Thrombospondin-1 and CD47 signaling regulate healing of thermal injury in mice.
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. We now demonstrate that the absence of CD47 improves the rate of wound closure for a focal dermal second-degree thermal 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. 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 TGF-β1-dependent fibrosis of these wounds.
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
David R
DR
Soto-Pantoja
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Howard Hughes Medical Institute-National Institutes of Health Research Scholars Program, Bethesda, MD 20814, USA.
Hubert B
HB
Shih
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Justin B
JB
Maxhimer
Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.
Katherine L
KL
Cook
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Arunima
A
Ghosh
Division of Pulmonary, Allergy and Critical Care Medicine and the Vascular Medicine Institute of the University of Pittsburgh, Pittsburgh, PA 15213, USA.
Jeffrey S
JS
Isenberg
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: droberts@helix.nih.gov.
David D
DD
Roberts
D000818:Animals; D002056:Burns / Q000503:physiopathology*; D051928:CD47 Antigen / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism; D007150:Immunohistochemistry; D017078:Laser-Doppler Flowmetry; D051379:Mice; D008810:Mice, Inbred C57BL; D060172:Morpholinos / Q000235:genetics; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D012867:Skin / Q000503:physiopathology*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D019700:Thrombospondin 1 / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology*
D051928:CD47 Antigen; C497895:Cd47 protein, mouse; D060172:Morpholinos; D051899:Smad2 Protein; D051900:Smad3 Protein; D019700:Thrombospondin 1; D053773:Transforming Growth Factor beta1; C585483:Thbs1 protein, mouse; D003094:Collagen
CD47; TGF-β1; Thrombospondin-1; Wound healing