The transforming growth factor β (TGF-β) signaling pathway affects a variety of processes, including cell proliferation, differentiation and development. However, the role of this pathway in generation of mouse pluripotent stem cells (PSCs) remains unclear. Researchers from Institute of Biochemistry and Cell Biology (SIBCB), Institutes for Biological Sciences, CAS, reported the novel function of TGF-β signaling in generation and maintenance of PSCs.
Embryonic development is a highly complicated event and is under strict regulations, but how the development of early embryos occurs normally remains largely unknown. Mouse pluripotent stem cells have been widely used to study the molecular mechanisms involved in early embryonic development. They can be derived from early embryos called embryonic stem cells (ESCs), and also be generated from differentiated cells named iPSCs (induced pluripotent stem cells). LIF/STAT3, FGF/MEK/ERK and Wnt/β-catenin pathways are involved in the generation and maintenance of pluripotency. TGF-β signaling plays important roles in the maintenance of mouse epiblast stem cells and human ESCs.
Under the supervision of Prof. JING Naihe from SIBCB, Dr. TAN Fangzhi and colleagues found that SB431542 (SB43), a TGF-β signaling inhibitor, together with histone deacetylase inhibitor Valproic acid, could substitute for Oct4 to reprogram mouse embryonic fibroblasts into iPSCs. Mechanistic studies showed that SB43 could enhance mesenchymal-epithelial transition and upregulate the expression of many genes involved in Oct4 replacement. Moreover, inhibition of TGF-β signaling could sustain iPSCs and ESCs pluripotency in the presence of LIF. TGF-β signaling inhibitor SB43 could replace FGF/MEK/ERK signaling inhibitor PD03 in the traditional LIF/PD03/CHIR condition, leading to a novel culture condition for mouse iPSCs and ESCs. ERK activity was inhibited under both conditions.
These results indicate that TGF-β acts as a modulator to generate iPSCs and maintain pluripotency.
This study entitled “Inhibition of TGF-β Signaling can Substitute for Oct4 in Reprogramming and Maintain Pluripotency” has been published online in Journal of Biological Chemistry on Dec 29, 2014.
This work was funded by the the "Strategic Priority Research Program" of the Chinese Academy of Sciences, National Key Basic Research and Development Program of China, National Natural Science Foundation of China.
CONTACT:
JING Naihe, Principal Investigator
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Shanghai 200031, China.
Tel.: +86-21-5492-1381;
Fax: +86-21-5492-1011;
E-mail: njing@sibcb.ac.cn.
Fig1. A-B. TGF-β signaling inhibitor SB431542 can substitute for Oct4 in reprogramming. Abbreviations: “OSKM” stands for the combination of Oct4, Sox2, Klf4, c-Myc; “SKM” stands for the combination of Sox2, Klf4, c-Myc. C. SB431542 can sustain the pluripotency of ESCs.(Image provided by Prof. JING Naihe`s group)
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