Calreticulin Enhances Porcine Wound Repair by Diverse Biological Effects

Nanney, Lillian B.; Woodrell, Christopher D.; Greives, Timothy J.; Cardwell, Nancy L.; Pollins, Alonda C.; Bancroft, Tara A.; Chesser, Adrianne S.; Michalak, Marek; Rahman, Mahbubur; Siebert, John W.; Gold, Leslie I.

doi:10.2353/ajpath.2008.071027

Cited by 89 publications

(150 citation statements)

References 79 publications

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“…Previous studies showing CRT stimulation of wound healing and its expression in fibrotic tissues suggested that CRT might be involved in the regulation of collagen (6,7). However, direct evidence for collagen regulation by CRT and elucidation of potential mechanisms by which CRT might regulate collagens have not been previously defined.…”

Section: Discussionmentioning

confidence: 95%

“…Vectashield was purchased from Vector Laboratories (Burlingame, CA), and goat serum was purchased from MP Biomedicals (Solon, OH). Recombinant rabbit calreticulin was a gift from Dr. Leslie Gold (New York University) (6). Calreticulin was stored in 10 mM Tris, 3 mM CaCl 2 , pH 7.0.…”

Section: Methodsmentioning

confidence: 99%

“…In addition, exogenous CRT treatment enhances wound healing and increases proliferation and migration of fibroblasts (6). Therefore, we asked whether the differences in collagen between the wild type and CRT Ϫ/Ϫ MEFs were due to intracellular CRT or extracellular/cell surface CRT.…”

Section: ϫ/ϫmentioning

confidence: 99%

“…There is evidence to suggest the involvement of CRT in tissue remodeling and wound healing. In a porcine dermal wound healing model, topical application of purified CRT increases the rate of wound healing and wound tensile strength (6). Proteomic data show up-regulation of CRT expression with fibrosis in a rat model of unilateral ureteric obstruction kidney fibrosis and in a mouse model of bleomycininduced lung fibrosis (7).…”

mentioning

confidence: 99%

“…4 In vitro, exogenous CRT treatment causes proliferation of fibroblasts, endothelial cells, and keratinocytes and increases keratinocyte and fibroblast migration (6).…”

mentioning

confidence: 99%

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Intracellular Calreticulin Regulates Multiple Steps in Fibrillar Collagen Expression, Trafficking, and Processing into the Extracellular Matrix

Graham

Sweetwyne

Pallero

et al. 2010

Journal of Biological Chemistry

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Calreticulin (CRT), a chaperone and Ca2؉ regulator, enhances wound healing, and its expression correlates with fibrosis in animal models, suggesting that CRT regulates production of the extracellular matrix. However, direct regulation of collagen matrix by CRT has not been previously demonstrated. We investigated the role of CRT in the regulation of fibrillar collagen expression, secretion, processing, and deposition in the extracellular matrix by fibroblasts. Mouse embryonic fibroblasts deficient in CRT (CRT ؊/؊ MEFs) have reduced transcript levels of fibrillar collagen I and III and less soluble collagen as compared with wild type MEFs. Correspondingly, fibroblasts engineered to overexpress CRT have increased collagen type I transcript and protein. Collagen expression appears to be regulated by endoplasmic reticulum (ER) calcium levels and intracellular CRT, because thapsigargin treatment reduced collagen expression, whereas addition of exogenous recombinant CRT had no effect. CRT ؊/؊ MEFs exhibited increased ER retention of collagen, and collagen and CRT were co-immunoprecipitated from isolated cell lysates, suggesting that CRT is important for trafficking of collagen through the ER. CRT ؊/؊ MEFs also have reduced type I procollagen processing and deposition into the extracellular matrix. The reduced collagen matrix deposition is partly a consequence of reduced fibronectin matrix formation in the CRT-deficient cells. Together, these data show that CRT complexes with collagen in cells and that CRT plays critical roles at multiple stages of collagen expression and processing. These data identify CRT as an important regulator of collagen and suggest that intracellular CRT signaling plays an important role in tissue remodeling and fibrosis.Calreticulin (CRT), 3 also known as the C1q receptor, is an endoplasmic reticulum (ER) chaperone, and a modulator of intracellular calcium signaling. CRT also is a multifunctional protein that is present in numerous cellular compartments, including the ER, cytoplasm, nucleus, at the cell surface, and as a released protein (1-5). There is evidence to suggest the involvement of CRT in tissue remodeling and wound healing. In a porcine dermal wound healing model, topical application of purified CRT increases the rate of wound healing and wound tensile strength (6). Proteomic data show up-regulation of CRT expression with fibrosis in a rat model of unilateral ureteric obstruction kidney fibrosis and in a mouse model of bleomycininduced lung fibrosis (7). The mechanisms by which CRT regulates tissue remodeling are not well understood, although fibronectin matrix deposition and modulation of cell adhesion, motility, proliferation, and matrix metalloproteinase expression have been implicated (6, 8 -13).CRT has effects on the extracellular matrix (ECM) and cellular responses to the ECM. Fibroblasts overexpressing CRT have increased fibronectin mRNA, protein, and matrix deposition, and cells lacking CRT express less fibronectin than wild type cells (9,14). CRT in the ER is thought to reg...

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Section: Discussionmentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

Section: ϫ/ϫmentioning

confidence: 99%

mentioning

confidence: 99%

“…4 In vitro, exogenous CRT treatment causes proliferation of fibroblasts, endothelial cells, and keratinocytes and increases keratinocyte and fibroblast migration (6).…”

mentioning

confidence: 99%

See 3 more Smart Citations

Intracellular Calreticulin Regulates Multiple Steps in Fibrillar Collagen Expression, Trafficking, and Processing into the Extracellular Matrix

Graham

Sweetwyne

Pallero

et al. 2010

Journal of Biological Chemistry

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Protein Moonlighting and Human Health and Idiopathic Human Disease

2016

Protein Moonlighting in Biology and Medicine

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Injected biodegradable polyurethane scaffolds support tissue infiltration and delay wound contraction in a porcine excisional model

Adolph

Pollins

et al. 2015

J Biomed Mater Res

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The filling of wound cavities with new tissue is a challenge. We previously reported on the physical properties and wound healing kinetics of prefabricated, gas-blown polyurethane (PUR) scaffolds in rat and porcine excisional wounds. To address the capability of this material to fill complex wound cavities, this study examined the in vitro and in vivo reparative characteristics of injected PUR scaffolds employing a sucrose porogen. Using the porcine excisional wound model, we compared reparative outcomes to both preformed and injected scaffolds as well as untreated wounds at 9, 13, and 30 days after scaffold placement. Both injected and preformed scaffolds delayed wound contraction by 19% at 9 days and 12% at 13 days compared to non-treated wounds. This stenting effect proved transient since both formulations degraded by day 30. Both types of scaffolds significantly inhibited the undesirable alignment of collagen and fibroblasts through day 13. Injected scaffolds were highly compatible with sentinel cellular events of normal wound repair cell proliferation, apoptosis, and blood vessel density. The present study provides further evidence that either injected or preformed PUR scaffolds facilitate wound healing, support tissue infiltration and matrix production, delay wound contraction, and reduce scarring in a clinically relevant animal model, which underscores their potential utility as a void-filling platform for large cutaneous defects.

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Calreticulin Enhances Porcine Wound Repair by Diverse Biological Effects

Cited by 89 publications

References 79 publications

Intracellular Calreticulin Regulates Multiple Steps in Fibrillar Collagen Expression, Trafficking, and Processing into the Extracellular Matrix

Intracellular Calreticulin Regulates Multiple Steps in Fibrillar Collagen Expression, Trafficking, and Processing into the Extracellular Matrix

Protein Moonlighting and Human Health and Idiopathic Human Disease

Injected biodegradable polyurethane scaffolds support tissue infiltration and delay wound contraction in a porcine excisional model

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