Sympathetic nerves and arrector pili muscles form a dual component niche to regulate hair follicle stem cells

Piloerection (goosebump) requires concerted actions of the hair follicle, the arrector pili muscle (APM), and the sympathetic nerve, providing a model to study interactions across epithelium, mesenchyme, and nerves. Here, we show that APMs and sympathetic nerves form a dual component niche to modulate hair follicle stem cell (HFSC) activity. Sympathetic nerves form synapse-like structures with HFSCs and regulate HFSCs through norepinephrine, whereas APMs maintain sympathetic innervation to HFSCs. Without norepinephrine signaling, HFSCs enter a deep quiescence state by down-regulating cell cycle machinery and mitochondria metabolism, while up-regulating quiescence regulators Lhx2, Foxp1, and Fgf18. During development, HFSC progeny secrets Sonic Hedgehog (SHH) to direct the formation of this APM-sympathetic nerve niche, which in turn controls hair follicle regeneration in adults. Our results reveal a reciprocal interdependence between a regenerative tissue and its niche at different stages, and illustrate that nerves can modulate stem cell quiescence through synapses and neurotransmitters. The sympathetic nerves influence hair follicle stem cells through binding of norepinephrine to the adrenergic receptor beta 2 (Adrb2). Deletion of Adrb2 specifically from hair follicle stem cells using the K15-crePGR reporter allows us to uncover molecular changes downstream of adrenergic signaling. Hair follicle stem cells (CD34+, a6+, Sca1-) from control and K15-CrePGR; Adrb2 fl/fl mice were isolated using FACS.