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. Despite its significance, the molecular mechanisms underlying SC aging in different adult stem cell types remain poorly understood. This study identifies the transcription factor Lef1, the splicing regulator Srsf3, and a subset of DNA damage response microRNAs (DDR-miRs) as a common molecular axis underlying SC aging. Lef1 was found to be the most consistently downregulated transcription factor during aging, common to 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 study used in vitro reporter assays for mirtron biogenesis to identify age-associated cytoplasmic translocation and functional attenuation of Srsf3 as the causal molecular alteration responsible for impaired miRNA biogenesis under reduced Wnt signaling. Consistent with these in vitro findings, DDR capacity was reduced in aged SCs in vivo. The study also found that stem cell-specific Lef1 deletion in either intestinal or epidermal stem cells in young mice induced premature DDR impairment and elicited inflammatory and senescence-like phenotypes in remote organs, including the brain, skin, and kidney. These findings define the decay of the Lef1-Srsf3-miRNA axis as a core molecular alteration underlying SC aging and reveal that local SC aging may contribute to organismal aging.