Dermal Adipose Tissue Secretes HGF to Promote Human Hair Growth and Pigmentation

Abstract

Hair follicles (HFs) are immersed within dermal white adipose tissue (dWAT), yet human adipocyte‒HF communication remains unexplored. Therefore, we investigated how perifollicular adipocytes affect the physiology of human anagen scalp HFs. Quantitative immunohistomorphometry, X-ray microcomputed tomography, and transmission electron microscopy showed that the number and size of perifollicular adipocytes declined during anagen‒catagen transition, whereas fluorescence-lifetime imaging revealed increased lipid oxidation in adipocytes surrounding the bulge and/or sub-bulge region. Exvivo, dWAT tendentially promoted hair shaft production, and significantly stimulated hair matrix keratinocyte proliferation and HF pigmentation. Both dWAT pericytes and PREF1/DLK1+ adipocyte progenitors secreted HGF during human HF‒dWAT co-culture, for which the c-Met receptor was expressed in the hair matrix and dermal papilla. These effects were reproduced using recombinant HGF and abrogated by an HGF-neutralizing antibody. Laser-capture microdissection‒based microarray analysis of the hair matrix showed that dWAT-derived HGF upregulated keratin (K) genes (K27, K73, K75, K84, K86) and TCHH. Mechanistically, HGF stimulated Wnt/β-catenin activity in the human hair matrix (increased AXIN2, LEF1) by upregulating WNT6 and WNT10B, and inhibiting SFRP1 in the dermal papilla. Our study demonstrates that dWAT regulates human hair growth and pigmentation through HGF secretion, and thus identifies dWAT and HGF as important novel molecular and cellular targets for therapeutic intervention in human hair growth and pigmentation disorders.