解析复发性自然流产中蜕膜缺陷及间充质干细胞的治疗潜力：单细胞分辨率研究。

Deciphering decidual deficiencies in recurrent spontaneous abortion and the therapeutic potential of mesenchymal stem cells at single-cell resolution.

机构信息

Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.

Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Medicine School of Nantong University, Nantong, Jiangsu, China.

出版信息

Stem Cell Res Ther. 2024 Jul 29;15(1):228. doi: 10.1186/s13287-024-03854-6.

DOI:10.1186/s13287-024-03854-6

PMID:39075579

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11287859/

Abstract

BACKGROUND

Recurrent spontaneous abortion (RSA) is a challenging condition that affects the health of women both physically and mentally, but its pathogenesis and treatment have yet to be studied in detail. In recent years, Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) have been shown to be effective in treating various diseases. Current understanding of RSA treatment using WJ-MSCs is limited, and the exact mechanisms of WJ-MSCs action in RSA remains largely unclear. In this study, we explored the decidual deficiencies in RSA and the therapeutic potential of WJ-MSCs at single-cell resolution.

METHODS

Three mouse models were established: a normal pregnancy group, an RSA group, and a WJ-MSC treatment group. Decidual tissue samples were collected for single-cell RNA sequencing (scRNA-seq) and functional verification, including single-cell resolution in situ hybridization on tissues (SCRINSHOT) and immunofluorescence.

RESULTS

We generated a single-cell atlas of decidual tissues from normal pregnant, RSA, and WJ-MSC-treated mice and identified 14 cell clusters in the decidua on day 14. Among these cell populations, stromal cells were the most abundant cell clusters in the decidua, and we further identified three novel subclusters (Str_0, Str_1, and Str_2). We also demonstrated that the IL17 and TNF signaling pathways were enriched for upregulated DEGs of stromal cells in RSA mice. Intriguingly, cell-cell communication analysis revealed that Str_1 cell-related gene expression was greatly reduced in the RSA group and rescued in the WJ-MSC treatment group. Notably, the interaction between NK cells and other cells in the RSA group was attenuated, and the expression of Spp1 (identified as an endometrial toleration-related marker) was significantly reduced in the NK cells of the RSA group but could be restored by WJ-MSC treatment.

CONCLUSION

Herein, we implemented scRNA-seq to systematically evaluate the cellular heterogeneity and transcriptional regulatory networks associated with RSA and its treatment with WJ-MSCs. These data revealed potential therapeutic targets of WJ-MSCs to remodel the decidual subpopulations in RSA and provided new insights into decidua-derived developmental defects at the maternal-foetal interface.

摘要

背景

复发性自然流产（RSA）是一种具有挑战性的疾病，它会对女性的身心健康造成影响，但 RSA 的发病机制和治疗方法尚未得到详细研究。近年来，Wharton 胶衍生的间充质干细胞（WJ-MSCs）已被证明在治疗各种疾病方面具有疗效。目前对于使用 WJ-MSCs 治疗 RSA 的认识有限，WJ-MSCs 在 RSA 中的作用机制在很大程度上仍不清楚。在这项研究中，我们以单细胞分辨率探索 RSA 的蜕膜缺陷和 WJ-MSCs 的治疗潜力。

方法

建立了三种小鼠模型：正常妊娠组、RSA 组和 WJ-MSC 治疗组。收集蜕膜组织样本进行单细胞 RNA 测序（scRNA-seq）和功能验证，包括组织的单细胞分辨率原位杂交（SCRINSHOT）和免疫荧光。

结果

我们生成了来自正常妊娠、RSA 和 WJ-MSC 治疗的小鼠蜕膜组织的单细胞图谱，并在第 14 天的蜕膜中鉴定出 14 个细胞簇。在这些细胞群体中，基质细胞是蜕膜中最丰富的细胞簇，我们进一步鉴定出三个新的亚簇（Str_0、Str_1 和 Str_2）。我们还证明，IL17 和 TNF 信号通路在 RSA 小鼠基质细胞的上调 DEGs 中富集。有趣的是，细胞间通讯分析表明，Str_1 细胞相关基因在 RSA 组中的表达大大降低，而在 WJ-MSC 治疗组中得到恢复。值得注意的是，RSA 组中 NK 细胞与其他细胞的相互作用减弱，而 RSA 组中 NK 细胞的 Spp1（鉴定为子宫内膜耐受相关标记物）表达显著降低，但可通过 WJ-MSC 治疗恢复。