Downregulation of CDC42 inhibits the proliferation and stemness of human trophoblast stem cell via EZRIN/YAP inactivation

Bi Shilei; Zhang Lizi; Huang Lijun; Ma Weixu; Meng Nan; Deng Weinan; Li Yulian; Liang Yingyu; Huang Minshan; Xu Pei; Liu Mingxing; Chen Jingsi; Tu Zhaowei; Wang Zhijian; Wang Haibin; Lu Jinhua; Chen Dunjin; Du Lili

doi:10.1007/s00441-022-03653-6

Downregulation of CDC42 inhibits the proliferation and stemness of human trophoblast stem cell via EZRIN/YAP inactivation

Cell Tissue Res. 2022 Sep;389(3):573-585. doi: 10.1007/s00441-022-03653-6. Epub 2022 Jun 25.

Authors

Bi Shilei^#^{1

2

3

4}, Zhang Lizi⁵, Huang Lijun^#^{1

2

3

4}, Ma Weixu^{1

2

3

4}, Meng Nan⁶, Deng Weinan^{1

2

3

4}, Li Yulian^{1

2

3

4}, Liang Yingyu^{1

2

3

4}, Huang Minshan^{1

2

3

4}, Xu Pei^{1

2

3

4}, Liu Mingxing^{1

2

3

4}, Chen Jingsi^{1

2

3

4}, Tu Zhaowei^{1

2

3

4}, Wang Zhijian⁵, Wang Haibin⁶, Lu Jinhua^#⁷, Chen Dunjin^#^{8

9

10

11}, Du Lili^#^{12

13

14

15}

Affiliations

¹ Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangdong, Guangzhou, China.
² Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China.
³ Guangdong Engineering and Technology Research Center of Maternal-Fetal Medicine, Guangzhou, China.
⁴ Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, Guangzhou, China.
⁵ Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
⁶ Fujian Provincial Key Laboratory of Reproductive Health Research, School of Medicine, Xiamen University, Xiamen, Fujian, China.
⁷ Fujian Provincial Key Laboratory of Reproductive Health Research, School of Medicine, Xiamen University, Xiamen, Fujian, China. jinhua888@126.com.
⁸ Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangdong, Guangzhou, China. gzdrchen@gzhmu.edu.cn.
⁹ Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China. gzdrchen@gzhmu.edu.cn.
¹⁰ Guangdong Engineering and Technology Research Center of Maternal-Fetal Medicine, Guangzhou, China. gzdrchen@gzhmu.edu.cn.
¹¹ Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, Guangzhou, China. gzdrchen@gzhmu.edu.cn.
¹² Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangdong, Guangzhou, China. lilidugysy@gzhmu.edu.cn.
¹³ Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China. lilidugysy@gzhmu.edu.cn.
¹⁴ Guangdong Engineering and Technology Research Center of Maternal-Fetal Medicine, Guangzhou, China. lilidugysy@gzhmu.edu.cn.
¹⁵ Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, Guangzhou, China. lilidugysy@gzhmu.edu.cn.

^# Contributed equally.

PMID: 35751703
DOI: 10.1007/s00441-022-03653-6

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.

Keywords: CDC42; EZRIN; Human trophoblast stem cell; Placenta; Recurrent spontaneous abortion; YAP.

MeSH terms

Cell Proliferation
Cytoskeletal Proteins / metabolism*
Down-Regulation
Female
Humans
Placenta* / metabolism
Pregnancy
Stem Cells
Trophoblasts* / cytology
Trophoblasts* / metabolism
YAP-Signaling Proteins / metabolism*
cdc42 GTP-Binding Protein / metabolism*

Substances

Cytoskeletal Proteins
YAP-Signaling Proteins
YAP1 protein, human
ezrin
CDC42 protein, human
cdc42 GTP-Binding Protein

Abstract

MeSH terms

Substances

Grants and funding