CD49f Enhances Multipotency and Maintains Stemness Through the Direct Regulation of OCT4 and SOX2

Abstract

CD49f (integrin subunit a6) regulates signaling pathways in a variety of cellular activities. However, the role of CD49f in regulating the differentiation and pluripotency of stem cells has not been fully investigated. Therefore, in this study, human mesenchymal stem cells (hMSCs) were induced to form spheres under nonadherent culture conditions, and we found that the CD49f-positive population was enriched in MSC spheres compared with MSCs in a monolayer. The expression of CD49f regulated the ability of hMSCs to form spheres and was associated with an activation of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway. Furthermore, the forced expression of CD49f modulated the proliferation and differentiation potentials of hMSCs through prolonged activation of PI3K/AKT and suppressed the level of p53. We showed that the pluripotency factors OCT4 and SOX2 were recruited to the putative promoter region of CD49f, indicating that OCT4 and SOX2 play positive roles in the expression of CD49f. Indeed, CD49f expression was upregulated in human embryonic stem cells (hESCs) compared with hMSCs. The elevated level of CD49f expression was significantly decreased upon embryoid body formation in hESCs. In hESCs, the knockdown of CD49f downregulated PI3K/AKT signaling and upregulated the level of p53, inducing differentiation into three germ layers. Taken together, our data suggest that the cell-surface protein CD49f has novel and dynamic roles in regulating the differentiation potential of hMSCs and maintaining pluripotency. STEM CELLS 2012;30:876-887 Disclosure of potential conflicts of interest is found at the end of this article.

Control of mesenchymal stem cell phenotype and differentiation depending on cell adhesion mechanism

“…In particular, many reports have shown that integrin signalling regulates stem cell differentiation (Smadja et al, 2014;Yu et al, 2012). These results indicate that control of integrin signalling is valuable for stem cell regulation.…”

Expansion of breast cancer stem cells with fibrous scaffolds

“…37 CD49f has been used for enrichment of normal cells and CSCs, 38,39 which maintains the pluripotency and stemness through the direct regulation of OCT4 and SOX2. 40 In our study, transcriptional factors related to stem cells, including SOX2 and OCT3/4, and breast CSC signatures, including SOX4 and CD49f, were enhanced in MCF-7 cultured on fibrous scaffolds by 1.77 AE 0.25-fold, 2.22 AE 0.23-fold, 1.56 AE 0.25-fold, and 2.92 AE 0.33-fold, respectively, relative to cells on TCP (Fig. 5a).…”

Optimization of culture medium for the isolation and propagation of human breast cancer cells from primary tumour biopsies

“…They also suggested that BCSCs would be enriched in the CD44 + CD24 -cells if they were combined with the CD49f + phenotype (Ghebeh et al, 2013). CD49f was also determined as a marker of BCSCs in previous studies (Meyer et al, 2010;Yu et al, 2012 However, Medium D and Medium M also supported stromal cell proliferation. Regarding CD90 expression, more than 50% of the primary cells in Medium D and Medium M tested positive for this marker, whereas this population only accounted for about 25% of the primary cells grown in Medium DB.…”