Augmented STAT5 signaling bypasses multiple impediments to lactogen-mediated proliferation in human β-cells

Hainan Chen, Jeffrey W. Kleinberger, Karen K. Takane, Fatimah Salim, Nathalie Fiaschi-Taesch, Kyrie Pappas, Ramon Parsons, Jing Jiang, Yue Zhang, Hongtao Liu, Peng Wang, Aaron S. Bender, Stuart J. Frank, Andrew F. Stewart

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Pregnancy in rodents is associated with a two- to threefold increase in β-cell mass, which is attributable to large increases in β-cell proliferation, complimented by increases in β-cell size, survival, and function and mediated mainly by the lactogenic hormones prolactin (PRL) and placental lactogens. In humans, however, β-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 β-cells. Surprisingly, adult human β-cells express little or no PRLR. As expected, restoration of the hPRLR in human β-cells rescued JAK2-STAT5 signaling in response to PRL. However, rescuing hPRLR-STAT5 signaling nevertheless failed to confer proliferative ability on adult human β-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 β-cell cycle entry. Collectively, the findings show that human β-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.

Original languageEnglish
Pages (from-to)3784-3797
Number of pages14
JournalDiabetes
Volume64
Issue number11
DOIs
StatePublished - Nov 2015

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