Intrapatient Variations in Type 1 Diabetes-specific iPS Cell Differentiation Into Insulin-producing Cells

The discovery of insulin changed the course of history in the treatment of diabetes. However, despite tremendous progress in insulin formulations and treatment strategies, insulin treatment still cannot fully prevent chronic complications and intensive insulin treatment to improve metabolic control, has often paralleled an increased risk of severe hypoglycemia. A cure for Type 1 diabetes should include: ? Restoration of self tolerance, to prevent recurrence of autoimmunity ? Restoration of physiologic metabolism by replacement of the biologic function (insulin producing cells) that was partially of completely impaired as a result of the disease process. ? Prevention of destruction of the new insulin producing cells by the recipient immune system in the absence of any treatment that could introduce an additional risk to the patient, which could be comparable to, or higher than the risk imposed by disease progression under exogenous insulin treatment. Pancreatic islets could be considered an ideal and more physiologic alternative to insulin, as they can restore metabolic control after transplantation, preventing the development of chronic complications. In fact, islets are capable of perfectly timed insulin release and can keep glucose levels in the normal range, functioning for an entire lifetime, if they are not destroyed by the recipient's immune system. Significant progress has been recently reported in the translational research approach towards the development of a cure for Type 1 diabetes. There is now strong evidence for the technical feasibility of human islet isolation and purification procedures. Proof of function of isolated human islets has been clearly established both in animal models and in pilot clinical trials of human islet allotransplantation in patients with surgical and Type 1 diabetes. Additional research in now needed to improve the current clinical results in terms of long term prevention of rejection and recurrence of autoimmunity, the development of safe, non diabetogenic immunomodulation strategies and ultimately the achievement of donor specific immune tolerance. If success will be achieved in these areas, then we will face the critical challenge of identifying sufficient and suitable sources of insulin producing tissue to treat the increasing number of patients who could benefit from this form of therapy and which would not be limited to Type 1 diabetes. That is why the work on xenogeneic islets, embryonic and adult stem cells, islet regeneration and proliferation, as well as engineering of insulin producing cells must be continued, to identify the most ideal source of insulin producing tissue that could be utilized on a large scale once the impediments and limitations of immunosuppression will be resolved.

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Genome wide approaches reveal new genes and pathways involved in human T helper cell differentiation and type 1 diabetes

New Biotechnology ◽

10.1016/j.nbt.2010.01.324 ◽

2010 ◽

Vol 27 ◽

pp. S14

Author(s):

R. Lahesmaa

Keyword(s):

Type 1 Diabetes ◽

Cell Differentiation ◽

T Helper Cell ◽

Helper Cell ◽

T Helper ◽

New Genes ◽

Genome Wide

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A nanofibrous encapsulation device for safe delivery of insulin-producing cells to treat type 1 diabetes

Science Translational Medicine ◽

10.1126/scitranslmed.abb4601 ◽

2021 ◽

Vol 13 (596) ◽

pp. eabb4601

Author(s):

Xi Wang ◽

Kristina G. Maxwell ◽

Kai Wang ◽

Daniel T. Bowers ◽

James A. Flanders ◽

...

Keyword(s):

Type 1 Diabetes ◽

Stem Cell ◽

Cell Penetration ◽

Β Cells ◽

Safe Delivery ◽

Insulin Producing Cells ◽

Chemically Induced ◽

Immunocompetent Mice ◽

Highly Porous

Transplantation of stem cell–derived β (SC-β) cells represents a promising therapy for type 1 diabetes (T1D). However, the delivery, maintenance, and retrieval of these cells remain a challenge. Here, we report the design of a safe and functional device composed of a highly porous, durable nanofibrous skin and an immunoprotective hydrogel core. The device consists of electrospun medical-grade thermoplastic silicone-polycarbonate-urethane and is soft but tough (~15 megapascal at a rupture strain of >2). Tuning the nanofiber size to less than ~500 nanometers prevented cell penetration while maintaining maximum mass transfer and decreased cellular overgrowth on blank (cell-free) devices to as low as a single-cell layer (~3 micrometers thick) when implanted in the peritoneal cavity of mice. We confirmed device safety, indicated as continuous containment of proliferative cells within the device for 5 months. Encapsulating syngeneic, allogeneic, or xenogeneic rodent islets within the device corrected chemically induced diabetes in mice and cells remained functional for up to 200 days. The function of human SC-β cells was supported by the device, and it reversed diabetes within 1 week of implantation in immunodeficient and immunocompetent mice, for up to 120 and 60 days, respectively. We demonstrated the scalability and retrievability of the device in dogs and observed viable human SC-β cells despite xenogeneic immune responses. The nanofibrous device design may therefore provide a translatable solution to the balance between safety and functionality in developing stem cell–based therapies for T1D.

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A pro-endocrine pancreatic transcriptional program established during development is retained in human gallbladder epithelial cells

10.1101/2021.03.02.433636 ◽

2021 ◽

Author(s):

Mugdha V. Joglekar ◽

Subhshri Sahu ◽

Wilson KM Wong ◽

Sarang N. Satoor ◽

Charlotte X. Dong ◽

...

Keyword(s):

Type 1 Diabetes ◽

Epithelial Cells ◽

Immune Cells ◽

Adult Mouse ◽

Islet Autoimmunity ◽

List Type ◽

Insulin Production ◽

Human Gallbladder ◽

Insulin Producing Cells

AbstractObjectivePancreatic islet β-cells are factories for insulin production; however ectopic expression of insulin is also well recognized. The gallbladder is a next-door neighbour to the developing pancreas. Here, we wanted to understand if gallbladders contain functional insulin-producing cells.DesignWe compared developing and adult mouse as well as human gallbladder epithelial cells and islets using immunohistochemistry, flow cytometry, ELISAs, RNA-sequencing, real-time PCR, chromatin immunoprecipitation and functional studies.ResultsWe demonstrate that the epithelial lining of developing, as well as adult mouse and human gallbladders naturally contain interspersed cells that retain the capacity to actively transcribe, translate, package, and release insulin. We show for the first time that human gallbladders also contain functional insulin-secreting cells with the potential to naturally respond to glucose in vitro and in situ. Notably, in a NOD mouse model of type 1 diabetes, we observed that insulin-producing cells in the gallbladder are not targeted by autoimmune cells. Conclusion: In summary, our biochemical, transcriptomic, and functional data in human gallbladder epithelial cells collectively demonstrate their potential for insulin-production under pathophysiological conditions, and open newer areas for type 1 diabetes research and therapy.Significance of the studyWhat is already known about this subject?Developing pancreas and gallbladder are next-door neighbours and share similar developmental pathways.Human Gallbladder-derived progenitor cells were shown to differentiate into insulin-producing cells.What are the new findings?Gallbladder epithelium contains interspersed cells that can transcribe, translate, package and secrete insulin.Insulin-producing cells in the gallbladder are not destroyed by immune cells in an animal model of type 1 diabetes (T1D).Our studies demonstrating the absence of insulin splice variants in human gallbladder cells, and higher splice forms in human islets, suggest a potential mechanism (via defective ribosomal products) in escaping islet autoimmunity.How might it impact clinical practice?Deciphering mechanisms of protection of insulin-producing cells from immune cells in the gallbladder could help in developing strategies to prevent islet autoimmunity in T1D.

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