Single-cell transcriptome analysis reveals abnormal angiogenesis and placentation by loss of imprinted glutaminyl-peptide cyclotransferase.

Jing GUO; Jihong ZHENG; Ruixia LI; Jindong YAO; He ZHANG; Xu WANG; Chao ZHANG

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Single-cell transcriptome analysis reveals abnormal angiogenesis and placentation by loss of imprinted glutaminyl-peptide cyclotransferase.

Author: Jing GUO ¹ ; Jihong ZHENG ¹ ; Ruixia LI ² ; Jindong YAO ¹ ; He ZHANG ³ ; Xu WANG ⁴ ; Chao ZHANG ⁵
Author Information

1. Fundamental Research Center, Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
2. Obstetrics & Gynecology Hospital of Fudan University, Fudan University School of Medicine, Shanghai 200433, China.
3. Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China.
4. Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA. xzw0070@auburn.edu.
5. Fundamental Research Center, Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. zhangchao@tongji.edu.cn.
Publication Type:Journal Article
Keywords: Angiogenesis; Glutaminyl-peptide cyclotransferase-knockout(Qpct-/-) mice; Overgrowth; Placenta; Single-cell sequencing
MeSH: Animals; Female; Pregnancy; Mice; Placentation/genetics*; Single-Cell Analysis; Gene Expression Profiling; Mice, Knockout; Transcriptome; Placenta/blood supply*; Neovascularization, Pathologic/genetics*; Genomic Imprinting; Single-Cell Gene Expression Analysis; Angiogenesis
From: Journal of Zhejiang University. Science. B 2025;26(6):589-608
CountryChina
Language:English
Abstract: Imprinted genes play a key role in regulating mammalian placental and embryonic development. Here, we generated glutaminyl-peptide cyclotransferase-knockout (Qpct^-/-) mice utilizing the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) platform and identified Qpct as a novel anti-angiogenic factor in regulating mouse placentation. Compared with Qpct^+/+ mice, placentae and embryos (Qpct^-/+ and Qpct^-/-) showed significant overgrowth at embryonic Day 12.5 (E12.5), E15.5, and E18.5. Using single-cell transcriptome analysis of 32 309 cells from Qpct^+/+ and Qpct^-/- mouse placentae, we identified 13 cell clusters via single-nucleus RNA sequencing (snRNA-seq) (8880 Qpct^+/+ and 13 577 Qpct^-/- cells) and 20 cell clusters via single-cell RNA sequencing (scRNA-seq) (6567 Qpct^+/+ and 3285 Qpct^-/- cells). Furthermore, we observed a global up-regulation of pro-angiogenic genes in the Qpct^-/- background. Immunohistochemistry assays revealed a notable increase in the number of blood vessels in the decidual and labyrinthine layers of E15.5 Qpct^-/+ and Qpct^-/- mice. Moreover, the elevation of multiple pairs of ligand-receptor interactions was observed in decidual cells, endothelial cells, and macrophages, promoting angiogenesis and inflammatory response. Our findings indicate that loss of maternal Qpct leads to altered phenotypic characteristics of placentae and embryos and promotes angiogenesis in murine placentae.