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Cited by 77Pancreatic function and diabetesDiabetes and associated disordersTGF-β signaling in diseases

A smad signaling network regulates islet cell proliferation

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El-Gohary, Yousef, Tulachan, Sidhartha, Wiersch, John, Guo, Ping, Welsh, Carey, Prasadan, Krishna, Paredes, Jose, Shiota, Chiyo +4 more·2014·Diabetes
DOI 10.2337/db13-0432PMC PMC3868054
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Abstract

Pancreatic β-cell loss and dysfunction are critical components of all types of diabetes. Human and rodent β-cells are able to proliferate, and this proliferation is an important defense against the evolution and progression of diabetes. Transforming growth factor-β (TGF-β) signaling has been shown to affect β-cell development, proliferation, and function, but β-cell proliferation is thought to be the only source of new β-cells in the adult. Recently, β-cell dedifferentiation has been shown to be an important contributory mechanism to β-cell failure. In this study, we tie together these two pathways by showing that a network of intracellular TGF-β regulators, smads 7, 2, and 3, control β-cell proliferation after β-cell loss, and specifically, smad7 is necessary for that β-cell proliferation. Importantly, this smad7-mediated proliferation appears to entail passing through a transient, nonpathologic dedifferentiation of β-cells to a pancreatic polypeptide–fold hormone-positive state. TGF-β receptor II appears to be a receptor important for controlling the status of the smad network in β-cells. These studies should help our understanding of properly regulated β-cell replication.

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  • Prior work has shown that inhibition of Tgfb2 and Smad2 was associated with islet dedifferentiation.

    “Prior work has shown that inhibition of Tgfb2 and Smad2 was associated with islet dedifferentiation [47].”

    From β-Cell pre-mir-21 induces dysfunction and loss of cellular identity by targeting transforming growth factor beta 2 (Tgfb2) and Smad family member 2 (Smad2) mRNAs (2021) · cites this paper as [47]

    The Introduction and Results ('Smad7+ Cells Represent Dedifferentiated β-Cells'; page unavailable) describe reduced Smad2/3 signaling and Smad7-positive β-cells that appear to dedifferentiate after partial pancreatectomy. But the paper studies TGF-β receptor II and the TGF-β1 ligand, not inhibition of Tgfb2; it also does not directly show that Smad2 inhibition causes dedifferentiation. (LLM, conf=0.86)

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Research works printed but not linked: 47

  1. [1]Dor Y Brown J Martinez OI Melton DA Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 2004; 429: 41– 46 15129273
  2. [2]Georgia S Bhushan A Beta cell replication is the primary mechanism for maintaining postnatal beta cell mass. J Clin Invest 2004; 114: 963– 968 15467835 PMC518666
  3. [3]El-Gohary Y Tulachan S Branca M Whole-mount imaging demonstrates hypervascularity of the pancreatic ducts and other pancreatic structures. Anat Rec (Hoboken) 2012; 295: 465– 473 22282427
  4. [4]Inada A Nienaber C Katsuta H Carbonic anhydrase II-positive pancreatic cells are progenitors for both endocrine and exocrine pancreas after birth. Proc Natl Acad Sci USA 2008; 105: 19915– 19919 19052237 PMC2604974
  5. [6]Cozar-Castellano I Fiaschi-Taesch N Bigatel TA Molecular control of cell cycle progression in the pancreatic beta-cell. Endocr Rev 2006; 27: 356– 370 16638909
  6. [7]Goto Y Nomura M Tanaka K Genetic interactions between activin type IIB receptor and Smad2 genes in asymmetrical patterning of the thoracic organs and the development of pancreas islets. Dev Dyn 2007; 236: 2865– 2874 17849440
  7. [8]Rane SG Lee JH Lin HM Transforming growth factor-beta pathway: role in pancreas development and pancreatic disease. Cytokine Growth Factor Rev 2006; 17: 107– 119 16257256
  8. [9]Ungefroren H Groth S Sebens S Lehnert H Gieseler F Fändrich F Differential roles of Smad2 and Smad3 in the regulation of TGF-β1-mediated growth inhibition and cell migration in pancreatic ductal adenocarcinoma cells: control by Rac1. Mol Cancer 2011; 10: 67 21624123 PMC3112431
  9. [10]Harmon EB Apelqvist AA Smart NG Gu X Osborne DH Kim SK GDF11 modulates NGN3+ islet progenitor cell number and promotes beta-cell differentiation in pancreas development. Development 2004; 131: 6163– 6174 15548585
  10. [11]Miralles F Czernichow P Scharfmann R Follistatin regulates the relative proportions of endocrine versus exocrine tissue during pancreatic development. Development 1998; 125: 1017– 1024 9463348
  11. [12]Tulachan SS Tei E Hembree M TGF-beta isoform signaling regulates secondary transition and mesenchymal-induced endocrine development in the embryonic mouse pancreas. Dev Biol 2007; 305: 508– 521 17418116 PMC1968155
  12. [13]Brown KA Pietenpol JA Moses HL A tale of two proteins: differential roles and regulation of Smad2 and Smad3 in TGF-beta signaling. J Cell Biochem 2007; 101: 9– 33 17340614
  13. [14]Goulley J Dahl U Baeza N Mishina Y Edlund H BMP4-BMPR1A signaling in beta cells is required for and augments glucose-stimulated insulin secretion. Cell Metab 2007; 5: 207– 219 17339028
  14. [15]Smart NG Apelqvist AA Gu X Conditional expression of Smad7 in pancreatic beta cells disrupts TGF-beta signaling and induces reversible diabetes mellitus. PLoS Biol 2006; 4: e39 16435884 PMC1351925
  15. [16]Park SH Fine tuning and cross-talking of TGF-beta signal by inhibitory Smads. J Biochem Mol Biol 2005; 38: 9– 16 15715940
  16. [17]Yan X Liu Z Chen Y Regulation of TGF-beta signaling by Smad7. Acta Biochim Biophys Sin (Shanghai) 2009; 41: 263– 272 19352540 PMC7110000
  17. [18]Peshavaria M Larmie BL Lausier J Regulation of pancreatic beta-cell regeneration in the normoglycemic 60% partial-pancreatectomy mouse. Diabetes 2006; 55: 3289– 3298 17130472
  18. [19]Talchai C Xuan S Lin HV Sussel L Accili D Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure. Cell 2012; 150: 1223– 1234 22980982 PMC3445031
  19. [20]Soriano P Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet 1999; 21: 70– 71 9916792
  20. [21]Postic C Shiota M Niswender KD Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase. J Biol Chem 1999; 274: 305– 315 9867845
  21. [22]Herrera PL Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages. Development 2000; 127: 2317– 2322 10804174
  22. [23]Gu G Dubauskaite J Melton DA Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. Development 2002; 129: 2447– 2457 11973276
  23. [24]Schonhoff SE Giel-Moloney M Leiter AB Neurogenin 3-expressing progenitor cells in the gastrointestinal tract differentiate into both endocrine and non-endocrine cell types. Dev Biol 2004; 270: 443– 454 15183725
  24. [26]Zhang YQ Kanzaki M Furukawa M Shibata H Ozeki M Kojima I Involvement of Smad proteins in the differentiation of pancreatic AR42J cells induced by activin A. Diabetologia 1999; 42: 719– 727 10382592
  25. [27]El-Gohary Y Tulachan S Guo P Smad signaling pathways regulate pancreatic endocrine development. Dev Biol 2013; 378: 83– 93 23603491 PMC3711209
  26. [28]Kiehne K Otte JM Fölsch UR Herzig KH Growth factors in development and diseases of the exocrine pancreas. Pancreatology 2001; 1: 15– 23 12120262
  27. [29]Yamanaka Y Friess H Büchler M Beger HG Gold LI Korc M Synthesis and expression of transforming growth factor beta-1, beta-2, and beta-3 in the endocrine and exocrine pancreas. Diabetes 1993; 42: 746– 756 8482432
  28. [30]Shi Y Massagué J Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 2003; 113: 685– 700 12809600
  29. [31]Liu G Arnaud-Dabernat S Kritzik MR Kayali AG Zhang YQ Sarvetnick N PYY in the expanding pancreatic epithelium. Endocrine 2006; 30: 103– 112 17185798
  30. [32]Teitelman G Alpert S Polak JM Martinez A Hanahan D Precursor cells of mouse endocrine pancreas coexpress insulin, glucagon and the neuronal proteins tyrosine hydroxylase and neuropeptide Y, but not pancreatic polypeptide. Development 1993; 118: 1031– 1039 7903631
  31. [33]Herrera PL Defining the cell lineages of the islets of Langerhans using transgenic mice. Int J Dev Biol 2002; 46: 97– 103 11902693
  32. [34]Herrera PL Huarte J Sanvito F Meda P Orci L Vassalli JD Embryogenesis of the murine endocrine pancreas; early expression of pancreatic polypeptide gene. Development 1991; 113: 1257– 1265 1811941
  33. [35]Gannon M Shiota C Postic C Wright CV Magnuson M Analysis of the Cre-mediated recombination driven by rat insulin promoter in embryonic and adult mouse pancreas. Genesis 2000; 26: 139– 142 10686610
  34. [36]Madisen L Zwingman TA Sunkin SM A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci 2010; 13: 133– 140 20023653 PMC2840225
  35. [37]Ju W Ogawa A Heyer J Deletion of Smad2 in mouse liver reveals novel functions in hepatocyte growth and differentiation. Mol Cell Biol 2006; 26: 654– 667 16382155 PMC1346892
  36. [38]Datto MB Frederick JP Pan L Borton AJ Zhuang Y Wang XF Targeted disruption of Smad3 reveals an essential role in transforming growth factor beta-mediated signal transduction. Mol Cell Biol 1999; 19: 2495– 2504 10082515 PMC84042
  37. [39]Russ HA Bar Y Ravassard P Efrat S In vitro proliferation of cells derived from adult human beta-cells revealed by cell-lineage tracing. Diabetes 2008; 57: 1575– 1583 18316362
  38. [40]Billestrup N Otonkoski T Dedifferentiation for replication of human beta-cells: a division between mice and men? Diabetes 2008; 57: 1457– 1458 18511447
  39. [41]Russ HA Sintov E Anker-Kitai L Insulin-producing cells generated from dedifferentiated human pancreatic beta cells expanded in vitro. PLoS ONE 2011; 6: e25566 21984932 PMC3184150
  40. [42]Russ HA Ravassard P Kerr-Conte J Pattou F Efrat S Epithelial-mesenchymal transition in cells expanded in vitro from lineage-traced adult human pancreatic beta cells. PLoS ONE 2009; 4: e6417 19641613 PMC2712769
  41. [43]Morton RA Geras-Raaka E Wilson LM Raaka BM Gershengorn MC Endocrine precursor cells from mouse islets are not generated by epithelial-to-mesenchymal transition of mature beta cells. Mol Cell Endocrinol 2007; 270: 87– 93 17363142 PMC1987709
  42. [44]Like AA Chick WL Mitotic division in pancreatic beta cells. Science 1969; 163: 941– 943 4884632
  43. [45]Yew KH Prasadan KL Preuett BL Interplay of glucagon-like peptide-1 and transforming growth factor-beta signaling in insulin-positive differentiation of AR42J cells. Diabetes 2004; 53: 2824– 2835 15504962
  44. [46]Nomura M Li E Smad2 role in mesoderm formation, left-right patterning and craniofacial development. Nature 1998; 393: 786– 790 9655392
  45. [48]Nomura M, Teramoto N, Morinaga H, Takayanagi R. Crucial roles of TGF-β signaling for pancreatic islet development and glucose-responsive insulin secretion. Presented at the Keystone Symposium "Islet and Beta Cell Biology (Z3)," Snowbird, UT, 6–11 April 2008
  46. [49]Xiao X Wiersch J El-Gohary Y TGFβ receptor signaling is essential for inflammation-induced but not β-cell workload-induced β-cell proliferation. Diabetes 2013; 62: 1217– 1226 23248173 PMC3609557
  47. [50]Herrera PL Orci L Vassalli JD Two transgenic approaches to define the cell lineages in endocrine pancreas development. Mol Cell Endocrinol 1998; 140: 45– 50 9722167

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Authors
El-Gohary, Y., Tulachan, S., Wiersch, J., Guo, P., Welsh, C., Prasadan, K., Paredes, J., Shiota, C., Xiao, X., Wada, Y., Diaz, M., & Gittes, G.
Affiliations
  • Division of Pediatric Surgery, Department of Surgery, Children’s Hospital of Pittsburgh, Pittsburgh, PA
  • St. Elizabeth Youngstown Hospital (US)
  • The University of Texas at San Antonio Health Science Center (US)
  • University of Pittsburgh (US)
  • Children's Hospital of Pittsburgh (US)
  • Niigata University (JP)
  • National Institutes of Health (US)
Corresponding author
Gittes, George
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2013-12-13
Volume
63
Issue
1
Pages
224-236
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db13-0432
PMC
PMC3868054
OpenAlex
W2146161926
Cited by
77
References
2
Citations by year
2026: 1 · 2025: 4 · 2024: 2 · 2023: 3 · 2022: 4 · 2021: 8 · 2020: 6 · 2019: 3 · 2018: 7 · 2017: 3 · 2016: 11 · 2015: 13 · 2014: 9 · 2013: 2 · 2012: 1
FWCI
11.51
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetes (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK064952, R01DK083541)
  • National Institute of Environmental Health Sciences (Z01ES101603)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords
beta-cell proliferation, Smad7, Smad2, Smad3, TGF-beta signaling, beta-cell dedifferentiation, pancreatic polypeptide, TGFBR2, pancreatic endocrine cells, beta cell destruction
MeSH terms
Animals, Mice, Transgenic, Phosphorylation, Signal Transduction, Transforming Growth Factor beta, Receptors, Transforming Growth Factor beta, Cell Proliferation, Insulin-Secreting Cells, Mice, Smad Proteins, Cell Dedifferentiation

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