PMID- 35641477 OWN - NLM STAT- PubMed-not-MEDLINE VI - 10 IP - 1 TI - Neuron-to-vessel signaling is a required feature of aberrant stem cell commitment after soft tissue trauma. PG - 43 CI - © 2022. The Author(s). LA - eng PT - Journal Article PL - China TA - Bone Res JT - Bone research JID - 101608652 IS - 2095-4700 (Print) LID - 10.1038/s41413-022-00216-x [doi] FAU - Qin, Qizhi AU - Qin Q AD - Department of Pathology, Johns Hopkins University, Baltimore, MD, 21205, USA. FAU - Gomez-Salazar, Mario AU - Gomez-Salazar M AD - Department of Pathology, Johns Hopkins University, Baltimore, MD, 21205, USA. FAU - Cherief, Masnsen AU - Cherief M AD - Department of Pathology, Johns Hopkins University, Baltimore, MD, 21205, USA. FAU - Pagani, Chase A AU - Pagani CA AD - Center for Organogenesis and Trauma, Department of Surgery, University of Texas, Southwestern, TX, USA. FAU - Lee, Seungyong AU - Lee S AD - Department of Pathology, Johns Hopkins University, Baltimore, MD, 21205, USA. FAU - Hwang, Charles AU - Hwang C AD - Department of Plastic Surgery, Harvard, Cambridge, MA, 02138, USA. FAU - Tower, Robert J AU - Tower RJ AUID- ORCID: http://orcid.org/0000-0001-5856-5758 AD - Center for Organogenesis and Trauma, Department of Surgery, University of Texas, Southwestern, TX, USA. AD - Department of Orthopaedics, Johns Hopkins University, Baltimore, MD, 21205, USA. FAU - Onggo, Sharon AU - Onggo S AD - Department of Pathology, Johns Hopkins University, Baltimore, MD, 21205, USA. FAU - Sun, Yuxiao AU - Sun Y AD - Center for Organogenesis and Trauma, Department of Surgery, University of Texas, Southwestern, TX, USA. FAU - Piplani, Abhinav AU - Piplani A AD - Department of Pathology, Johns Hopkins University, Baltimore, MD, 21205, USA. FAU - Li, Zhao AU - Li Z AD - Department of Pathology, Johns Hopkins University, Baltimore, MD, 21205, USA. FAU - Ramesh, Sowmya AU - Ramesh S AD - Department of Pathology, Johns Hopkins University, Baltimore, MD, 21205, USA. FAU - Clemens, Thomas L AU - Clemens TL AD - Department of Orthopaedics, Johns Hopkins University, Baltimore, MD, 21205, USA. AD - Baltimore Veterans Administration Medical Center, Baltimore, MD, 21201, USA. FAU - Levi, Benjamin AU - Levi B AD - Center for Organogenesis and Trauma, Department of Surgery, University of Texas, Southwestern, TX, USA. Benjamin.Levi@utsouthwestern.edu. FAU - James, Aaron W AU - James AW AUID- ORCID: http://orcid.org/0000-0002-2002-622X AD - Department of Pathology, Johns Hopkins University, Baltimore, MD, 21205, USA. awjames@jhmi.edu. IS - 2095-4700 (Linking) PMC - PMC9156761 LR - 20220716 DP - 2022 Jun 01 DEP - 20220601 AB - The functional interdependence of nerves and blood vessels is a well-established concept during tissue morphogenesis, yet the role of neurovascular coupling in proper and aberrant tissue repair is an emerging field of interest. Here, we sought to define the regulatory relationship of peripheral nerves on vasculature in a severe extremity trauma model in mice, which results in aberrant cell fate and heterotopic ossification (HO). First, a high spatial degree of neurovascular congruency was observed to exist within extremity injury associated heterotopic ossification. Vascular and perivascular cells demonstrate characteristic responses to injury, as assessed by single cell RNA sequencing. This vascular response to injury was blunted in neurectomized mice, including a decrease in endothelial proliferation and type H vessel formation, and a downregulation of key transcriptional networks associated with angiogenesis. Independent mechanisms to chemically or genetically inhibit axonal ingrowth led to similar deficits in HO site angiogenesis, a reduction in type H vessels, and heterotopic bone formation. Finally, a combination of single cell transcriptomic approaches within the dorsal root ganglia identified key neural-derived angiogenic paracrine factors that may mediate neuron-to-vascular signaling in HO. These data provide further understanding of nerve-to-vessel crosstalk in traumatized soft tissues, which may reflect a key determinant of mesenchymal progenitor cell fate after injury.