scholarly journals Inducible Pluripotent Stem Cells as a Potential Cure for Diabetes

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 278
Author(s):  
Kevin Verhoeff ◽  
Sarah J. Henschke ◽  
Braulio A. Marfil-Garza ◽  
Nidheesh Dadheech ◽  
Andrew Mark James Shapiro
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Islet Cells ◽  
Artificial Pancreas ◽  
Glucose Monitoring ◽  
Organ Donor ◽  
Subcutaneous Insulin ◽  
Islet Cell Transplantation ◽  
Brittle Diabetes ◽  
Novel Approach

Over the last century, diabetes has been treated with subcutaneous insulin, a discovery that enabled patients to forego death from hyperglycemia. Despite novel insulin formulations, patients with diabetes continue to suffer morbidity and mortality with unsustainable costs to the health care system. Continuous glucose monitoring, wearable insulin pumps, and closed-loop artificial pancreas systems represent an advance, but still fail to recreate physiologic euglycemia and are not universally available. Islet cell transplantation has evolved into a successful modality for treating a subset of patients with ‘brittle’ diabetes but is limited by organ donor supply and immunosuppression requirements. A novel approach involves generating autologous or immune-protected islet cells for transplant from inducible pluripotent stem cells to eliminate detrimental immune responses and organ supply limitations. In this review, we briefly discuss novel mechanisms for subcutaneous insulin delivery and define their shortfalls. We describe embryological development and physiology of islets to better understand their role in glycemic control and, finally, discuss cell-based therapies for diabetes and barriers to widespread use. In response to these barriers, we present the promise of stem cell therapy, and review the current gaps requiring solutions to enable widespread use of stem cells as a potential cure for diabetes.

scholarly journals Selection for CD26- and CD49A+ cells from pluripotent stem cells-derived islet-like clusters improves therapeutic activity in diabetic mice

2021 ◽  
Author(s):  
Kfir Molakandov ◽  
Denise A. Berti ◽  
Avital Beck ◽  
Ofer Elhanani ◽  
Michael D. Walker ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Therapy ◽  
Pluripotent Stem Cells ◽  
Islet Cells ◽  
Diabetic Mice ◽  
Cell Capture ◽  
Physiological Control ◽  
C Peptide ◽  
Selection For

Abstract Background. Cell therapy of diabetes aims at restoring the physiological control of blood glucose by transplantation of functional pancreatic islet cells. A potentially unlimited source of cells for such transplantations would be islet cells derived from an in vitro differentiation of human pluripotent stem cells (hESC/hiPSC). The islet-like clusters (ILC) produced by the known differentiation protocols contain various cell populations. Among these, the β-cells that express both insulin and the transcription factor Nkx6.1 seem to be the most efficient to restore normoglycemia in diabetes animal models. Our aim was to find markers allowing selection of these efficient cells. Methods. Functional Cell-Capture Screening (FCCS) was used to identify markers that preferentially capture the cells expressing both insulin and Nkx6.1, from hESC-derived ILC cells. In order to test whether selection for such markers could improve cell therapy in diabetic mouse models, we used ILC produced from a clinical-grade line of hESC by a refined differentiation protocol adapted to up-scalable bioreactors. Re-aggregated MACS sorted cells were encapsulated in microspheres made of alginate modified to reduce foreign body reaction. Implantation was done intraperitoneally in STZ-treated C57BL/6 immuno-competent mice. Results. CD49A (integrin alpha1) was identified by FCCS as a marker for cells that express insulin (or C-peptide) as well as Nkx6.1 in ILC derived by hESC differentiation. The ILC fraction enriched in CD49A+ cells rapidly reduced glycemia when implanted in diabetic mice, whereas mice receiving the CD49A depleted population remained highly diabetic. CD49A-enriched ILC cells also produced higher levels of human C-peptide in the blood of transplanted mice. However, the difference between CD49A-enriched and total ILC cells remained small. Another marker, CD26 (DPP4), was identified by FCCS as binding insulin-expressing cells which are Nkx6.1 negative. Depletion of CD26+ cells followed by enrichment for CD49A+ cells increased insulin+/Nkx6.1+ cells fraction to ~70%. The CD26-/CD49A+ enriched ILC exhibited improved function over non-sorted ILC or CD49A+ cells in diabetic mice and maintain prolonged blood C-peptide levels.Conclusions. Refining the composition of ILC differentiated from hPSC by negative selection to remove cells expressing CD26 and positive selection for CD49A expressing cells could enable more effective cell therapy of diabetes.

Co-culture with Mature Islet Cells Augments the Differentiation of Insulin-Producing Cells from Pluripotent Stem Cells

2014 ◽  
Vol 11 (1) ◽  
pp. 62-74 ◽  
Author(s):  
Bea Jun Oh ◽  
Seung-Hoon Oh ◽  
Jin Myung Choi ◽  
Sang-Man Jin ◽  
Woo-Young Shim ◽  
...  
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Islet Cells ◽  
Insulin Producing Cells

scholarly journals A Donor Transmitted Melanoma in Pancreatic Islet Cell Transplantation

2021 ◽  
Vol 2 (2) ◽  
Author(s):  
Thomas Foord ◽  
James Gilbert ◽  
Nick Coupe
Keyword(s):  
Pancreatic Islet ◽  
Islet Cells ◽  
Organ Donor ◽  
Screening Tests ◽  
Transplant Recipients ◽  
Islet Cell Transplantation ◽  
Pancreatic Islet Cell ◽  
Donor Population ◽  
The Uk

Transmission of cancer through organ donation is a rare but notable complication of transplantation, affecting 0.05% of transplant recipients in the UK. In this case a metastatic melanoma was transmitted through transplantation of pancreatic islet cells. Current screening practices make cases such as this incredibly infrequent, but the occurrence of such an event can significantly impact the health of the recipient. As the organ donor population increases in age and risk factors for malignancy, decisions around transplantation of high-risk organs may become more common in surgical practice. This case study discusses the genuine risk of donor transmitted cancer to the average transplant recipient and investigates the potential use of additional screening tests to stratify this risk in the future.

scholarly journals Selection for CD49A+ and CD26- cells in pancreatic islet-like clusters differentiated from human pluripotent stem cells improves their therapeutic activity in diabetic mice

2020 ◽  
Author(s):  
Kfir Molakandov ◽  
Denise A. Berti ◽  
Avital Beck ◽  
Ofer Elhanani ◽  
Michael D. Walker ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Therapy ◽  
Pancreatic Islet ◽  
Pluripotent Stem Cells ◽  
Islet Cells ◽  
Single Cells ◽  
Human Pluripotent Stem Cells ◽  
Diabetic Mice ◽  
C Peptide ◽  
Selection For

Abstract BackgroundCell therapy of diabetes aims at restoring the physiological control of blood glucose by transplantation of functional pancreatic islet cells. Human islets from post-mortem donations have shown efficiency but the demand for islets vastly exceeds the availability of donations. A potentially unlimited source of cells for such transplantations would be islet cells derived from in vitro differentiation of human pluripotent stem cells (hPSC), such as embryonic stem cells (hESC). The islet-like clusters (ILC) produced by the known differentiation protocols contain various cell populations. Among these, the beta cells that express both insulin and the transcription factor Nkx6.1 seem to be the most efficient to restore normoglycemia in diabetes animal models. Our aim was to find markers allowing selection of these efficient cells.MethodsFunctional Cell-Capture Screening (FCCS), using an array of antibodies to cell surface proteins, was used to identify markers that preferentially capture the cells expressing insulin, or expressing both insulin and Nkx6.1, from hESC-derived ILC cells. In order to test whether selection for such markers could improve cell therapy in diabetic mouse models, we used ILC produced from a clinical-grade line of hESC by a refined differentiation protocol adapted to up-scalable bioreactors. The ILC, dissociated to single cells, were fractionated by Magnetic Activated Cell Sorting (MACS) for presence of the marker. The sorted cells, re-aggregated into clusters, were encapsulated in microspheres made of alginate modified to reduce foreign body reaction. Implantation was done intraperitoneally in C57BL/6 immuno-competent mice that were made diabetic by prior injections of Streptozotocin (STZ).ResultsCD49A (integrin alpha1) was identified by FCCS as a marker for cells double positive (DP) for insulin (and C-peptide) as well as Nkx6.1 in ILC derived by hESC differentiation. After sorting by MACS with CD49A antibodies, the ILC fraction enriched in CD49A+ cells rapidly reduced glycemia when implanted in the diabetic mice, whereas mice receiving the CD49A depleted population remained highly diabetic. CD49A-enriched ILC cells also produced significantly higher levels of human C-peptide in mouse blood. Another marker, CD26 (DPP4, dipeptidyl peptidase-4), was identified by FCCS as binding insulin-expressing cells which are Nkx6.1-negative. Depletion of CD26+ cells followed by enrichment for CD49A+ cells increased DP cells to over 70%. After this double selection, the CD26 depleted/CD49A enriched ILC were more active than non-sorted ILC to reduce glycemia in the diabetic mice.ConclusionsRefining the composition of ILC differentiated from hPSC by negative selection to remove cells expressing CD26 and positive selection for CD49A expressing cells can enable more effective cell therapy of diabetes.

scholarly journals WNT-targeted compound and phytoestrogen promoted cardiogenic differentiation of human induced pluripotent stem cells (hiPSCs) in vitro

2021 ◽  
pp. 1
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Red Clover ◽  
Cardiac Regeneration ◽  
Protective Role ◽  
Novel Approach ◽  
Human Ipscs ◽  
Induced Pluripotent

Background and objectives: Despite the advances made in the prevention and treatment of cardiovascular diseases (CVD) in the last decade, they are still the leading cause of death in males at the rate of 50% worldwide. Considering the protective role of estrogen to decrease CVD rates in young females, it was suggested that using hormone therapy can be considered to improve heart regeneration. Using in vitro induced pluripotent stem cells (iPSCs) has become one of the most significant tools in CVD treatment in both genders. We design a novel optimal protocol for the differentiation of iPSCs to cardiomyocytes which may be valuable for CVD treatment in men. Methods: Human iPSCs were initially cultivated on mouse embryonic fibroblasts and then, transferred to a specific culture medium for differentiation process. In vitro differentiation of iPSCs into cardiomyocytes was induced at three phases on RPMI-1640 medium including CHIR99021 (5 µM) on days 0–3, BMP4 (20 ng/mL), and bFGF (100 ng/mL) on days 3–5, 10 µM of XAV939 on 6–8, and phytoestrogen + ascorbic acid on days 8–13. Scanning electron microscopy and Real-time PCR using specific primers were applied to confirm produced cardiomyocytes. Results: We found that the simultaneous use of small chemical molecules such as CHIR99021 and XAV 939, growth factors, such as BMP4, bFGF, and herbal-derived phytoestrogen from red clover could efficiently differentiate hiPSCs from the mesoderm and cardiomyocytes after 13 days. Using phytoestrogen increased the induction of cardiac markers including cTnT and GATA-4 in a shorter time; consequently, the proposed formulation has the potential to be used in developing a novel approach for cardiac repair or regeneration. Conclusion: Presented data indicated that the serial use of XAV939 and phytoestrogen at different times and stages can successfully induce cardiogenesis from hiPSCs. Thus, the proposed approach can be used for improved translational strategies for cardiac regeneration with fewer side effects.

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