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(American Journal of Pathology. 2008;173:610-630.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.071027

Calreticulin Enhances Porcine Wound Repair by Diverse Biological Effects

Lillian B. Nanney*{dagger}, Christopher D. Woodrell{ddagger}, Mathew R. Greives{ddagger}, Nancy L. Cardwell*, Alonda C. Pollins*, Tara A. Bancroft{ddagger}, Adrianne Chesser{ddagger}, Marek Michalak§, Mohammad Rahman{ddagger}, John W. Siebert{ddagger} and Leslie I. Gold{ddagger}

From the Departments of Plastic Surgery* and Cell and Developmental Biology,{dagger} Vanderbilt University School of Medicine, Nashville, Tennessee; the Departments of Medicine and Pathology,{ddagger} New York University School of Medicine, New York, New York; and the Department of Biochemistry,§ University of Alberta, Edmonton, Alberta, Canada

Extracellular functions of the endoplasmic reticulum chaperone protein calreticulin (CRT) are emerging. Here we show novel roles for exogenous CRT in both cutaneous wound healing and diverse processes associated with repair. Compared with platelet-derived growth factor-BB-treated controls, topical application of CRT to porcine excisional wounds enhanced the rate of wound re-epithelialization. In both normal and steroid-impaired pigs, CRT increased granulation tissue formation. Immunohistochemical analyses of the wounds 5 and 10 days after injury revealed marked up-regulation of transforming growth factor-β3 (a key regulator of wound healing), a threefold increase in macrophage influx, and an increase in the cellular proliferation of basal keratinocytes of the new epidermis and of cells of the neodermis. In vitro studies confirmed that CRT induced a greater than twofold increase in the cellular proliferation of primary human keratinocytes, fibroblasts, and microvascular endothelial cells (with 100 pg/ml, 100 ng/ml, and 1.0 pg/ml, respectively). Moreover, using a scratch plate assay, CRT maximally induced the cellular migration of keratinocytes and fibroblasts (with 10 pg/ml and 1 ng/ml, respectively). In addition, CRT induced concentration-dependent migration of keratinocytes, fibroblasts macrophages, and monocytes in chamber assays. These in vitro bioactivities provide mechanistic support for the positive biological effects of CRT observed on both the epidermis and dermis of wounds in vivo, underscoring a significant role for CRT in the repair of cutaneous wounds.






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Copyright © 2008 by the American Society for Investigative Pathology.