Single-cell profiling reveals mechanisms of uncontrolled inflammation and glycolysis in decidual stromal cell subtypes in recurrent miscarriage
- PMID: 36355621
- DOI: 10.1093/humrep/deac240
Single-cell profiling reveals mechanisms of uncontrolled inflammation and glycolysis in decidual stromal cell subtypes in recurrent miscarriage
Abstract
Study question: Do distinct subpopulations of decidual stromal cells (DSCs) exist and if so, are given subpopulations enriched in recurrent miscarriage (RM)?
Summary answer: Three subpopulations of DSCs were identified from which inflammatory DSCs (iDSCs) and glycolytic DSCs (glyDSCs) are significantly enriched in RM, with implicated roles in driving decidual inflammation and immune dysregulation.
What is known already: DSCs play crucial roles in establishing and maintaining a successful pregnancy; dysfunction of DSCs has been considered as one of the key reasons for the development of RM.
Study design, size, duration: We collected 15 early decidual samples from five healthy donors (HDs) and ten RM patients to perform single-cell RNA sequencing (scRNA-seq). A total of 43 RM patients and 37 HDs were enrolled in the validation cohort.
Participants/materials, setting, methods: Non-immune cells and immune cells of decidual tissues were sorted by flow cytometry to perform scRNA-seq. We used tissue microarrays (TMA) to validate three distinct subpopulations of DSCs. The expression of inflammatory and glycolytic proteins by DSCs was validated by immunohistochemistry (IHC) and multiplex immunohistochemistry (mIHC). Different subsets of decidual NK (dNK) cells and macrophages were also validated by multicolor flow cytometry and mIHC. Cell ligand-receptor and spatial analyses between DSCs and immune cells were analyzed by mIHC.
Main results and the role of chance: We classify the DSCs into three subtypes based on scRNA-seq data: myofibroblastic (myDSCs), inflammatory (iDSCs) and glycolytic (glyDSCs), with the latter two being significantly enriched in RM patients. The distribution patterns of DSC subtypes in the RM and HD groups were validated by mIHC. Single-cell analyses indicate that the differentiation of iDSCs and glyDSCs may be coupled with the degrees of hypoxia. Consequently, we propose a pathological model in which a vicious circle is formed and fueled by hypoxic stress, uncontrolled inflammation and aberrant glycolysis. Furthermore, our results show that the inflammatory SPP1+ macrophages and CD18+ dNK cells are preferentially increased in the decidua of RM patients. Cell ligand-receptor and mIHC spatial analyses uncovered close interactions between pathogenic DSCs and inflammatory SPP1+ macrophages and CD18+ NK cells in RM patients.
Large scale data: The raw single-cell sequence data reported in this paper were deposited at the National Omics Data Encyclopedia (www.biosino.org), under the accession number OEP002901.
Limitations, reasons for caution: The number of decidual samples for scRNA-seq was limited and in-depth functional studies on DSCs are warranted in future studies.
Wider implications of the findings: Identification of three DSC subpopulations opens new avenues for further investigation of their roles in RM patients.
Study funding/competing interest(s): This study was supported by the Strategic Priority Research Program (No. XDB29030302), Frontier Science Key Research Project (QYZDB-SSW-SMC036), Chinese Academy of Sciences; National Key Research and Development Program of China (2021YFE0200600), National Natural Science Foundation of China (No. 31770960), Shanghai Municipal Science and Technology Major Project (No. 2019SHZDZX02, HS2021SHZX001), and Shanghai Committee of Science and Technology (17411967800). All authors report no conflict of interest.
Keywords: decidual stromal cell; glycolysis; immune regulation; inflammation; recurrent miscarriage; single-cell RNA sequencing.
© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
Similar articles
-
CD24+ decidual stromal cells: a novel heterogeneous population with impaired regulatory T cell induction and potential association with recurrent miscarriage.Fertil Steril. 2024 Mar;121(3):519-530. doi: 10.1016/j.fertnstert.2023.11.025. Epub 2023 Nov 29. Fertil Steril. 2024. PMID: 38036240
-
Decreased nitric oxide content mediated by asymmetrical dimethylarginine and protein l-arginine methyltransferase 3 in macrophages induces trophoblast apoptosis: a potential cause of recurrent miscarriage.Hum Reprod. 2021 Nov 18;36(12):3049-3061. doi: 10.1093/humrep/deab225. Hum Reprod. 2021. PMID: 34647126
-
miRNAs in decidual NK cells: regulators worthy of attention during pregnancy.Reprod Biol Endocrinol. 2021 Oct 2;19(1):150. doi: 10.1186/s12958-021-00812-2. Reprod Biol Endocrinol. 2021. PMID: 34600537 Free PMC article. Review.
-
Pigment epithelium-derived factor, a novel decidual natural killer cells-derived factor, protects decidual stromal cells via anti-inflammation and anti-apoptosis in early pregnancy.Hum Reprod. 2020 Jul 1;35(7):1537-1552. doi: 10.1093/humrep/deaa118. Hum Reprod. 2020. PMID: 32544239
-
Human Innate Lymphoid Cells: Their Functional and Cellular Interactions in Decidua.Front Immunol. 2018 Aug 14;9:1897. doi: 10.3389/fimmu.2018.01897. eCollection 2018. Front Immunol. 2018. PMID: 30154799 Free PMC article. Review.
Cited by
-
Regulatory T cell adoptive transfer alters uterine immune populations, increasing a novel MHC-IIlow macrophage associated with healthy pregnancy.Front Immunol. 2023 Oct 13;14:1256453. doi: 10.3389/fimmu.2023.1256453. eCollection 2023. Front Immunol. 2023. PMID: 37901247 Free PMC article.
-
Editorial: Unravelling human placental (patho-) physiology at the epigenetic and transcriptome level.Front Cell Dev Biol. 2023 Jun 23;11:1228803. doi: 10.3389/fcell.2023.1228803. eCollection 2023. Front Cell Dev Biol. 2023. PMID: 37427377 Free PMC article. No abstract available.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Medical
Research Materials
Miscellaneous