Abstract / Summary
The skin is a highly innervated organ in which neural circuits continuously interact with epithelial, immune, and stromal compartments to coordinate tissue function. Historically, sensory and sympathetic nerves were viewed primarily as conduits for environmental input and autonomic output. However, recent studies demonstrate that cutaneous nerves serve as epithelial stem cell niches across compartments and regulate homeostasis, regeneration, healing, and adaptation to environmental change. In this Review, we discuss how sensory and sympathetic innervation is established during skin development and how epithelial tissues actively instruct the formation, specialization, and maturation of cutaneous neural circuits. We then examine emerging evidence that sensory and autonomic nerves regulate epithelial stem cells via direct neurotransmitter signaling, as well as through neuroimmune and neurostromal interactions. These mechanisms enable neural circuits to integrate local environmental cues with systemic physiological signals, including temperature, stress, circadian rhythms, and metabolic state. We further explore how aging alters neuroepithelial interactions and discuss evidence that age-associated degeneration of cutaneous innervation may impair stem cell function and tissue resilience. In parallel, we review growing evidence for sex-dependent differences in neural regulation, highlighting studies in which males and females achieve similar physiological outcomes via distinct neuroimmune and neuroendocrine mechanisms. Together, these findings support a neuroepithelial model of skin in which neural circuits regulate stem cell behavior and tissue adaptation throughout the lifespan. Interactions among neural, epithelial, immune, and stromal networks across biological contexts, including development, regeneration, aging, and sex, may reveal conserved mechanisms with broad therapeutic potential for preserving tissue function and resilience.