HSC population dynamics CB001 samples
Ontology highlight
ABSTRACT:
PROVIDER: EGAS00001003397 | EGA |
REPOSITORIES: EGA
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Project description:<p>Hematopoietic stem cell (HSC) mutations can result in clonal hematopoiesis (CH) with heterogeneous clinical outcomes. Here, we investigated how the cell state preceding <em>Tet2</em> mutation impacts the pre-malignant phenotype. Using an inducible system for clonal analysis of myeloid progenitors, we found that the epigenetic features of clones at similar differentiation status were highly heterogeneous and functionally responded differently to <em>Tet2</em> mutation. Cell differentiation stage also influenced <em>Tet2</em> mutation response indicating that the cell of origin's epigenome modulates clone-specific behaviors in CH. Molecular features associated with higher risk outcomes include <em>Sox4</em> that sensitized cells to <em>Tet2</em> inactivation, inducing dedifferentiation, altered metabolism and increasing the <em>in vivo</em> clonal output of mutant cells, as confirmed in primary GMP and HSC models. Our findings validate the hypothesis that epigenetic features can predispose specific clones for dominance, explaining why identical genetic mutations can result in different phenotypes.</p>
1970-01-01 | MTBLS9914 | MetaboLights
Project description:Array analysis of My-bi and Ly-bi HSC identifies candidate molecules for myeloid-bias. Collectively the data show that HSC in adults are largely epigenetically fixed in differentiation and self-renewal behavior. A direct examination of the epigenetic mechanisms that imprint HSC is difficult. However, an indirect way of assessing the effects of epigenetic imprinting is to look for the expressed gene programs of different types of HSC. Therefore, we performed an array analysis in collaboration with Dr. Michael Cooke. My-bi and Ly-bi HSC were identified in clonally repopulated hosts. The analysis returned 218 differentially expressed genes (M-bM-^IM-% Log2 M-bM-^IM-%2, p< 0.05) of which 36 were found to be overexpressed in My-bi HSC and the rest was overexpressed in Ly-bi HSC (Appendix A). There was no difference in expression levels for genes known to be involved in fate decisions during differentiation. This agrees well with our data that lineage bias is a stable function of a HSC, and does not reflect a differentiated type of cell. Gene expression profiles of myeloid-biased (My-bi) and lymphoid-biased (Ly-bi) stem cells were analyzed. Clonally repopulated hosts were generated by limiting dilution of bone marrow into ablated hosts and lineage bias was determined. Single My-bi (Tenor) and Ly-bi (Mort) repopulated hosts were sacrificed and Donor type HSC were enriched for Sca-1+, Lin- cells. Two technical replicates of RNA extract were run from each clone.
2013-05-01 | E-GEOD-41702 | biostudies-arrayexpress
Project description:Mouse muscle stem cells, defined as Pax7+ satellite cells, can initiate rhabdomyosarcoma when transformed by oncogenic Kras and concomitant loss of p53. Mouse Pax7+ satellite cells were transformed in vitro and in vivo utilizing the Cre-ER/loxp system. We wanted to address two major questions: do the in vitro and in vivo tumors cluster together compared to another mouse to another mouse derived soft-tissue sarcoma AND which human soft-tissue sarcoma do the in vivo derived tumors resemble transcriptionally? Therefore, tumors from cells transformed in vitro and tumors from mice that restrict the oncogenic lesions to Pax7+ satellite cells in vivo were compared to answer these two questions.
2011-06-01 | E-GEOD-22798 | biostudies-arrayexpress
Project description:Array analysis of My-bi and Ly-bi HSC identifies candidate molecules for myeloid-bias. Collectively the data show that HSC in adults are largely epigenetically fixed in differentiation and self-renewal behavior. A direct examination of the epigenetic mechanisms that imprint HSC is difficult. However, an indirect way of assessing the effects of epigenetic imprinting is to look for the expressed gene programs of different types of HSC. Therefore, we performed an array analysis in collaboration with Dr. Michael Cooke. My-bi and Ly-bi HSC were identified in clonally repopulated hosts. The analysis returned 218 differentially expressed genes (≥ Log2 ≥2, p< 0.05) of which 36 were found to be overexpressed in My-bi HSC and the rest was overexpressed in Ly-bi HSC (Appendix A). There was no difference in expression levels for genes known to be involved in fate decisions during differentiation. This agrees well with our data that lineage bias is a stable function of a HSC, and does not reflect a differentiated type of cell.
2013-05-01 | GSE41702 | GEO
Project description:The human blood system is maintained through the differentiation and massive amplification of a limited number of long-lived hematopoietic stem cells (HSCs). Perturbations to this process underlie a diverse set of diseases, but the clonal contributions to human hematopoiesis and how this changes with age remain incompletely understood. While recent insights have emerged from barcoding studies in model systems, simultaneous detection of cell states and phylogenies from natural barcodes in humans has been challenging, which has limited the ability to explore functional differences between HSC clones. Here, we introduce an improved single-cell lineage tracing system based on deep detection of naturally-occurring mitochondrial DNA (mtDNA) mutations with simultaneous readout of transcriptional states and chromatin accessibility. We use this system to define the clonal architecture of HSCs, and map the physiological state and output of these clones. We uncover functional heterogeneity in HSC clones, which is stable over months and manifests as differences in total HSC output as well as biases toward the production of different mature blood and immune lineages. We also find that the diversity of HSC clones decreases dramatically with age leading to an oligoclonal structure with multiple distinct clonal expansions. Our study thus provides the first clonally-resolved and cell-state aware atlas of human hematopoiesis at single-cell resolution revealing an unappreciated functional diversity of human HSC clones both in young and aged individuals and more broadly paves the way for refined studies of clonal dynamics across a range of tissues in human health and disease.
2024-02-26 | GSE259285 | GEO
Project description:The human blood system is maintained through the differentiation and massive amplification of a limited number of long-lived hematopoietic stem cells (HSCs). Perturbations to this process underlie a diverse set of diseases, but the clonal contributions to human hematopoiesis and how this changes with age remain incompletely understood. While recent insights have emerged from barcoding studies in model systems, simultaneous detection of cell states and phylogenies from natural barcodes in humans has been challenging, which has limited the ability to explore functional differences between HSC clones. Here, we introduce an improved single-cell lineage tracing system based on deep detection of naturally-occurring mitochondrial DNA (mtDNA) mutations with simultaneous readout of transcriptional states and chromatin accessibility. We use this system to define the clonal architecture of HSCs, and map the physiological state and output of these clones. We uncover functional heterogeneity in HSC clones, which is stable over months and manifests as differences in total HSC output as well as biases toward the production of different mature blood and immune lineages. We also find that the diversity of HSC clones decreases dramatically with age leading to an oligoclonal structure with multiple distinct clonal expansions. Our study thus provides the first clonally-resolved and cell-state aware atlas of human hematopoiesis at single-cell resolution revealing an unappreciated functional diversity of human HSC clones both in young and aged individuals and more broadly paves the way for refined studies of clonal dynamics across a range of tissues in human health and disease.
2024-02-26 | GSE259284 | GEO
Project description:The human blood system is maintained through the differentiation and massive amplification of a limited number of long-lived hematopoietic stem cells (HSCs). Perturbations to this process underlie a diverse set of diseases, but the clonal contributions to human hematopoiesis and how this changes with age remain incompletely understood. While recent insights have emerged from barcoding studies in model systems, simultaneous detection of cell states and phylogenies from natural barcodes in humans has been challenging, which has limited the ability to explore functional differences between HSC clones. Here, we introduce an improved single-cell lineage tracing system based on deep detection of naturally-occurring mitochondrial DNA (mtDNA) mutations with simultaneous readout of transcriptional states and chromatin accessibility. We use this system to define the clonal architecture of HSCs, and map the physiological state and output of these clones. We uncover functional heterogeneity in HSC clones, which is stable over months and manifests as differences in total HSC output as well as biases toward the production of different mature blood and immune lineages. We also find that the diversity of HSC clones decreases dramatically with age leading to an oligoclonal structure with multiple distinct clonal expansions. Our study thus provides the first clonally-resolved and cell-state aware atlas of human hematopoiesis at single-cell resolution revealing an unappreciated functional diversity of human HSC clones both in young and aged individuals and more broadly paves the way for refined studies of clonal dynamics across a range of tissues in human health and disease.
2023-11-18 | GSE219014 | GEO
Project description:The human blood system is maintained through the differentiation and massive amplification of a limited number of long-lived hematopoietic stem cells (HSCs). Perturbations to this process underlie a diverse set of diseases, but the clonal contributions to human hematopoiesis and how this changes with age remain incompletely understood. While recent insights have emerged from barcoding studies in model systems, simultaneous detection of cell states and phylogenies from natural barcodes in humans has been challenging, which has limited the ability to explore functional differences between HSC clones. Here, we introduce an improved single-cell lineage tracing system based on deep detection of naturally-occurring mitochondrial DNA (mtDNA) mutations with simultaneous readout of transcriptional states and chromatin accessibility. We use this system to define the clonal architecture of HSCs, and map the physiological state and output of these clones. We uncover functional heterogeneity in HSC clones, which is stable over months and manifests as differences in total HSC output as well as biases toward the production of different mature blood and immune lineages. We also find that the diversity of HSC clones decreases dramatically with age leading to an oligoclonal structure with multiple distinct clonal expansions. Our study thus provides the first clonally-resolved and cell-state aware atlas of human hematopoiesis at single-cell resolution revealing an unappreciated functional diversity of human HSC clones both in young and aged individuals and more broadly paves the way for refined studies of clonal dynamics across a range of tissues in human health and disease.
2023-11-18 | GSE219248 | GEO
Project description:The human blood system is maintained through the differentiation and massive amplification of a limited number of long-lived hematopoietic stem cells (HSCs). Perturbations to this process underlie a diverse set of diseases, but the clonal contributions to human hematopoiesis and how this changes with age remain incompletely understood. While recent insights have emerged from barcoding studies in model systems, simultaneous detection of cell states and phylogenies from natural barcodes in humans has been challenging, which has limited the ability to explore functional differences between HSC clones. Here, we introduce an improved single-cell lineage tracing system based on deep detection of naturally-occurring mitochondrial DNA (mtDNA) mutations with simultaneous readout of transcriptional states and chromatin accessibility. We use this system to define the clonal architecture of HSCs, and map the physiological state and output of these clones. We uncover functional heterogeneity in HSC clones, which is stable over months and manifests as differences in total HSC output as well as biases toward the production of different mature blood and immune lineages. We also find that the diversity of HSC clones decreases dramatically with age leading to an oligoclonal structure with multiple distinct clonal expansions. Our study thus provides the first clonally-resolved and cell-state aware atlas of human hematopoiesis at single-cell resolution revealing an unappreciated functional diversity of human HSC clones both in young and aged individuals and more broadly paves the way for refined studies of clonal dynamics across a range of tissues in human health and disease.
2023-11-18 | GSE219167 | GEO
Project description:The human blood system is maintained through the differentiation and massive amplification of a limited number of long-lived hematopoietic stem cells (HSCs). Perturbations to this process underlie a diverse set of diseases, but the clonal contributions to human hematopoiesis and how this changes with age remain incompletely understood. While recent insights have emerged from barcoding studies in model systems, simultaneous detection of cell states and phylogenies from natural barcodes in humans has been challenging, which has limited the ability to explore functional differences between HSC clones. Here, we introduce an improved single-cell lineage tracing system based on deep detection of naturally-occurring mitochondrial DNA (mtDNA) mutations with simultaneous readout of transcriptional states and chromatin accessibility. We use this system to define the clonal architecture of HSCs, and map the physiological state and output of these clones. We uncover functional heterogeneity in HSC clones, which is stable over months and manifests as differences in total HSC output as well as biases toward the production of different mature blood and immune lineages. We also find that the diversity of HSC clones decreases dramatically with age leading to an oligoclonal structure with multiple distinct clonal expansions. Our study thus provides the first clonally-resolved and cell-state aware atlas of human hematopoiesis at single-cell resolution revealing an unappreciated functional diversity of human HSC clones both in young and aged individuals and more broadly paves the way for refined studies of clonal dynamics across a range of tissues in human health and disease.
2023-11-18 | GSE219106 | GEO