α-Ketoglutarate Promotes Pancreatic Progenitor-Like Cell Proliferation.

A major source of beta cell generation is pancreatic progenitor-like cell differentiation. Multiple studies have confirmed that stem cell metabolism plays important roles in self-renewal and proliferation. In the absence of glucose, glutamine provides the energy for cell division and growth. Furthermore, alpha-ketoglutarate (alpha KG), a precursor for glutamine synthesis, is sufficient for enabling glutamine-independent cell proliferation. We have demonstrated that alpha KG contributes to the large-scale proliferation of pancreatic progenitor-like cells that can provide an ample amount of clinically relevant beta cells. We compared the mRNA expression of a subset of genes, the abundance of ATP, reactive oxide species, mitochondrial number, and the colony-forming frequency between mouse pancreatic CD133(+) and CD133(-) cells. We employed Real-Time PCR, immunostaining and passage assays to investigate self-renewal and proliferation of pancreatic progenitor-like cells in a 3D culture system in the presence and absence of alpha KG. The energy metabolism of CD133(+) cells was more prone to oxidative phosphorylation. However, in the 3D culture system, when alpha KG was supplemented to the culture medium, the proliferation of the pancreatic progenitor-like cells was significantly elevated. We confirmed that the presence of alpha KG correlated with the up-regulation of Ten-Eleven Translocation (Tet). alpha KG can promote the proliferation of pancreatic progenitor-like cells via the up-regulation of Tet.