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Location of indigenous human HSCs reveals functional properties of HSCs that are dictated by anatomic and cellular architecture of bone marrow I

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE47934 | GEO | 2013/08/01

SECONDARY ACCESSION(S): PRJNA208389

REPOSITORIES: GEO

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Location of indigenous human HSCs reveals functional properties of HSCs that are dictated by anatomic and cellular architecture of bone marrow II

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.

2013-08-01 | GSE47935 | GEO

Location of indigenous human HSCs reveals functional properties of HSCs that are dictated by anatomic and cellular architecture of bone marrow II

2013-08-01 | E-GEOD-47935 | biostudies-arrayexpress

Location of indigenous human HSCs reveals functional properties of HSCs that are dictated by anatomic and cellular architecture of bone marrow I

2013-08-01 | E-GEOD-47934 | biostudies-arrayexpress

mRNA profiles of bone marrow and splenic hematopoietic stem cells after 5-FU challenge

Project description:Under stress hematopoiesis, previous studies have suggested the migration of hematopoietic stem cells (HSCs) from bone marrow (BM) to extramedullary sites such as spleen. However, there is little direct evidence of HSC migration from BM to spleen. Here, we induced myeloablation via 5-fluorouracil (5-FU) and showed the direct evidence of HSC migration from BM to spleen during hematopoietic regeneration via a photoconvertible fluorophore. We found that during hematopoietic regeneration, there were mechanistic differences for HSC migration during early (day 3 to 8) and late phase (day 11 to 14). During steady-state, HSCs preferentially migrated to BM rather than spleen, but during the early phase HSC migration to spleen predominated. Indeed, in the early phase, HSC mobilization from BM was induced in G-CSF-dependent manners, while HSCs in the late phase gained significantly enhanced cell-autonomous motility, which was independent of chemotaxis. Collectively, HSC migration was dynamically changed during hematopoietic regeneration.

2023-12-01 | GSE248234 | GEO

Transcriptome data of bone marrow hematopoietic stem cells (HSCs) with premature aging

Project description:Recent advances have taken advantage of various animal models in HSC aging research, including certain gene mutations, chemicals, and ionizing radiation (IR). To identify the underlying mechanisms and phenotype switching in HSC aging, we employed IR-induced premature HSC aging model and performed RNA-seq of HSCs from the bone marrow (BM) of mice at three months post IR and their age-matched control mice (Ctrl).

2023-08-08 | GSE211007 | GEO

N-cadherin expressing bone and marrow stromal progenitor cells maintain reserve hematopoietic stem cells

Project description:Regulation of hematopoietic stem cells (HSCs) by bone marrow (BM) niches has been extensively studied; however, whether and how HSC subpopulations are distinctively regulated by BM niches remain unclear. Here, we functionally distinguished reserve HSCs (rHSCs) from primed HSCs (pHSCs) based on their response to chemotherapy and examined how they are dichotomously regulated by BM niches. Both pHSCs and rHSCs supported long-term hematopoiesis in homeostasis; however, pHSCs were sensitive but rHSCs were resistant to chemotherapy. Surviving rHSCs restored the HSC pool and supported hematopoietic regeneration after chemotherapy. The rHSCs were preferentially maintained in the endosteal region that enriches N-cadherin+ (Ncad+) bone-lining cells in homeostasis and post-chemotherapy. N-cad+ cells were functional bone and marrow stromal progenitor cells (BMSPCs), giving rise to osteoblasts, adipocytes, and chondrocytes in vitro and in vivo. Finally, ablation of Ncad+ niche cells or deletion of SCF from N-cad+ niche cells impaired rHSC maintenance during homeostasis and regeneration.

2019-01-15 | GSE104887 | GEO

Manipulating niche composition limits damage to haematopoietic stem cells during Plasmodium infection

Project description:Severe infections are a major stress on haematopoiesis, where the consequences for haematopoietic stem cells (HSCs) have only recently started to emerge. HSC function critically depends on the integrity of complex bone marrow (BM) niches, however whether the BM microenvironment plays a role in mediating the effects of infection on HSCs remains an open question. Here, using a murine model of malaria and combining single cell RNA sequencing, mathematical modelling, transplantation assays and intravital microscopy, we show that haematopoiesis is reprogrammed upon infection, whereby the HSC compartment turns over significantly faster than in steady-state and HSC function is drastically affected as a result. Interferon is found to affect both haematopoietic and mesenchymal BM cells and we specifically identify a dramatic loss of osteoblasts and alterations in endothelial cell function. Osteo-active parathyroid hormone treatment abolishes infection-triggered HSC proliferation and, coupled with Reactive Oxygen Species quenching, enables partial rescuing of HSC function.

2020-09-10 | GSE156410 | GEO

CCCTC-binding factor is essential for the mouse hematopoietic stem cell maintenance and quiescence

Project description:Hematopoiesis is a series of lineage differentiation programs initiated from hematopoietic stem cells (HSCs) in the bone marrow (BM). To maintain lifelong hematopoiesis, the pool of HSCs is precisely maintained by diverse molecular mechanisms. CCCTC-binding factor (CTCF) is a DNA-binding zinc-finger protein which regulates its target gene expression by organizing higher order chromatin structures. Currently, the role for CTCF in controlling HSC homeostasis is unknown. By using a tamoxifen-induced CTCF conditional knockout mouse system, we demonstrate that CTCF is a critical regulator for the homeostatic maintenance of adult HSCs by retaining HSC cell cycle quiescence. Acute systemic CTCF ablation leads to a severe BM failure and rapid shrinkage of multiple c-Kithi progenitor populations, including Sca-1+ HSCs in adult mice. Similarly, a hematopoietic system-confined CTCF depletion elicits an acute loss of HSCs and highly increased mortality. Mixed BM chimeras reconstituted together with the supporting BM reveal that CTCF deficiency-mediated HSC depletion is a cell-autonomous effect. Although c-Kithi myeloid progenitors were severely reduced after ablating Ctcf gene, c-Kitint common lymphoid progenitors and their progenies were less affected by the lack of CTCF. Whole transcriptome analyses show that CTCF deficiency results in an enhanced expression of the cell cycle-promoting program and CTCF-depleted HSCs express higher level of reactive oxygen species (ROS). Importantly, in vivo treatment with the antioxidant partially rescued the c-Kithi population and their quiescence. We conclude that CTCF is a pivotal player in maintaining adult HSC pool likely through regulating ROS-dependent HSC quiescence. We used gene expression microarray to elucidate CTCF-regulated gene profiles of the Lin−Sca-1+c-Kithi (LSKs) stem/progenitor populations.

2017-10-31 | GSE88995 | GEO

Gene expression profiling of LT-HSCs and ST-HSCs conditionally expressing MLL-ENL

Project description:We have developed a new conditional transgenic mouse showing that MLL-ENL, at an endogenous-like expression level, induces leukemic transformation selectively in LT-HSCs. To investigate the molecular mechanism of leukemic transformation in LT-HSCs conditionally expressing MLL-ENL, we preliminarily performed comprehensive gene expression profiling of CreER-transduced LT-HSCs and ST-HSCs using cDNA microarray analysis. For initial screening of candidate genes invloved in the leukemic transformation, total RNA was extracted from colony-forming cells derived from LT-HSCs and ST-HSCs transduced with CreER or mock. Four samples were analyzed, and CreER-transduced LT/ST-HSC-derived cells were compared with mock-transduced LT/ST-HSC-derived cells, while CreER/mock-transduced LT-HSC-derived cells were compared with CreER/mock-transduced ST-HSC-derived cells.

2013-07-17 | E-GEOD-48539 | biostudies-arrayexpress

Expression analysis of wild type and CCP3 deficient LT-HSCs

Project description:All hematopoietic lineages are derived from a limited pool of hematopoietic stem cells (HSCs). Although the mechanisms underlying HSC self-renewal have been extensively studied, little is known about the role of protein glutamylation and deglutamylation in hematopoiesis. Here we show that carboxypeptidase CCP3 is most highly expressed in BM cells among CCP members. CCP3 deficiency impairs HSC self-renewal and hematopoiesis. Deubiquitinase BAP1 is a substrate for CCP3 in HSCs. BAP1 is glutamylated at Glu651 by TTLL5 and TTLL7, and BAP1-E651A mutation abrogates BAP1 glutamylation. BAP1 glutamylation accelerates its ubiquitination to trigger its degradation. CCP3 can remove glutamylation of BAP1 to promote its stability, which enhances Hoxa1 expression leading to HSC self-renewal. Bap1E651A mice produce higher numbers of LT-HSCs and peripheral blood cells. Moreover, TTLL5 and TTLL7 deficiencies sustain BAP1 stability to promote HSC self-renewal and hematopoiesis. Therefore, glutamylation and deglutamylation of BAP1 modulate HSC self-renewal and hematopoiesis.

2019-10-03 | GSE138298 | GEO

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