CD34 + Progenitors Promote Ageing‐Associated Valve Sclerosis through the PDGFR–JNK–JUNB Pathway

Aortic valve sclerosis (AVS), characterised by fibrocalcific remodelling without significant hemodynamic obstruction, represents a critical window for early clinical intervention; however, its underlying cellular drivers during ageing remain poorly understood. Here, genetic lineage tracing and single‐cell RNA sequencing (scRNA‐seq) techniques were used to examine the temporal and spatial functions of CD34 + valvular interstitial cells (VICs) in ageing‐associated AVS. Human scRNA‐seq datasets were used in combination with natural ageing and D‐galactose (D‐gal)‐induced mouse models, and a significant age‐dependent downregulation of CD34 in VICs was identified. Lineage tracing and bone marrow (BM) chimeras confirmed that non‐BM CD34 + progenitor VICs (prog‐VICs), rather than bone marrow‐derived cells, serve as the origin of periostin + myofibroblast‐like VICs (myo‐VICs) during ageing. Functionally, the systemic or non‐BM‐specific ablation of CD34 + cells or the CD34 + Periostin + transitional subpopulation markedly attenuated age‐related leaflet thickening and fibrotic remodelling. Mechanistically, the JNK–JUNB signalling pathway, mediated by PDGFR, was found to be crucial for the pathological transdifferentiation of CD34 + prog‐VICs into periostin + myo‐VICs. Non‐BM CD34 + prog‐VICs were found to aggravate senescence‐associated AVS; thus, targeting the PDGFR–JNK–JUNB axis or preserving the prog‐VIC identity may offer therapeutic avenues to arrest early calcific aortic valve disease (CAVD) progression.