Augmented Stat5 Signaling Bypasses Multiple Impediments to Lactogen-Mediated Proliferation in Human β-Cells
Pregnancy in rodents is associated with a two- to three-fold increase in beta cell mass, attributable to large increases in beta cell proliferation, complimented by increases in beta cell size, survival and function, mediated mainly by the lactogenic hormones, prolactin (PRL) and placental lactogens (PLs). In humans, however, beta cell mass does not increase as dramatically in pregnancy, and PRL fails to activate proliferation in human islets in vitro. To determine why, we explored the PRL-prolactin receptor (hPRLR)-JAK2-STAT5-cyclin-cdk signaling cascade in human beta cells. Surprisingly, adult human beta cells express little or no PRLR. As expected, restoration of the hPRLR in human beta cells rescued JAK2-STAT5 signaling in response to PRL. However, rescuing hPRLR-STAT5 signaling nevertheless failed to confer proliferative ability on adult human beta cells in response to PRL. Surprisingly, mouse (but not human) Stat5a overexpression led to upregulation of cyclins D1-3 and cdk4, as well as their nuclear translocation, all associated with beta cell cycle entry. Collectively, the findings show that human beta cells fail to proliferate in response to PRL for multiple reasons, one of which is a paucity of functional PRLRs, and that murine Stat5 overexpression is able to bypass these impediments.