TY - JOUR
T1 - Cripto-1 is required for hypoxia to induce cardiac differentiation of mouse embryonic stem cells
AU - Bianco, Caterina
AU - Cotten, Catherine
AU - Lonardo, Enza
AU - Strizzi, Luigi
AU - Baraty, Christina
AU - Mancino, Mario
AU - Gonzales, Monica
AU - Watanabe, Kazuhide
AU - Nagaoka, Tadahiro
AU - Berry, Colin
AU - Arai, Andrew E.
AU - Minchiotti, Gabriella
AU - Salomon, David S.
N1 - Funding Information:
Supported by Intramural Research program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, by a grant from the Associazione Italiana per la Ricerca sul Cancro (to G.M.), and by a grant of the Faculty of Medicine, University of Glaskow (to C.B.).
PY - 2009
Y1 - 2009
N2 - Cripto-1 is a membrane-bound protein that is highly expressed in embryonic stem cells and in human tumors. In the present study, we investigated the effect of low levels of oxygen, which occurs naturally in rapidly growing tissues, on Cripto-1 expression in mouse embryonic stem (mES) cells and in human embryonal carcinoma cells. During hypoxia, Cripto-1 expression levels were significantly elevated in mES cells and in Ntera-2 or NCCIT human embryonal carcinoma cells, as compared with cells growing with normal oxygen levels. The transcription factor hypoxia-inducible factor-1α directly regulated Cripto-1 expression by binding to hypoxia-responsive elements within the promoter of mouse and human Cripto-1 genes in mES and NCCIT cells, respectively. Furthermore, hypoxia modulated differentiation of mES cells by enhancing formation of beating cardiomyocytes as compared with mES cells that were differentiated under normoxia. However, hypoxia failed to induce differentiation of mES cells into cardiomyocytes in the absence of Cripto-1 expression, demonstrating that Cripto-1 is required for hypoxia to fully differentiate mES cells into cardiomyocytes. Finally, cardiac tissue samples derived from patients who had suffered ischemic heart disease showed a dramatic increase in Cripto-1 expression as compared with nonischemic heart tissue samples, suggesting that hypoxia may also regulate Cripto-1 in vivo.
AB - Cripto-1 is a membrane-bound protein that is highly expressed in embryonic stem cells and in human tumors. In the present study, we investigated the effect of low levels of oxygen, which occurs naturally in rapidly growing tissues, on Cripto-1 expression in mouse embryonic stem (mES) cells and in human embryonal carcinoma cells. During hypoxia, Cripto-1 expression levels were significantly elevated in mES cells and in Ntera-2 or NCCIT human embryonal carcinoma cells, as compared with cells growing with normal oxygen levels. The transcription factor hypoxia-inducible factor-1α directly regulated Cripto-1 expression by binding to hypoxia-responsive elements within the promoter of mouse and human Cripto-1 genes in mES and NCCIT cells, respectively. Furthermore, hypoxia modulated differentiation of mES cells by enhancing formation of beating cardiomyocytes as compared with mES cells that were differentiated under normoxia. However, hypoxia failed to induce differentiation of mES cells into cardiomyocytes in the absence of Cripto-1 expression, demonstrating that Cripto-1 is required for hypoxia to fully differentiate mES cells into cardiomyocytes. Finally, cardiac tissue samples derived from patients who had suffered ischemic heart disease showed a dramatic increase in Cripto-1 expression as compared with nonischemic heart tissue samples, suggesting that hypoxia may also regulate Cripto-1 in vivo.
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U2 - 10.2353/ajpath.2009.090218
DO - 10.2353/ajpath.2009.090218
M3 - Article
C2 - 19834060
AN - SCOPUS:73649120251
SN - 0002-9440
VL - 175
SP - 2146
EP - 2158
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 5
ER -
