Abstract
Pain is a central feature of soft tissue trauma, which under certain contexts, results in aberrant osteochondral differentiation of tissue-specific stem cells. Here, the role of sensory nerve fibers in this abnormal cell fate decision is investigated using a severe extremity injury model in mice. Soft tissue trauma results in NGF (Nerve growth factor) expression, particularly within perivascular cell types. Consequently, NGF-responsive axonal invasion occurs which precedes osteocartilaginous differentiation. Surgical denervation impedes axonal ingrowth, with significant delays in cartilage and bone formation. Likewise, either deletion of Ngf or two complementary methods to inhibit its receptor TrkA (Tropomyosin receptor kinase A) lead to similar delays in axonal invasion and osteochondral differentiation. Mechanistically, single-cell sequencing suggests a shift from TGFβ to FGF signaling activation among pre-chondrogenic cells after denervation. Finally, analysis of human pathologic specimens and databases confirms the relevance of NGF-TrkA signaling in human disease. In sum, NGF-mediated TrkA-expressing axonal ingrowth drives abnormal osteochondral differentiation after soft tissue trauma. NGF-TrkA signaling inhibition may have dual therapeutic use in soft tissue trauma, both as an analgesic and negative regulator of aberrant stem cell differentiation.
Highlights
Pain is a central feature of soft tissue trauma, which under certain contexts, results in aberrant osteochondral differentiation of tissue-specific stem cells
Our study demonstrates the potential central paracrine relationships between pericytes, tropomyosin receptor kinase A (TrkA)-expressing axons, and mesenchymal progenitor cells in aberrant mesenchymal stem cell differentiation after trauma
Using receptor–ligand matching, our experiments suggested that diverse growth and differentiation factors are present at the transcriptional level with DRG-derived sensory axons, and their cognate receptors were present with mesenchymal cells at the injury site
Summary
Pain is a central feature of soft tissue trauma, which under certain contexts, results in aberrant osteochondral differentiation of tissue-specific stem cells. NGF-TrkA signaling inhibition may have dual therapeutic use in soft tissue trauma, both as an analgesic and negative regulator of aberrant stem cell differentiation. A clinically relevant small-molecule inhibitor of TrkA likewise abolished this aberrant cell fate differentiation mitigating HO formation To explain these observations, single-cell sequencing (scSeq) suggested a shift from transforming growth factor-β (TGFβ) to fibroblast growth factor (FGF) signaling activation among pre-chondrogenic cells following the loss of neural inputs. NGF-responsive, TrkA-expressing peripheral neurons positively regulate trauma-induced HO These findings suggest that NGF-TrkA signaling inhibition may have dual therapeutic use in soft tissue trauma, both as an analgesic and a negative regulator of aberrant stem cell differentiation
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