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

Yulia Shwartz ¹ Meryem Gonzalez-Celeiro ¹ Chih-Lung Chen ² Sung-Jan Lin Sung-Jan Lin ² Ya-Chieh Hsu ¹ Ya-Chieh Hsu Ya-Chieh Hsu

¹Department of Stem Cell and Regenerative Biology, Harvard University, USA
²Department of Biomedical Engineering, National Taiwan University, Taiwan China

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.