Abstract
Placental dysplasia increases the risk of recurrent spontaneous abortion (RSA). However, the underlying mechanism regulating placental development remains unclear. In this study, we showed that the expression of CDC42 was decreased in the villous tissue of RSA samples compared to healthy controls. Further examination demonstrated that CDC42 deficiency led to the differentiation of human trophoblast stem cells (hTSCs) and inhibited their proliferation. Genetic manipulation of YAP and EZRIN in hTSCs revealed that CDC42 regulates the stemness and proliferation of hTSCs; this is dependent on EZRIN, which translocates YAP into the nucleus. Moreover, the expression pattern of EZRIN, YAP, and Ki67 was also abnormal in the villous tissue of RSA samples, consistent with in vitro experiments. In summary, these findings suggest that the CDC42/EZRIN/YAP pathway plays an important role in placental development.
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Acknowledgements
We thank Accdon (www.accdon.com) for its linguistic assistance during the preparation of this manuscript. We thank Professor Zhu Dawang from Xiamen University for the pCMV-3×flag YAP–5SA plasmid. We are also grateful to all participants for their valuable contributions.
Funding
This study was supported by grants from the National Natural Science Foundation of China (Nos. 81830045, 82071652, 81801446, and 31971071), National Key R&D Program of China (2017YFC1001402, 2018YFC1004102, and 2016YFC1000405), Science and Technology Projects in Guangzhou (202102010005, 202102010006), Guangzhou Municipal Health Commission (2019GX03), and the General Program of Guangdong Province Natural Science Foundation (Nos. 2021A1515011039 and 2020A1515010273).
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S.B., L.D., D.C., and H.W. designed the study; Y.L., P.X., M.L., L.H., M.H., and Y.L. were involved in the collection of human samples; S.B., L.H., L.Z., W.D., W.M., and N.M. performed the experiments; S.B., L.D., J.L., J.C., Z.B., W.T., and Z.W. analyzed the data and wrote the manuscript; and all authors read and approved the final version of the manuscript.
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Ethical approval for our study was acquired from the Medical Ethics Committee of The Third Affiliated hospital of Guangzhou Medical University (ethics approval number: 20170126). This study was performed following Declaration of Helsinki. All recruited volunteers provided written informed consents.
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Shilei, B., Lizi, Z., Lijun, H. et al. Downregulation of CDC42 inhibits the proliferation and stemness of human trophoblast stem cell via EZRIN/YAP inactivation. Cell Tissue Res 389, 573–585 (2022). https://doi.org/10.1007/s00441-022-03653-6
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DOI: https://doi.org/10.1007/s00441-022-03653-6