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

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.