Publications
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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Published
Mar. 22, 2019 2:39 PM
- Last modified
June 26, 2026 11:49 AM
