 or 100 mg/kg per day of a GPR44 antagonist starting from the transplantation day until day 4 (short-term study) or day 17 (long-term study) post transplantation. IVGTT was performed on mice at day 10 and day 15 post transplantation. After termination of the study, metabolic variables, circulating human proinflammatory cytokines, and hepatocyte growth factor (HGF) were analysed in the grafted human islets. Results PGD2 or proinflammatory cytokines induced apoptosis in human islets whereas GPR44 inhibition reversed this effect. GPR44 inhibition antagonised the reduction in glucose-stimulated insulin secretion induced by HG and IL-1β in human islets. This was accompanied by activation of the Akt–glycogen synthase kinase 3β signalling pathway together with phosphorylation and inactivation of forkhead box O-1and upregulation of pancreatic and duodenal homeobox-1 and HGF. Administration of the GPR44 antagonist for up to 17 days to diabetic mice transplanted with a marginal number of human islets resulted in reduced fasting blood glucose and lower glucose excursions during IVGTT. Improved glucose regulation was supported by increased human C-peptide levels compared with the vehicle group at day 4 and throughout the treatment period. GPR44 inhibition reduced plasma levels of TNF-α and growth-regulated oncogene-α/chemokine (C-X-C motif) ligand 1 and increased the levels of HGF in human islets. Conclusions/interpretation Inhibition of GPR44 in human islets has the potential to improve islet function and survival rate under inflammatory and hyperglycaemic stress. This may have implications for better survival rate of islets following transplantation.

• Legøy, Thomas Aga; Mathisen, Andreas Frøslev; Salim, Zaidon; Vethe, Heidrun; Bjørlykke, Yngvild & Abadpour, Shadab [Show all 11 contributors for this article] (2020). In vivo environment swiftly restricts human pancreatic progenitors toward mono-hormonal identity via a HNF1A/HNF4A mechanism. Frontiers in Cell and Developmental Biology. 8:109, p. 1–14. doi: 10.3389/fcell.2020.00109. Full text in Research Archive Show summary

  Generating insulin-producing β-cells from human induced pluripotent stem cells is a promising cell replacement therapy for improving or curing insulin-dependent diabetes. The transplantation of end-stages differentiating cells into living hosts was demonstrated to improve β-cell maturation. Nevertheless, the cellular and molecular mechanisms outlining the transplanted cells’ response to the in vivo environment are still to be properly characterized. Here we use global proteomics and large-scale imaging techniques to demultiplex and filter the cellular processes and molecular signatures modulated by the immediate in vivo effect. We show that in vivo exposure swiftly confines in vitro generated human pancreatic progenitors to single hormone expression. The global proteome landscape of the transplanted cells was closer to native human islets, especially in regard to energy metabolism and redox balance. Moreover, our study indicates a possible link between these processes and certain epigenetic regulators involved in cell identity. Pathway analysis predicted HNF1A and HNF4A as key regulators controlling the in vivo islet-promoting response, with experimental evidence suggesting their involvement in confining islet cell fate following xeno-transplantation.

• Berishvili, Ekaterine; Kaiser, Laurent; Cohen, Marie; Berney, Thierry; Scholz, Hanne Bjørnson & Fløisand, Yngvar [Show all 7 contributors for this article] (2020). Treatment of COVID-19 Pneumonia: the Case for Placenta-derived Cell Therapy. Stem Cell Reviews and Reports (SCRR). ISSN 2629-3269. p. 1–8. doi: 10.1007/s12015-020-10004-x. Full text in Research Archive Show summary

  Nearly 500’000 fatalities due to COVID-19 have been reported globally and the death toll is still rising. Most deaths are due to acute respiratory distress syndrome (ARDS), as a result of an excessive immune response and a cytokine storm elicited by severe SARS-CoV-2 lung infection, rather than by a direct cytopathic effect of the virus. In the most severe forms of the disease therapies should aim primarily at dampening the uncontrolled inflammatory/immune response responsible for most fatalities. Pharmacological agents - antiviral and anti-inflammatory molecules - have not been able so far to achieve compelling results for the control of severe COVID-19 pneumonia. Cells derived from the placenta and/or fetal membranes, in particular amniotic epithelial cells (AEC) and decidual stromal cells (DSC), have established, well-characterized, potent anti-inflammatory and immune-modulatory properties that make them attractive candidates for a cell-based therapy of COVID19 pneumonia. Placenta-derived cells are easy to procure from a perennial source and pose minimal ethical issues for their utilization. In view of the existing clinical evidence for the innocuousness and efficiency of systemic administration of DSCs or AECs in similar conditions, we advocate for the initiation of clinical trials using this strategy in the treatment of severe COVID-19 disease.

• Amini, Maryam; Niemi, Essi Maria; Hisdal, Jonny; Kalvøy, Håvard; Tronstad, Christian & Scholz, Hanne [Show all 8 contributors for this article] (2020). Monitoring the quality of frozen-thawed venous segments using bioimpedance spectroscopy. Physiological Measurement. ISSN 0967-3334. 41(4). doi: 10.1088/1361-6579/ab85b7. Full text in Research Archive Show summary

  Objective: Storage at temperatures as low as −80 °C and below (cryopreservation) is considered a method for long-term preservation of cells and tissues, and especially blood vessel segments, which are to be used for clinical operations such as transplantation. However, the freezing and thawing processes themselves can induce injuries to the cells and tissue by damaging the structure and consequently functionality of the cryopreserved tissue. In addition, the level of damage is dependent on the rate of cooling and warming used during the freezing-thawing process. Current methods for monitoring the viability and integrity of cells and tissues after going through the freezing-thawing cycle are usually invasive and destructive to the cells and tissues. Therefore, employing monitoring methods which are not destructive to the cryopreserved tissues, such as bioimpedance measurement techniques, is necessary. In this study we aimed to design a bioimpedance measurement setup to detect changes in venous segments after freezing-thawing cycles in a noninvasive manner. Approach: A bioimpedance spectroscopy measurement technique with a two-electrode setup was employed to monitor ovine jugular vein segments after each cycle during a process of seven freezing-thawing cycles. Main results: The results demonstrated changes in the impedance spectra of the measured venous segments after each freezing-thawing cycle. Significance: This indicates that bioimpedance spectroscopy has the potential to be developed into a novel method for non-invasive and non-destructive monitoring of the viability of complex tissue after cryopreservation.

• Brandhorst, Heide; Brandhorst, Daniel; Abraham, Anju; Acreman, Samuel; Schive, Simen Walberg & Scholz, Hanne [Show all 7 contributors for this article] (2020). Proteomic profiling reveals the ambivalent character of the mesenchymal stem cell secretome: Assessing the effect of preconditioned media on isolated human islets. Cell Transplantation. ISSN 0963-6897. 29, p. 1–13. doi: 10.1177/0963689720952332. Full text in Research Archive Show summary

  Previous studies in rodents have indicated that function and survival of transplanted islets can be substantially improved by mesenchymal stem cells (MSC). The few human islet studies to date have confirmed these findings but have not determined whether physical contact between MSC and islets is required or whether the benefit to islets results from MSC-secreted proteins. This study aimed to investigate the protective capacity of MSC-preconditioned media for human islets. MSC were cultured for 2 or 5 days in normoxia or hypoxia before harvesting the cell-depleted media for human islet culture in normoxia or hypoxia for 6–8 or 3–4 days, respectively. To characterize MSC-preconditioned media, proteomic secretome profiling was performed to identify angiogenesis- and inflammation-related proteins. A protective effect of MSC-preconditioned media on survival and in vitro function of hypoxic human islets was observed irrespective of the atmosphere used for MSC preconditioning. Islet morphology changed markedly when media from hypoxic MSC were used for culture. However, PDX-1 and insulin gene expression did not confirm a change in the genetic phenotype of these islets. Proteomic profiling of preconditioned media revealed the heterogenicity of the secretome comprising angiogenic and antiapoptotic as well as angiostatic or proinflammatory mediators released at an identical pattern regardless whether MSC had been cultured in normoxic or hypoxic atmosphere. These findings do not allow a clear discrimination between normoxia and hypoxia as stimulus for protective MSC capabilities but indicate an ambivalent character of the MSC angiogenesis- and inflammation-related secretome. Nevertheless, culture of human islets in acellular MSC-preconditioned media resulted in improved morphological and functional islet integrity suggesting a disbalance in favor of protective factors. Further approaches should aim to eliminate potentially detrimental factors to enable the production of advanced clinical grade islet culture media with higher protective qualities.

• Kogler, Stian; Harrison, Sean; Aizenshtadt, Aleksandra; Skottvoll, Frøydis Sved; Abadpour, Shadab & Krauss, Stefan [Show all 10 contributors for this article] (2020). “Organoid-in-a-column” coupled on-line with liquid chromatography-mass spectrometry. BioRxiv. ISSN 0362-4331. doi: 10.1101/2020.09.08.282756. Full text in Research Archive
• Nano, Rita; Kerr-Conte, Julie; Scholz, Hanne; Engelse, Marten; Karlsson, Marie & Saudek, Frantisek [Show all 19 contributors for this article] (2020). Heterogeneity of Human Pancreatic Islet Isolation Around Europe: Results of a Survey Study. Transplantation. ISSN 0041-1337. 104(12), p. 190–196. doi: 10.1097/TP.0000000000002777. Full text in Research Archive
• Legøy, Thomas Aga; Vethe, Heidrun; Abadpour, Shadab; Strand, Berit Løkensgard; Scholz, Hanne & Paulo, Joao A. [Show all 9 contributors for this article] (2020). Encapsulation boosts islet-cell signature in differentiating human induced pluripotent stem cells via integrin signalling. Scientific Reports. 10(10), p. 1–16. doi: 10.1038/s41598-019-57305-x. Full text in Research Archive Show summary

  Cell replacement therapies hold great therapeutic potential. Nevertheless, our knowledge of the mechanisms governing the developmental processes is limited, impeding the quality of differentiation protocols. Generating insulin-expressing cells in vitro is no exception, with the guided series of differentiation events producing heterogeneous cell populations that display mixed pancreatic islet phenotypes and immaturity. The achievement of terminal differentiation ultimately requires the in vivo transplantation of, usually, encapsulated cells. Here we show the impact of cell confinement on the pancreatic islet signature during the guided differentiation of alginate encapsulated human induced pluripotent stem cells (hiPSCs). Our results show that encapsulation improves differentiation by significantly reshaping the proteome landscape of the cells towards an islet-like signature. Pathway analysis is suggestive of integrins transducing the encapsulation effect into intracellular signalling cascades promoting differentiation. These analyses provide a molecular framework for understanding the confinement effects on hiPSCs differentiation while confirming its importance for this process.

• Abadpour, Shadab; Aizenshtadt, Aleksandra; Olsen, Petter Angell; Shoji, Kayoko; Wilson, Steven Ray Haakon & Krauss, Stefan [Show all 7 contributors for this article] (2020). Pancreas-on-a-Chip Technology for Transplantation Applications. Current Diabetes Reports. ISSN 1534-4827. 20. doi: 10.1007/s11892-020-01357-1. Full text in Research Archive Show summary

  Abstract Purpose of Review Human pancreas-on-a-chip (PoC) technology is quickly advancing as a platform for complex in vitro modeling of islet physiology. This review summarizes the current progress and evaluates the possibility of using this technology for clinical islet transplantation. Recent Findings PoC microfluidic platforms have mainly shown proof of principle for long-term culturing of islets to study islet function in a standardized format. Advancement in microfluidic design by using imaging-compatible biomaterials and biosensor technology might provide a novel future tool for predicting islet transplantation outcome. Progress in combining islets with other tissue types gives a possibility to study diabetic interventions in a minimal equivalent in vitro environment. Summary Although the field of PoC is still in its infancy, considerable progress in the development of functional systems has brought the technology on the verge of a general applicable tool that may be used to study islet quality and to replace animal testing in the development of diabetes interventions.

• Bergström, Marcus; Müller, Malin; Karlsson, Marie; Scholz, Hanne; Vethe, Nils Tore & Korsgren, Olle (2019). Comparing the Effects of the mTOR Inhibitors Azithromycin and Rapamycin on In Vitro Expanded Regulatory T Cells. Cell Transplantation. ISSN 0963-6897. 28(12), p. 1603–1613. doi: 10.1177/0963689719872488. Full text in Research Archive Show summary

  Adoptive transfer of autologous polyclonal regulatory T cells (Tregs) is a promising option for reducing graft rejection in allogeneic transplantation. To gain therapeutic levels of Tregs there is a need to expand obtained cells ex vivo, usually in the presence of the mTOR inhibitor Rapamycin due to its ability to suppress proliferation of non-Treg T cells, thus promoting a purer Treg yield. Azithromycin is a bacteriostatic macrolide with mTOR inhibitory activity that has been shown to exert immunomodulatory effects on several types of immune cells. In this study we investigated the effects of Azithromycin, compared with Rapamycin, on Treg phenotype, growth, and function when expanding bulk, naïve, and memory Tregs. Furthermore, the intracellular concentration of Rapamycin in CD4+ T cells as well as in the culture medium was measured for up to 48 h after supplemented. Treg phenotype was assessed by flow cytometry and Treg function was measured as inhibition of responder T-cell expansion in a suppression assay. The concentration of Rapamycin was quantified with liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Azithromycin and Rapamycin both promoted a FoxP3-positive Treg phenotype in bulk Tregs, while Rapamycin also increased FoxP3 and FoxP3+Helios positivity in naïve and memory Tregs. Furthermore, Rapamycin inhibited the expansion of naïve Tregs, but also increased their suppressive effect. Rapamycin was quickly degraded in 37°C medium, yet was retained intracellularly. While both compounds may benefit expansion of FoxP3+ Tregs in vitro, further studies elucidating the effects of Azithromycin treatment on Tregs are needed to determine its potential use.

• Vethe, Heidrun; Ghila, Luiza; Berle, Magnus; Hoareau, Laurence; Haaland, Øystein Ariansen & Scholz, Hanne [Show all 9 contributors for this article] (2019). The effect of WnT pathway modulators on human iPSC-derived pancreatic beta cell maturation. Frontiers in Endocrinology. 10:293(MAY), p. 1–13. doi: 10.3389/fendo.2019.00293. Full text in Research Archive Show summary

  Current published protocols for targeted differentiation of human stem cells toward pancreatic β-cells fail to deliver sufficiently mature cells with functional properties comparable to human islet β-cells. We aimed to assess whether Wnt-modulation could promote the final protocol stages of β-cell maturation, building our hypothesis on our previous findings of Wnt activation in immature hiPSC-derived stage 7 (S7) cells compared to adult human islets and with recent data reporting a link between Wnt/PCP and in vitro β-cell maturation. In this study, we stimulated canonical and non-canonical Wnt signaling in hiPSC-derived S7 cells using syntetic proteins including WNT3A, WNT4, WNT5A and WNT5B, and we inhibited endogenous Wnt signaling with the Tankyrase inhibitor G007-LK (TKi). Whereas neither canonical nor non-canonical Wnt stimulation alone was able to mature hiPSC-derived S7 cells, WNT-inhibition with TKi increased the fraction of monohormonal cells and global proteomics of TKi-treated S7 cells showed a proteomic signature more similar to adult human islets, suggesting that inhibition of endogenous Wnt contributes toward final β-cell maturation.

• Legøy, Thomas Aga; Ghila, Luiza; Vethe, Heidrun; Abadpour, Shadab; Mathisen, Andreas Frøslev & Paulo, Joao A. [Show all 9 contributors for this article] (2019). In vivo hyperglycemia exposure elicits distinct period-dependent effects on human pancreatic progenitor differentiation, conveyed by oxidative stress. Acta Physiologica. ISSN 1748-1708. 23:247577, p. 1–16. doi: 10.1111/apha.13433. Full text in Research Archive Show summary

  Aim: The loss of insulin‐secreting β‐cells, ultimately characterizing most diabetes forms, demands the development of cell replacement therapies. The common endpoint for all ex vivo strategies is transplantation into diabetic patients. However, the effects of hyperglycaemia environment on the transplanted cells were not yet properly assessed. Thus, the main goal of this study was to characterize global effect of brief and prolonged in vivo hyperglycaemia exposure on the cell fate acquisition and maintenance of transplanted human pancreatic progenitors. Methods: To rigorously study the effect of hyperglycaemia, in vitro differentiated human‐induced pluripotent stem cells (hiPSC)‐derived pancreatic progenitors were xenotransplanted in normoglycaemic and diabetic NSG rat insulin promoter (RIP)‐diphtheria toxin receptor (DTR) mice. The transplants were retrieved after 1‐week or 1‐month exposure to overt hyperglycaemia and analysed by large‐scale microscopy or global proteomics. For this study we pioneer the use of the NSG RIP‐DTR system in the transplantation of hiPSC, making use of its highly reproducible specific and absolute β‐cell ablation property in the absence of inflammation or other organ toxicity. Results: Here we show for the first time that besides the presence of an induced oxidative stress signature, the cell fate and proteome landscape response to hyperglycaemia was different, involving largely different mechanisms, according to the period spent in the hyperglycaemic environment. Surprisingly, brief hyperglycaemia exposure increased the bihormonal cell number by impeding the activity of specific islet lineage determinants. Moreover, it activated antioxidant and inflammation protection mechanisms signatures in the transplanted cells. In contrast, the prolonged exposure was characterized by decreased numbers of hormone + cells, low/absent detoxification signature, augmented production of oxygen reactive species and increased apoptosis. Conclusion: Hyperglycaemia exposure induced distinct, period‐dependent, negative effects on xenotransplanted human pancreatic progenitor, affecting their energy homeostasis, cell fate acquisition and survival.

• Zur-Mühlen, Bengt von; Scholz, Hanne; Hellman, Jarl; Korsgren, Olle & Lundgren, Torbjørn (2019). Treating diabetes with islet transplantation:Lessons learnt from the Nordic network for clinical islet transplantation. In Orlando, Giuseppe (Eds.), Transplantation, Bioengineering, and Regeneration of the Endocrine Pancreas. Elsevier. ISSN 9780128148334. doi: 10.1016/B978-0-12-814833-4.00048-4. Full text in Research Archive
• Vethe, Heidrun; Legøy, Thomas Aga; Abadpour, Shadab; Strand, Berit Løkensgard; Scholz, Hanne & Paulo, Joao A. [Show all 9 contributors for this article] (2019). Encapsulation boosts islet-cell signature in differentiating human induced pluripotent stem cells via integrin signalling. BioRxiv. ISSN 0362-4331. doi: 10.1101/791442. Full text in Research Archive
• Korsgren, Olle & Scholz, Hanne (2019). Cellular therapies in preclinical and clinical islet transplantation: Mesenchymal stem cells. In Orlando, Giuseppe (Eds.), Transplantation, Bioengineering, and Regeneration of the Endocrine Pancreas. Elsevier. ISSN 9780128148334. doi: 10.1016/B978-0-12-814833-4.00064-2. Full text in Research Archive
• Schuetz, Christian; Anazawa, Takayuki; Cross, Sarah E.; Labriola, Leticia; Meier, Raphael P.H. & Redfield, Robert R. [Show all 9 contributors for this article] (2018). β cell replacement therapy: The next 10 years. Transplantation. ISSN 0041-1337. 102(2), p. 215–229. doi: 10.1097/TP.0000000000001937. Full text in Research Archive
• Abadpour, Shadab; Halvorsen, Bente; Sahraoui, Afaf; Korsgren, Olle; Aukrust, Pål & Scholz, Hanne (2018). Interleukin-22 reverses human islet dysfunction and apoptosis triggered by hyperglycemia and LIGHT. Journal of Molecular Endocrinology. ISSN 0952-5041. 60(3), p. 171–183. doi: 10.1530/JME-17-0182. Full text in Research Archive
• Sokolova, Marina; Sahraoui, Afaf; Høyem, Merete; Øgaard, Jonas; Lien, Egil & Aukrust, Pål [Show all 9 contributors for this article] (2018). NLRP3 inflammasome mediates oxidative stress-induced pancreatic islet dysfunction. American Journal of Physiology. Endocrinology and Metabolism. ISSN 0193-1849. 315(5), p. E912–E923. doi: 10.1152/ajpendo.00461.2017. Full text in Research Archive
• Eich, Torsten M.; Ståhle, Magnus; Gustafsson, Bengt; Horneland, Rune; Lempinen, Marko & Lundgren, Torbjörn [Show all 12 contributors for this article] (2018). Calcium: A Crucial Potentiator for Efficient Enzyme Digestion of the Human Pancreas. Cell Transplantation. ISSN 0963-6897. 27(7), p. 1031–1038. doi: 10.1177/0963689718779350. Full text in Research Archive Show summary

  Background: Effective digestive enzymes are crucial for successful islet isolation. Supplemental proteases are essential because they synergize with collagenase for effective pancreatic digestion. The activity of these enzymes is critically dependent on the presence of Ca2+ ions at a concentration of 5–10 mM. The present study aimed to determine the Ca2+ concentration during human islet isolation and to ascertain whether the addition of supplementary Ca2+ is required to maintain an optimal Ca2+ concentration during the various phases of the islet isolation process. Methods: Human islets were isolated according to standard methods and isolation parameters. Islet quality control and the number of isolations fulfilling standard transplantation criteria were evaluated. Ca2+ was determined by using standard clinical chemistry routines. Islet isolation was performed with or without addition of supplementary Ca2+ to reach a Ca2+ of 5 mM. Results: Ca2+ concentration was markedly reduced in bicarbonate-based buffers, especially if additional bicarbonate was used to adjust the pH as recommended by the Clinical Islet Transplantation Consortium. A major reduction in Ca2+ concentration was also observed during pancreatic enzyme perfusion, digestion, and harvest. Additional Ca2+ supplementation of media used for dissolving the enzymes and during digestion, perfusion, and harvest was necessary in order to obtain the concentration recommended for optimal enzyme activity and efficient liberation of a large number of islets from the human pancreas. Conclusions: Ca2+ is to a large extent consumed during clinical islet isolation, and in the absence of supplementation, the concentration fell below that recommended for optimal enzyme activity. Ca2+ supplementation of the media used during human pancreas digestion is necessary to maintain the concentration recommended for optimal enzyme activity. Addition of Ca2+ to the enzyme blend has been implemented in the standard isolation protocols in the Nordic Network for Clinical Islet Transplantation.

• Schive, Simen Walberg; Fjukstad, Ragnhild; Josefsen, Dag; Katavic, Marina; Abadpour, Shadab & Gullestad, Hans Petter [Show all 8 contributors for this article] (2018). Automated isolation and expansion of human adipose tissuederived stem cells for a seamless translation into clinical trials. CellR4 (repair, Replacement, Regenerative&Reprogramming. ISSN 2329-7042. 6(2), p. e2519–e2519. Full text in Research Archive
• Vethe, Heidrun; Bjørlykke, Yngvild; Ghila, Luiza; Paulo, Joao A.; Scholz, Hanne & Gygi, Steven P. [Show all 8 contributors for this article] (2017). Probing the missing mature β-cell proteomic landscape in differentiating patient iPSC-derived cells. Scientific Reports. 7:4780, p. 1–14. doi: 10.1038/s41598-017-04979-w. Full text in Research Archive
• Schive, Simen Walberg; Mirlashari, Mohammad Reza; Hasvold, Grete; Wang, Mengyu; Josefsen, Dag & Gullestad, Hans Petter [Show all 10 contributors for this article] (2017). Human Adipose-Derived Mesenchymal Stem Cells Respond to Short-Term Hypoxia by Secreting Factors Beneficial for Human Islets in Vitro and Potentiate Antidiabetic Effect in Vivo. Cell Medicine. 9, p. 103–116. doi: 10.3727/215517917X693401. Full text in Research Archive
• Brandhorst, Daniel; Brandhorst, Heide; Acreman, Samuel; Schive, Simen Walberg; Scholz, Hanne & Johnson, Paul R.V. (2017). Hypoxia-induced damage in human islets is reduced with the use of mesenchymal stem cell–preconditioned medium. Transplantation Proceedings. ISSN 0041-1345. 49(10), p. 2330–2332. doi: 10.1016/j.transproceed.2017.11.003. Full text in Research Archive
• Hals, Ingrid Kathrin; Ohki, Tsuyoshi; Singh, Rinku; Ma, Zuheng; Björklund, Anneli & Balasuriya, Chandima Nirupa Dilruks [Show all 8 contributors for this article] (2017). Hyperoxia reduces insulin release and induces mitochondrial dysfunction with possible implications for hyperoxic treatment of neonates. Physiological Reports. 5(19). doi: 10.14814/phy2.13447. Full text in Research Archive Show summary

  We previously showed that hyperoxia in vitro negatively affects beta cells of the rat. Here, we tested for possible clinical significance as well as mitochondrial interactions by hyperoxia, using human islets (function and viability), INS‐1 832/13 cells (mitochondrial metabolism), and mouse neonates (effects in vivo). Lastly, we assessed relevant parameters in a cohort of individuals born preterm and then exposed to hyperoxia. Human islets and INS‐1 832/13 cells were exposed to 24 h of hyperoxia (90–92% oxygen). Mouse neonates were subjected to 5 days of continuous hyperoxia. Individuals born preterm were evaluated in terms of glucose homeostasis and beta cell function by HbA1c and the HOMA2 formula. In human islets, hyperoxia significantly reduced glucose‐stimulated insulin secretion by 42.2 ± 5.3% and viability assessed by MTT by 22.5 ± 5.4%. Hyperoxia down‐regulated mitochondrial complex II by 21 ± 5% and upregulated complex III by 26 ± 10.1% and complex IV by 37 ± 10.6%. Partly similar effects on mitochondrial complexes were found in hyperoxia‐exposed INS‐1 832/13 cells. Exposure to hyperoxia swiftly reduced oxygen consumption in these cells and increased mitochondrial uncoupling. Hyperoxia transiently but significantly reduced insulin release in mouse neonates. Individuals born preterm displayed higher HbA1c versus controls, as well as insulin resistance. Thus, hyperoxia exerts negative effects in vitro on human beta cells and results indicate inhibitory effects on insulin secretion in vivo in mouse neonates. Negative effects may be lessened by the demonstrated swift and profound mitochondrial adaptability. Our findings open the possibility that hyperoxia could negatively affect beta cells of preterm human neonates.

• Abadpour, Shadab; Göpel, Sven O; Schive, Simen Walberg; Korsgren, Olle; Foss, Aksel & Scholz, Hanne (2017). Glial cell-line derived neurotrophic factor protects human islets from nutrient deprivation and endoplasmic reticulum stress induced apoptosis. Scientific Reports. 7(1). doi: 10.1038/s41598-017-01805-1. Full text in Research Archive
• Schive, Simen Walberg; Foss, Aksel; Sahraoui, Afaf; Kloster-Jensen, Kristine; Hafsahl, Geir & Kvalheim, Gunnar [Show all 15 contributors for this article] (2017). Cost and clinical outcome of islet transplantation in Norway 2010-2015. Clinical Transplantation. ISSN 0902-0063. 31:e12871(1), p. 1–8. doi: 10.1111/ctr.12871. Full text in Research Archive Show summary

  Islet transplantation is a minimally invasive β-cell replacement strategy. Islet transplantation is a reimbursed treatment in Norway. Here, we summarize the cost and clinical outcome of 31 islet transplantations performed at Oslo University Hospital (OUS) from January 2010 to June 2015. Patients were retrospectively divided into three groups. Thirteen patients received either one or two islet transplantation alone (ITA), while five patients received islet transplantation after previous solid organ transplantation. For the group receiving 2 ITA, Kaplan-Meier estimates show an insulin independence of 20% more than 4 years after their last transplantation. An estimated 70% maintain at least partial graft function, defined as fasting C-peptide >0.1 nmol L−1, and 47% maintain a HbA1c below 6.5% or 2 percent points lower than before ITA. For all groups combined, we estimate that 44% of the patients have a 50% reduction in insulin requirement 4 years after the initial islet transplantation. The average cost for an islet transplantation procedure was 347 297±60 588 NOK, or 35 424±6182 EUR, of which isolation expenses represent 34%. We hereby add to the common pool of growing experience with islet transplantation and also describe the cost of the treatment at our center.

• Hals, Ingrid Kathrin; Singh, Rinku; Ma, Zuheng; Scholz, Hanne; Björklund, Anneli & Grill, Valdemar Erik Robert (2016). Culture at low glucose up-regulates mitochondrial function in pancreatic β cells with accompanying effects on viability. Islets. ISSN 1938-2014. 8(6), p. 165–176. doi: 10.1080/19382014.2016.1246637. Full text in Research Archive
• Kloster-Jensen, Kristine; Sahraoui, Afaf; Vethe, Nils Tore; Korsgren, Olle; Bergan, Stein & Foss, Aksel [Show all 7 contributors for this article] (2016). Treatment with tacrolimus and sirolimus reveals no additional adverse effects on human islets in vitro compared to each drug alone but they are reduced by adding glucocorticoids. Journal of Diabetes Research. ISSN 2314-6745. 2016. doi: 10.1155/2016/4196460. Full text in Research Archive Show summary

  Tacrolimus and sirolimus are important immunosuppressive drugs used in human islet transplantation; however, they are linked to detrimental effects on islets and reduction of long-term graft function. Few studies investigate the direct effects of these drugs combined in parallel with single drug exposure. Human islets were treated with or without tacrolimus (30 μg/L), sirolimus (30 μg/L), or a combination thereof for 24 hrs. Islet function as well as apoptosis was assessed by glucose-stimulated insulin secretion (GSIS) and Cell Death ELISA. Proinflammatory cytokines were analysed by qRT-PCR and Bio-Plex. Islets exposed to the combination of sirolimus and tacrolimus were treated with or without methylprednisolone (1000 μg/L) and the expression of the proinflammatory cytokines was investigated. We found the following: (i) No additive reduction in function and viability in islets existed when tacrolimus and sirolimus were combined compared to the single drug. (ii) Increased expression of proinflammatory cytokines mRNA and protein levels in islets took place. (iii) Methylprednisolone significantly decreased the proinflammatory response in islets induced by the drug combination. Although human islets are prone to direct toxic effect of tacrolimus and sirolimus, we found no additive effects of the drug combination. Short-term exposure of glucocorticoids could effectively reduce the proinflammatory response in human islets induced by the combination of tacrolimus and sirolimus.

• Halvorsen, Bente; Santilli, Francesca; Scholz, Hanne; Sahraoui, Afaf; Gulseth, Hanne Løvdal & Wium, Cecilie [Show all 20 contributors for this article] (2016). LIGHT/TNFSF14 is increased in patients with type 2 diabetes mellitus and promotes islet cell dysfunction and endothelial cell inflammation in vitro. Diabetologia. ISSN 0012-186X. 59, p. 2134–2144. doi: 10.1007/s00125-016-4036-y. Full text in Research Archive Show summary

  Aims/hypothesis: Activation of inflammatory pathways is involved in the pathogenesis of type 2 diabetes mellitus. On the basis of its role in vascular inflammation and in metabolic disorders, we hypothesised that the TNF superfamily (TNFSF) member 14 (LIGHT/TNFSF14) could be involved in the pathogenesis of type 2 diabetes mellitus. <p>Methods: Plasma levels of LIGHT were measured in two cohorts of type 2 diabetes mellitus patients (191 Italian and 40 Norwegian). Human pancreatic islet cells and arterial endothelial cells were used to explore regulation and relevant effects of LIGHT in vitro. <p>Results: Our major findings were: (1) in both diabetic cohorts, plasma levels of LIGHT were significantly raised compared with sex- and age-matched healthy controls (n = 32); (2) enhanced release from activated platelets seems to be an important contributor to the raised LIGHT levels in type 2 diabetes mellitus; (3) in human pancreatic islet cells, inflammatory cytokines increased the release of LIGHT and upregulated mRNA and protein levels of the LIGHT receptors lymphotoxin β receptor (LTβR) and TNF receptor superfamily member 14 (HVEM/TNFRSF14); (4) in these cells, LIGHT attenuated the insulin release in response to high glucose at least partly via pro-apoptotic effects; and (5) in human arterial endothelial cells, glucose boosted inflammatory response to LIGHT, accompanied by an upregulation of mRNA levels of HVEM (also known as TNFRSF14) and LTβR (also known as LTBR). <p>Conclusions/interpretation: Our findings show that patients with type 2 diabetes mellitus are characterised by increased plasma LIGHT levels. Our in vitro findings suggest that LIGHT may contribute to the progression of type 2 diabetes mellitus by attenuating insulin secretion in pancreatic islet cells and by contributing to vascular inflammation.

• Sahraoui, Afaf; Winzell, Maria Sörhede; Gorman, Tracy; Smith, Dave M.; Skrtic, Stanko & Høyem, Merete [Show all 11 contributors for this article] (2015). The effects of exendin-4 treatment on graft failure: An animal study using a novel revascularized minimal human islet transplant model. PLOS ONE. 10(3). doi: 10.1371/journal.pone.0121204. Full text in Research Archive Show summary

  Islet transplantation has become a viable clinical treatment, but is still compromised by long-term graft failure. Exendin-4, a glucagon-like peptide 1 receptor agonist, has in clinical studies been shown to improve insulin secretion in islet transplanted patients. However, little is known about the effect of exendin-4 on other metabolic parameters. We therefore aimed to determine what influence exendin-4 would have on revascularized minimal human islet grafts in a state of graft failure in terms of glucose metabolism, body weight, lipid levels and graft survival. Introducing the bilateral, subcapsular islet transplantation model, we first transplanted diabetic mice with a murine graft under the left kidney capsule sufficient to restore normoglycemia. After a convalescent period, we performed a second transplantation under the right kidney capsule with a minimal human islet graft and allowed for a second recovery. We then performed a left-sided nephrectomy, and immediately started treatment with exendin-4 with a low (20μg/kg/day) or high (200μg/kg/day) dose, or saline subcutaneously twice daily for 15 days. Blood was sampled, blood glucose and body weight monitored. The transplanted human islet grafts were collected at study end point and analyzed. We found that exendin-4 exerts its effect on failing human islet grafts in a bell-shaped dose-response curve. Both doses of exendin-4 equally and significantly reduced blood glucose. Glucagon-like peptide 1 (GLP-1), C-peptide and pro-insulin were conversely increased. In the course of the treatment, body weight and cholesterol levels were not affected. However, immunohistochemistry revealed an increase in beta cell nuclei count and reduced TUNEL staining only in the group treated with a low dose of exendin-4 compared to the high dose and control. Collectively, these results suggest that exendin-4 has a potential rescue effect on failing, revascularized human islets in terms of lowering blood glucose, maintaining beta cell numbers, and improving metabolic parameters during hyperglycemic stress.

• Hals, Ingrid Katrin; Bruerberg, Simon Gustafsen; Ma, Zuheng; Scholz, Hanne; Björklund, Anneli & Grill, Valdemar Erik Robert (2015). Mitochondrial respiration in insulin-producing β-cells: General characteristics and adaptive effects of hypoxia. PLOS ONE. doi: 10.1371/journal.pone.0138558. Full text in Research Archive Show summary

  Objective: To provide novel insights on mitochondrial respiration in β-cells and the adaptive effects of hypoxia. Methods and Design Insulin-producing INS-1 832/13 cells were exposed to 18 hours of hypoxia followed by 20– 22 hours re-oxygenation. Mitochondrial respiration was measured by high-resolution respirometry in both intact and permeabilized cells, in the latter after establishing three functional substrate-uncoupler-inhibitor titration (SUIT) protocols. Concomitant measurements included proteins of mitochondrial complexes (Western blotting), ATP and insulin secretion. Results: Intact cells exhibited a high degree of intrinsic uncoupling, comprising about 50% of oxygen consumption in the basal respiratory state. Hypoxia followed by re-oxygenation increased maximal overall respiration. Exploratory experiments in peremabilized cells could not show induction of respiration by malate or pyruvate as reducing substrates, thus glutamate and succinate were used as mitochondrial substrates in SUIT protocols. Permeabilized cells displayed a high capacity for oxidative phosphorylation for both complex I- and II-linked substrates in relation to maximum capacity of electron transfer. Previous hypoxia decreased phosphorylation control of complex I-linked respiration, but not in complex II-linked respiration. Coupling control ratios showed increased coupling efficiency for both complex I- and IIlinked substrates in hypoxia-exposed cells. Respiratory rates overall were increased. Also previous hypoxia increased proteins of mitochondrial complexes I and II (Western blotting) in INS-1 cells as well as in rat and human islets. Mitochondrial effects were accompanied by unchanged levels of ATP, increased basal and preserved glucose-induced insulin secretion. Conclusions: Exposure of INS-1 832/13 cells to hypoxia, followed by a re-oxygenation period increases substrate-stimulated respiratory capacity and coupling efficiency. Such effects are accompanied by up-regulation of mitochondrial complexes also in pancreatic islets, highlighting adaptive capacities of possible importance in an islet transplantation setting. Results also indicate idiosyncrasies of β-cells that do not respire in response to a standard inclusion of malate in SUIT protocols.

• Schive, Simen Walberg; Scholz, Hanne; Sahraoui, Afaf; Kloster-Jensen, Kristine; Hafsahl, Geir & Korsgren, Olle [Show all 8 contributors for this article] (2015). Graft function 1 year after pregnancy in an islet-transplanted patient. Transplant International. ISSN 0934-0874. 28(10), p. 1235–1239. doi: 10.1111/tri.12596. Full text in Research Archive
• Kloster-Jensen, Kristine; Vethe, Nils Tore; Bremer, Sara; Abadpour, Shadab; Korsgren, Olle & Foss, Aksel [Show all 8 contributors for this article] (2015). Intracellular sirolimus concentration is reduced by tacrolimus in human pancreatic islets in vitro. Transplant International. ISSN 0934-0874. 28(10), p. 1152–1161. doi: 10.1111/tri.12617. Full text in Research Archive
• Halvorsen, Bente; Holm, Sverre; Yndestad, Arne; Scholz, Hanne; Sagen, Ellen Lund & Nebb, Hilde Irene [Show all 9 contributors for this article] (2014). Interleukin-10 increases reverse cholesterol transport in macrophages through its bidirectional interaction with liver X receptor α. Biochemical and Biophysical Research Communications - BBRC. ISSN 0006-291X. 450(4), p. 1525–1530. doi: 10.1016/j.bbrc.2014.07.036. Full text in Research Archive
• Shi, Jihua; Scholz, Hanne; Huitfeldt, Henrik & Line, Pål Dag (2014). The effect of hepatic progenitor cells on experimental hepatocellular carcinoma in the regenerating liver. Scandinavian Journal of Gastroenterology. ISSN 0036-5521. 49(1), p. 99–108. doi: 10.3109/00365521.2013.854406. Full text in Research Archive
• Sahraoui, Afaf; Kloster-Jensen, Kristine; Ueland, Thor; Korsgren, Olle; Foss, Aksel & Scholz, Hanne (2014). Anakinra and tocilizumab enhance survival and function of human islets during culture: Implications for clinical islet transplantation. Cell Transplantation. ISSN 0963-6897. 23(10), p. 1199–1211. doi: 10.3727/096368913X667529. Full text in Research Archive
• Shi, Jihua; Liu, Shuzheng; Wierød, Lene; Scholz, Hanne Bjørnson; Anmarkrud, Jarl Andreas & Huitfeldt, Henrik [Show all 8 contributors for this article] (2013). RAF-targeted therapy for hepatocellular carcinoma in the regenerating liver. Journal of Surgical Oncology. ISSN 0022-4790. 107(4), p. 393–401. doi: 10.1002/jso.23224. Full text in Research Archive
• Lekva, Tove; Bollerslev, Jens; Sahraoui, Afaf; Scholz, Hanne Bjørnson; Bøyum, Hege Hestetun & Evang, Johan Arild [Show all 9 contributors for this article] (2013). Thioredoxin Interacting Protein Is a Potential Regulator of Glucose and Energy Homeostasis in Endogenous Cushing's Syndrome. PLOS ONE. 8(5). doi: 10.1371/journal.pone.0064247. Full text in Research Archive
• Basu, Arpita; Alaupovic, Petar; Wu, Mingyuan; Jenkins, Alica J.; Yu, Yongxin & Nankervis, Alison J. [Show all 19 contributors for this article] (2012). Plasma Lipoproteins and Preeclampsia in Women with Type 1 Diabetes: A Prospective Study. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 97(5), p. 1752–1762. doi: 10.1210/jc.2011-3255. Full text in Research Archive
• Yu, Y; Hanssen, Kristian Folkvord; Kalyanaraman, V; Chirindel, A; Jenkins, AJ & Nankervis, AJ [Show all 19 contributors for this article] (2012). Reduced soluble receptor for advanced glycation end-products (sRAGE) scavenger capacity precedes pre-eclampsia in Type 1 diabetes. BJOG: An International Journal of Obstetrics and Gynaecology. ISSN 1470-0328. 119(12), p. 1512–1520. doi: 10.1111/j.1471-0528.2012.03463.x. Full text in Research Archive
• Andersen, Geir Øystein; Ueland, Thor; Knudsen, Eva Cecilie; Scholz, Hanne Bjørnson; Yndestad, Arne & Sahraoui, Afaf [Show all 12 contributors for this article] (2011). Activin A Levels Are Associated With Abnormal Glucose Regulation in Patients With Myocardial Infarction Potential Counteracting Effects of Activin A on Inflammation. Diabetes. ISSN 0012-1797. 60(5), p. 1544–1551. doi: 10.2337/db10-1493. Full text in Research Archive
• Azar, Madona; Basu, Arpita; Jenkins, Alica J.; Nankervis, Alison J.; Hanssen, Kristian Folkvord & Scholz, Hanne Bjørnson [Show all 12 contributors for this article] (2011). Serum Carotenoids and Fat-Soluble Vitamins in Women With Type 1 Diabetes and Preeclampsia A longitudinal study. Diabetes Care. ISSN 0149-5992. 34(6), p. 1258–1264. doi: 10.2337/dc10-2145. Full text in Research Archive
• Lund, Tormod; Mangsbo, Sara; Scholz, Hanne Bjørnson; Gjorstrup, P.; Tötterman, Thomas H. & Korsgren, Olle [Show all 7 contributors for this article] (2010). Resolvin E1 Reduces Proinflammatory Markers in Human Pancreatic Islets in vitro. Experimental and clinical endocrinology & diabetes. ISSN 0947-7349. 18(4), p. 237–244. doi: 10.1055/s-0029-1241825. Full text in Research Archive
• Ueland, Thor; Fougner, Stine Lyngvi; Godang, Kristin; Lekva, Tove; Schurgers, LJ & Scholz, Hanne Bjørnson [Show all 10 contributors for this article] (2010). Associations between Body Composition, Circulating Interleukin-1 Receptor Antagonist, Osteocalcin, and Insulin Metabolism in Active Acromegaly. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 95(1), p. 361–368. doi: 10.1210/jc.2009-0422. Full text in Research Archive
• Lund, Tormod; Korsgren, Olle; Aursnes, Ingrid Augusta Stølen; Scholz, Hanne Bjørnson & Foss, Aksel (2010). Sustained Reversal of Diabetes Following Islet Transplantation to Striated Musculature in the Rat. Journal of Surgical Research. ISSN 0022-4804. 160(1), p. 145–154. doi: 10.1016/j.jss.2008.11.009. Full text in Research Archive
• Yu, Y; Jenkins, AJ; Nankervis, AJ; Hanssen, Kristian Folkvord; Scholz, Hanne Bjørnson & Henriksen, Tore [Show all 21 contributors for this article] (2009). Anti-angiogenic factors and pre-eclampsia in type 1 diabetic women. Diabetologia. ISSN 0012-186X. 52(1), p. 160–168. doi: 10.1007/s00125-008-1182-x. Full text in Research Archive
• Scholz, Hanne Bjørnson; Lund, Tormod; Dahle, Maria Krudtaa; Collins, Jon L.; Ole, Korsgren & Wang, Jacob Edward [Show all 7 contributors for this article] (2009). The synthetic liver X receptor agonist GW3965 reduces tissue factor and inflammatory responses in human islets in vitro. Diabetologia. ISSN 0012-186X. 52(7), p. 1352–1362. doi: 10.1007/s00125-009-1366-z. Full text in Research Archive
• Lund, Tormod; Fosby, Bjarte; Scholz, Hanne Bjørnson; Korsgren, Olle & Foss, Aksel (2008). Glucocorticoids reduce proinflammatory cytokines and tissue factor in vitro and improve function of transplanted human islets in vivo. Transplant International. ISSN 0934-0874. 21(7), p. 669–678. Full text in Research Archive
• Lund, Tormod; Korsgren, Olle; Aursnes, Ingrid Augusta Stølen; Scholz, Hanne Bjørnson & Foss, Aksel (2008). Sustained Reversal of Diabetes Following Islet Transplantation to Striated Musculature in the Rat. Journal of Surgical Research. ISSN 0022-4804. Full text in Research Archive
• Halvorsen, Bente; Wæhre, Torgun; Scholz, Hanne; Damås, Jan Kristian; Yndestad, Arne & Aukrust, Pål (2006). Role of interleukin-10 in atherogenesis and plaque stabilization. Future Cardiology. ISSN 1479-6678. 2(1), p. 75–83. Full text in Research Archive
• Sandberg, Wiggo Johan; Yndestad, Arne; Øie, Erik; Smith, Camilla; Ueland, Thor & Ovchinnikova, Olga [Show all 17 contributors for this article] (2006). Enhanced T-cell expression of RANK ligand in acute coronary syndrome - Possible role in plaque destabilization. Arteriosclerosis, Thrombosis and Vascular Biology. ISSN 1079-5642. 26. Full text in Research Archive
• Smith, Camilla; Damås, Jan Kristian; Otterdal, Kari; Øie, Erik; Sandberg, Wiggo Johan & Yndestad, Arne [Show all 15 contributors for this article] (2006). Increased levels of neutrophil-activating peptide-2 in acute coronary syndromes - Possible role of platelet-mediated vascular inflammation. Journal of the American College of Cardiology. ISSN 0735-1097. 48(8), p. 1591–1599. Full text in Research Archive

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• Carlsson, Per Ola; Hu, Xiaomeng; Scholz, Hanne; Ingvast, Sofie; Lundgren, Torbjörn & Scholz, Tim [Show all 12 contributors for this article] (2025). Survival of Transplanted Allogeneic Beta Cells with No Immunosuppression. doi: 10.1056/NEJMoa2503822. Full text in Research Archive
• Scholz, Hanne & Ræder, Helge (2023). Response to Comment on Carrasco et al. Spatial Environment Affects HNF4A Mutation-Specific Proteome Signatures and Cellular Morphology in hiPSC-Derived β-Like Cells. Diabetes 2022;71:862-869. Diabetes. ISSN 0012-1797. 72(5). doi: 10.2337/dbi23-0007. Full text in Research Archive
• Legøy, Thomas Aga; Mathisen, Andreas Frøslev; Scholz, Hanne; Paulo, Joao; Ræder, Helge & Ghila, Luiza Mihaela [Show all 7 contributors for this article] (2022). Molecular mechanisms affecting islet like cell fate acquisition in differentiating iPSC derived β-like cells”. Full text in Research Archive
• Ghila, Luiza Mihaela; Furuyama, Kenichiro; Grey, Shane T.; Scholz, Hanne & Chera, Simona (2022). Editorial: Beta-Cell Fate: From Gene Circuits to Disease Mechanisms. Frontiers in Genetics. 13. doi: 10.3389/fgene.2022.822440. Full text in Research Archive
• Abadpour, Shadab; Niemi, Essi Maria; Orrhult, Linnea Strid; Nogueira, Liebert Parreiras; Haugen, Håvard Jostein & Josefsen, Dag [Show all 10 contributors for this article] (2021). 307.7: 3D Bioprinting of Functional Islets With Adipose-derived Stromal Cells in an Alginate/Nanocellulose Scaffold. Transplantation. ISSN 0041-1337. p. S25–S25. doi: 10.1097/01.tp.0000804424.50335.7e. Full text in Research Archive
• Wang, Chencheng; Abadpour, Shadab; Aizenshtadt, Alexandra; Chera, Simona; Ghila, Luiza Mihaela & Ræder, Helge [Show all 7 contributors for this article] (2021). Glucose during in vitro pancreatic beta cells regeneration: friends or for? Full text in Research Archive
• Wang, Chencheng; Abadpour, Shadab; Aizenshtadt, Alexandra; Chera, Simona; Ghila, Luiza Mihaela & Ræder, Helge [Show all 7 contributors for this article] (2021). 402.2: High Glucose Concentration Increases KATP Channel Activity but Suppresses Mitochondrial Respiration Ability in Insulin-producing Cells Regenerated From Stem Cells. Transplantation. ISSN 0041-1337. p. S27–S27. doi: 10.1097/01.tp.0000804436.14096.44. Full text in Research Archive
• Olsen, Christine; Scholz, Hanne; Wilson, Steven Ray Haakon & Lundanes, Elsa (2020). Towards online reduction and protein digestion of secreted proteins from pancreatic islets of Langerhans related to diabetes mellitus type I. Full text in Research Archive Show summary

  What is diabetes mellitus type 1, and how can liquid chromatography assist in the search for a cure? The human pancreas is involved in control of metabolism and energy consumption by both an exocrine and an endocrine function. In the exocrine tissue, a multitude of digestive enzymes are produced and secreted into the small intestine to assist in breaking down proteins, fats and carbohydrates. The endocrine tissue, islets of Langerhans (5% of the total pancreatic mass) are responsible for regulation of the blood glucose levels. The vital metabolic hormone insulin is synthesized in one of five major cell types in the islets, called β-cells [1]. However, there are two types of chronic diseases related to insulin deficiency; an autoimmune disease causes selectively destruction of the β-cells in the islets or the body cannot effectively use the produced insulin, called diabetes mellitus type 1 and type 2, respectively. Diabetes mellitus type 1 or type 2 have been diagnosed in 250 000 Norwegians (approx. 4.7% of the Norwegian population), where 28 000 have been diagnosed with type 1 diabetes mellitus (0.5%) [2]. The most common treatment is exogenous insulin therapy. When insulin was discovered in 1920s the mortality of diabetes type 1 was reduced from a guaranteed fatal diagnosis to a manageable condition with a normal lifespan within the 1950s. However, secondary complications due to diabetic nephropathy, retinopathy and neuropathy led to a renewed interest in β-cell replacement therapy. Progress in β-cell replacement with either pancreas or islet transplantation has led to impressive 1- and 5-year insulin independence rates of approximately 85% and 50 %, respectively [3]. To assist in further progress in β-cell replacement therapy, liquid chromatography with mass spectrometry detection (LC-MS) of the secreted proteins from the pancreas and the islets will aid in the understanding of the treatment of diabetes mellitus type 1. In this work, we seek to enable fully online determination of proteins (in a bottom-up approach) by combining reduction and protein digestion upstream LC-MS (Figure 1). Online protein digestion has been successfully executed with immobilized enzyme reactors (IMERs) in different formats [4-6], but most of the samples have been reduced and alkylated prior to online digestion. We hope to enable real-time determination of proteins with disulfide bonds (such as insulin) by incorporation of a photochemical system for rapid reduction of disulfide bonds [7].

• Shi, Jihua; Scholz, Hanne Bjørnson & Line, Pål Dag (2012). "Recurrence" of Hepatocellular Carcinoma after Surgery: Experimental Evidence for Participation of Hepatic Progenitor Cells. Liver transplantation. ISSN 1527-6465. 18, p. S160–S160. Full text in Research Archive
• Wu, M.; Du, M; Jenkins, A.; Nankervis, AJ; Hanssen, Kristian Folkvord & Scholz, Hanne Bjørnson [Show all 18 contributors for this article] (2010). CIRCULATING CYTOKINES PREDICT PRE-ECLAMPSIA IN TYPE 1 DIABETES MELLITUS. Journal of Investigative Medicine. ISSN 1081-5589. 58(2), p. 392–392. Full text in Research Archive
• Azar, Madona; Lyons, Timothy J.; Wu, Mingyuan; Jenkins, Alicia; Scholz, Hanne & Aston, Christopher E. [Show all 13 contributors for this article] (2010). VITAMIN D DEFICIENCY AND PREECLAMPSIA IN PREGNANT WOMEN WITH TYPE 1 DIABETES MELLITUS. Journal of Investigative Medicine. ISSN 1081-5589. 58(2), p. 385–385. Full text in Research Archive
• Schöb, Franziska Jessica; Dysthe, Dag Kristian; Scholz, Hanne; Binder, Alexander & Malthe-Sørenssen, Anders (2026). From Pixels to Phenotypes: Deep Learning on Label-Free Microscopy Data for Cell Fate Prediction How Algorithms Help Us See More. Universitetet i Oslo. Full text in Research Archive Show summary

  In this thesis, we used supervised deep learning on label-free microscopy data to predict cell fate and state from purely visual information, without relying on fluorescent labeling or manual segmentation. Across three studies, we combined phase-contrast and holotomographic imaging with convolutional neural networks to tackle problems that are central to stem cell biology and cancer research: predicting the differentiation efficiency of induced pluripotent stem cell clones, identifying germ-layer lineages in differentiating cultures, and detecting macrophage-induced cancer cell death. By building segmentation-free pipelines that operated directly on image patches, we reduced the need for explicit cell masks and made our methods easier to deploy in realistic, noisy experimental settings. The overarching results showed that biological label-free images contained sufficient morphological information for deep networks to recover biologically meaningful patterns, but also revealed clear limits to what static morphology could predict. In stem cell differentiation, our models already distinguished high- from lowefficiency clones early in the protocol, and learned image cues that matched intuitive notions of colony coverage and uniformity. In germlayer prediction, endpoint-trained models decoded lineage identity from holotomographic morphology and reconstructed a plausible timeline of lineage divergence when applied retrospectively, while struggling more in mixed cultures with overlapping lineages. In the cancer cell death study, deep learning distinguished dying from alive cells at the time of death, yet early prediction beyond a short pre-death window remained difficult, indicating that death morphology emerged abruptly rather than gradually over many hours. Together, these findings support the view that deep learning on label-free microscopy could provide non-destructive, scalable readouts of cell fate, while emphasizing the need for time-aware models, richer training labels, and improved domain generalization to fully exploit biological label-free imaging in biomedical workflows.

• Kwak, Dongho; Jensenius, Alexander Refsum; Danielsen, Anne; Scholz, Hanne & Olsen, Petter Angell (2023). Music for cells? Rhythmic mechanical stimulations of cell cultures. Universitetet i Oslo. Full text in Research Archive Show summary

  This dissertation investigates how acoustic parameters and musical elements can be generated and manipulated to induce beneficial mechanical stimulations and alterations in cell cultures. The research has been conducted as part of a life science convergence environment, and the theoretical framework and experimental method in this dissertation are derived from three different disciplines: biology, music technology, and physics. The theoretical discussions centre around biological cell sensing mechanisms, the physical limitations and potentiality of audible sound to be used as mechano-acoustic cellular stimuli, and the concept of rhythm from biology and music technology perspectives. The methods include audio signal processing, physical characterisation of the experimental setup, various biological assays, and microscopic image feature extraction. Such a radically interdisciplinary approach culminated in laboratory experiments involving sound vibrations of human cell cultures using a vertical vibration system controlled by synthesized audio signals. The experimental variables included: No Vibration (NV, control), Continuous Vibration (CV), Regular Pulse (RP), and Variable Pulse (VP). The CV condition was categorised as non-rhythmic in this dissertation, while RP and VP were categorised as rhythmic conditions. The results demonstrate alterations in F-actin filament structure (length, thickness, angle) and the tendency of increased levels of cells in the G1-phase cell cycle in vibrated cell cultures. The “effect” was more apparent under the non-rhythmic (CV) condition than rhythmic conditions (RP and VP). The results also show that F-actin filament structural properties are negatively correlated (r < -.9), and the number of cells in the G1-phase cycle is positively correlated (r > .9) in relation to the magnitudes of mechanical parameters (RMS acceleration and shear stress). Nevertheless, the biological mechanism(s) responsible for the observed effects has yet to be characterised. The results from this dissertation inspire further studies on the effects of rhythmic mechanoacoustic stimulation on cellular biological rhythms (e.g., regulation of CLOCK, PER, and CRY genes).

• Scholz, Hanne (2006). Human macrophage function in the pathogenesis of atherosclerosis. Universitetet i Oslo. ISSN 9788280722133. Full text in Research Archive

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