4.8 Article

Reinforcing one-carbon metabolism via folic acid/Folr1 promotes β-cell differentiation

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NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -

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NATURE PORTFOLIO
DOI: 10.1038/s41467-021-23673-0

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资金

  1. European Research Council under the Horizon 2020 Research and Innovation Programme [772365]
  2. Swedish Research Council
  3. Novo Nordisk Foundation
  4. Ragnar Soderberg's Foundation
  5. Strategic Research Programme in Diabetes
  6. Stem Cells & Regenerative Medicine at the Karolinska Institutet
  7. NordForsk (NorPreSS) [83539]
  8. Karolinska Institutet
  9. European Research Council (ERC) [772365] Funding Source: European Research Council (ERC)

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Research in zebrafish and neonatal pig islets revealed that overexpression of folate receptor 1 (folr1) and treatment with folinic acid can promote beta-cell differentiation, originating from ductal cells. Comparative metabolomic analysis suggested that changes in pyrimidine, carnitine, and serine pathways may contribute to beta-cell regeneration.
Diabetes can be caused by an insufficiency in beta-cell mass. Here, we performed a genetic screen in a zebrafish model of beta-cell loss to identify pathways promoting beta-cell regeneration. We found that both folate receptor 1 (folr1) overexpression and treatment with folinic acid, stimulated beta-cell differentiation in zebrafish. Treatment with folinic acid also stimulated beta-cell differentiation in cultures of neonatal pig islets, showing that the effect could be translated to a mammalian system. In both zebrafish and neonatal pig islets, the increased beta-cell differentiation originated from ductal cells. Mechanistically, comparative metabolomic analysis of zebrafish with/without beta-cell ablation and with/without folinic acid treatment indicated beta-cell regeneration could be attributed to changes in the pyrimidine, carnitine, and serine pathways. Overall, our results suggest evolutionarily conserved and previously unknown roles for folic acid and one-carbon metabolism in the generation of beta-cells. Regeneration of insulin-producing beta-cells may become a future alternative treatment of diabetes. Here the authors report a genetic screen in a zebrafish model that mimics the loss of beta-cells in diabetes, and identified that the folate receptor Folr1 or folinic acid treatment can stimulate beta-cell regeneration.

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