Mapping the first stages of mesoderm commitment during differentiation of human embryonic stem cells.
Our understanding of how mesodermal tissue is formed has been limited by the absence of specific and reliable markers of early mesoderm commitment. We report that mesoderm commitment from human embryonic stem cells (hESCs) is initiated by epithelial-to-mesenchymal transition (EMT) as shown by gene expression profiling and by reciprocal changes in expression of the cell surface proteins, EpCAM/CD326 and NCAM/CD56. Molecular and functional assays reveal that the earliest CD326-CD56+ cells, generated from hESCs in the presence of activin A, BMP4, VEGF, and FGF2, represent a multipotent mesoderm-committed progenitor population. CD326-CD56+ progenitors are unique in their ability to generate all mesodermal lineages including hematopoietic, endothelial, mesenchymal (bone, cartilage, fat, fibroblast), smooth muscle, and cardiomyocytes, while lacking the pluripotency of hESCs. CD326-CD56+ cells are the precursors of previously reported, more lineage-restricted mesodermal progenitors. These findings present a unique approach to study how germ layer specification is regulated and offer a promising target for tissue engineering.
Evseenko
Denis
D
Department of Pathology and Laboratory Medicine, and Broad Stem Cell Research Center and Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Zhu
Yuhua
Y
Schenke-Layland
Katja
K
Kuo
Jeffrey
J
Latour
Brooke
B
Ge
Shundi
S
Scholes
Jessica
J
Dravid
Gautam
G
Li
Xinmin
X
MacLellan
W Robb
WR
Crooks
Gay M
GM
D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D019002:CD56 Antigen / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D000071858:Epithelial Cell Adhesion Molecule; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008648:Mesoderm / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism
D000951:Antigens, Neoplasm; D015415:Biomarkers; D019002:CD56 Antigen; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule