单细胞转录组分析揭示印迹基因谷氨酰基环化酶缺失导致异常的血管生成和胎盘形成

郭婧; 郑继红; 李瑞霞; 姚劲东; 张赫; 王旭; 张超

doi:10.1631/jzus.B2400099

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单细胞转录组分析揭示印迹基因谷氨酰基环化酶缺失导致异常的血管生成和胎盘形成

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Research Article | Updated：2025-06-24

单细胞转录组分析揭示印迹基因谷氨酰基环化酶缺失导致异常的血管生成和胎盘形成
Single-cell transcriptome analysis reveals abnormal angiogenesis and placentation by loss of imprinted glutaminyl-peptide cyclotransferase
浙江大学学报（英文版）（B辑：生物医学和生物技术） 2025年26卷第6期页码：589-608
Affiliations：

1.Fundamental Research Center, Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
2.Lingang Laboratory, Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai 201306, China
3.Obstetrics & Gynecology Hospital of Fudan University, Fudan University School of Medicine, Shanghai 200433, China
4.Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
5.Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
6.HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA
Funds：

the National Natural Science Foundation of China(32271165);the Interdisciplinary Project in Ocean Research of Tongji University(2022-2-ZD-02)
DOI：10.1631/jzus.B2400099
中图分类号：
CSTR：
收稿日期：2024-02-25，

修回日期：2024-08-08，

纸质出版日期：2025-06-15
Accepted：

郭婧,郑继红,李瑞霞等.单细胞转录组分析揭示印迹基因谷氨酰基环化酶缺失导致异常的血管生成和胎盘形成[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2025,26(06):589-608.

Jing GUO, Jihong ZHENG, Ruixia LI, et al. Single-cell transcriptome analysis reveals abnormal angiogenesis and placentation by loss of imprinted glutaminyl-peptide cyclotransferase[J]. Journal of zhejiang university-science b (biomedicine & biotechnology), 2025, 26(6): 589-608.
郭婧,郑继红,李瑞霞等.单细胞转录组分析揭示印迹基因谷氨酰基环化酶缺失导致异常的血管生成和胎盘形成[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2025,26(06):589-608. DOI： 10.1631/jzus.B2400099.

Jing GUO, Jihong ZHENG, Ruixia LI, et al. Single-cell transcriptome analysis reveals abnormal angiogenesis and placentation by loss of imprinted glutaminyl-peptide cyclotransferase[J]. Journal of zhejiang university-science b (biomedicine & biotechnology), 2025, 26(6): 589-608. DOI： 10.1631/jzus.B2400099.

摘要

印迹基因在哺乳动物胎盘和胚胎发育的调控中起重要作用。本研究利用CRISPR/Cas9技术系统，构建了谷氨酰基环化酶

Qpct

基因敲除小鼠，并确定

Qpct

是调控小鼠胎盘形成中的一个新抗血管生成基因。与

Qpct

+/+

小鼠相比，

Qpct

‒/+

和

Qpct

‒/‒

小鼠的胎盘和胚胎在E12.5、E15.5和E18.5时表现出明显的过度生长。本研究对32 309个来自

Qpct

+/+

和

Qpct

‒/‒

小鼠胎盘的细胞进行单细胞转录组分析，利用snRNA-seq技术鉴定了13个细胞群（包括8880个

Qpct

+/+

细胞和13 577个

Qpct

‒/‒

细胞），并通过scRNA-seq技术识别出20个细胞群（包括6567个

Qpct

+/+

细胞和3285个

Qpct

‒/‒

细胞）。此外，本研究观察到

Qpct

‒/‒

小鼠中促血管生成基因的表达水平上调。免疫组化分析显示，在E15.5的

Qpct

‒/+

和

Qpct

‒/‒

小鼠的蜕膜层和迷宫层中，血管数量显著增加。此外，在蜕膜层、内皮细胞和巨噬细胞中，多种受体-配体对的相互作用增强，促进了血管生成和炎症反应。本研究结果表明，母本

Qpct

缺失可导致胎盘和胚胎的表型特征发生改变，并促进小鼠胎盘中血管的生成。

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 signi

ficant 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.

关键词

Keywords

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