Vitamin B12 is a limiting factor for induced cellular plasticity and tissue repair PMID: 37973897

ADC Targets in Oncology

2026-04-10

Vitamin B12 is a limiting factor for induced cellular plasticity and tissue repair

Nat Metab. 2023 Nov 16. doi: 10.1038/s42255-023-00916-6.

Marta Kovatcheva ¹ , Elena Melendez ² , Dafni Chondronasiou ² , Federico Pietrocola ² ³ , Raquel Bernad ² , Adrià Caballe ² , Alexandra Junza ⁴ ⁵ , Jordi Capellades ⁴ ⁶ , Adrián Holguín-Horcajo ⁷ ⁸ , Neus Prats ² , Sylvere Durand ⁹ ¹⁰ , Meritxell Rovira ⁷ ⁸ , Oscar Yanes ⁴ ⁵ , Camille Stephan-Otto Attolini ² , Guido Kroemer ⁹ ¹⁰ ¹¹ , Manuel Serrano ¹² ¹³ ¹⁴

Affiliations

1. Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. [email protected].
2. Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
3. Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
4. Universitat Rovira i Virgili, Department of Electronic Engineering, IISPV, Tarragona, Spain.
5. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
6. Institut d'Investigació Sanitària Pere Virgili (IISPV), Metabolomics Platform, Reus, Spain.
7. Department of Physiological Science, School of Medicine, Universitat de Barcelona (UB), L'Hospitalet de Llobregat, Spain.
8. Pancreas Regeneration: Pancreatic Progenitors and Their Niche Group, Regenerative Medicine Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Spain.
9. Metabolomics and Cell Biology Platforms UMS AMMICa/UMR 1138, Institut Gustave Roussy, Villejuif, France.
10. Equipe labellisée par la Ligue contre le cancer, Centre de Recherche des Cordeliers, Inserm U1138, Université de Paris, Sorbonne Université, Institut Universitaire de France, Paris, France.
11. Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
12. Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. [email protected].
13. Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain. [email protected].
14. Altos Labs, Cambridge Institute of Science, Cambridge, UK. [email protected].

Abstract

Transient reprogramming by the expression of OCT4, SOX2, KLF4 and MYC (OSKM) is a therapeutic strategy for tissue regeneration and rejuvenation, but little is known about its metabolic requirements. Here we show that OSKM reprogramming in mice causes a global depletion of vitamin B₁₂ and molecular hallmarks of methionine starvation. Supplementation with vitamin B₁₂ increases the efficiency of reprogramming both in mice and in cultured cells, the latter indicating a cell-intrinsic effect. We show that the epigenetic MARK H3K36me3, which prevents illegitimate initiation of transcription outside promoters (cryptic transcription), is sensitive to vitamin B₁₂ levels, providing evidence for a link between B₁₂ levels, H3K36 methylation, transcriptional fidelity and efficient reprogramming. Vitamin B₁₂ supplementation also accelerates tissue repair in a model of ulcerative colitis. We conclude that vitamin B₁₂, through its key role in one-carbon metabolism and epigenetic dynamics, improves the efficiency of in vivo reprogramming and tissue repair.