The impact of dynamic caudal type homeobox 2 expression on the differentiation of human trophoblast lineage during implantation

Lujuan Rong; Lifeng Xiang; Zongyong Ai; Baohua Niu; Yaqing Wang; Yu Yin; Chun Feng; Gaohui Shi; Tingwei Chen; Jie Yang; Xi Luo; Yun Bai; Xiaoting Zhou; Xiaoping Liu; Haishan Zheng; Yang Ke; Tianqing Li; Ze Wu

doi:10.1111/cpr.13729

Cell Proliferation ›› 2024, Vol. 57 ›› Issue (12) : e13729 DOI: 10.1111/cpr.13729

ORIGINAL ARTICLE

The impact of dynamic caudal type homeobox 2 expression on the differentiation of human trophoblast lineage during implantation

Lujuan Rong ¹^,²^,³^,⁴^,⁵
, Lifeng Xiang ²^,³^,⁵^,⁶
, Zongyong Ai ⁵
, Baohua Niu ⁵
, Yaqing Wang ⁷^,⁸
, Yu Yin ⁵
, Chun Feng ⁵
, Gaohui Shi ⁵
, Tingwei Chen ⁵
, Jie Yang ⁵
, Xi Luo ²^,³^,⁴^,⁶
, Yun Bai ²^,³^,⁴^,⁶
, Xiaoting Zhou ²^,³^,⁴^,⁶
, Xiaoping Liu ²^,³^,⁴^,⁶
, Haishan Zheng ²^,³^,⁴
, Yang Ke ²^,³^,⁴^,⁶
, Tianqing Li ⁵^,^†
, Ze Wu ²^,³^,⁴^,⁶^,^†

Author information +

¹. Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, China

². Department of Reproductive Medicine, The First People’s Hospital of Yunnan Province, Kunming, Yunnan, China

³. The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China

⁴. Department of Reproductive Medicine, NHC Key Laboratory of Healthy Birth and Birth Defect Prevention in Western China (Co-building), The First People’s Hospital of Yunnan Province, Kunming, Yunnan, China

⁵. State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan, China

⁶. KUST-YPFPH Reproductive Medicine Joint Research Center, Kunming, Yunnan, China

⁷. University of Science and Technology of China, Hefei, Anhui, China

⁸. Suzhou Institute for Advanced Research, University of Science and Technology of China, Suzhou, Jiangsu, China

litq@lpbr.cn

wuzes2010@163.com

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Abstract

The trophoblast lineage differentiation represents a rate-limiting step in successful embryo implantation. Adhesion, invasion and migration processes within the trophoblast are governed by several transcription factors. Among them, CDX2 is a critical regulator shaping the destiny of the trophoblast. While its altered expression is a linchpin initiating embryo implantation in mice, the precise influence of CDX2 on the functionality and lineage differentiation of early human trophoblast remains unclear. In this study, we employed well-established human trophoblast stem cell (hTSC) lines with CDX2 overexpression coupled with a 3D in vitro culture system for early human embryos. We revealed that the downregulation of CDX2 is a prerequisite for syncytialization during human embryo implantation based on immunofluorescence, transcriptome analysis, CUT-tag sequencing and the construction of 3D human trophoblast organoids. While CDX2 overexpression inhibited syncytialization, it propelled hTSC proliferation and invasive migration. CDX2 exerted its influence by interacting with CGA, PTGS2, GCM1, LEF1 and CDH2, thereby hindering premature differentiation of the syncytiotrophoblast. CDX2 overexpression enhanced the epithelial–mesenchymal transition of human trophoblast organoids. In summary, our study provides insights into the molecular characteristics of trophoblast differentiation and development in humans, laying a theoretical foundation for advancing research in embryo implantation.

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Lujuan Rong, Lifeng Xiang, Zongyong Ai, Baohua Niu, Yaqing Wang, Yu Yin, Chun Feng, Gaohui Shi, Tingwei Chen, Jie Yang, Xi Luo, Yun Bai, Xiaoting Zhou, Xiaoping Liu, Haishan Zheng, Yang Ke, Tianqing Li, Ze Wu. The impact of dynamic caudal type homeobox 2 expression on the differentiation of human trophoblast lineage during implantation. Cell Proliferation, 2024, 57(12): e13729 DOI:10.1111/cpr.13729

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