All β Cells Contribute Equally to Islet Growth and Maintenance

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Abstract
In healthy adult mice, the β cell population is not maintained by stem cells but instead by the replication of differentiated β cells. It is not known, however, whether all β cells contribute equally to growth and maintenance, as it may be that some cells replicate while others do not. Understanding precisely which cells are responsible for β cell replication will inform attempts to expand β cells in vitro, a potential source for cell replacement therapy to treat diabetes. Two experiments were performed to address this issue. First, the level of fluorescence generated by a pulse of histone 2B–green fluorescent protein (H2BGFP) expression was followed over time to determine how this marker is diluted with cell division; a uniform loss of label across the entire β cell population was observed. Second, clonal analysis of dividing β cells was completed; all clones were of comparable size. These results support the conclusion that the β cell pool is homogeneous with respect to replicative capacity and suggest that all β cells are candidates for in vitro expansion. Given similar observations in the hepatocyte population, we speculate that for tissues lacking an adult stem cell, they are replenished equally by replication of all differentiated cells. The β cells of the pancreas are responsible for insulin production and their destruction results in type I diabetes. β cell maintenance, growth, and regenerative repair is thought to occur predominately, if not exclusively, through the replication of existing β cells, not via an adult stem cell. It was previously unknown, however, whether all β cells divide at the same rate, or if multiple subpopulations of β cells exist, some highly replicative and others very slowly dividing, possibly postmitotic. We performed two types of experiments to determine whether all β cells are alike: label-retaining analysis and clonal analysis. Our results indicate that all β cells contribute equally to islet growth and maintenance.