Abstract
We previously showed that Calreticulin (CRT), a chaperone of the endoplasmic reticulum, has profound effects on the process of wound healing by increasing both epithelial migration and granulation tissue formation in models of impaired porcine and murine repair. In the present study, using the scratch plate assay as an in vitro model of wound repair, we show that CRT (10−6–10−9 M) induces cell migration/wound closure in human keratinocytes and fibroblasts that is equivalent to EGF (positive control). Furthermore, by an MTS proliferation assay, CRT stimulated cellular proliferation of human keratinocytes (2-fold), fibroblasts (100-fold), and vascular endothelial cells (1.2-fold). Markedly increased cellular proliferation was confirmed by anti-ki67 immunostaining (IHC) which was confined to basal keratinocytes in the CRT-(5 mg/ml) treated porcine and murine wounds during reepithelialization and in numerous cells of the granulation tissue. Also, CRT increased dermal depth and granulation tissue formation between days 6–14 following injury (p < 0.05). The effect of CRT on the dermal layer was qualitatively different than PDGF or PBS as there was a remarkably higher number of dermal cells that reconstituted the CRT-treated pig wounds, a more organized pattern of collagen organization by picrosirrius red staining, and greater fibronectin and TGF-β3 by IHC. CRT also increased tensile strength in a rat incisional wound model (p < 0.005 @ 21 days). By Mac-138 IHC of porcine wounds, we observed an increase in macrophages in the wound bed compared to PDGF (p < 0.013). Since the uptake of apoptotic cells by phagocytes is a CRT-dependent process, this finding suggests a potential role for CRT as a bacteriocidal and/or debriding agent. Unlike PDGF, CRT positively affects both the epithelial and dermal aspects of repair. Our studies suggest that CRT accelerates and improves the rate and quality of wound repair by affecting many cells involved in the repair process.
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