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Original Article | Open Access

Neuron-to-vessel signaling is a required feature of aberrant stem cell commitment after soft tissue trauma

Qizhi Qin1,, Mario Gomez-Salazar1,, Masnsen Cherief1, Chase A. Pagani2, Seungyong Lee1, Charles Hwang3, Robert J. Tower2,4, Sharon Onggo1, Yuxiao Sun2, Abhinav Piplani1, Zhao Li1, Sowmya Ramesh1, Thomas L. Clemens4,5, Benjamin Levi2( ), Aaron W. James1 ( )
Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA
Center for Organogenesis and Trauma, Department of Surgery, University of Texas, Southwestern, TX, USA
Department of Plastic Surgery, Harvard, Cambridge, MA 02138, USA
Department of Orthopaedics, Johns Hopkins University, Baltimore, MD 21205, USA
Baltimore Veterans Administration Medical Center, Baltimore, MD 21201, USA

These authors contributed equally: Qizhi Qin, Mario Gomez-Salazar

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Abstract

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.

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Bone Research
Volume 10,
December 2022
Article number: 43
DOI: 10.1038/s41413-022-00216-x
Cite this article:
Qin Q, Gomez-Salazar M, Cherief M, et al. Neuron-to-vessel signaling is a required feature of aberrant stem cell commitment after soft tissue trauma. Bone Research, 2022, 10: 43. https://doi.org/10.1038/s41413-022-00216-x

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Received: 23 November 2021
Revised: 04 April 2022
Accepted: 29 April 2022
Published: 01 June 2022
© The Author(s) 2022

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