CCN2 is required for recruitment of Sox2-expressing cells during cutaneous tissue repair

Journal of Cell Communication and Signaling - Tập 9 - Trang 341-346 - 2014
Matthew Tsang1, Andrew Leask1
1Departments of Dentistry and Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Canada

Tóm tắt

Connective tissue growth factor (CTGF/CCN2), a member of the CCN family of matricellular proteins is upregulated in both fibrosis as well as tissue repair. Recently, we showed that, in mice, CCN2 expression by fibroblasts was required for dermal fibrogenesis, but not for cutaneous tissue repair. Lineage tracing analysis linked the ability of CCN2 to promote fibrosis to the requirement for CCN2 to recruit cells expressing the progenitor cell marker Sox2 to fibrotic connective tissue and for differentiating these cells into myofibroblasts. Herein, we show that although loss of CCN2 expression by Sox2-expressing cells does not impair cutaneous tissue repair, CCN2 was required for recruitment of cells derived from Sox2-expressing cells to the wound area. Collectively, these results are consistent with the notion that neither CCN2 nor Sox2-expressing progenitor cells are essential for cutaneous tissue repair and that CCN2 represents a specific anti-fibrotic target.

Tài liệu tham khảo

Duffield JS (2014) CCN2 is required for the TGF-β induced activation of Smad1-Erk1/2 signaling network. Cellular and molecular mechanisms in kidney fibrosis. J Clin Invest 124:2299–2306 Grotendorst GR (1997) Connective tissue growth factor: a mediator of TGF-beta action on fibroblasts. Cytokine Growth Factor Rev 8:171–179 Hinz B, Phan SH, Thannickal VJ, Prunotto M, Desmoulière A, Varga J, De Wever O, Mareel M, Gabbiani G (2012) Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am J Pathol 180:1340–1355 Holmes A, Abraham DJ, Sa S, Shiwen X, Black CM, Leask A (2001) CTGF and SMADs, maintenance of scleroderma phenotype is independent of SMAD signaling. J Biol Chem 276:10594–10601 Igarashi A, Okochi H, Bradham DM, Grotendorst GR (1993) Regulation of connective tissue growth factor gene expression in human skin fibroblasts and during wound repair. Mol Biol Cell 4:637–645 Kapoor M, Liu S, Huh K, Parapuram S, Kennedy L, Leask A (2008) Connective tissue growth factor promoter activity in normal and wounded skin. Fibrogenesis Tissue Repair 1:3 Lau LF, Lam SC (1999) The CCN family of angiogenic regulators: the integrin connection. Exp Cell Res 248:44–57 Leask A, Abraham DJ (2006) All in the CCN family: essential matricellular signalling modulators emerge from the bunker. J Cell Sci 119:4803–4810 Liu S, Taghavi R, Leask A (2010) Connective tissue growth factor is induced in bleomycin-induced skin scleroderma. J Cell Commun Signal 4:25–30 Liu S, Shi-wen X, Abraham DJ, Leask A (2011) CCN2 is required for bleomycin-induced skin fibrosis in mice. Arthritis Rheum 63:239–246 Liu S, Parapuram SK, Leask A (2013) Fibrosis caused by loss of PTEN expression in mouse fibroblasts is crucially dependent on CCN2. Arthritis Rheum 65:2940–2944 Liu S, Herault Y, Pavlovic G, Leask A (2014a) Skin progenitor cells contribute to bleomycin-induced skin fibrosis. Arthritis Rheumatol 66:707–713 Liu S, Thompson K, Leask A (2014b) CCN2 expression by fibroblasts is not required for cutaneous tissue repair. Wound Repair Regen 22:119–124 Mori T, Kawara S, Shinozaki M, Hayashi N, Kakinuma T, Igarashi A, Takigawa M, Nakanishi T, Takehara K (1999) Role and interaction of connective tissue growth factor with transforming growth factor-beta in persistent fibrosis: a mouse fibrosis model. J Cell Physiol 181:153–159 Nakerakanti SS, Bujor AM, Trojanowska M (2011) CCN2 is required for the TGF-β induced activation of Smad1-Erk1/2 signaling network. PLoS ONE 6:e21911 Perbal B (2013) CCN proteins: a centralized communication network. J Cell Commun Signal 7:169–177 Rajkumar VS, Sundberg C, Abraham DJ, Rubin K, Black CM (1999) Activation of microvascular pericytes in autoimmune Raynaud’s phenomenon and systemic sclerosis. Arthritis Rheum 42:930–941 Riser BL, Najmabadi F, Perbal B, Peterson DR, Rambow JA, Riser ML, Sukowski E, Yeger H, Riser SC. (2009) CCN3 (NOV) is a negative regulator of CCN2 (CTGF) and a novel endogenous inhibitor of the fibrotic pathway in an in vitro model of renal disease. Am J Pathol 174:1725–34 Shi-wen X, Stanton LA, Kennedy L, Pala D, Chen Y et al (2006) CCN2 is necessary for adhesive responses to transforming growth factor-beta1 in embryonic fibroblasts. J Biol Chem 281:10715–10726 Sundberg C, Ivarsson M, Gerdin B, Rubin K (1996) Pericytes as collagen-producing cells in excessive dermal scarring. Lab Invest 74:452–466 Wang Q, Usinger W, Nichols B, Gray J, Xu L, Seeley TW, Brenner M, Guo G, Zhang W, Oliver N, Lin A, Yeowell D (2011) Cooperative interaction of CTGF and TGF-β in animal models of fibrotic disease. Fibrogenesis Tissue Repair 4:4