Cell cycle regulators control mesoderm specification in human pluripotent stem cells.
Grandy, Rodrigo A
The Journal of biological chemistry
American Society for Biochemistry and Molecular Biology Inc.
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Yiangou, L., Grandy, R. A., Osnato, A., Ortmann, D., Sinha, S., & Vallier, L. (2019). Cell cycle regulators control mesoderm specification in human pluripotent stem cells.. The Journal of biological chemistry, 294 (47), 17903-17914. https://doi.org/10.1074/jbc.ra119.008251
The mesoderm is one of the three germ layers produced during gastrulation from which muscle, bones, kidneys, and the cardiovascular system originate. Understanding the mechanisms that control mesoderm specification could inform many applications, including the development of regenerative medicine therapies to manage diseases affecting these tissues. Here, we used human pluripotent stem cells (hPSCs) to investigate the role of cell cycle in mesoderm formation. To this end, using small molecules or conditional gene knockdown, we inhibited proteins controlling G1 and G2/M cell cycle phases during the differentiation of hPSCs into lateral plate, cardiac, and presomitic mesoderm. These loss-of-function experiments revealed that regulators of the G1 phase such as cyclin-dependent kinases (CDKs) and phosphorylation of retinoblastoma protein (pRb) are necessary for efficient mesoderm formation in a context-dependent manner. Further investigations disclosed that inhibition of the G2/M regulator CDK1 decreases bone morphogenetic protein (BMP) signaling activity specifically during lateral plate mesoderm formation while reducing fibroblast growth factor (FGF)/extracellular signaling-regulated kinase 1/2 (ERK1/2) activity in all mesoderm subtypes. Taken together, our findings reveal that cell cycle regulators direct mesoderm formation by controlling the activity of key developmental pathways.
Mesoderm, Humans, Ubiquitin-Protein Ligases, Cyclin-Dependent Kinases, Protein Kinase Inhibitors, Cell Cycle, Cell Differentiation, MAP Kinase Signaling System, Cell Lineage, Retinoblastoma Binding Proteins, Human Embryonic Stem Cells
This work was supported by the Wellcome Trust PhD program (PSAG/048 to L.Y.); the European Research Council advanced grant New-Chol (ERC: 741707 to L.V. and R.A.G), a BHF Senior Research Fellowship (FS/13/29/30024 to S.S.), a core support grant from the Wellcome and Medical Research Council to the Wellcome – Medical Research Council Cambridge Stem Cell Institute (PSAG028) and a core support grant from the Wellcome to the Wellcome Sanger Institute (WT206194).
European Commission Horizon 2020 (H2020) ERC (741707)
European Commission Horizon 2020 (H2020) Societal Challenges (668294-2 INTENS)
British Heart Foundation (FS/13/29/30024)
British Heart Foundation (FS/13/65/30441)
External DOI: https://doi.org/10.1074/jbc.ra119.008251
This record's URL: https://www.repository.cam.ac.uk/handle/1810/297106
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