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Saber, Nelly Causing

University of British Columbia

Diabetes affects over 500 million people worldwide. It is characterized by abnormally high blood glucose levels (hyperglycemia) due to the insufficient production or action of insulin. Hyperglycemia can eventually lead to cardiovascular issues, nerve damage, kidney failure, blindness, and other complications. Continuous blood glucose monitoring and exogenous insulin administration can help control blood glucose levels, but people living with diabetes still experience episodes of hyper- and hypoglycemia. Whole pancreas or islet transplantation can improve glycemic control but is limited by the scarcity of cadaveric donors. Human pluripotent stem cells are a potentially unlimited source of insulin-producing beta cells that could be used to treat people with diabetes. Clinical trials are currently underway testing the safety and efficacy of human stem cell-derived pancreatic progenitors in people with type 1 diabetes. Since pre-clinical animal studies mostly utilized male rodents and it has previously been shown that different factors can influence endocrine cell specification and function, the studies described in this thesis investigated whether the site of implantation and sex had an impact on the differentiation and maturation of pancreatic progenitors. Here I implanted pancreatic progenitors under the kidney capsule in male and female immunodeficient mice and found that these cells developed glucose-stimulated human insulin secretion sooner in females than males. However, I did not observe any sex differences in the acquisition of glucose-stimulated human insulin secretion when pancreatic progenitors were implanted in the gonadal fat pad or macroencapsulation devices, which are retrievable devices that serve to contain the cells. Additionally, despite the role of estrogen in beta cell development and function, there was no difference in the acquisition of glucose-stimulated human insulin secretion in ovariectomized and sham ovariectomized female mice. Furthermore, macroencapsulation devices appeared to promote the faster maturation of pancreatic progenitors compared to other implantation sites including under the kidney capsule or in the gonadal fat pad. Overall, it appears that the implantation site has more of an impact on the endocrine cell specification and function of pancreatic progenitor cells than the sex of the recipient in mice.

Text

2024-08-19

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/88965

Genome Science and Technology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/