Development of a humanized mouse model with functional human materno-fetal interface immunity.

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Shuai Dong, Cong Fu, Chang Shu, Min Xie, Yan Li, Jun Zou, Yi-Zi Meng, Peng Xu, Yan-Hong Shan, Hui-Min Tian, Jin He, Yong-Guang Yang, Zheng Hu
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Abstract

Materno-fetal immunity possesses specialized characteristics to ensure pathogen clearance while maintaining tolerance to the semiallogeneic fetus. Most of our understanding on human materno-fetal immunity is based on conventional rodent models that may not precisely represent human immunological processes owing to the huge evolutionary divergence. Herein, we developed a pregnant human immune system (HIS) mouse model through busulfan preconditioning, which hosts multilineage human immune subset reconstitution at the materno-fetal interface. Human materno-fetal immunity exhibits a tolerogenic feature at the midgestation stage (embryonic day [E] 14.5), and human immune regulatory subsets were detected in the decidua. However, the immune system switches to an inflammatory profile at the late gestation stage (E19). A cell-cell interaction network contributing to the alternations in the human materno-fetal immune atmosphere was revealed based on single-cell RNA-Seq analysis, wherein human macrophages played crucial roles by secreting several immune regulatory mediators. Furthermore, depletion of Treg cells at E2.5 and E5.5 resulted in severe inflammation and fetus rejection. Collectively, these results demonstrate that the pregnant HIS mouse model permits the development of functional human materno-fetal immunity and offers a tool for human materno-fetal immunity investigation to facilitate drug discovery for reproductive disorders.

开发具有人类母胎界面免疫功能的人源化小鼠模型。
母胎免疫具有特殊性,可确保清除病原体,同时保持对半同种胎儿的耐受性。我们对人类母胎免疫的认识大多基于传统的啮齿类动物模型,由于进化上的巨大差异,这些模型可能无法精确代表人类的免疫过程。在此,我们通过硫丹预处理建立了妊娠人类免疫系统(HIS)小鼠模型,该模型在母胎界面上承载了多线程人类免疫亚群重建。人类母胎免疫在妊娠中期(胚胎14.5天)表现出耐受性特征,在蜕膜中检测到人类免疫调节亚群。然而,免疫系统在妊娠晚期(E19)转为炎症特征。单细胞 RNA-Seq 分析揭示了导致人类母胎免疫氛围变化的细胞-细胞相互作用网络,其中人类巨噬细胞通过分泌多种免疫调节介质发挥了关键作用。此外,在E2.5和E5.5阶段消耗Treg细胞会导致严重的炎症和胎儿排斥反应。总之,这些结果表明,妊娠 HIS 小鼠模型允许开发功能性人类母胎免疫,并为人类母胎免疫研究提供了一种工具,有助于发现治疗生殖系统疾病的药物。
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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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