Decay of the Lef1-Srsf3-microRNA axis impairs DNA damage response and underlies stem cell aging

Stem cell (SC) aging is a complex process that contributes to tissue dysfunction and organismal aging. However, the underlying molecular mechanisms shared across diverse adult SC types are not well understood. In this study, we identified Lef1, Srsf3, and DDR-miRs as a common molecular axis underlying SC aging. Lef1 was found to be consistently downregulated in aged stem cells from various tissues, including mesenchymal stem/stromal cells (MSCs) and hematopoietic stem/progenitor cells (HSCs), and this reduction was also observed in other tissue SC types in both mice and humans based on reanalysis of public RNA-seq datasets. In young MSCs, Lef1 knockdown reproduced a miRNA expression profile similar to that of aged MSCs. The causal molecular alteration responsible for impaired miRNA biogenesis under reduced Wnt signaling was identified as age-associated cytoplasmic translocation and functional attenuation of Srsf3. Consistent with these in vitro findings, DDR capacity was reduced in aged SCs in vivo. Local SC aging may contribute to organismal aging by inducing premature DNA damage response impairment and eliciting inflammatory and senescence-like phenotypes in remote organs. These findings define the decay of the Lef1-Srsf3-miRNA axis as a core molecular alteration underlying SC aging.