Overview of the Role for Calreticulin in the Enhancement of Wound Healing through Multiple Biological Effects

Abstract

Calreticulin (CRT), an intracellular chaperone protein crucial for the proper folding and transport of proteins through the endoplasmic reticulum, has more recent acclaim as a critical regulator of extracellular functions, particularly in mediating cellular migration and as a requirement for phagocytosis of apoptotic cells. Consistent with these functions, we show that the topical application of CRT has profound effects on the process of wound healing by causing a dose-dependent increase in epithelial migration and granulation tissue formation in both murine and porcine normal and impaired animal models of skin injury. These effects of CRTare substantiated, in vitro, as we show that CRT strongly induces cell migration/wound closure of human keratinocytes and fibroblasts, using a wound/scratch plate assay, and stimulates cellular proliferation of human keratinocytes, fibroblasts, and vascular endothelial cells, providing mechanistic insight into how CRT functions in repair. Similarly, in both animal models, the histology of the wounds show marked proliferation of basal keratinocytes and dermal fibroblasts, dense cellularity of the dermis with notably increased numbers of macrophages and well-organized collagen fibril deposition. Thus, CRT profoundly affects the wound healing process by recruiting cells essential for repair into the wound, stimulating cell growth, and increasing extracellular matrix production.

Calreticulin promotes cell motility and enhances resistance to anoikis through STAT3–CTTN–Akt pathway in esophageal squamous cell carcinoma

“…Overexpression of CRT-enhanced wound closure by stimulating cell migration in human keratinocytes and fibroblasts (Gold et al, 2006). In both murine-and porcineimpaired animal models of skin injury, CRT increased epithelial migration and granulation tissue formation (Gold et al, 2006;Hayashida et al, 2006). In this study, we showed that CRT knockdown decreased the migration and invasion capacity of ESCC cells with accompanying repression of CTTN protein levels.…”

“…CRT is known to bind to the C-terminal cytoplasmic tail KXGFFKR sequence motif of a 2 -integrin. Overexpression of CRT-enhanced wound closure by stimulating cell migration in human keratinocytes and fibroblasts (Gold et al, 2006). In both murine-and porcineimpaired animal models of skin injury, CRT increased epithelial migration and granulation tissue formation (Gold et al, 2006;Hayashida et al, 2006).…”

“…CRT has also been implicated in a variety of functions outside of the endoplasmic reticulum, including cell adhesion, integrindependent Ca 2 þ signaling and expression of steroidsensitive genes (Michalak et al, 1999). CRT enhances cell migration and wound healing (Gold et al, 2006), and influences apoptosis positively or negatively via modulation of intracellular calcium stores (Mesaeli and Phillipson, 2004;Vanoverberghe et al, 2004;Chen et al, 2005). Recent evidence has shown that CRT protects fibroblasts from anoikis through binding to LRP1 and TSP-1 (Pallero et al, 2008).…”

Calreticulin Enhances Porcine Wound Repair by Diverse Biological Effects

“…The complementary in vitro experiments showing the effect of CRT on cellular migration and proliferation, two key processes that enable wound repair, provide a mechanistic explanation for the accelerated and enhanced effect observed of CRT on porcine wound repair. In companion studies, in which we used a diabetic murine model of excisional cutaneous repair, 4,84 we obtained the same biological effects with the identical pharmacological dose (5.0 mg/ml) of CRT on parameters of wound repair as shown herein in the porcine model. Further understanding the mechanisms of action of CRT (eg, receptors, signaling pathways, domain structure/ function) on keratinocytes, fibroblasts, endothelial cells, and monocytes/macrophages from both intracellular and extracellular perspectives is important for a better understanding of the in-depth role of CRT as a stress/injuryinduced protein with significant impact on a diverse range of reparative responses.…”

Arginylated Calreticulin at Plasma Membrane Increases Susceptibility of Cells to Apoptosis

“…CRT resides mainly in the ER and is a Ca 2ϩ -binding protein that function as a Ca 2ϩ buffer and molecular chaperone, although it has also been linked to a number of processes occurring outside the ER lumen (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), which implies other subcellular localizations for CRT other than the ER. However, the subcellular origin, biochemical features, and the precise molecular mechanism responsible for targeting CRT to the plasma membrane is not fully understood.…”