A Subset of TREM2+ Dermal Macrophages Secretes Oncostatin M to Maintain Hair Follicle Stem Cell Quiescence and Inhibit Hair Growth

Abstract

Graphical Abstract Highlights d JAK-STAT5 signaling maintains quiescence in hair follicle stem cells (HFSCs) d Oncostatin M (OSM) acts upstream of JAK-STAT5 signaling to maintain HFSC quiescence d A subset of TREM2 + macrophages in the mouse skin is the source of OSM d Specific ablation of macrophages in the mouse skin is associated with anagen entry SUMMARY Hair growth can be induced from resting mouse hair follicles by topical application of JAK inhibitors, suggesting that JAK-STAT signaling is required for maintaining hair follicle stem cells (HFSCs) in a quiescent state.Here, we show that Oncostatin M (OSM), an IL-6 family cytokine, negatively regulates hair growth by signaling through JAK-STAT5 to maintain HFSC quiescence. Genetic deletion of the OSM receptor or STAT5 can induce premature HFSC activation, suggesting that the resting telogen stage is actively maintained by the hair follicle niche. Single-cell RNA sequencing revealed that the OSM source is not intrinsic to the hair follicle itself and is instead a subset of TREM2 + macrophages that is enriched within the resting follicle and deceases immediately prior to HFSC activation. In vivo inhibition of macrophage function was sufficient to induce HFSC proliferation and hair cycle induction. Together these results clarify how JAK-STAT signaling actively inhibits hair growth.

Immune cell regulation of the hair cycle

“…Macrophages numbers increase during mid‐telogen, and a subset of TREM2+ macrophages maintain HFSC quiescence by producing OSM …”

“…Ablation of macrophages using clodronate liposomes or genetic/pharmacologic methods leads to anagen.…”

“…During this phase of “rest,” the bulge and ORS keratinocytes are mitotically quiescent, and the hair shaft (“club hair”) remains anchored in the HF. This apparent “quiescence” of the HF is the result of active inhibitory macro‐ and microenvironment signals from cell types comprising the HF niche, including the Krt6+ inner bulge, arrector pili muscle, subdermal adipocytes and HF‐associated immune cells . In the period immediately following catagen, the HF is in a state of refractory telogen, in which the threshold for anagen re‐entry is higher, due in part to the increased concentrations of BMPs secreted by neighbouring adipocytes .…”

“…Systemic administration of clodronate liposomes during mid‐telogen, which ablates phagocytic cells (including macrophages, but also other cell types), has been shown to induce early anagen re‐entry in mice. Single‐cell RNA sequencing of murine macrophages during telogen identified a rare subset of TREM2+ macrophages (coined “trichophages”) that produce oncostatin M (OSM), a potent inhibitor of HFSC proliferation and differentiation . OSM maintains HFSC quiescence via the JAK‐STAT5 pathway, and anagen can be induced by topical janus kinase (JAK) inhibitors in wild‐type C57BL/6 mice in telogen .…”

“…More specific methods of inhibiting macrophages in the dermis during telogen (ie. with genetic, immunological and pharmacological means) also initiates the telogen‐to‐anagen transition in C57BL/6 mice …”