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Augmented Stat5 Signaling Bypasses Multiple Impediments to Lactogen-Mediated Proliferation in Human β-Cells

Published on Nov 1, 2015in Diabetes7.199
· DOI :10.2337/db15-0083
Hainan Chen1
Estimated H-index: 1
,
Jeffrey W. Kleinberger6
Estimated H-index: 6
(UMB: University of Maryland, Baltimore)
+ 11 AuthorsAndrew F. Stewart56
Estimated H-index: 56
Abstract
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.
  • References (49)
  • Citations (26)
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References49
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#1David M. Blodgett (UMMS: University of Massachusetts Medical School)H-Index: 9
#2Anetta Nowosielska (UMMS: University of Massachusetts Medical School)H-Index: 11
Last. Philip diIorio (UMMS: University of Massachusetts Medical School)H-Index: 11
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Understanding distinct gene expression patterns of normal adult and developing fetal human pancreatic α- and β-cells is crucial for developing stem cell therapies, islet regeneration strategies, and therapies designed to increase β-cell function in patients with diabetes (type 1 or 2). Toward that end, we have developed methods to highly purify α-, β-, and δ-cells from human fetal and adult pancreata by intracellular staining for the cell-specific hormone content, sorting the subpopulations by f...
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#1Andrew F. Stewart (ISMMS: Icahn School of Medicine at Mount Sinai)H-Index: 56
#2Mehboob A. Hussain (Johns Hopkins University)H-Index: 16
Last. Rohit N. Kulkarni (Harvard University)H-Index: 58
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This is the third in a series of Perspectives on intracellular signaling pathways coupled to proliferation in pancreatic β-cells. We contrast the large knowledge base in rodent β-cells with the more limited human database. With the increasing incidence of type 1 diabetes and the recognition that type 2 diabetes is also due in part to a deficiency of functioning β-cells, there is great urgency to identify therapeutic approaches to expand human β-cell numbers. Therapeutic approaches might include ...
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The replacement or regeneration of pancreatic β cells has the potential to reverse the progression of diabetes mellitus. This Review discusses the physiology of normal β-cell replication, the signalling pathways and epigenetic mechanisms that regulate entry to the cell cycle in β cells, and approaches for discovering novel molecules that drive β-cell replication. The potential and challenges of implementing strategies that replace or regenerate β-cells in humans is also discussed.
75 CitationsSource
#1Bas Brouwers (Katholieke Universiteit Leuven)H-Index: 6
#2Geoffroy de Faudeur (Katholieke Universiteit Leuven)H-Index: 4
Last. Anica Schraenen (Katholieke Universiteit Leuven)H-Index: 15
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Summary The human growth hormone ( hGH ) minigene is frequently used in the derivation of transgenic mouse lines to enhance transgene expression. Although this minigene is present in the transgenes as a secondcistron, and thus not thought to be expressed, we found that three commonly used lines, Pdx1-Cre Late , RIP-Cre , and MIP-GFP , each expressed significant amounts of hGH in pancreatic islets. Locally secreted hGH binds to prolactin receptors on β cells, activates STAT5 signaling, and induce...
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Prolactin (PRL) and placental lactogen stimulate beta cell replication and insulin production in vitro and in vivo. The molecular mechanisms by which lactogens promote beta cell expansion are unclear. We treated rat insulinoma cells with a PRL receptor (PRLR) siRNA to determine if PRLR signaling is required for beta cell DNA synthesis and cell survival and to identify beta cell cycle genes whose expression depends upon lactogen action. Effects of PRLR knockdown were compared with those of PRL tr...
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#2Talitha van der Meulen (Salk Institute for Biological Studies)H-Index: 11
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Elucidating the pathophysiology and molecular attributes of common disorders as well as developing targeted and effective treatments hinges on the study of the relevant cell type and tissues. Pancreatic beta cells within the islets of Langerhans are centrally involved in the pathogenesis of both type 1 and type 2 diabetes. Describing the differentiated state of the human beta cell has been hampered so far by technical (low resolution microarrays) and biological limitations (whole islet preparati...
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Harnessing control of human β-cell proliferation has proven frustratingly difficult. Most G1/S control molecules, generally presumed to be nuclear proteins in the human β-cell, are in fact constrained to the cytoplasm. Here, we asked whether G1/S molecules might traffic into and out of the cytoplasmic compartment in association with activation of cell cycle progression. Cdk6 and cyclin D3 were used to drive human β-cell proliferation and promptly translocated into the nucleus in association with...
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Expansion of pancreatic β-cells is a key goal of diabetes research, yet induction of adult human β-cell replication has proven frustratingly difficult. In part, this reflects a lack of understanding of cell cycle control in the human β-cell. Here, we provide a comprehensive immunocytochemical “atlas” of G1/S control molecules in the human β-cell. This atlas reveals that the majority of these molecules, previously known to be present in islets, are actually present in the β-cell. More importantly...
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