THSD4 promotes hair growth by facilitating dermal papilla and hair matrix interactions.

Introduction: Aging causes striking changes in the extracellular matrix (ECM) in hair follicles, which has a profound influence on hair growth. How the ECM of dermal papilla (DP), the master regulator of hair growth, changes during aging remains largely unknown. Methods: Herovici staining, Western Blotting and immunofluorescence were used to assess DP ECM and protein expression in hair follicles. Bulk and single cell RNA-sequencing were used to analyze gene expression and predict upstream and downstream regulators of target genes. Skin organoid and mouse models were used for functional validation of molecular mechanisms. Results: Aged follicle DP shows drastic depletion of ECM in which Thrombospondin Type 1 Domain Containing 4 (Thsd4) is highly downregulated. THSD4 is specifically expressed in the interface between DP and hair matrix (HM). It promotes hair growth by enhancing the interaction between dermal (DP) and epithelial cells (HM) through the SDC4-THSD4-CXCL1 signaling axis in both skin organoids and mouse models. Murine dorsal hair follicles show upregulated THSD4, enhanced DP-HM interaction, and hair growth following exposure to low temperature. Conclusions: THSD4 is a key micro- and macro-environmental mediator to promote hair growth by facilitating epidermal-mesenchymal interactions during aging. These findings demonstrate the therapeutic potential of low-temperature treatment for treating unwanted hair loss.