We have recently shown that human pluripotent stem cell (hPSC) derived pancreatic islets (SC-islets) develop adult-like glucose stimulated insulin secretion (GSIS) during an extended maturation period (up to 6 weeks) in an optimized culture media and rotating suspension culture (Balboa et al. Nat. Biotech 2022). However, SC-islets retain several features suggesting a transcriptomic and metabolic immaturity. These include: 1) Limited glucose-responsive mitochondrial metabolism and respiration, 2) Low expression patterns of maturity-associated genes and transcription factors, and 3) Strong insulin secretory responses to disallowed exogenous fuels. 

Building on these findings we have now been able to study elements of metabolic maturation following extended in vivo engraftment in mice. The results suggest that core elements of mitochondrial metabolism become more “adult-like” over 4 months of engraftment, correlating with an improvement of dynamic functionality and expression profiles of maturity-associated genes. We further demonstrate that these hallmarks of SC-islet maturity are predominantly derived from mitochondrial development, including the enrichment of mitochondria themselves as well as associated metabolic machinery/enzymes. While other elements of metabolic immaturity remain, extended engraftment times robustly trigger a progressively adult-like metabolism.

Overall, it is increasingly evident that the SC-islets represent a genuine pancreatic endocrine lineage and that they are able to evolve into long-lived, physiologically functional, and vascularized endocrine tissue. It is also strikingly evident that the maturation of beta cells is a combination of multiple overlapping processes that do not necessarily arise in complete synchrony.