Impact of peripheral nerves on mesenchymal cell fate in extremity trauma

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Project Summary Heterotopic ossification (HO) is characterized by the aberrant osteochondral differentiation of tissue resident mesenchymal progenitor cells. HO afflicts nearly 20% of extremity trauma, amputation and large surface area burn patients and is clinically preceded by pain. Currently, no treatments exist to prevent initiation, reverse disease progression, or limit pain through efficacious, non-opioid mechanisms. In the course of analyzing our validated trauma-induced HO model, we observed nerve ingrowth as an early response to trauma. Using a unique human traumatic HO dataset of early and late HO lesions, we have confirmed this early and maladaptive nerve ingrowth precedes HO. Additionally, we discovered that surgical denervation potently inhibits early stages of HO formation. In follow up studies, we uncovered the role of nerve growth factor (NGF) as the primary stimulus of this pre-HO nerve ingrowth and, unexpectedly, that perivascular cells (pericytes and vascular smooth muscle cells) appear to be the primary source of this neurotrophin. To elucidate the role of NGF induced nerve ingrowth on HO, we performed complementary studies which suggest that nerve ingrowth may activate mesenchymal progenitor cell TGFβ1 signaling to drive aberrant chondrogenic differentiation among local mesenchymal progenitor HO precursor cells. These observations have led to our central hypothesis that perivascular derived NGF stimulates TrkA-expressing sensory dendrite ingrowth into the HO site, which in turn releases TGFβ1 to stimulate mesenchymal progenitor cell osteochondral differentiation. As such, the following aims are proposed: Aim 1: Define the role of perivascular NGF in controlling sensory nerve ingrowth at sites of HO initiation and progression. Using established animal models, we hypothesize that tissue-specific deletion of Ngf in pericytes (Pdgfrb-CreERT2;Ngffl/fl) or vascular smooth muscle cells (vSMCs; Myh11-CreERT2;Ngffl/fl) will abrogate peripheral nerve ingrowth and HO formation at sites of trauma. Aim 2: Test the role of TGFβ1 signaling in sensory nerve-mesenchymal progenitor cell cross talk in HO. Using established animal models, we hypothesize that sensory nerves positively regulate mesenchymal progenitor cell osteochondral differentiation through a TGFβ1 dependent process. Aim 3: Define a potential role for anti-NGF neutralizing antibodies as a novel HO therapeutic intervention. We hypothesize that Fasinumab (an NGF neutralizing antibody) represents a dual analgesic and negative regulator of HO disease progression, which blunts pathologic nerve ingrowth.