Single-cell mapping of progressive fetal-to-adult transition in human hematopoiesis [HSPCs single-cell RNAseq]
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ABSTRACT:
PROVIDER: PRJNA665467 | ENA |
REPOSITORIES: ENA
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Project description:Whereas the human fetal immune system is poised to generate immune tolerance and suppress inflammation in utero, an adult-like immune system emerges to orchestrate anti-pathogen immune responses in post-natal life. It has been posited that cells of the adult immune system arise as a discrete ontological “layer” of hematopoietic stem-progenitor cells (HSPCs) and their progeny; evidence supporting this model in humans has, however, been inconclusive. Here, we combine bulk and single-cell transcriptional profiling of lymphoid, myeloid, and HSPCs from fetal, perinatal, and adult developmental stages to demonstrate that the fetal-to-adult transition occurs progressively along a continuum of maturity—with a substantial degree of interindividual variation at the time of birth—rather than via a transition between discrete waves. These findings have important implications in the design of strategies for prophylaxis against infection in the newborn, and for the use of umbilical cord blood (UCB) in the setting of transplantation. Naïve CD4 and CD8 T cells, and CD34+ hematopoietic stem and progenitor cells (HSPCs) were isolated from human samples of three different groups: Fetal (18-23 gestational weeks), full-term newborn (37+ gestational weeks at birth), and adults age 23 to 53. For each group, five independent donors were analyzed, but not all cell types could be sequenced for every patient.
2020-09-25 | GSE158490 | GEO
Project description:Single-cell mapping of progressive fetal-to-adult transition in human hematopoiesis. [CD4 & CD8 single-cell RNAseq]
| PRJNA665472 | ENA
Project description:Single-cell mapping of progressive fetal-to-adult transition in human hematopoiesis. [CD4 - bulk RNAseq]
| PRJNA665473 | ENA
Project description:Whereas the human fetal immune system is poised to generate immune tolerance and suppress inflammation in utero, an adult-like immune system emerges to orchestrate anti-pathogen immune responses in post-natal life. It has been posited that cells of the adult immune system arise as a discrete ontological “layer” of hematopoietic stem-progenitor cells (HSPCs) and their progeny; evidence supporting this model in humans has, however, been inconclusive. Here, we combine bulk and single-cell transcriptional profiling of lymphoid, myeloid, and HSPCs from fetal, perinatal, and adult developmental stages to demonstrate that the fetal-to-adult transition occurs progressively along a continuum of maturity—with a substantial degree of interindividual variation at the time of birth—rather than via a transition between discrete waves. These findings have important implications in the design of strategies for prophylaxis against infection in the newborn, and for the use of umbilical cord blood (UCB) in the setting of transplantation. Naïve CD4 and CD8 T cells, and CD34+ hematopoietic stem and progenitor cells (HSPCs) were isolated from human samples of three different groups: Fetal (18-23 gestational weeks), full-term newborn (37+ gestational weeks at birth), and adults age 23 to 53. For each group, five independent donors were analyzed, but not all cell types could be sequenced for every patient.
2020-09-25 | GSE158492 | GEO
Project description:Whereas the human fetal immune system is poised to generate immune tolerance and suppress inflammation in utero, an adult-like immune system emerges to orchestrate anti-pathogen immune responses in post-natal life. It has been posited that cells of the adult immune system arise as a discrete ontological “layer” of hematopoietic stem-progenitor cells (HSPCs) and their progeny; evidence supporting this model in humans has, however, been inconclusive. Here, we combine bulk and single-cell transcriptional profiling of lymphoid, myeloid, and HSPCs from fetal, perinatal, and adult developmental stages to demonstrate that the fetal-to-adult transition occurs progressively along a continuum of maturity—with a substantial degree of interindividual variation at the time of birth—rather than via a transition between discrete waves. These findings have important implications in the design of strategies for prophylaxis against infection in the newborn, and for the use of umbilical cord blood (UCB) in the setting of transplantation. Naïve CD4 and CD8 T cells, and CD34+ hematopoietic stem and progenitor cells (HSPCs) were isolated from human samples of three different groups: Fetal (18-23 gestational weeks), full-term newborn (37+ gestational weeks at birth), and adults age 23 to 53. For each group, five independent donors were analyzed, but not all cell types could be sequenced for every patient.
2020-09-25 | GSE158491 | GEO
Project description:Hematopoiesis is a process of constitutive regeneration whereby hematopoietic stem and progenitor cells (HSPCs) constantly replenish mature blood cells. During maturation and aging, HSPCs alter their output to support the shifting demands of prenatal development and postnatal maturation both at homeostasis and in response to stress. How HSPC ontogeny changes throughout life is unknown; studies to date have largely focused on analysis of specific individual ages, particularly those done at single cell resolution. Here, we performed single cell RNA-seq of human HSPCs from early prenatal development into mature adulthood, demonstrating dynamic remodeling of HSPC transcriptional states and differentiation trajectories over time. We identified age-specific gene expression patterns of lineage commitment throughout human life, and developed an approach for identifying, prospectively purifying, and functionally validating age-specific HSPC states. Together, our findings define the temporal evolution of hematopoiesis during human development and maturation, and uncover principles applicable to age-biased blood diseases.
2024-07-29 | GSE189161 | GEO
Project description:Hematopoiesis generates a variety of cell types after M3434 culture. We treated HSPCs with small-molecule inhibitors of Acly (SB204990), Gls (CB-839), or Vehicle (DMSO) and compared them to freshly isolated HSPCs by single-cell RNA-seq and single-cell ATAC-seq to examine the diverse cell types emerging from these conditions.
2022-11-02 | GSE217080 | GEO
Project description:Myelofibrosis is a severe myeloproliferative neoplasm characterised by increased numbers of abnormal bone marrow megakaryocytes that induce progressive fibrosis, destroying the hematopoietic microenvironment. To determine the cellular and molecular basis for aberrant megakaryopoiesis in myelofibrosis, we performed high-throughput single-cell transcriptome profiling of 50,702 hematopoietic stem/progenitor cells (HSPCs), and single-cell proteomics, genomics and functional assays. We identified an aberrant pathway for direct megakaryocyte differentiation from the earliest stages of hematopoiesis in myelofibrosis and associated aberrant molecular signatures, including surface antigens selectively expressed by JAK2-mutant HSPCs. Myelofibrosis megakaryocyte progenitors were heterogeneous, with distinct expression of fibrosis and proliferation-associated genes and putative therapy targets. We validated the integrin G6B as a promising JAK2-mutant clone-specific surface antigen, warranting further development as an immunotherapeutic target. Our study paves the way for selective immunotherapeutic targeting in myelofibrosis and more broadly illustrates the power of single-cell multi-omics to discover tumor-specific therapeutic targets and mediators of tissue fibrosis.
2020-06-30 | GSE131593 | GEO
Project description:Lentiviral vectors (LVs) are used for delivery of genes into hematopoietic stem and progenitor cells (HSPCs) in clinical trials worldwide. LVs, in contrast to retroviral vectors, are not associated with insertion site-associated malignant clonal expansions and, thus, are considered safer. Here, however, we present a case of markedly abnormal dysplastic clonal hematopoiesis affecting the erythroid, myeloid, and megakaryocytic lineages in a rhesus macaque transplanted with HSPCs that were transduced with a LV containing a strong retroviral murine stem cell virus (MSCV) constitutive promoter-enhancer in the LTR. Nine insertions were mapped in the abnormal clone, resulting in overexpression and aberrant splicing of several genes of interest, including the cytokine stem cell factor and the transcription factor PLAG1. This case represents the first clear link between lentiviral insertion-induced clonal expansion and a clinically abnormal transformed phenotype following transduction of normal primate or human HSPCs, which is concerning, and suggests that strong constitutive promoters should not be included in LVs.
2020-06-25 | GSE153130 | GEO
Project description:Single cell RNA sequencing of human hematopoiesis
| PRJNA791122 | ENA