Nociceptive sensory neuron-derived NGF orchestrates a fibrotic mesenchymal stromal cell neurogenic niche to drive tendon pathological fibrosis

Excessive fibrosis, rather than endogenous tissue regeneration, often results from peripheral tissue injury repair, presenting a significant clinical challenge due to its poor reversibility and limited treatment options. A key factor contributing to this outcome is the aberrant commitment of mesenchymal stromal cells (MSCs) to a fibrotic lineage. However, the upstream signals driving this pathological differentiation remain unclear. In this study, we identify nociceptive sensory neuron rather than local cell-derived nerve growth factor (NGF) as a critical signaling factor guiding the formation of the fibrotic MSCs neurogenic niche, thereby driving MSC-mediated fibrosis. Using nociceptive sensory denervation and NGF knockout genetic models, we demonstrate that disrupting sensory nerve innervation significantly reduces MSC-mediated fibrosis. In vitro, NGF promotes MSC fibrotic commitment through the TrkA and hypoxia-inducible factor-1α (Hif1α) signaling pathways. Therapeutically, local administration of TPX-0005 (also known as repotrectinib), a clinically used TrkA inhibitor, partially reverses excessive fibrosis and improves long-term healing outcomes. Our findings reveal a previously unrecognized neurogenic axis, highlighting the functional specificity of nociceptive sensory neuron-derived NGF in peripheral tissue repair and emphasizing the regulation of MSC neurogenic niche as a promising strategy for fibrosis prevention and treatment. Nociceptive sensory nerves infiltrate the peripheral trauma area, mediating the biased repair response due to the formation of fibrotic mesenchymal stromal cells (MSCs) neurogenic niche. Nociceptive sensory neuron-derived nerve growth factor activates the TrkA receptors in MSCs and triggers the Hif1α-Twist1 pathway, driving the differentiation of MSCs into myofibroblasts to mediate fibrosis. TPX-0005 exerts therapeutic effects by inhibiting TrkA to reverse fibrosis.