SC-beta Cell in vivo Maturation

Stem cell-derived β (SC-β) cells are an emerging regenerative therapy to compensate for loss of functional β cell mass in diabetes. Glucose-stimulated insulin secretion in SC-β cells is variable in vitro but stabilizes after transplantation and maturation under the kidney capsule of mice. We identified mechanisms correlated with functional maturation using RNA-sequencing and co-expression network analysis. In vivo maturation enhanced glucose-stimulated but not basal insulin secretion, up-regulated β cell hormones IAPP and ADCYAP1, increased expression of maturation markers MAFA, UCN3, and SIX2, and resolved endocrine identity of incompletely specified polyhormonal cells produced during differentiation. Transplantation promoted calcium signalling, induced exocytotic machinery supporting hormone secretion and improved stimulus-secretion coupling that fine-tunes insulin secretion. Growth hormone signalling emerged as candidate driver of in vivo maturation and was confirmed in vitro. Also, a large co-expression module correlated with HbA1c and was enriched in genes up-regulated during in vivo maturation but down-regulated in hyperglycaemic and palmitate stress conditions, suggesting that transcriptional maturation of SC-β cells in vivo mirrors processes lost in diabetic β cells.