Human Pancreatic β-Cell G1/S Molecule Cell Cycle Atlas

Abstract

Expansion of pancreatic β-cells is a key goal of diabetes research, yet induction of adult human β-cells replication has proven frustratingly difficult. In part, this reflects a lack of understanding of cell cycle control in the human β-cells. Here, we provide a comprehensive immunocytochemical "atlas" of G1/S control molecules in the human β-cells. This atlas reveals that the majority of these molecules, previously known to be present in islets, are actually present in the β-cells. More importantly, and in contrast to anticipated results, the human β-cells G1/S atlas reveals that almost all of the critical G1/S cell cycle control molecules are located in the cytoplasm of the quiescent human β-cells. Indeed, the only nuclear G1/S molecules are the cell cycle inhibitors, pRb, p57, and variably, p21: none of the cyclins or cdks necessary to drive human β-cells proliferation are present in the nuclear compartment. This observation may provide an explanation for the refractoriness of human β-cells to proliferation. Thus, in addition to known obstacles to human β-cells proliferation, restriction of G1/S molecules to the cytoplasm of the human β-cells represents an unanticipated obstacle to therapeutic human β-cells expansion. Diabetes 62:2450-2459, 2013. © 2013 by the American Diabetes Association.