Generation of stem cell-derived β-cells from patients with type 1 diabetes

Jeffrey R. Millman^1,2, Chunhui Xie³, Alana Van Dervort⁴, Mads Gurtler³, Felicia W. Pagliuca⁵ & Douglas A. Melton³

DOI: 10.1038/ncomms11463

Speaker: Irwin Puc (傅立宇)                                      Time: 15:00-16:00, Jun. 7, 2017

Commentator: Dr. Chia-Ching Wu (吳佳慶)                       Place: Room 601

Abstract:

The Beta cells (β-cell) is one of four major types of cells present in the islets of Langerhans (Pancreas), these β-cell synthesizes and secretes the hormone insulin mainly in response to glucose but also in response to several nutrients, hormones and nervous stimuli¹. In type 1 diabetes (T1DM), the phenomenon is more severe and is mainly due to the autoimmune attack of autoreactive T-cells against islet β-cells. It is assumed that about 70–90% of the β-cell mass is lost at the time of clinical presentationt². Diabetic patients, particularly those suffering from type 1 diabetes, can potentially be cured through transplantation of new β-cells. Transplantation of exogenous β-cells to replace dead or dysfunctional endogenous β-cells is a potential strategy for controlling blood glucose levels in diabetic patients. Allogeneic transplantation of cadaveric islets has already been performed on patients making them insulin independent for 5 years or longer via this strategy, but this approach is limited due to, the scarcity and quality of donor islets, complications that arises during the transplantation procedure also the requirement that the patients must remain onimmunosupressants for life. The generation of an unlimited supply of human β-cells from stem cells could potentially extend this therapy to millions of new patients. In this study Stem cells derived β-cells (SC- β cells) from Type 1 Diabetic patient (T1D-β) hiPSC where successfully generated for the first time. These cells, referred to as T1D SC-β cells, express markers found in β -cells, they show to be functionally indistinguishable from normal non diabetic β-cells (ND SC- β) in vitro and in vivo, and prevent alloxan-induced diabetes in mice. Insulin secretion is increased in these T1D SC-β cells in response to several categories of anti-diabetic drugs. Furthermore, they demonstrated that these cells respond to different types of chemically induced stress, developed an in vitro disease model of T1D SC- β cell stress and demonstrate a partial rescue of this stress phenotype with treatment of an Alk5 inhibitor. The overall data demonstrates that T1D SC- β cells can be used to better study diabetes and as a potential autologous source for cell replacement therapy.

References

1.      Kulkarni, R. N. (2004). The islet Beta-cell. The International Journal of Biochemistry & Cell Biology, 36, 365-371. doi: 10.1016/j.biocel.2003.08.010

2.      Cernea, S., & Dobreanu, M. (2013). Diabetes and beta cell function: from mechanisms to evaluation and clinical implications. National Center for Biotechnology Information, 23(3), 266-280. doi: 10.11613/BM.2013.033