Maintenance of embryonic stem cell pluripotency by Nanog-mediated reversal of mesoderm specification.
Embryonic stem cells (ESCs) can be propagated indefinitely in culture, while retaining the ability to differentiate into any cell type in the organism. The molecular and cellular mechanisms underlying ESC pluripotency are, however, poorly understood. We characterize a population of early mesoderm-specified (EM) progenitors that is generated from mouse ESCs by bone morphogenetic protein stimulation. We further show that pluripotent ESCs are actively regenerated from EM progenitors by the action of the divergent homeodomain-containing protein Nanog, which, in turn, is upregulated in EM progenitors by the combined action of leukemia inhibitory factor and the early mesoderm transcription factor T/Brachyury. These findings uncover specific roles of leukemia inhibitory factor, Nanog, and bone morphogenetic protein in the self-renewal of ESCs and provide novel insights into the cellular bases of ESC pluripotency.
Suzuki
Atsushi
A
Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Raya
Angel
A
Kawakami
Yasuhiko
Y
Morita
Masanobu
M
Matsui
Takaaki
T
Nakashima
Kinichi
K
Gage
Fred H
FH
Rodríguez-Esteban
Concepción
C
Izpisúa Belmonte
Juan Carlos
JC
D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005326:Fetal Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000494:pharmacology; D053605:Leukemia Inhibitory Factor; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D000071317:Nanog Homeobox Protein; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D000098908:Brachyury Protein
D004268:DNA-Binding Proteins; D005326:Fetal Proteins; D018398:Homeodomain Proteins; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D000071317:Nanog Homeobox Protein; D012333:RNA, Messenger; D020825:T-Box Domain Proteins; D000098908:Brachyury Protein; C507838:Lif protein, mouse; C475540:Nanog protein, mouse