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.
Highlights
The mononuclear phagocyte system plays a multi-faceted role in maintaining tissue homeostasis and responding to pathological processes such as autoimmune diseases, cancer, and aberrant wound healing
dorsal skinfold window chamber (DWC) surgery and implantation of a polymeric poly(lactic-co-glycolic acid) (PLGA) thin film 1mm in diameter decreased the frequency of blood monocytes by nearly four-fold 1 day post-injury, followed by a three-fold elevation by 3 days post-injury compared to blood taken at day 0 prior to surgery (Fig. 1a,b)
We have previously demonstrated that localized delivery of the small molecule FTY720 from PLGA thin films enhances the recruitment of Ly6Clo monocytes to inflamed peri-implant tissue and supports arteriogenesis[20, 34]
Summary
The mononuclear phagocyte system plays a multi-faceted role in maintaining tissue homeostasis and responding to pathological processes such as autoimmune diseases, cancer, and aberrant wound healing. Ly6Clo monocytes present later during inflammation secrete high levels of vascular endothelial growth factor (VEGF) and IL-10 and can induce endothelial cell proliferation to promote arteriogenesis[14, 18, 19]. We utilize cell labeling strategies to selectively track the fate of either classical Ly6Chi or non-classical Ly6Clo monocytes in response to biomaterial implantation within cutaneous wounds. FTY720 promotes in situ generation of wound healing macrophages and vascular remodeling within ischemic skeletal muscle These results shed light on the fate of specific monocyte populations following biomaterial implantation after injury and indicate that non-classical monocytes are a promising therapeutic target for harnessing pro-regenerative inflammation to promote repair
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