Human pancreatic [beta]-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.