Extracellular matrix metalloproteinase inducer/CD147 promotes myofibroblast differentiation by inducing α‐smooth muscle actin expression and collagen gel contraction: implications in tissue remodeling

Abstract

Extracellular matrix metalloproteinase inducer (EMMPRIN) is a cell surface glycoprotein enriched on tumor cells and normal epithelia. It is mainly known for its ability to induce matrix metalloproteinase production in fibroblasts following epithelial-stromal interaction. We sought to examine whether EMMPRIN has a broader role promoting fibroblast-to-myofibroblast differentiation. Because alpha-smooth muscle actin (alphaSMA) is considered a marker of this differentiation process, we analyzed the effect of EMMPRIN on its expression in corneal and skin fibroblasts by Western blots, immunocytochemistry, and a functional assay of collagen lattice contraction. Increasing EMMPRIN expression by cDNA transfection or by treatment with exogenously added recombinant EMMPRIN resulted in an up-regulation of alphaSMA expression. EMMPRIN also increased the contractile properties of the treated fibroblasts as demonstrated by the immunohistochemical appearance of stress fibers and by the accelerated contraction of fibroblast-embedded collagen lattices. Blocking EMMPRIN expression by small interfering RNA inhibited alphaSMA and collagen gel contraction induced not only by EMMPRIN but also by transforming growth factor-beta, a major mediator of myofibroblast differentiation that also regulated EMMPRIN expression. These findings, combined with the fact that EMMPRIN and alphaSMA colocalized to the same cells in the stroma of pathological corneas, expand on the mechanism by which EMMPRIN remodels extracellular matrix during wound healing and cancer.

HAb18G/CD147 promotes epithelial–mesenchymal transition through TGF-β signaling and is transcriptionally regulated by Slug

“…In this study, we showed that CD147 is upregulated by TGF-b and mediates EMT in tumor formation, and that this change is coupled with the induction of MMP-2 secretion, the inhibition of apoptosis and the acceleration of the cell cycle. The fact that HAb18G/CD147 expression by the normal hepatic cell line QZG and by primary mouse hepatocytes was upregulated by TGF-b1 was consistent with the observation that CD147 was upregulated by TGF-b1 in both corneal fibroblasts and epithelial cells during tissue remodeling (Gabison et al, 2005;Huet et al, 2008). HAb18G/CD147 expression in QZG cells was also upregulated spontaneously in a time-dependent manner in serum-free medium without TGF-b1 treatment, suggesting a resistance to cell death under starvation conditions, as HAb18G/CD147 was reported to enhance the survival of HCC cells through inhibition of starvation-induced autophagy (Gou et al, 2009).…”

Basigin/CD147 Promotes Renal Fibrosis after Unilateral Ureteral Obstruction

“…42 Generally, the wound repair process is characterized by the activation of quiescent fibroblasts and their differentiation into myofibroblasts. 30 Hyaluronan promotes ␣-SMA expression in fibroblasts and orchestrates TGF-␤-dependent maintenance of the myofibroblast phenotype. 10,11 Little is known about the precise mechanism underlying how hyaluronan induces ␣-SMA in fibroblasts, but it is assumed that the hyaluronan macromolecular assembly in the pericellular environment contributes to mediate various signaling.…”

“…Furthermore, Bsg promotes the differentiation of fibroblasts into myofibroblasts by inducing ␣-SMA expression in corneal fibroblasts. 30 We previously generated Bsg-deficient mice (Bsg Ϫ/Ϫ ) and reported several abnormalities, including male and female sterility, progressive retinal degeneration, increased cell proliferation on mixed lymphocyte culture, decreased memory function, and abnormal sensory function. [31][32][33] Most recently, we also found that Bsg is an E-selectin ligand and is involved in renal ischemia/reperfusion injury.…”

EMMPRIN Modulates Epithelial Barrier Function through a MMP–Mediated Occludin Cleavage

“…17 Protein loading was verified by Ponceau Red staining and by comparison with the intensity of GAPDH bands.…”

“…17 Cells were then incubated for 18 hours in SHEM medium with 10% FCS and for a further 24 hours in serum-free SHEM medium with or without NaCl addition before analysis.…”