Embryonic vitamin D deficiency programs hematopoietic stem cells to induce type 2 diabetes

Jisu Oh, Amy E. Riek, Kevin T. Bauerle, Adriana Dusso, Kyle P. McNerney, Ruteja A. Barve, Isra Darwech, Jennifer E. Sprague, Clare Moynihan, Rong M. Zhang, Greta Kutz, Ting Wang, Xiaoyun Xing, Daofeng Li, Marguerite Mrad, Nicholas M. Wigge, Esmeralda Castelblanco, Alejandro Collin, Monika Bambouskova, Richard D. Head, Mark S. Sands and Carlos Bernal-Mizrachi ()
Additional contact information
Jisu Oh: Washington University School of Medicine
Amy E. Riek: Washington University School of Medicine
Kevin T. Bauerle: Washington University School of Medicine
Adriana Dusso: Washington University School of Medicine
Kyle P. McNerney: Washington University School of Medicine
Ruteja A. Barve: Washington University School of Medicine
Isra Darwech: Washington University School of Medicine
Jennifer E. Sprague: VA Medical Center
Clare Moynihan: Washington University School of Medicine
Rong M. Zhang: Washington University School of Medicine
Greta Kutz: Washington University School of Medicine
Ting Wang: Washington University School of Medicine
Xiaoyun Xing: Washington University School of Medicine
Daofeng Li: Washington University School of Medicine
Marguerite Mrad: Washington University School of Medicine
Nicholas M. Wigge: Washington University School of Medicine
Esmeralda Castelblanco: Washington University School of Medicine
Alejandro Collin: CONICET, Universidad Nacional de Córdoba
Monika Bambouskova: Washington University School of Medicine
Richard D. Head: Washington University School of Medicine
Mark S. Sands: Washington University School of Medicine
Carlos Bernal-Mizrachi: Washington University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Environmental factors may alter the fetal genome to cause metabolic diseases. It is unknown whether embryonic immune cell programming impacts the risk of type 2 diabetes in later life. We demonstrate that transplantation of fetal hematopoietic stem cells (HSCs) made vitamin D deficient in utero induce diabetes in vitamin D-sufficient mice. Vitamin D deficiency epigenetically suppresses Jarid2 expression and activates the Mef2/PGC1a pathway in HSCs, which persists in recipient bone marrow, resulting in adipose macrophage infiltration. These macrophages secrete miR106-5p, which promotes adipose insulin resistance by repressing PIK3 catalytic and regulatory subunits and down-regulating AKT signaling. Vitamin D-deficient monocytes from human cord blood have comparable Jarid2/Mef2/PGC1a expression changes and secrete miR-106b-5p, causing adipocyte insulin resistance. These findings suggest that vitamin D deficiency during development has epigenetic consequences impacting the systemic metabolic milieu.

Date: 2023
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DOI: 10.1038/s41467-023-38849-z

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