Lifelong haematopoiesis is established by hundreds of precursors throughout mammalian ontogeny

Ganuza, Miguel; Hall, Trent; Finkelstein, David; Chabot, Ashley; Kang, Guolian; McKinney‐Freeman, Shannon

doi:10.1038/ncb3607

Cited by 73 publications

(89 citation statements)

References 55 publications

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“…1-4, table S1) different barcodes, with 88.3% (±7.6; mean ± SD, table S1) of cells being barcoded. This number is in keeping with estimated numbers of several hundred embryonic HSC progenitors (16), suggesting that barcode induction in Tie2 MeriCreMer Rosa26 PolyloxExpress mice at E9.5 covers emerging HSC quantitatively. When restricting the analysis to HSC and progenitors retrieved collectively from all major adult mouse bones, on average 377 ± 128 (mean ± SD from Exp.…”

Section: Polyloxexpress Integrates Lineage Information and Transcriptsupporting

confidence: 75%

Resolving fate and transcriptome of hematopoietic stem cell clones

Pei

Shang

Wang

et al. 2020

Preprint

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Adult bone marrow harbors a mosaic of hematopoietic stem cell (HSC) clones of embryonic origin, and recent work suggests that such clones may have coherent lineage fates. To probe under physiological conditions whether HSC clones with different fates are transcriptionally distinct, we developed PolyloxExpress -a Cre recombinase-dependent DNA substrate for in situ barcoding that allows parallel readout of barcodes and transcriptomes in single cells. We describe differentiation-inactive, multilineage and lineage-restricted HSC clones, find that they reside in distinct regions of the transcriptional landscape of hematopoiesis, and identify corresponding gene signatures. All clone types contain proliferating HSCs, indicating that differentiationinactive HSCs can undergo symmetric self-renewal. Our work establishes an approach for studying determinants of stem cell fate in vivo and provides molecular evidence for fate coherence of HSC clones.

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Section: Polyloxexpress Integrates Lineage Information and Transcriptsupporting

confidence: 75%

Resolving fate and transcriptome of hematopoietic stem cell clones

Pei

Shang

Wang

et al. 2020

Preprint

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“…Although the intra-arterial hematopoietic clusters (IACs) in mouse and human embryos contain hundreds of HSPCs, only 1-3 of them are functional adult-repopulating HSCs Kumaravelu et al, 2002;Yokomizo and Dzierzak, 2010). IACs in mouse embryos also contain between ~150 (as measured by ex vivo maturation followed by transplantation) to ~600 (determined by multicolor lineage tracing) immature precursors of HSCs (pre-HSCs) that mature into HSCs either within or prior to colonizing the FL (Ganuza et al, 2017;Kieusseian et al, 2012;Rybtsov et al, 2016;Taoudi et al, 2008). FL HSCs ultimately take up permanent residence in the bone marrow (BM) where they mature into adult BM HSCs (Bowie et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Transcriptional regulatory network controlling the ontogeny of hematopoietic stem cells

Gao

Chen

Howell

et al. 2019

Preprint

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Hematopoietic stem cell (HSC) ontogeny is accompanied by dynamic changes in gene regulatory networks. We performed RNA-Seq and histone mark ChIP-Seq to define the transcriptomes and epigenomes of cells representing key developmental stages of HSC ontogeny in the mouse. The five populations analyzed were embryonic day 10.5 (E10.5) endothelium and hemogenic endothelium from the major arteries (dorsal aorta, umbilical and vitelline), an enriched population of pre-hematopoietic stem cells (pre-HSCs), fetal liver HSCs, and adult bone marrow HSCs. We observed dynamic and combinatorial epigenetic changes that mark regulatory DNA sequences including gene promoters and enhancers. Using epigenetic signatures, we identified enhancers for each developmental stage. Only 12% of enhancers are primed, and 78% are active, suggesting the vast majority of enhancers are established de novo at the developmental stages where they are required to control their target genes, without prior priming in earlier stages. We constructed developmental-stage-specific transcriptional regulatory networks during HSC ontogeny by linking enhancers and predicted bound transcription factors to their target promoters using a novel computational algorithm. Our computational analyses predicted known transcriptional regulators for the endothelial-to-hematopoietic transition, validating our overall approach, and identified putative novel transcription factors whose regulon activities correlate with the emergence of pre-HSCs. We validated roles for the broadly expressed transcription factors SP3 and MAZ in arterial hemogenic endothelium. Our data and computational analyses provide a useful resource for uncovering regulators of HSC formation.

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“…In fact, regeneration of the hematopoietic system after cell transplantation into an irradiated host is still considered to be the gold standard for a functional definition of HSCs. Minimally invasive methods for marking of HSCs [5][6][7][8][9][10][11][12][13][14][15] recently allowed studying the hematopoietic system in unperturbed, that is, not transplanted, settings, thereby adding new insights into the functional role of HSCs and their progenitor populations. Based on these new findings, it appears that multipotent progenitors (MPPs) ensure the long-term supply with functional, differentiated hematopoietic cells in the homeostatic situation, while rarely depending on the turnover of the HSC population.…”

Section: Introductionmentioning

confidence: 99%

Hematopoietic Stem Cell Dynamics Are Regulated by Progenitor Demand: Lessons from a Quantitative Modeling Approach

et al. 2019

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The prevailing view on murine hematopoiesis and on hematopoietic stem cells (HSCs) in particular derives from experiments that are related to regeneration after irradiation and HSC transplantation. However, over the past years, different experimental techniques have been developed to investigate hematopoiesis under homeostatic conditions, thereby providing access to proliferation and differentiation rates of hematopoietic stem and progenitor cells in the unperturbed situation. Moreover, it has become clear that hematopoiesis undergoes distinct changes during aging with large effects on HSC abundance, lineage contribution, asymmetry of division, and self‐renewal potential. However, it is currently not fully resolved how stem and progenitor cells interact to respond to varying demands and how this balance is altered by an aging‐induced shift in HSC polarity. Aiming toward a conceptual understanding, we introduce a novel in silico model to investigate the dynamics of HSC response to varying demand. By introducing an internal feedback within a heterogeneous HSC population, the model is suited to consistently describe both hematopoietic homeostasis and regeneration, including the limited regulation of HSCs in the homeostatic situation. The model further explains the age‐dependent increase in phenotypic HSCs as a consequence of the cells' inability to preserve divisional asymmetry. Our model suggests a dynamically regulated population of intrinsically asymmetrically dividing HSCs as suitable control mechanism that adheres with many qualitative and quantitative findings on hematopoietic recovery after stress and aging. The modeling approach thereby illustrates how a mathematical formalism can support both the conceptual and the quantitative understanding of regulatory principles in HSC biology.

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Lifelong haematopoiesis is established by hundreds of precursors throughout mammalian ontogeny

Cited by 73 publications

References 55 publications

Resolving fate and transcriptome of hematopoietic stem cell clones

Resolving fate and transcriptome of hematopoietic stem cell clones

Transcriptional regulatory network controlling the ontogeny of hematopoietic stem cells

Hematopoietic Stem Cell Dynamics Are Regulated by Progenitor Demand: Lessons from a Quantitative Modeling Approach

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