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
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)
📖 Papers frequently viewed together
19 Authors (Hail Kim, ..., Michael S. German)
310 Citations
233 Citations
3 Authors (Carol Huang, ..., James C. Cross)
154 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
#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
view all 14 authors...
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...
112 CitationsSource
#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
view all 7 authors...
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 ...
57 CitationsSource
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
view all 21 authors...
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...
80 CitationsSource
#1Ramamani Arumugam (Duke University)H-Index: 10
#2Don Fleenor (Duke University)H-Index: 8
Last. Michael Freemark (Duke University)H-Index: 39
view all 3 authors...
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...
11 CitationsSource
#1Christopher Benner (Salk Institute for Biological Studies)H-Index: 44
#2Talitha van der Meulen (Salk Institute for Biological Studies)H-Index: 11
Last. Mark O. Huising (UC Davis: University of California, Davis)H-Index: 32
view all 6 authors...
Background Insulin producing beta cell and glucagon producing alpha cells are colocalized in pancreatic islets in an arrangement that facilitates the coordinated release of the two principal hormones that regulate glucose homeostasis and prevent both hypoglycemia and diabetes. However, this intricate organization has also complicated the determination of the cellular source(s) of the expression of genes that are detected in the islet. This reflects a significant gap in our understanding of mouse...
125 CitationsSource
#1Alexandra C. Nica (Swiss Institute of Bioinformatics)H-Index: 21
#2Halit Ongen (Swiss Institute of Bioinformatics)H-Index: 26
Last. Emmanouil T. Dermitzakis (Swiss Institute of Bioinformatics)H-Index: 84
view all 8 authors...
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...
111 CitationsSource
#1Yang Jiao (UPenn: University of Pennsylvania)H-Index: 26
#2Sebastian Rieck (UPenn: University of Pennsylvania)H-Index: 5
Last. Klaus H. Kaestner (UPenn: University of Pennsylvania)H-Index: 91
view all 4 authors...
Aims/hypothesis Increased beta cell proliferation during pregnancy is mediated by the Janus kinase 2/signal transducer and activator of transcription 5 (JAK2/STAT5) signalling pathway in response to increased lactogen levels. Activation of the pathway leads to transcriptional upregulation of Cish (encoding cytokine-inducible SH2 domain-containing protein), a member of the suppressor of cytokine signalling (SOCS) family of genes, forming a negative-feedback loop. Here, we examined whether conditi...
7 CitationsSource
#1Nathalie M. Fiaschi-Taesch (University of Pittsburgh)H-Index: 21
#2Jeffrey W. Kleinberger (University of Pittsburgh)H-Index: 4
Last. Andrew F. Stewart (University of Pittsburgh)H-Index: 56
view all 12 authors...
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...
43 CitationsSource
#1Nathalie M. Fiaschi-Taesch (University of Pittsburgh)H-Index: 21
#2Jeffrey W. Kleinberger (University of Pittsburgh)H-Index: 4
Last. Andrew F. Stewart (University of Pittsburgh)H-Index: 56
view all 11 authors...
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...
42 CitationsSource
Cited By26
#1Rosemary LiH-Index: 2
#2Nagesha Guthalu Kondegowda (Beckman Research Institute)
Last. Rupangi C. VasavadaH-Index: 28
view all 7 authors...
Diabetes occurs due to a loss of functional β-cells, resulting from β-cell death and dysfunction. Lactogens protect rodent and human β-cells in vitro and in vivo against triggers of β-cell cytotoxicity relevant to diabetes, many of which converge onto a common pathway, endoplasmic reticulum (ER) stress. However, whether lactogens modulate the ER stress pathway is unknown. This study examines if lactogens can protect β-cells against ER stress and mitigate diabetes incidence in Akita mice, a roden...
#1Rafał Sibiak (Poznan University of Medical Sciences)H-Index: 1
#2Maurycy Jankowski (Poznan University of Medical Sciences)H-Index: 4
Last. Ewa Wender-Ożegowska (Poznan University of Medical Sciences)H-Index: 14
view all 6 authors...
Placental lactogen (PL) is a peptide hormone secreted throughout pregnancy by both animal and human specialized endocrine cells. PL plays an important role in the regulation of insulin secretion in pancreatic β-cells, stimulating their proliferation and promoting the expression of anti-apoptotic proteins. Cases of pregnancy affected by metabolic conditions, including obesity and diabetes, are related to alterations in the PL secretion pattern. Whereas obesity is most often associated with lower ...
#1Ryland D Mortlock (SC: University of Southern California)
#2Senta Georgia (SC: University of Southern California)H-Index: 14
Last. Stacey D. Finley (SC: University of Southern California)H-Index: 12
view all 3 authors...
Introduction: Hormones signal through various receptors and cascades of biochemical reactions to expand beta cell mass during pregnancy. Harnessing this phenomenon to treat beta cell dysfunction requires quantitative understanding of the signaling at the molecular level. This study explores how different regulatory elements impact JAK-STAT signaling through the prolactin receptor in pancreatic beta cells. Methods: A mechanistic computational model was constructed to describe the key reactions an...
#1Annette Møldrup (Novo Nordisk)H-Index: 16
#2Martin Nerup Lindberg (Agilent Technologies)
Last. Jens Høiriis Nielsen (UCPH: University of Copenhagen)H-Index: 30
view all 6 authors...
AIM: During pregnancy, the maternal beta-cell mass is increased in order to adapt to the physiological changes in insulin demand. Lactogenic hormones stimulate rodent beta-cell attachment and proliferation in vitro. The aim of this study was to identify adhesion molecules involved in expansion of the beta-cell mass during pregnancy in the rat. METHODS: Quantitative RT-PCR was used to evaluate the expression of several integrins and laminins in isolated neonatal rat islets in response to growth h...
#1Joon Ho Moon (KAIST)H-Index: 1
#2Yeong Gi Kim (KAIST)H-Index: 2
Last. Hail Kim (KAIST)H-Index: 20
view all 18 authors...
A sufficient β-cell mass is crucial for preventing diabetes, and perinatal β-cell proliferation is important in determining the adult β-cell mass. However, it is not yet known how perinatal β-cell proliferation is regulated. Here, we report that serotonin regulates β-cell proliferation through serotonin receptor 2B (HTR2B) in an autocrine/paracrine manner during the perinatal period. In β-cell–specific Tph1 knockout (Tph1 βKO) mice, perinatal β-cell proliferation was reduced along with the loss ...
1 CitationsSource
#1Yue Zhang (UAB: University of Alabama at Birmingham)H-Index: 12
#2Sajina Gc (UAB: University of Alabama at Birmingham)
Last. Stuart J. Frank (UAB: University of Alabama at Birmingham)H-Index: 45
view all 8 authors...
Abstract Human growth hormone (GH) binds and activates GH receptor (GHR) and prolactin (PRL) receptor (PRLR). LNCaP human prostate cancer cells express only GHR. A soluble fragment of IGF-1 receptor (IGF-1R) extracellular domain (sol IGF-1R) interacts with GHR and blocks GH signaling. We now explore sol IGF-1R's specificity for inhibiting GH signaling via GHR vs. PRLR and test GHR and PRLR extracellular domain inhibition determinants. Although T47D human breast cancer cells express GHR and PRLR,...
#1Valérie Bernard (Université Paris-Saclay)H-Index: 5
#2Jacques Young (Université Paris-Saclay)H-Index: 22
Last. Nadine Binart (Université Paris-Saclay)H-Index: 41
view all 3 authors...
The principal role of prolactin in mammals is the regulation of lactation. Prolactin is a hormone that is mainly synthesized and secreted by lactotroph cells in the anterior pituitary gland. Prolactin signalling occurs via a unique transmembrane prolactin receptor (PRL-R). The structure of the PRL-R has now been elucidated and is similar to that of many biologically fundamental receptors of the class 1 haematopoietic cytokine receptor family such as the growth hormone receptor. The PRL-R is expr...
3 CitationsSource
#1Fan Zhong (Fudan University)H-Index: 1
#2Yan Jiang (Fudan University)H-Index: 1
Endogenous pancreatic β cell regeneration is a potential strategy for β cell expansion or neogenesis to treat diabetes. Regeneration can occur through stimulation of existing β cell replication or conversion of other pancreatic cells into β cells. Recently, various strategies and approaches for stimulation of endogenous β cell regeneration have been evaluated, but they were not suitable for clinical application. In this paper, we comprehensively review these strategies, and further discuss vario...
1 CitationsSource
#1Xin Zhao (Nanjing Medical University)H-Index: 1
#2Yili Xu (Nanjing Medical University)H-Index: 3
Last. Xiaohong Wu (Nanjing Medical University)H-Index: 4
view all 8 authors...
During pregnancy, maternal pancreatic β-cells undergo a compensatory expansion in response to the state of insulin resistance, where prolactin (PRL) plays a major role. Retinoblastoma protein (Rb) ...
#1Sian Jazmine Shakara Simpson ('KCL': King's College London)H-Index: 2
#2Lorna Smith ('KCL': King's College London)H-Index: 1
Last. James E. Bowe ('KCL': King's College London)H-Index: 15
view all 3 authors...
Pregnancy involves a progressive increase in insulin resistance and the β-cells must adapt to compensate and prevent gestational diabetes (GDM). In this review we discuss the evidence for placental peptides, including placental lactogen, hepatocyte growth factor, adiponectin and leptin, playing a role in the islet adaptation to pregnancy. The difficulties of translating data from rodent models into human pregnancy are covered and we summarise studies investigating associations between serum plac...
2 CitationsSource