Fibroblasts as key regulators of neuro-mesenchymal niches in homeostasis, inflammation and disease

Abstract Fibroblasts, once viewed as inert producers of extracellular matrix (ECM), are now recognized as dynamic and heterogeneous regulators of tissue identity, homeostasis, and repair. Single-cell and spatial transcriptomic studies have revealed extensive transcriptional and positional diversity among fibroblast populations, demonstrating that they integrate developmental, anatomical, and niche-derived signals to instruct neighboring cells. A particularly striking dimension of this regulatory capacity is their bidirectional engagement with the nervous system. Across diverse organs, fibroblasts engage in reciprocal signaling with neurons and glia, defining what we term neuro-mesenchymal niches: spatially organized microenvironments in which fibroblast-derived neurotrophins, ECM cues, and direct cell-cell contacts shape neuronal growth, survival, and function, while neural inputs, neurotransmitters, neuropeptides, and contact-mediated signals, reciprocally regulate fibroblast identity, proliferation, and activation. In this Review, we synthesize current understanding of the developmental origins, heterogeneity, and canonical functions of fibroblasts, and integrate emerging evidence on fibroblast-neuron crosstalk across the skin, peripheral nerve, lung, musculoskeletal system, intestine and central nervous system (CNS). We further examine how dysregulation of these niches contributes to pathological outcomes including fibrosis, chronic pain, denervation, and neuroinflammation. Conceptualizing fibroblasts as central organizers of neuro-mesenchymal niches provides a unifying framework for dissecting stromal-neural communication and identifies new therapeutic opportunities at the interface of regenerative medicine, neurology, and immunology.