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

Abstract

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.