Pronounced proliferation of non-beta cells in response to beta-cell mitogens in isolated human islets of Langerhans.

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  • Additional Information
    • Source:
      Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
    • Publication Information:
      Original Publication: London : Nature Publishing Group, copyright 2011-
    • Subject Terms:
      Insulin-Secreting Cells/*metabolism ; Islets of Langerhans/*metabolism ; Mitogens/*pharmacology; C-Peptide/metabolism ; Cell Division ; Cell Proliferation/drug effects ; Cell Proliferation/physiology ; Epidermal Growth Factor/metabolism ; Female ; Glucagon/metabolism ; Glucose/metabolism ; Harmine/pharmacology ; Heparin-binding EGF-like Growth Factor/metabolism ; Heparin-binding EGF-like Growth Factor/pharmacology ; Humans ; Insulin/metabolism ; Insulin-Secreting Cells/physiology ; Islets of Langerhans/physiology ; Male ; Mitogens/immunology ; Mitogens/metabolism ; Pancreatic Ducts/metabolism ; Primary Cell Culture ; Signal Transduction/drug effects
    • Abstract:
      The potential to treat diabetes by increasing beta-cell mass is driving a major effort to identify beta-cell mitogens. Demonstration of mitogen activity in human beta cells is frequently performed in ex vivo assays. However, reported disparities in the efficacy of beta-cell mitogens led us to investigate the sources of this variability. We studied 35 male (23) and female (12) human islet batches covering a range of donor ages and BMI. Islets were kept intact or dispersed into single cells and cultured in the presence of harmine, glucose, or heparin-binding epidermal growth factor-like growth factor (HB-EGF), and subsequently analyzed by immunohistochemistry or flow cytometry. Proliferating cells were identified by double labeling with EdU and Ki67 and glucagon, c-peptide or Nkx6.1, and cytokeratin-19 to respectively label alpha, beta, and ductal cells. Harmine and HB-EGF stimulated human beta-cell proliferation, but the effect of glucose was dependent on the assay and the donor. Harmine potently stimulated alpha-cell proliferation and both harmine and HB-EGF increased proliferation of insulin- and glucagon-negative cells, including cytokeratin 19-positive cells. Given the abundance of non-beta cells in human islet preparations, our results suggest that assessment of beta-cell mitogens requires complementary approaches and rigorous identification of cell identity using multiple markers.
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    • Grant Information:
      R01 DK058096 United States DK NIDDK NIH HHS; U24 DK098085 United States DK NIDDK NIH HHS; UC4 DK098085 United States DK NIDDK NIH HHS
    • Accession Number:
      0 (C-Peptide)
      0 (Heparin-binding EGF-like Growth Factor)
      0 (Insulin)
      0 (Mitogens)
      4FHH5G48T7 (Harmine)
      62229-50-9 (Epidermal Growth Factor)
      9007-92-5 (Glucagon)
      IY9XDZ35W2 (Glucose)
    • Publication Date:
      Date Created: 20210529 Date Completed: 20211119 Latest Revision: 20230617
    • Publication Date:
      20230620
    • Accession Number:
      PMC8163757
    • Accession Number:
      10.1038/s41598-021-90643-3
    • Accession Number:
      34050242