The Genetic Landscape of β-Cell Proliferation: Toward a Road Map.

Abstract

β-Cell failure underlies much of the pathogenesis of type 1 and type 2 diabetes, and restoring β-cell mass, for example by stimulating proliferation, has been an active area of investigation. β-Cells are generally, although not universally, quiescent. Numerous studies have documented the low but nonzero replicative capacity of both rodent and human β-cells (1,2). Further, in adult rodent models, it appears that β-cell proliferation can occur in response to injury (3), nutrients (4), or pregnancy (5,6). In humans, the matter may be more complicated, with many pathways under consideration (7). Therefore, understanding what regulates β-cell proliferation could have important implications for regenerative medicine, as the mechanisms underlying this process may lead to new avenues for therapeutic intervention. Gene-expression profiling of β-cells has been challenging because islets comprise a heterogeneous cell population. Early efforts profiled intact islets without regard to cell type; for example, Affymetrix profiling of islets from pregnant mice (8,9) pointed to pathways potentially responsible for the proliferative response during pregnancy. For the most part, such a strategy is reasonable in rodent islets as they are typically composed of >80% β-cells. In human islets, however, β-cells barely make up 50% of the population. Transcriptomic analysis of individual cell types in the human islet, based on sorting cells by …