Injury-induced hair growth response is promoted by tissue macrophages via insulin-like growth factor 1

Abstract Hair follicles (HFs) produce hair to mediate the first line of defense in mammals. HFs undergo cyclical production of hair (anagen), and while this process is unsynchronized during adulthood, external cues, including shaving, induce synchronized anagen and bolster the surface barrier. Herein, we show that macrophages were crucial in promoting anagen. Shaving triggered the accumulation of macrophages to the secondary hair germs (SHG), which underwent proliferation as early as Day3 post-induction. Constitutive ablation of macrophages markedly delayed anagen, and targeted ablation of macrophages at Day 3, but not at Day 0 or Day 6 post-shaving, impaired SHG activation with delayed anagen. Anagen entry was dependent on Folr2 +tissue macrophages, but not on CCR2 +monocyte-derived macrophages. Single-cell RNA-sequencing and cell-cell communication analyses revealed that Folr2 +macrophages communicated with the SHGs via Igf1 (encoding insulin-like growth factor 1 or IGF1). Ablation of macrophages and deletion of IGF1 from macrophages decreased AKT signaling in SHG and led to delayed anagen, both which were rescued via injection of recombinant IGF1 in vivo. Single-cell ATAC-sequencing revealed that the lack of IGF1-from macrophages resulted in alteration of transcription factor motif enrichment and decreased chromatin accessibility in various genes in SHGs, demonstrating that macrophages primed the SHGs to enter anagen by promoting IGF1R signaling. These results highlight the importance of immune-tissue crosstalk in facilitating hair growth and provide impetus for strategies to promote hair growth.