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Identification Of Fibrocirculators: Circulating Non-hematopoietic Cells Homing To Sites Of Injury To Orchestrate Tissue Fibrosis
Dominic Henn, MD1,2, Kellen Chen, PhD2, Artem Trotsyuk, BS2, Clark A. Bonham, Jr., BS2, Dharshan Sivaraj, BS2, Tobias Fehlmann, MS3, Friedericke Grandtke, MS3, Hudson C. Kussie, BS2, Katharina S. Fischer, MD2, Savana Huskins, BS2, Sydney R. Steele, BS2, Autumn Greco, BS2, Michael Januszyk, MD,PhD4, Andreas Keller, PhD3, Michael T. Longaker, MD2, Geoffrey C. Gurtner, MD2.
1Dept. of Plastic Surgery, UT Southwestern Medical Center, Dallas, TX, USA, 2Hagey Laboratory for Pediatric Regenerative Medicine, Div. of Plastic Surgery, Stanford University, Stanford, CA, USA, 3Chair for Clinical Bioinformatics, Saarland University, Saarbruecken, Germany, 4Hagey Laboratory for Pediatric Regenerative Medicine, Div. of Plastic Surgery, Stanford University, Stangord, CA, USA.

Purpose: The majority of circulating cells that are recruited to sites of injury are derived from the hematopoietic system, predominantly consisting of immune cells, such as monocytes/macrophages, neutrophils, and T cells. Whether non-hematopoietic mesenchymal cells are present in the circulation and involved in tissue repair after injury has remained a topic of debate. Methods: Lineage tracing with two transgenic mouse models (Col1-GFP and VavCre-mTmG), parabiosis, flow cytometry, confocal microscopy, and single-cell RNA sequencing (scRNA-seq) were used to analyze circulating cellular subpopulations recruited to excisional wounds and ischemic skin flaps at acute (3 and 7 days) and chronic (1, 3, and 6 months) stages. Next, GFP-expressing circulating collagen producing cells were systemically depleted using GFP-specific CD8+ T killer cells (Just eGFP death inducing, or JEDI) and the effect on tissue repair was determined using scRNA-seq and analysis of collagen ultrastructure. Results: We identified non-hematopoietic circulating fibroblast-like cells, termed "fibrocirculators", that exhibit stem cell characteristics and produce collagen. These cells were most abundant during the chronic remodeling stage of tissue repair (1 month post injury) and persisted within the tissue up to 6 months after injury. Fibrocirculators exhibited multiple interactions with myeloid cells and their homing to sites of injury was triggered by the tumor necrosis factor (TNF) pathway, specifically by TNFSF12/TWEAK. Targeted systemic depletion of fibrocirculators using JEDI T cells accelerated wound healing, decreased fibrotic collagen architecture, and reduced pro-fibrotic gene expression of wound fibroblasts. Conclusion: We have identified a novel population of circulating non-hematopoietic mesenchymal cells that are recruited to sites of injury and exhibit pro-fibrotic characteristics. Targeted depletion of these cells may lead to novel therapeutic opportunities for chronic fibrotic conditions such as hypertrophic scars and pulmonary fibrosis.


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