ß-cell regeneration is a key goal of diabetes research. Progression through cell cycle is associated with pRb inactivation via sequential phosphorylation by the “early” cyclins/cdks (D-cyclins cdk4/6) and the “late” cyclins/cdks (cyclin A/E and cdk1/2). In ß-cells, activation of either “early” or “late” G1/S cyclins and/or cdks is an efficient approach to induce cycle entry, but it is unknown whether combined expression of early and late cyclins/cdks might have synergistic or additive effects. Thus, we explored whether a combination of both “early” and “late” cyclins and cdks might more effectively drive human ß-cell cell cycle entry than either group alone. We also sought to determine whether authentic replication with expansion of adult human ß-cells could be demonstrated.

“Late” cyclins/cdks do not traffic in response to the induction of replication by “early” cyclins/cdks in human ß-cells, but are capable of nuclear translocation when overexpressed. “Early” plus “late” cyclins/cdks, acting via pRb phosphorylation on distinct residues, complementarily induce greater proliferation in human ß-cells than either group alone. Importantly, the combination of “early” and “late” cyclins/cdks clearly increased human ß-cell numbers in vitro.

These findings provide additional insight into human ß-cells expansion. They also provide a novel tool for assessing ß-cell expansion in vitro.

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