Plastic Surgery Research Council
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PSRC 60th Annual Meeting

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Improved Wound Healing by Transplantation of Macrophages
Michael Hu, MD, MPH, MS, Graham Walmsley, AB, Kipp Weiskopf, BS, Robert Rennert, BA, Jayakumar Rajadas, PhD, Geoffrey Gurtner, MD, Irving Weissman, MD, H. Peter Lorenz, MD, Michael Longaker, MD, MBA.
Stanford, Stanford, CA, USA.

PURPOSE
Macrophages are essential to normal wound healing. Mice lacking macrophages demonstrate impaired wound healing via reduced neovascularization, granulation tissue formation, and reepithelialization. Although many studies have either depleted macrophages or reduced their activity in the context of wound healing, none have investigated the effects of directly increasing the number of macrophages in the wound site. Here we seek to investigate the effects of increasing the number of macrophages present in the wound site during the initial stages of cutaneous wound healing.
METHODS
Macrophages derived from the bone marrow of FVB-Tg(CAG-luc,-GFP)L2G85Chco/J mice, which express firefly luciferase and cytoplasmic eGFP constitutively in all cells, were seeded onto pullulan-collagen composite dermal hydrogels and transplanted (2.5 x 105 cells per wound) into 6-mm full-thickness splinted excisional wounds on the dorsum of FVB/NJ mice at the time of wounding. Un-seeded hydrogels were used as controls and wound healing outcomes were assessed. The survival, localization, and behavior of transplanted macrophages in the wound site were characterized using IVIS imaging, histologic analysis of GFP fluorescence, and Maisson’s trichrome staining. To investigate how macrophages respond on a transcriptional level to the wound environment, macrophages were FACS-isolated for microfluidic single-cell qPCR analysis on the basis of GFP expression at days 0, 1, 4, and 7 post-transplant from the wound site.
RESULTS
Macrophage-seeded hydrogels demonstrated improved wound healing as compared to un-seeded hydrogel controls on days 4-12 (*p<0.05). The average time for complete wound healing was 11.2 days in the macrophage group versus 13.3 days in the control group (*p<0.001). IVIS imaging showed survival of transplanted macrophages through day 7 of wound healing. Microfluidic single cell analysis revealed remarkable plasticity in the transcriptional response of macrophages to the wound environment through day 7 of healing. Analysis of scar on day 14 showed no significant difference between treatment and control groups.
CONCLUSIONS
Here we demonstrate that by increasing the number of macrophages in the wound site past physiologic levels, wound healing can be improved. These findings hold promise for translational medicine aimed at improving the outcome of wound healing across a broad range of diseases. In patients with chronic wounds, autologous transplantation of macrophages derived from bone marrow aspirate may represent a viable therapeutic strategy.


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