IGF2BP3-dependent glutamine/BCAA metabolic rewiring rejuvenates aged human adipose-derived stem cells for enhanced tissue regeneration

  • Cell Discov. 2026 Jan 20;12(1):5. doi: 10.1038/s41421-025-00860-7.
Zichao Li  #  1  2  3 ,  Lin Feng  #  4  5 ,  Xinxin Wei  #  5  6 ,  Huichen Li  #  5 ,  Yifu Zhu  #  3 ,  Hongtao Wang  1 ,  Jiaqi Liu  1 ,  Liang Luo  1 ,  Zhao Zheng  1 ,  Baoqiang Song  7 ,  Liangliang Shen  8  9 ,  Dahai Hu  10
Affiliations
  • 1. Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
  • 2. Department of Plastic and Aesthetic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
  • 3. Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
  • 4. Department of Basic Medicine, Xi'an Medical University, Xi'an, Shaanxi, China.
  • 5. Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, China.
  • 6. Department of Stomatology, Weifang People's Hospital, Weifang, Shandong, China.
  • 7. Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China. [email protected].
  • 8. Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, China. [email protected].
  • 9. State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, China. [email protected].
  • 10. Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China. [email protected].
  • # Contributed equally.
PMID: 41559031 DOI: 10.1038/s41421-025-00860-7
Abstract

Aging impairs the regenerative capacity and differentiation potential of human adipose-derived stem cells (hASCs), but the mechanisms underlying their functional decline remain unclear. Through systematic functional assays and in vivo experiments, we first confirmed age-associated reductions in hASC self-renewal, lineage plasticity, and tissue repair efficacy. By integrating multiomics profiling and functional validation, we identified a metabolically active ACTA2+TAGLN+ subpopulation that was enriched mainly in infant-derived hASCs (I-hASCs) and characterized by increased catabolism of branched-chain Amino acids (BCAAs) and glutamine. Mechanistically, the RNA-binding protein IGF2BP3, which is predominantly expressed in the ACTA2+TAGLN+ subpopulation, sustains hASC stemness by stabilizing BCAT1 and GLS mRNAs via METTL3-mediated m6A modification, thereby preserving redox homeostasis and mitochondrial energy production. Furthermore, age-related attenuation of the IGF2BP3-m6A-BCAT1/GLS axis contributed to metabolic reprogramming, driving senescence-associated functional collapse in elderly-derived hASCs (E-hASCs). Strikingly, rescue experiments demonstrated that genetic restoration of BCAT1/GLS or supplementation with BCAAs/glutamine significantly rejuvenated E-hASCs, restoring their proliferation, differentiation, and in vivo wound-healing capacities. These findings identify IGF2BP3 as a central regulator of hASC aging by linking m6A epitranscriptomic modifications to metabolic reprogramming and establish the IGF2BP3-m6A-BCAT1/GLS axis as a druggable node in aged hASCs. This study proposed two therapeutic strategies: nutrient supplementation to rescue metabolic deficits and m6A modulation to stabilize key mRNAs, providing a clinically feasible protocol to optimize elderly-derived hASCs for tissue regeneration.

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