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Collagen I regulates the self‐renewal of mouse embryonic stem cells through α2β1 integrin‐ and DDR1‐dependent Bmi‐1
Author(s) -
Suh Han Na,
Han Ho Jae
Publication year - 2011
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.22697
Subject(s) - collagen receptor , microbiology and biotechnology , integrin , ddr1 , chemistry , mapk/erk pathway , small interfering rna , cellular differentiation , signal transduction , biology , receptor , receptor tyrosine kinase , biochemistry , gene , transfection
Adhesion of cells to extracellular matrix (ECM) influences vital aspects of anchorage‐dependent cell behavior including survival, proliferation, and differentiation. However, the role of collagen I in mouse embryonic stem cells (mESCs) is not well‐known. Therefore, in the present study we examined the effect of collagen I on mESC self‐renewal and related signal pathways. Collagen I (10 µg/ml) maintained mESCs in an undifferentiated state (Nanog, OCT4, and SSEA‐1) and did not affect differentiation (GATA4, Tbx5, Fgf5, and Cdx2) in the presence of leukemia inhibitory factor (LIF). Treatment with collagen I bound both α2β1 integrin and discoidin domain receptor 1 (DDR1), and stimulated intracellular signaling pathways. Collagen I‐bound α2β1 integrin increased integrin‐linked kinase (ILK) phosphorylation, cleaved Notch protein expression in the nuclear fraction, and Gli‐1 mRNA expression. In addition, collagen I‐bound DDR1 increased GTP‐bound Ras, phosphoinositide 3‐kinase (PI3K) p85α catalytic subunit protein expression, and Akt and ERK phosphorylation. Importantly, collagen I increased Bmi‐1 protein expression in the nucleus which was blocked by small interfering RNA (siRNA) specific for Gli‐1 and ERK, showing that parallel pathways of integrins and DDR1 merge at Bmi‐1. Furthermore, collagen I‐induced p16 decrease and p‐Rb increase were reversed by Bmi‐1‐specific siRNA. Moreover, Bmi‐1 silencing abolished the collagen I‐induced increase of proliferation indices and undifferentiation markers. These results indicate that collagen I stimulates the self‐renewal of mESCs mediated by Bmi‐1 through α2β1 integrin‐dependent ILK, Notch, Gli‐1, and DDR1‐dependent Ras, PI3K/Akt, and ERK. J. Cell. Physiol. 226: 3422–3432, 2011. © 2011 Wiley Periodicals, Inc.