Single‐cell transcriptome profiling reveals molecular heterogeneity in human umbilical cord tissue and culture‐expanded mesenchymal stem cells

Wang, Quanlei; Li, Jinlu; Wang, Shengpeng; Deng, Qiuting; Wang, Kuixing; Dai, Xi; An, Yanru; Dong, Guoyi; Ke, Weilin; Chen, Fang; Liu, Longqi; Yang, Huanming; Du, Yutao; Zhao, Weihua; Shang, Zhouchun

doi:10.1111/febs.15834

Cited by 14 publications

(16 citation statements)

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“…The cells were then partitioned into gel beads in emulsion in the GemCode instrument, followed by reverse transcription, cDNA amplification, shearing, and adaptor-sample index attachment. Then, the 10X Genomics libraries were further prepared for the DNBSEQ platform as previously reported ( Wang et al, 2021 ). Briefly, the single-cell libraries were amplified using 10 cycles of polymerase chain reaction (PCR) and circularized by incubating with splint oligo (BGI) and T4 DNA ligase (BGI), followed by fragment size selection with PEG32 (BGI), rolling circle amplification (RCA), and sequenced using 100 bp paired-end on the DNBSEQ platform.…”

Section: Methodsmentioning

confidence: 99%

“…It is reported that heterogeneity of gene expression and distinct subpopulations exist in human primary Wharton’s jelly–derived MSCs by scRNA-seq ( Sun et al, 2020 ). Moreover, our previous study reveals molecular heterogeneity in human umbilical cord tissue and culture-expanded MSCs using scRNA-seq ( Wang et al, 2021 ). However, unlike the bone marrow-, adipose-, and umbilical cord-derived MSCs ( Liu et al, 2019 ; Sun et al, 2020 ; Wang et al, 2021 ), our knowledge about the heterogeneity of PMSCs at the single-cell level is still limited, especially the intersection between transcriptome and chromatin accessibility.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, our previous study reveals molecular heterogeneity in human umbilical cord tissue and culture-expanded MSCs using scRNA-seq ( Wang et al, 2021 ). However, unlike the bone marrow-, adipose-, and umbilical cord-derived MSCs ( Liu et al, 2019 ; Sun et al, 2020 ; Wang et al, 2021 ), our knowledge about the heterogeneity of PMSCs at the single-cell level is still limited, especially the intersection between transcriptome and chromatin accessibility. Here, we integrate scRNA-seq and scATAC-seq tools to explore the molecular processes involved in PMSCs and provide a comprehensive and advanced resource revealing the cellular heterogeneity of PMSCs at single cell multiomics level.…”

Section: Introductionmentioning

confidence: 99%

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Integrative Single-Cell RNA-Seq and ATAC-Seq Analysis of Mesenchymal Stem/Stromal Cells Derived from Human Placenta

Wang

et al. 2022

Front. Cell Dev. Biol.

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Mesenchymal stem/stromal cells derived from placenta (PMSCs) are an attractive source for regenerative medicine because of their multidifferentiation potential and immunomodulatory capabilities. However, the cellular and molecular heterogeneity of PMSCs has not been fully characterized. Here, we applied single-cell RNA sequencing (scRNA-seq) and assay for transposase-accessible chromatin sequencing (scATAC-seq) techniques to cultured PMSCs from human full-term placenta. Based on the inferred characteristics of cell clusters, we identify several distinct subsets of PMSCs with specific characteristics, including immunomodulatory-potential and highly proliferative cell states. Furthermore, integrative analysis of gene expression and chromatin accessibility showed a clearer chromatin accessibility signature than those at the transcriptional level on immunomodulatory-related genes. Cell cycle gene-related heterogeneity can be more easily distinguished at the transcriptional than the chromatin accessibility level in PMSCs. We further reveal putative subset-specific cis-regulatory elements regulating the expression of immunomodulatory- and proliferation-related genes in the immunomodulatory-potential and proliferative subpopulations, respectively. Moreover, we infer a novel transcription factor PRDM1, which might play a crucial role in maintaining immunomodulatory capability by activating PRDM1-regulon loop. Collectively, our study first provides a comprehensive and integrative view of the transcriptomic and epigenomic features of PMSCs, which paves the way for a deeper understanding of cellular heterogeneity and offers fundamental biological insight of PMSC subset-based cell therapy.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Integrative Single-Cell RNA-Seq and ATAC-Seq Analysis of Mesenchymal Stem/Stromal Cells Derived from Human Placenta

Wang

et al. 2022

Front. Cell Dev. Biol.

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“…In brief, because only individual c has the corresponding mother blood whole genome sequence variants, this sample was used as our training sample, for which each cell’s fetal or maternal origin was determined by demuxlet 53 using Cell Ranger-aligned BAM file from FS, Mid_S and Mat_S and WGS VCF file. And then, a fetal SNP dataset reference was built based on the corresponding umbilical single cell RNA sequencing data for each section from our previous study 54 . Using the difference ratio between a single cell SNP and the corresponding fetal SNP dataset reference, we calculated the Ratio of Mahalanobis distance of fetal cells and maternal cells usingthe following formulas:…”

Section: Methodsmentioning

confidence: 99%

Single-cell transcriptional profiling reveals cellular and molecular divergence in human maternal-fetal interface

Wang

et al. 2022

Preprint

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Placenta play essential role in successful pregnancy, as the most important organ connecting and interplaying between mother and fetus. However, the cellular and molecular characteristics of fetal origin and maternal origin cell populations within the fetomaternal interface still is poorly understood. Here, we profiled the transcriptomes of single cells with well-defined maternal-fetal origin that consecutively localized from fetal section (FS), middle section (Mid_S) to maternal section (Mat_S) within the human full-term placenta. Then, we initially identified the cellular and molecular heterogeneity of cytotrophoblast cell (CTB) and stromal cell (STR) with the spatial location and fetal/maternal origin, also highlighted STR cells from fetal origins showed greater proliferation ability in Mat_S compared to cells from FS or Mid_S. Further, by integrating analysis with the first-trimester placental single cell transcriptome data, we revealed that a subpopulation of trophoblast progenitor-like cells (TPLCs) existed in the full-term placenta and mainly distributed in Mid_S, with high expression of pool of putative cell surface makers and unique molecular features. Moreover, through the extravillous cytotrophoblast (EVT) subsets differentiation trajectory and regulation network analysis, we proposed a putative key transcription factor PRDM6 that promoted the differentiation of endovascular extravillous trophoblast cells (enEVT). Finally, based on the integrated analyses of single cell transcriptional profiling of preeclampsia (PE) and match-trimester normal placenta, we highlighted the defective EVT subgroup composition and down-regulation of PRDM6 may lead to an abnormal enEVT differentiation process in PE. Together, our study offers important resources for better understanding of human placenta, stem cell-based therapy as well as PE, and provides new insights on the study of tissue heterogeneity, the clinical prevention and control of PE as well as the maternal-fetal interface.

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“…In this regard, the hypoxic culture environment has shown beneficial effects on preserving the stemness properties of MSCs and their multilineage differentiation capacity [ 35 , 51 , 52 , 53 , 54 , 55 ]. Interestingly, a molecular heterogeneity has been demonstrated between cell profiles of MSCs in vitro and in vivo [ 56 ]. A single-cell RNA sequencing analysis found that genes related to telomere length maintenance, including NHP2, CCT6A, RUVBL1 and APEX1, were highly expressed in culture-expanded human umbilical cord MSCs.…”

Section: Changes Induced In Mscs During In Vitro Expansionmentioning

confidence: 99%

Heterogeneity of In Vitro Expanded Mesenchymal Stromal Cells and Strategies to Improve Their Therapeutic Actions

et al. 2022

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Beneficial properties of mesenchymal stromal cells (MSCs) have prompted their use in preclinical and clinical research. Accumulating evidence has been provided for the therapeutic effects of MSCs in several pathologies, including neurodegenerative diseases, myocardial infarction, skin problems, liver disorders and cancer, among others. Although MSCs are found in multiple tissues, the number of MSCs is low, making in vitro expansion a required step before MSC application. However, culture-expanded MSCs exhibit notable differences in terms of cell morphology, physiology and function, which decisively contribute to MSC heterogeneity. The changes induced in MSCs during in vitro expansion may account for the variability in the results obtained in different MSC-based therapy studies, including those using MSCs as living drug delivery systems. This review dissects the different changes that occur in culture-expanded MSCs and how these modifications alter their therapeutic properties after transplantation. Furthermore, we discuss the current strategies developed to improve the beneficial effects of MSCs for successful clinical implementation, as well as potential therapeutic alternatives.

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Single‐cell transcriptome profiling reveals molecular heterogeneity in human umbilical cord tissue and culture‐expanded mesenchymal stem cells

Cited by 14 publications

References 58 publications

Integrative Single-Cell RNA-Seq and ATAC-Seq Analysis of Mesenchymal Stem/Stromal Cells Derived from Human Placenta

Integrative Single-Cell RNA-Seq and ATAC-Seq Analysis of Mesenchymal Stem/Stromal Cells Derived from Human Placenta

Single-cell transcriptional profiling reveals cellular and molecular divergence in human maternal-fetal interface

Heterogeneity of In Vitro Expanded Mesenchymal Stromal Cells and Strategies to Improve Their Therapeutic Actions

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