STUDYING PANCREATIC BETA CELL DEVELOPMENT AND DIABETES PATHOGENESIS USING HUMAN PLURIPOTENT STEM CELLS

Abstract

Human pluripotent stem cells (hPSCs) possess unlimited capacity to proliferate and can differentiate to any cell type. Additionally, induced pluripotent stem cells (iPSCs) can be generated from any somatic cell of diabetic patients and carry the genetic imprint of the disease. Therefore, hPSCs are excellent tools for recapitulating human pancreatic beta cell development and for understanding the molecular mechanisms underlying different types of diabetes. We utilized hPSC technology for addressing a myriad of knowledge gaps; in dissecting novel routes to beta cell development, investigating the role of key developmental markers and modeling of insulin resistance (IR) and neonatal diabetes in humans. Using hPSCs, we showed that a novel PDX1-/NKX6.1+ pancreatic progenitor population exists during human embryonic development, similar to the pancreatic mesenchyme, that can give rise to functional insulin-secreting beta cells. We also investigated the role of key transcription factors such as RFX3 and RFX6 in hPSC-derived pancreatic progenitors, thus revealing that the two markers work in concert to regulate endocrine progenitor commitment, while having heterogeneity in expression within the endocrine-committed sub-populations. We also established a novel model for studying the etiology of genetic IR in a population which is at the highest risk of developing type 2 diabetes (T2D) by generating iPSCs from IR offspring of patients with T2D (IR-iPSCs). We showed that the IR-iPSCs augmented oxidative stress as well as high lactate secretion due to the genetic defects they harbor, compared to IS-iPSCs, which are the hallmarks of IR and T2D pathogenesis. We also utilized the iPSC model harboring homozygous deletion in the distal enhancer of PTF1a gene generated from a patient with permanent neonatal diabetes, to show that loss of PTF1a does not cause pancreatic agenesis and neonatal diabetes due to obliterated pancreatic progenitors or defects in pancreatic beta cell functionality. Furthermore, we propose a therapeutic option for such patients, wherein beta cells differentiated from patient-derived iPSCs could be utilized for cell therapy for treating neonatal diabetes in these patients, without the need for immunosuppression.

Date of Award	2022
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences