Immunolocalization of Tenascin-C, α9 Integrin Subunit, and αvβ6 Integrin During Wound Healing in Human Oral Mucosa

Abstract

Tenascin-C (TN-C) and its isoforms are multidomain extracellular matrix (ECM) proteins that are believed to be involved in the regulation of stromal-epithelial interactions. Some of the interactions between TN-C and cells are mediated by integrins. In this study we analyzed the expression of TN-C and its large molecular weight splice isoform (TN-C(L)) and the putative TN-C-binding alpha9 and alphavbeta6 integrins during human wound repair. In 3-day-old oral mucosal wounds, immunoreactivity for alpha9 integrin localized abundantly at the migrating basal wound epithelial cells. TN-C and TN-C(L) were localized in the matrix between and underneath alpha9-expressing epithelial cells. In parallel with gradual downregulation of alpha9 integrin immunoreactivity in 7-day and older wounds, the expression of alphavbeta6 integrin was temporarily induced. Integrin alphavbeta6 co-localized in the same area as TN-C and TN-C(L) immunoreactivity at the cell-cell contacts of the basal and suprabasal cell layers of the wound epithelium. During granulation tissue formation and reorganization from 7 to 28 days after wounding, TN-C and TN-C(L) were abundantly localized in the granulation tissue. The findings show that TN-C(L) is expressed under the migrating epithelial front and in the granulation tissue during matrix deposition in wound repair. Preferential localization of alpha9 integrin in migrating epithelial cells and of alphavbeta6 integrin in epithelium after wound closure suggests different functions for these integrins in wound repair.

Dynamic role of myofibroblasts in oral lesions

“…Cytokines, such as PDGF, granulocytemacrophage colony-stimulating factor (GM-CSF), heparin, integrin [20] , and TGF-β, and existing tractional forces stimulate protofibroblast differentiation through α-SMA expression, leading to their transformation into MFs. A study conducted on the role of tenacin in wound contraction demonstrated that increased tenacin expression correlated with MF differentiation [23] . However, interferon-γ, a basic fibroblast growth factor (bFGF), prostaglandin E2, and high cell density inhibit the differentiation of protofibroblasts to MFs [20] .…”

αvβ6 Integrin Regulates Renal Fibrosis and Inflammation in Alport Mouse

“…This finding is consistent with previous reports that ␣v␤6 is expressed at low levels in healthy adult epithelium but is up-regulated during tissue injury and repair. 10,11,13,15,17 …”

“…5,9,10 ␣v␤6 expression is generally restricted to epithelial cells where it is expressed at low levels in normal adult tissues and elevated during development, injury, and neoplasia. 9,[11][12][13] Although ␣v␤6 is expressed at relatively low levels in healthy adult kidney, its expression is prominent in the developing mouse kidney, particularly in the proximal tubules, loop of Henle, and collecting ducts. 11,12,14 Recently, elevated expression of ␣v␤6 has been reported for various forms of human kidney pathology.…”

Tenascin-C and carcinoma cell invasion in oral and urinary bladder cancer

“…Against the background that there is also a reexpression of oncTn-C during fibrosis, wound healing, and tissue remodeling, the synthesis of Tn-C by fibroblasts / myofibroblasts / CAFs can be explained as a sign of cellular activation and may be linked also to the migratory capability of stromal cells. [31][32][33][34] Since Tn-C critically modulates cell adhesion to fibronectin and modulates fibronectin assembly by fibroblasts, stromal and tumor derived Tn-C may have the same function and the final situation is more or less determined by the quantity and site-specific modulation of the deposited protein. Recently, it was indeed shown that the capability of Tn-C to prevent fibrillogenesis of fibronectin by fibroblasts depends on proteolytic processing and demasking of cryptic domains.…”

“…77,78 Interestingly, in concordance with invasion of neoplastic keratinocytes, a comparable co-organization of oncTn-C and the integrins a9 and avb6 was shown in healing wounds speaking well for a comprehensive mechanism during epithelial migration. 31 Up to now there are only few reports on the differential expression and possible function of Tn-C splicing variants in OSCC. In 1997, Mighell and coworkers published an interesting study describing the mRNA expression of splicing domains in normal, malignant, and reactive oral mucosae.…”