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

Expansion of pancreatic beta-cells is a key goal of diabetes research, yet induction of adult human beta-cell replication has proven frustratingly difficult. In part, this reflects a lack of understanding of cell cycle control in the human beta-cell. Here, we provide a comprehensive immunocytochemical atlas of G1/S control molecules in the human beta-cell. This atlas reveals that the majority of these molecules, previously known to be present in islets, are actually present in the beta-cell. More importantly, and in contrast to anticipated results, the human beta-cell 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 beta-cell. 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 beta-cell proliferation are present in the nuclear compartment. This observation may provide an explanation for the refractoriness of human beta-cells to proliferation. Thus, in addition to known obstacles to human beta-cell proliferation, restriction of G1/S molecules to the cytoplasm of the human beta-cell represents an unanticipated obstacle to therapeutic human beta-cell expansion.