期刊
SCIENTIFIC REPORTS
卷 11, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41598-021-90643-3
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资金
- National Institutes of Health [R01-DK-58096]
- Canadian Institutes of Health Research [MOP 77686]
- Cardiometabolic Health, Diabetes and Obesity research Network of Quebec
- NIH [2UC4DK098085]
- JDRF
- Fonds de Recherche Quebec-Sante
- Canada Research Chair in Diabetes and Pancreatic B Cell Function
This study examined 35 batches of human islets and found that Harmine and HB-EGF could stimulate human beta cell proliferation, while the effect of glucose varied depending on the experiment and donor. Non-beta cells were also affected by Harmine and HB-EGF stimulation, indicating the need for complementary approaches to assess beta-cell mitogens.
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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