Molecular Regulation of Secondary Hair Follicle Stem Cell by S100a4 in Cashmere Goat

Secondary hair follicle stem cells (HFSCs) are essential for cashmere fiber regeneration, yet the molecular mechanisms governing their activation and lineage progression remain poorly understood. Here, we identify S100a4 as a key regulator of secondary HFSCs in cashmere goat. <i>S100a4</i> expression peaks during anagen and is markedly enriched in secondary HFSCs relative to hair matrix cells (HMCs), suggesting a role in initiating follicle regeneration. Functional assays show that <i>S100a4</i> promotes HFSCs into a dynamically regulated state that activates stem cell competence while facilitating differentiation, with overexpression upregulating epidermal and follicular differentiation markers (<i>Ivl</i>, <i>Cux1</i>, <i>K14</i>, <i>Klk5</i>), as well as pluripotency genes (<i>Itga6</i>, <i>Krt15</i>), while knockdown suppresses these programs. Proteomic analysis further reveals direct interactions between S100A4 and keratins critical for hair follicle and epidermal development (KRT5, KRT14, KRT8, KRT18), suggesting a structural and regulatory interface through which S100A4 modulates HFSC fate. Collectively, these results establish S100a4 as a central modulator of secondary HFSC function and provide mechanistic insight into the molecular control of hair follicle regeneration, with potential implications for improving cashmere fiber production.