Neuroepithelial regulation across development, regeneration, aging, and sex.
Publication Year:
2026
PubMed ID:
42800119
Funding Grants:
Public Summary:
Nerves in the skin do much more than detect touch, pain, and temperature. They also help control the stem cells that maintain and repair skin, working alongside immune cells and surrounding tissues. This review explores how skin and nerves develop together and communicate throughout life. We discuss how nerves help skin respond to changes in temperature, stress, daily biological rhythms, and the body’s energy needs. We also examine how aging can weaken these connections, potentially reducing the skin’s ability to maintain and repair itself, and how these processes differ between males and females. Understanding this communication could reveal new ways to support skin health, improve healing, and preserve tissue function as we age.
Scientific Abstract:
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.