Plastic Surgery Research Council
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PSRC 60th Annual Meeting
Program and Abstracts

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Thrombospondin-1 And CD47 Signaling Regulate Healing Of Thermal Injury In Mice
Justin B. Maxhimer, M.D.1, Hubert Shih, M.D.2, David Soto-Pantoja, Ph.D3, David Roberts, Ph.D3.
1UCLA Medical Center, Los Angeles, CA, USA, 2Stanford School of Medicine, Palo Alto, CA, USA, 3National Institutes of Health, Bethesda, MD, USA.

PURPOSE:
More than 2.5 million Americans suffer from burn injuries annually, and burn management is a major public health problem. Treatments have been developed to manage wound injuries employing skin grafts, various dressings and topical and systemic agents. However, these often achieve limited degrees of success. We previously reported that targeting the interaction of thrombospondin-1 with its signaling receptor CD47 or deletion of the genes encoding either of these proteins in mice improves recovery from soft tissue ischemic injuries as well as tissue injuries caused by ionizing radiation.
METHODS:
Thermal injury model was performed in WT, TSP1 null and CD47 null mice in the C57Bl/6 background. Wounded skin of mice was excised, and total RNA was isolated and analyzed for TGF-β, TSP1, VEGF and VEGFR2. Tissue was harvested, paraffin embedded, and stained using antibodies specific for phosphorylated TGF-β, p-SMAD2, p-SMAD3, SMAD4, CD31 or TSP1. Mice with inflicted wounds were subjected to Doppler imaging a week after injury to measuring blood flow in the wound.
RESULTS:
We now demonstrate that the absence of CD47 improves the rate of wound closure for a focal second-degree thermal dermal injury, whereas lack of thrombospondin-1 initially delays wound closure compared to healing in wild type mice. Doppler analysis of the wounded area showed increased blood flow in both CD47 and thrombospondin-1 null mice. Accelerated wound closure in the CD47 null mice was associated with increased fibrosis as demonstrated by a 4-fold increase in collagen fraction. Wound tissue of CD47 null mice showed increased thrombospondin-1 mRNA and protein expression and TGF-β1 mRNA levels. Activation of latent TGF-β1 was increased in thermally injured CD47- null tissue as assessed by phosphorylation of the TGF-β1 receptor-regulated transcription factors SMAD-2 and -3.
CONCLUSION:
Overall these results indicate that targeting CD47 may improve the speed of healing thermal injuries, but some level of CD47 expression may be required to limit the long term TGFβ-dependent fibrosis of these wounds.


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