title: Non-classical monocytes are biased progenitors of wound healing macrophages during soft tissue injury.
abstract: Successful tissue repair requires the activities of myeloid cells such as monocytes and macrophages that guide the progression of inflammation and healing outcome. Immunoregenerative materials leverage the function of endogenous immune cells to orchestrate complex mechanisms of repair; however, a deeper understanding of innate immune cell function in inflamed tissues and their subsequent interactions with implanted materials is necessary to guide the design of these materials. Blood monocytes exist in two primary subpopulations, characterized as classical inflammatory or non-classical. While classical monocytes extravasate into inflamed tissue and give rise to macrophages or dendritic cells, the recruitment kinetics and functional role of non-classical monocytes remains unclear. Here, we demonstrate that circulating non-classical monocytes are directly recruited to polymer films within skin injuries, where they home to a perivascular niche and generate alternatively activated, wound healing macrophages. Selective labeling of blood monocyte subsets indicates that non-classical monocytes are biased progenitors of alternatively activated macrophages. On-site delivery of the immunomodulatory small molecule FTY720 recruits S1PR3-expressing non-classical monocytes that support vascular remodeling after injury. These results elucidate a previously unknown role for blood-derived non-classical monocytes as contributors to alternatively activated macrophages, highlighting them as key regulators of inflammatory response and regenerative outcome.
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 315 Ferst Drive, Atlanta, GA, 30332, USA.
authors.forename: Claire E
authors.identifier: 0000-0002-4449-4319
authors.initials: CE
authors.lastname: Olingy
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 315 Ferst Drive, Atlanta, GA, 30332, USA.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: San Emeterio
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 315 Ferst Drive, Atlanta, GA, 30332, USA.
authors.forename: Molly E
authors.initials: ME
authors.lastname: Ogle
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 315 Ferst Drive, Atlanta, GA, 30332, USA.
authors.forename: Jack R
authors.initials: JR
authors.lastname: Krieger
authors.affiliation: Department of Biomedical Engineering, University of Virginia, Box 800759, Charlottesville, VA, 22908, USA.
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Bruce
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 315 Ferst Drive, Atlanta, GA, 30332, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: Pfau
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 315 Ferst Drive, Atlanta, GA, 30332, USA.
authors.forename: Brett T
authors.initials: BT
authors.lastname: Jordan
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 315 Ferst Drive, Atlanta, GA, 30332, USA.
authors.forename: Shayn M
authors.initials: SM
authors.lastname: Peirce
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 315 Ferst Drive, Atlanta, GA, 30332, USA. edward.botchwey@bme.gatech.edu.
authors.forename: Edward A
authors.identifier: 0000-0003-1140-5786
authors.initials: EA
authors.lastname: Botchwey
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism; D001672:Biocompatible Materials / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology; D020007:Implants, Experimental; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D012867:Skin / Q000098:blood supply / Q000473:pathology; D017695:Soft Tissue Injuries / Q000473:pathology*; D013234:Stem Cells / Q000473:pathology*; D014945:Wound Healing / Q000187:drug effects
chemical_list: D015703:Antigens, CD; D001672:Biocompatible Materials; D000068876:Fingolimod Hydrochloride