HSCs contribute actively to native multilineage hematopoiesis but with reduced differentiation capacity upon aging
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PROVIDER: PRJNA505320 | ENA |
REPOSITORIES: ENA
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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
2018-12-18 | GSE122473 | GEO
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 cells (HSCs) have the capacity to differentiate into vastly different types of mature blood cells. The epigenetic mechanisms regulating the multilineage ability, or multipotency of HSCs are not well understood. To test the hypothesis that cis regulatory elements that control fate decisions for all lineages are primed in HSCs, we used ATAC-seq to compare chromatin accessibility of HSCs with five unipotent cell types. We observed the highest similarity in accessibility profiles between Megakaryocyte Progenitors and HSCs, whereas B cells had the greatest number of regions with de novo gain in accessibility during differentiation. Despite these differences, we identified cis regulatory elements from all lineages that displayed epigenetic priming in HSCs. These findings provide new insights into the regulation of stem cell multipotency, as well as a resource to identify functional drivers of lineage fate.
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Project description:The production of hematopoietic stem cells (HSCs) from induced pluripotent stem cells (iPSCs) would have significant implications for medicine and biotechnology. We differentiated iPSCs to blood cells resembling the first repopulating HSCs of the human embryo. In immune deficient mice transplanted with iPSC-derived CD34+ cells, long term, low level bone marrow engraftment was seen in most animals. Although many animals were engrafted by myeloid, or myeloid and B lymphoid restricted progeny, 18% of mice receiving cells exposed to retinoids at day 3 of differentiation developed multilineage erythroid, myeloid and lymphoid cell engraftment (MLE), reflecting in vitro generation of HSCs or MPPs (termed iPSC-derived (i)HSCs). In a second cohort of mice, we observed in 36% of animals transplanted with cells receiving retinoids throughout differentiation. These studies identify conditions that yield engrafting iHSCs differentiated from human iPSCs and provide a foundation for the generation of cells for clinical translation.
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Project description:Demonstration of hematopoietic stem cells (HSCs) was first shown in the mouse and was dependent on recipient bone marrow (BM) to support in vivo multilineage hematopoietic reconstitution, thereby illustrating non-cell-autonomous requirements for HSC functions. Murine studies have defined microanatomic compartments in the BM comprised of osteoblasts, mesenchymal cells, subsets of vasculature, and innervating neural cells functioning as an HSC-supportive niche. Despite the potential clinical applications, analyses of putative HSCs in the BM of humans has not been examined. Here, using human bone biopsies, we provide evidence of HSC propensity to endosteal regions of Trabecular Bone Area (TBA). Independent of phenotypic definitions based on prospective isolation, functional studies indicate that human HSCs residing in the TBA of human and transplanted recipients had superior regenerative and self-renewal capacity and are molecularly distinct to those repopulating the Long Bone Area (LBA). Consistent with the non-cell-autonomous nature of HSC function, osteoblasts in the TBA possess unique characteristics and expressed a key network of factors including those involving Notch activity which could regulate TBA vs. LBA location of human HSCs in vivo. Our study illustrates that human-mouse xenografts provide a surrogate to indigenous human HSC in the BM, and demonstrates that BM architecture plays a critical role in defining functional properties of human HSCs. Total bone marrow cells were collected from NOD/SCID recipient adult mice. Osteoblast cells (OB) were sorted based on five paramater markers combination Lin- CD45- CD31- Sca1- CD51+ using a FACSAria II (BD). Total RNA from purified populations was extracted and amplified as described previously (Shojaei et al., 2005). Amplified-labeled RNA was hybridized to HG-U133Plus v2.0 chip.
2013-08-01 | E-GEOD-47935 | biostudies-arrayexpress
Project description:Studies of zebrafish hematopoiesis have been largely performed using mutagenesis approaches and retrospective analyses based upon gene expression patterns in whole embryos. We previously developed transplantation assays to test the repopulation potentials of candidate hematopoietic progenitor cells. We have been impaired, however, in determining cellular differentiation potentials by a lack of short-term functional assays. To enable more precise analyses of hematopoietic progenitor cells, we have created zebrafish kidney stromal (ZKS) cell lines. Culture of adult whole kidney marrow with ZKS cells results in the maintenance and expansion of hematopoietic precursor cells. Hematopoietic growth is dependent upon ZKS cells, and we show that ZKS cells express many growth factors and ligands previously demonstrated to be important in maintaining mammalian hematopoietic cells. In the absence of exogenous growth factors, ZKS cells maintain early hematopoietic precursors and support differentiation of lymphoid and myeloid cells. With the addition of zebrafish erythropoietin, ZKS cells also support the differentiation of erythroid precursors. These conditions have enabled the ability to ascertain more precisely the points at which hematopoietic mutants are defective. The development of robust in vitro assays now provide the means to track defined, functional outcomes for prospectively isolated blood cell subsets in the zebrafish.
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Project description:Demonstration of hematopoietic stem cells (HSCs) was first shown in the mouse and was dependent on recipient bone marrow (BM) to support in vivo multilineage hematopoietic reconstitution, thereby illustrating non-cell-autonomous requirements for HSC functions. Murine studies have defined microanatomic compartments in the BM comprised of osteoblasts, mesenchymal cells, subsets of vasculature, and innervating neural cells functioning as an HSC-supportive niche. Despite the potential clinical applications, analyses of putative HSCs in the BM of humans has not been examined. Here, using human bone biopsies, we provide evidence of HSC propensity to endosteal regions of Trabecular Bone Area (TBA). Independent of phenotypic definitions based on prospective isolation, functional studies indicate that human HSCs residing in the TBA of human and transplanted recipients had superior regenerative and self-renewal capacity and are molecularly distinct to those repopulating the Long Bone Area (LBA). Consistent with the non-cell-autonomous nature of HSC function, osteoblasts in the TBA possess unique characteristics and expressed a key network of factors including those involving Notch activity which could regulate TBA vs. LBA location of human HSCs in vivo. Our study illustrates that human-mouse xenografts provide a surrogate to indigenous human HSC in the BM, and demonstrates that BM architecture plays a critical role in defining functional properties of human HSCs. Lin- MNCs from human Umbilical Cord blood (CB) were injected via tail vein into sublethally irradiated NOD/SCID adult mice. After 10 weeks post-transplantation, engrafted-CB cells were sorted based on the co-expression of CD45 and CD34, and absence or presence of CD38 using a FACSAria II (BD). Total RNA from purified populations was extracted and amplified as described previously (Shojaei et al., 2005). Amplified-labeled RNA was hybridized to HG-U133Plus v2.0 chip.
2013-08-01 | E-GEOD-47934 | biostudies-arrayexpress
Project description:Eltrombopag, a small molecule thrombopoietin receptor (TPO-R) agonist and potent intracellular iron chelator, has shown remarkable efficacy to stimulate sustained multilineage hematopoiesis in patients with bone marrow failure syndromes, suggesting an effect at the most immature hematopoietic stem and multipotent progenitor level. While the functional and molecular effects of Eltrombopag on megakaryopoiesis have been carefully studied in the recent past, insights into its mechanistic impact on the earliest stages of hematopoiesis have been limited. Additionally, previous studies also revealed molecular pathway of Eltrombopag apart from stimulation of TPO signaling, detail characterization remains to be addressed. In this study, we investigated the effects of Eltrombopag, in comparison with TPO, on highly-purified primary hematopoietic stem cells (HSCs) from healthy human donors. The binding of Eltrombopag to TPO-R is species-specific to human and primate cells. we also utilized HSCs isolated mouse as separation-of-function models to directly assess the molecular effect of Eltrombopag on HSCs independent of TPOR stimulation.
2018-09-17 | GSE107429 | GEO
Project description:Eltrombopag, a small molecule thrombopoietin receptor (TPO-R) agonist and potent intracellular iron chelator, has shown remarkable efficacy to stimulate sustained multilineage hematopoiesis in patients with bone marrow failure syndromes, suggesting an effect at the most immature hematopoietic stem and multipotent progenitor level. While the functional and molecular effects of Eltrombopag on megakaryopoiesis have been carefully studied in the recent past, insights into its mechanistic impact on the earliest stages of hematopoiesis have been limited. Additionally, previous studies also revealed molecular pathway of Eltrombopag apart from stimulation of TPO signaling, detail characterization remains to be addressed. In this study, we investigated the effects of Eltrombopag, in comparison with TPO, on highly-purified primary hematopoietic stem cells (HSCs) from healthy human donors. The binding of Eltrombopag to TPO-R is species-specific to human and primate cells. we also utilized HSCs isolated mouse as separation-of-function models to directly assess the molecular effect of Eltrombopag on HSCs independent of TPOR stimulation.
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