Role of Mitochondria in the maturation and functionality of human pluripotent stem cell-derived pancreatic beta cells

Pancreatic beta-cells maintain glucose homeostasis in the body by regulating insulin exocytosis into the blood as the levels of blood glucose rise. Mitochondria in pancreatic beta-cells plays an important role in insulin secretion, as it metabolises substrates mainly glucose to produce ATP-generating signals that lead to insulin secretion, in a process termed glucose-stimulated insulin secretion (GSIS)1. Mitochondrial dysfunction has been reported in diabetes2–4 and human induced pluripotent stem cells (hiPSCs) from patients with insulin resistance. The role of mitochondrial dysfunction in the development of diabetes has been supported by data from rare and specific mitochondrial mutations such as the A3243G mutation in the mitochondrial DNA-encoded tRNA gene6 and hiPSCs from patients with mitochondrial diabetes showed a reduction in mitochondrial activity3,4. Human PSCs are differentiated into pancreatic beta-cells using in vitro-directed differentiation protocols designed to recapitulate the specific steps that occur during pancreas development. However, functional immaturity of the differentiated cells may limit its usage as a cell-based model for diseases or drug screening. As mitochondria play an important role in beta-cell functionality, thus the main objective of this project is to investigate the role of mitochondria in the maturation and functionality of hPSC-derived pancreatic ß-cells. More specifically, we study mitochondria morphology, dynamics and activity across all stages of a six-step scalable 3D-directed differentiation protocol.

Hamad Bin Khalifa University (HBKU)