Short-term BMP-4 treatment initiates mesoderm induction in human embryonic stem cells.
Human embryonic stem cells (hES cells) have unlimited self-renewal capacity and can differentiate into most, if not all, possible cell types. This unique property makes them valuable not only for investigation of early developmental processes, but also for regenerative medicine. Mesoderm-derived cardiac cells and hematopoietic cells both have the potential for various therapeutic applications. However, efficient induction of hES cell differentiation into mesoderm remains a challenge. Here, we showed that treatment of hES cells with bone morphogenetic protein-4 (BMP-4) exhibited differential effects: long-term treatment results in trophoblast and extra-embryonic endoderm differentiation, whereas short-term treatment can promote early mesoderm induction. The induction of mesoderm in hES cells occurs at a high efficiency as measured using several markers, such as Brachyury, WNT3, and MIXL1 expression. Moreover, these mesoderm progenitor cells can differentiate into cardiac and hematopoietic lineages in vitro. Further analysis showed that the mesoderm-inducing capacity of BMP-4 requires endogenous FGF and TGF-beta/Nodal/activin signaling activities. Thus, our results uncover a novel role for BMP-4 in regulation of hES cell differentiation and should provide insights into the mechanism of mesoderm induction in hES cells.
Zhang
Pengbo
P
Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, Beijing, China.
Li
Jian
J
Tan
Zhijia
Z
Wang
Chengyan
C
Liu
Ting
T
Chen
Lin
L
Yong
Jun
J
Jiang
Wei
W
Sun
Xiaomeng
X
Du
Liying
L
Ding
Mingxiao
M
Deng
Hongkui
H
D000469:Alkaline Phosphatase / Q000032:analysis; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects*; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics; D006801:Humans; D008648:Mesoderm / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D051379:Mice; D016685:Mitomycin / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction
C525809:BMP4 protein, human; D015415:Biomarkers; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D016685:Mitomycin; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D000469:Alkaline Phosphatase