CD49f enhances multipotency and maintains stemness through the direct regulation of OCT4 and SOX2.
CD49f (integrin subunit α6) 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.
Adult Stem Cell Research Center, Seoul National University, Seoul, Republic of Korea.
Kyung-Rok
KR
Yu
Se-Ran
SR
Yang
Ji-Won
JW
Jung
Hyongbum
H
Kim
Kinarm
K
Ko
Dong Wook
DW
Han
Sang-Bum
SB
Park
Soon Won
SW
Choi
Soo-Kyung
SK
Kang
Hans
H
Schöler
Kyung-Sun
KS
Kang
D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D039503:Integrin alpha6 / Q000096:biosynthesis*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000096:biosynthesis*; D015398:Signal Transduction / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D039503:Integrin alpha6; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt