Retro-orbital Infusion Of Human Mesenchymal Stromal Cells Accelerates Wound Healing Through Systemic Effects
Nina Kosaric, Wai Srifa, Harriet Kiwanuka, Matthew Porteus, Geoffrey Gurtner.
Stanford University, Stanford, CA, USA.
Background: Mesenchymal stromal cells (MSCs) are a promising therapeutic agent due to their pro-regenerative and immunomodulatory properties. Intravenous infusion of MSCs is desirable due to the minimal invasiveness of the procedure. A major obstacle of intravenous infusion is entrapment of MSCs in pulmonary capillaries after delivery, limiting the number of cells that reach their target site. Methods: Here, we use a murine excisional wound healing model to examine whether intravenous infusion of human fetal bone marrow-derived MSCs can accelerate wound healing. 1x106 MSCs or PBS were administered retro-orbitally on the day of wounding. Biodistribution of administered MSCs was evaluated in the lung, wound, blood, and spleen using FACS, and the rate of healing was quantified until full wound closure. Wounds were harvested 2 days following wounding and subjected to single cell RNA-Seq. Results: MSCs were significantly present in the lung 1 day following infusion (0.094 ±% 0.03 of live cells, n=3, p < 0.05), but undetectable in the wound, blood, and spleen during the first 3 days following infusion. Treated mice healed 3.8 days earlier (12.0 ± 0.80 days) than control mice (15.8 ± 0.44 days, n=5; p<0.001). We identified four transcriptionally distinct F4/80+ macrophage subpopulations within the wound. Distribution of clusters varied by treatment group: MSC-treated mice exhibited depletion of a cluster highly expressing pro-inflammatory genes (Cxcl10, Ifit2, Ly6c2), and enrichment of a cluster highly expressing genes involved in T cell suppression (Vsig4), B cell recruitment (Cxcl13), and genes expressed by activated macrophages (Arg1, Saa3).Conclusions: Despite a lack of evidence that retro-orbitally administered MSCs migrate beyond the lung, infusion of MSCs significantly accelerated wound healing, suggesting that they are able to potentiate a systemic therapeutic effect. This effect may be due to a shift from inflammatory to regenerative macrophages in the wound.
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