Collagen IV Significantly Enhances Migration and Transplantation of Embryonic Stem Cells: Involvement of α2β1 Integrin-Mediated Actin Remodeling

Abstract

Embryonic stem (ES) cell transplantation represents a potential means for the treatment of degenerative diseases and injuries. As appropriate distribution of transplanted ES cells in the host tissue is critical for successful transplantation, the exploration of efficient strategies to enhance ES cell migration is warranted. In this study we investigated ES cell migration under the influence of various extracellular matrix (ECM) proteins, which have been shown to stimulate cell migration in various cell models with unclear effects on ES cells. Using two mouse ES (mES) cell lines, ESC 26GJ9012-8-2 and ES-D3 GL, to generate embryoid bodies (EBs), we examined the migration of differentiating cells from EBs that were delivered onto culture surfaces coated with or without collagen I, collagen IV, Matrigel, fibronectin, and laminin. Among these ECM proteins, collagen IV exhibited maximal migration enhancing effect. mES cells expressed α2 and β1 integrin subunits and the migration enhancing effect of collagen IV was prevented by RGD peptides as well as antibodies against α2 and β1 integrins, indicating that the enhancing effect of collagen IV on cell migration was mediated by α2β1 integrin. Furthermore, staining of actin cytoskeleton that links to integrins revealed well-developed stress fibers and long filopodia in mES cells cultured on collagen IV, and the actindisrupting cytochalasin D abolished the collagen IV-enhanced cell migration. In addition, pretreatment of undifferentiated or differentiated mES cells with collagen IV resulted in improved engraftment and growth after transplantation into the subcutaneous tissue of nude mice. Finally, collagen IV pretreatment of osteogenically differentiated mES cells increased osteogenic differentiation-like tissue and decreased undifferentiation-like tissue in the grafts grown after transplantation. Our results demonstrated that collagen IV significantly enhanced the migration of differentiating ES cells through α2β1 integrin-mediated actin remodeling and could promote ES cell transplantation efficiency, which may be imperative to stem cell therapy.

Reduced migration of Ishikawa cells associated with downregulation of aquaporin-5

“…Other studies have demonstrated an increased expression of AQP3 in skin carcinoma, increased AQP4 expression in glioblastoma and increased AQP5 expression in pancreatic and colon cancer (21)(22)(23)(24). Cell migration is affected by numerous factors; it is time-dependent (25), significantly enhanced by collagen IV in embryonic stem cells (26), and it has been observed that even a lesion can induce an increase in the migration of human neural progenitor cells (27). The findings from this study demonstrate that AQP5 knockdown reduced the migration of EC cells, suggesting that AQP5 is involved in the development of EC.…”

Glioma Initiating Cells Form a Differentiation Niche Via the Induction of Extracellular Matrices and Integrin αV

“…Potential roles for ECMs in the stem cell niche and tumor microenvironment have been reported [12]. For example, COL4 significantly enhances the migration and differentiation of embryonic stem cells (ESCs) [13]. LAM is the most effective ECM for the maintenance of NSCs and GICs via its interaction with integrin α 6 [2], [14].…”

“…Our integrated proteomics showed that the protein expression of any integrin β subunits was not significant in differentiated GICs, suggesting that the heterodimers with multiple integrin β subunits may support GIC differentiation via the RGD-binding motif. Integrin α 2 is expressed in ESCs and NSCs [22], and it stimulates cell adhesion/migration [13]. Integrin α 5 is also expressed on NSCs [22] and human gliomas [23].…”

Resistance to the mTOR-inhibitor RAD001 elevates integrin α2- and β1-triggered motility, migration and invasion of prostate cancer cells

“…Obviously, metastatic spreading of RAD001-resistant prostate cancer is accelerated by two strategies: (1) by upregulating the α 2 expression level (quantitative regulation) and (2) by strengthening the relevance of α 2 in controlling invasion (qualitative regulation). In fact, cell migration has been demonstrated to depend on the number of α 2 integrin receptors expressed on the cell surface (Li et al , 2011), as well as on qualitative parameters, such as activation of intracellular signalling cascades and/or receptor cross-talk (Ning et al , 2005; Sawhney et al , 2006). We assume that the conversion of prostate cancer cells from a drug-sensitive to a drug-insensitive state is accompanied by an elevated α 2 level, α 2–cytoskeleton interaction and cytoskeleton-related signalling, finally enforcing actin turnover and remodelling.…”