Targeting the cell cycle inhibitor p57Kip2 promotes adult human β cell replication

Children with focal hyperinsulinism of infancy display a dramatic, non-neoplastic clonal expansion of beta cells that have undergone mitotic recombination, resulting in paternal disomy of part of chromosome 11. This disomic region contains imprinted genes, including the gene encoding the cell cycle inhibitor p57(KiP2) (CDKN1C), which is silenced as a consequence of the recombination event. We hypothesized that targeting p57(KiP2) could stimulate adult human beta cell replication. Indeed, when we suppressed CDKN1C expression in human islets obtained from deceased adult organ donors and transplanted them into hyperglycemic, immunodeficient mice, beta cell replication increased more than 3-fold. The newly replicated cells retained properties of mature beta cells, including the expression of beta cell markers such as insulin, PDX1, and NKX6.1. Importantly, these newly replicated cells demonstrated normal glucose-induced calcium influx, further indicating beta cell functionality. These findings provide a molecular explanation for the massive p cell replication that occurs in children with focal hyperinsulinism. These data also provided evidence that beta cells from older humans, in which baseline replication is negligible, can be coaxed to re-enter and complete the cell cycle while maintaining mature beta cell properties. Thus, controlled manipulation of this pathway holds promise for the expansion of beta cells in patients with type 2 diabetes.