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Single-cell transcriptomic landscape of nucleated cells in umbilical cord blood.

ABSTRACT: BACKGROUND:For both pediatric and adult patients, umbilical cord blood (UCB) transplant is a therapeutic option for a variety of hematologic diseases, such as blood cancers, myeloproliferative disorders, genetic diseases, and metabolic disorders. However, the level of cellular heterogeneity and diversity of nucleated cells in UCB has not yet been assessed in an unbiased and systemic fashion. In the present study, nucleated cells from UCB were subjected to single-cell RNA sequencing to simultaneously profile the gene expression signatures of thousands of cells, generating a rich resource for further functional studies. Here, we report the transcriptomes of 17,637 UCB cells, covering 12 major cell types, many of which can be further divided into distinct subpopulations. RESULTS:Pseudotemporal ordering of nucleated red blood cells identifies wave-like activation and suppression of transcription regulators, leading to a polarized cellular state, which may reflect nucleated red blood cell maturation. Progenitor cells in UCB also comprise 2 subpopulations with activation of divergent transcription programs, leading to specific cell fate commitment. Detailed profiling of cytotoxic cell populations unveiled granzymes B and K signatures in natural killer and natural killer T-cell types in UCB. CONCLUSIONS:Taken together, our data form a comprehensive single-cell transcriptomic landscape that reveals previously unrecognized cell types, pathways, and mechanisms of gene expression regulation. These data may contribute to the efficacy and outcome of UCB transplant, broadening the scope of research and clinical innovations.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC6497034 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Single-cell transcriptomic landscape of nucleated cells in umbilical cord blood.

Zhao Yi Y Li Xiao X Zhao Weihua W Wang Jingwan J Yu Jiawei J Wan Ziyun Z Gao Kai K Yi Gang G Wang Xie X Fan Bingbing B Wu Qinkai Q Chen Bangwei B Xie Feng F Wu Jinghua J Zhang Wei W Chen Fang F Yang Huanming H Wang Jian J Xu Xun X Li Bin B Liu Shiping S Hou Yong Y Liu Xiao X

GigaScience 20190501 5

<h4>Background</h4>For both pediatric and adult patients, umbilical cord blood (UCB) transplant is a therapeutic option for a variety of hematologic diseases, such as blood cancers, myeloproliferative disorders, genetic diseases, and metabolic disorders. However, the level of cellular heterogeneity and diversity of nucleated cells in UCB has not yet been assessed in an unbiased and systemic fashion. In the present study, nucleated cells from UCB were subjected to single-cell RNA sequencing to si ...[more]

PMID: 31049560

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Project description:BackgroundTrisomy 18 syndrome (Edwards syndrome, ES) is a type of aneuploidy caused by the presence of an extra chromosome 18. Aneuploidy is the leading cause of early pregnancy loss, intellectual disability, and multiple congenital anomalies. The research of trisomy 18 is progressing slowly, and the molecular characteristics of the disease mechanism and phenotype are still largely unclear.ResultsIn this study, we used the commercial Chromium platform (10× Genomics) to perform sc-ATAC-seq to measure chromatin accessibility in 11,611 single umbilical cord blood cells derived from one trisomy 18 syndrome patient and one healthy donor. We obtained 13 distinct major clusters of cells and identified them as 6 human umbilical cord blood mononuclear cell types using analysis tool. Compared with the NC group, the ES group had a lower ratio of T cells to NK cells, the ratio of monocytes/DC cell population did not change significantly, and the ratio of B cell nuclear progenitor and megakaryocyte erythroid cells was higher. The differential genes of ME-0 are enriched in Human T cell leukemia virus 1 infection pathway, and the differential peak genes of ME-1 are enriched in apopotosis pathway. We found that CCNB2 and MCM3 may be vital to the development of trisomy 18. CCNB2 and MCM3, which have been reported to be essential components of the cell cycle and chromatin.ConclusionsWe have identified 6 cell populations in cord blood. Disorder in megakaryocyte erythroid cells implicates trisomy 18 in perturbing fetal hematopoiesis. We identified a pathway in which the master differential regulatory pathway in the ME-0 cell population involves human T cell leukemia virus 1 infection, a pathway that is dysregulated in patients with trisomy 18 and which may increase the risk of leukemia in patients with trisomy 18. CCNB2 and MCM3 in progenitor may be vital to the development of trisomy 18. CCNB2 and MCM3, which have been reported to be essential components of the cell cycle and chromatin, may be related to chromosomal abnormalities in trisomy 18.

Project description:BackgroundNumerous studies have demonstrated that DNA methylation levels in the aryl hydrocarbon receptor repressor (AHRR) gene measured in cord blood are significantly associated with prenatal tobacco smoke exposure and can be used as a fetal exposure biomarker. The mechanism driving this demethylation has not been determined and it is unclear if all cord blood cell types are impacted. Nucleated red blood cells (nRBCs/CD235a+ cells) are developmentally immature RBCs that display genome-wide hypomethylation and are observed at increased frequency in the cord blood of smoking mothers. We tested if AHRR methylation levels in CD235a+ nRBCs or nRBC counts influenced AHRR methylation in whole cord blood.MethodsCord blood was collected from smoking (n = 34) and nonsmoking (n = 19) mothers and DNA was prepared from whole cord blood, isolated CD235a+ nRBCs, and CD14+ monocytes. AHRR methylation in cord blood DNA was measured using Illumina 850K arrays (cg05575921, chr5:373378). Pyrosequencing was used to compare methylation levels among cord blood, CD235a+, and CD14+ cells. We measured nRBC percentages using conventional complete blood counts and estimated percent nRBCs by a deconvolution model.ResultsMethylation levels in AHRR were significantly lower in nRBCs relative to whole cord blood and CD14+ monocytes. While AHRR methylation levels in the cell types were significantly correlated across all subjects, methylation values at the chr5:373378 CpG averaged 14.6% lower in nRBCs (range 0.4 to 24.8%; p = 3.8E-13) relative to CD14+, with nonsmokers showing a significantly greater hypomethylation (- 4.1%, p = 1.8E-02). Methylation level at the AHRR chr5:373378 CpG was strongly associated with self-reported smoking in both CD14+ monocytes (t test p = 5.7E-09) and nRBCs (p = 4.8E-08), as well as cotinine levels (regression p = 1.1E-07 and p = 3.6E-04, respectively). For subjects with whole blood 850K data, robust linear regression models adjusting for estimated cell type composition, either including nRBCs counts or estimates, modestly increased the association between smoking and cg05575921 methylation.ConclusionsPrenatal smoke exposure was highly significantly associated with AHRR methylation in cord blood, CD14+ monocytes, and CD235a+ nRBCs. AHRR methylation levels in nRBCs and nRBC counts had minimal effect on cord blood methylation measurements. However, regression models using estimated nRBCs or actual nRBC counts outperformed those lacking these covariates.

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Single-cell transcriptomic landscape of nucleated cells in umbilical cord blood.

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Single-cell transcriptomic landscape of nucleated cells in umbilical cord blood.

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