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. Overall design: 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.