BioProject

The beta (β) cell mass formed during embryogenesis is amplified by cell replication that occurs primarily during fetal and early postnatal development. More...

The beta (β) cell mass formed during embryogenesis is amplified by cell replication that occurs primarily during fetal and early postnatal development. Thereafter, β cells become functionally mature and their mass is maintained by a very low rate of replication. For those few β cells that replicate in adult life, it is not known how replication is initiated, uncoupled from β cell function nor whether this occurs in a specialized subset of β cells. To explore these issues with the aim of controlling replication of mature human β cells, we capitalized on a YAP overexpression system that induces cell cycle re-entry in stem cell derived-β cells. Singe cell RNA sequencing revealed an upregulation of components of the leukemia inhibitory factor (LIF) pathway upon cell cycle re-entry. Experimental activation of the LIF pathway induces replication and expansion of human stem cell derived- and adult β cells in vitro and in vivo. In both stem cell derived- and adult human β cells, the expression of the LIF receptor LIFR is restricted to a subset of β cells with distinct transcriptional profiles and defines a subpopulation of β cells with increased replication rates. Further analysis identified 15 transcription factors whose gene networks are active in replicating β cells. Overall, this study sheds light on regulatory networks that control β cell replication and reveals a heterogeneity in LIF responsiveness and replication competence. Overall design: Single cell analysis of LacZ- and YAPS6A-overexpressing beta cells using the 10X genomics platform and bulk RNA-seq analysis of LIFR+ and LIFR- sorted beta cells. Less...