Single cell transcriptomics of fate-restricted HSCs [scRNAseq HSC]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE188118 | GEO | 2023/02/22
REPOSITORIES: GEO
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Project description:HSC subtypes with distintic lineage restriction have been previously reported. Here we examine the transcriptome profiles of HSC subtypes with P-restricted, PEM-restricted or multilineage in vivo output.
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Project description:A hallmark of adult hematopoiesis is the continuous replacement of blood cells with limited lifespans. While active hematopoietic stem cell (HSC) contribution to multilineage hematopoiesis is the foundation of clinical HSC transplantation, recent reports have questioned the physiological contribution of HSCs to normal/steady-state adult hematopoiesis. Here, we use inducible lineage tracing from genetically marked adult HSCs and reveal robust HSC-derived multilineage hematopoiesis. This commences via defined progenitor cells, but varies substantially in between different hematopoietic lineages. By contrast, adult HSC contribution to hematopoietic cells with proposed fetal origins is neglible. Finally, we establish that the HSC contribution to multilineage hematopoiesis declines with increasing age. Therefore, while HSCs are active contributors to native adult hematopoiesis, it appears that the numerical increase of HSCs is a physiologically relevant compensatory mechanism to account for their reduced differentiation capacity with age
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Project description:Hematopoietic stem cell (HSC) differentiation into mature lineages has been studied under physiological conditions in vivo by genetic barcoding-driven lineage tracing. HSC clones differ in output (differentiation-inactive versus differentiation-active), and in fates (multilineage versus lineage-restricted). Single-cell sequencing data revealed transcriptome diversity of HSC and progenitors, and suggested differentiation pathways. However, molecular hallmarks of functionally distinct HSC clones have not been resolved because existing lineage tracing experiments did not provide transcriptomes, and single cell RNA sequencing lacked information on precursor-product relationships, and hence fate. To close this gap, here we introduce PolyloxExpress, a Cre recombinase-dependent DNA substrate for in situ barcoding in mice that is expressed as mRNA. PolyloxExpress barcoding allows parallel readout of clonal HSC fates (via comparison of barcodes in HSC and mature lineages), and transcriptomes (via single-cell RNA sequencing and barcode matching). Analysing a total of 91 individual HSC clones, we show that differentiation-inactive versus differentiation-active HSC clones reside in different regions of the transcriptional landscape. Inactive HSC clones are closer to the origin of the transcriptional trajectory, yet are proliferatively not more quiescent than active clones. Multilineage versus myelo-erythroid fate-restricted HSC clones show very few transcriptional differences at the HSC stage, yet pronounced fate-specific profiles at the multipotent progenitor stage. Projecting HSC clones with defined fates onto transcriptional landscapes provides a basis for future studies into the molecular determinants for stem cell fate.
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Project description:Hematopoietic stem cell (HSC) differentiation into mature lineages has been studied under physiological conditions in vivo by genetic barcoding-driven lineage tracing. HSC clones differ in output (differentiation-inactive versus differentiation-active), and in fates (multilineage versus lineage-restricted). Single-cell sequencing data revealed transcriptome diversity of HSC and progenitors, and suggested differentiation pathways. However, molecular hallmarks of functionally distinct HSC clones have not been resolved because existing lineage tracing experiments did not provide transcriptomes, and single cell RNA sequencing lacked information on precursor-product relationships, and hence fate. To close this gap, here we introduce PolyloxExpress, a Cre recombinase-dependent DNA substrate for in situ barcoding in mice that is expressed as mRNA. PolyloxExpress barcoding allows parallel readout of clonal HSC fates (via comparison of barcodes in HSC and mature lineages), and transcriptomes (via single-cell RNA sequencing and barcode matching). Analysing a total of 91 individual HSC clones, we show that differentiation-inactive versus differentiation-active HSC clones reside in different regions of the transcriptional landscape. Inactive HSC clones are closer to the origin of the transcriptional trajectory, yet are proliferatively not more quiescent than active clones. Multilineage versus myelo-erythroid fate-restricted HSC clones show very few transcriptional differences at the HSC stage, yet pronounced fate-specific profiles at the multipotent progenitor stage. Projecting HSC clones with defined fates onto transcriptional landscapes provides a basis for future studies into the molecular determinants for stem cell fate.
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Project description:The hematopoietic stem cell (HSC) compartment is heterogeneous, yet our understanding of the identities of different HSC subtypes is limited. Here we show that platelet integrin CD41 (M-NM-1IIb), currently thought to only transiently mark fetal HSCs, is expressed on an adult HSC subtype that accumulates with age. CD41+ HSCs were largely quiescent and exhibited myeloerythroid and megakaryocyte gene priming, governed by Gata1, whereas CD41- HSCs were more proliferative and exhibited lymphoid gene priming. When isolated without the use of blocking antibodies, CD41+ HSCs possessed long-term repopulation capacity upon serial transplantations and showed a marked myeloid-bias compared to CD41-HSCs, which yielded a more lymphoid-biased progeny. CD41-knockout mice displayed multilineage hematopoietic defects coupled with decreased quiescence and survival of HSCs, suggesting that CD41 is functionally relevant for HSC maintenance and hematopoietic homeostasis. Transplantation experiments indicated that CD41-KO associated defects are long-term transplantable and HSC-derived, and in part mediated through the loss of platelet mass leading to decreases in HSC exposure to important platelet released cytokines, such as TGFM-NM-21. In summary, our data provide a novel marker to identify a myeloid-biased HSC subtype that becomes prevalent with age, and highlights the dogma of HSC regulation by their progeny. For microarray analysis, 1000 HSCs were FACS sorted from pools of 4-5 mice directly into lysis buffer, RNA extracted and whole transcript amplification was performed as previously described (Gonzalez-Roca E, Garcia-Albeniz X, Rodriguez-Mulero S, Gomis RR, Kornacker K, Auer H. Accurate expression profiling of very small cell populations. PLoS One. 2010;5:e14418.)
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Project description:The hematopoietic stem cell (HSC) compartment is heterogeneous, yet our understanding of the identities of different HSC subtypes is limited. Here we show that platelet integrin CD41 (αIIb), currently thought to only transiently mark fetal HSCs, is expressed on an adult HSC subtype that accumulates with age. CD41+ HSCs were largely quiescent and exhibited myeloerythroid and megakaryocyte gene priming, governed by Gata1, whereas CD41- HSCs were more proliferative and exhibited lymphoid gene priming. When isolated without the use of blocking antibodies, CD41+ HSCs possessed long-term repopulation capacity upon serial transplantations and showed a marked myeloid-bias compared to CD41-HSCs, which yielded a more lymphoid-biased progeny. CD41-knockout mice displayed multilineage hematopoietic defects coupled with decreased quiescence and survival of HSCs, suggesting that CD41 is functionally relevant for HSC maintenance and hematopoietic homeostasis. Transplantation experiments indicated that CD41-KO associated defects are long-term transplantable and HSC-derived, and in part mediated through the loss of platelet mass leading to decreases in HSC exposure to important platelet released cytokines, such as TGFβ1. In summary, our data provide a novel marker to identify a myeloid-biased HSC subtype that becomes prevalent with age, and highlights the dogma of HSC regulation by their progeny.
2013-04-11 | GSE45561 | GEO