Timo Otonkoski, MD, PhD, Professor of Medical Stem Cell Research, University of Helsinki, Finland. Timo Otonkoski was trained as a Pediatric Endocrinologist at the Children’s Hospital, University of Helsinki. His main clinical specialties are childhood diabetes and hypoglycemia. His research has focused on the growth and development of the pancreatic islets. He has also made important contributions in the field of congenital hyperinsulinism and other forms of genetic insulin secretory dysfunction. Lately, he has shifted his main area of interest into the use of human pluripotent stem cells and genome editing to study beta-cell pathophysiology. His group has made fundamental discoveries of the pluripotent reprogramming of human cells, developed novel approaches for controlling their differentiation, and used this approach successfully to elucidate mechanisms of beta-cell dysfunction. The Otonkoski group belongs to the Centre of Excellence in Stem Cell Metabolism of the Academy of Finland. Dr. Otonkoski received the Albert Renold Prize of the EASD in 2019 for outstanding achievements in research on the islets of Langerhans.
Mechanisms of SC-beta cell functional maturation
Timo Otonkoski1.
1Biomedicum Stem Cell Centre, University of Helsinki, Helsinki, Finland
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.
Optimizing Differentiation to Stem Cell Beta Cells
