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, which is attributable to large increases in beta-cell proliferation, complimented by increases in beta-cell size, survival, and function and mediated mainly by the lactogenic hormones prolactin (PRL) and placental lactogens. In humans, however, beta-cell mass does not increase as dramatically during pregnancy, and PRL fails to activate proliferation in human islets in vitro. To determine why, we explored the human PRL-prolactin receptor (hPRLR)-Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (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 of which are 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 PRL receptors, and that murine Stat5 overexpression is able to bypass these impediments.