Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA335842 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3987050.fastq.gz | Fastqsanger.gz | |||
| SRR3987060.fastq.gz | Fastqsanger.gz | |||
| SRR3987070.fastq.gz | Fastqsanger.gz | |||
| SRR3987051.fastq.gz | Fastqsanger.gz | |||
| SRR3987061.fastq.gz | Fastqsanger.gz |
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Project description:We here show that the niche regulates the quality of the hematopoietic stem cells (HSCs) that are regenerated after transplantation. We find that a reduced level of Wnt5a in the niche regenerates dysfunctional HSCs, which do not successfully engraft secondary recipients. In particular, RNA sequencing shows a dysregulated Zeb1-associated gene expression of multiple genes involved in the small GTPase-dependent actin polymerization pathway. Misexpression of these genes results in reduced ability to direct polarized F-actin localization, leading to defects in adhesion, migratory behavior and homing to the bone marrow of secondary recipients. Our study further shows that the Wnt5a-haploinsufficient environment similarly affects BCR-ABLp185+ cells, which, in 42% of the studied recipients, fail to generate leukemia and, in the remaining cases, fail to transfer leukemia to secondary hosts. Thus, we show that Wnt5a in the niche is required to regenerate HSCs and leukemic cells with functional ability to rearrange the actin cytoskeleton which is required for successful engraftment.
2016-12-16 | GSE84993 | GEO
Project description:Hematopoietic stem cells (HSCs) primarily reside in the bone marrow where signals generated by stromal cells regulate their self-renewal, proliferation, and trafficking. Endosteal osteoblasts and perivascular stromal cells including endothelial cells3, CXCL12-abundant reticular (CAR) cells, leptin-receptor positive stromal cells, and nestin-GFP positive mesenchymal progenitors have all been implicated in HSC maintenance. However, it is unclear if specific hematopoietic progenitor cell (HPC) subsets reside in distinct niches defined by the surrounding stromal cells and the regulatory molecules they produce. CXCL12 (stromal-derived factor-1, SDF-1) regulates both HSCs and lymphoid progenitors and is expressed by all of these stromal cell populations. Here, we selectively deleted Cxcl12 from candidate niche stromal cell populations and characterized the effect on HPCs. Deletion of Cxcl12 from mineralizing osteoblasts has no effect on HSCs or lymphoid progenitors. Deletion of Cxcl12 from osterix-expressing stromal cells, which includes CAR cells and osteoblasts, results in constitutive HPC mobilization and a loss of B lymphoid progenitors, but HSC function is normal. Cxcl12 deletion in endothelial cells results in a modest loss of long-term repopulating activity. Strikingly, deletion of Cxcl12 in nestin-negative mesenchymal progenitors using Prx1-Cre is associated with a marked loss of HSCs, long-term repopulating activity, HSC quiescence, and common lymphoid progenitors. These data suggest that osterix-expressing stromal cells comprise a distinct niche that supports B lymphoid progenitors and retains HPC in the bone marrow, while expression of CXCL12 from stromal cells in the perivascular region, including endothelial cells and mesenchymal progenitors, support HSCs. Total of three samples of two groups analyzed. Replica samples of CXCL12-abundant reticular (CAR) cells from two CXCL12-GFP knock-in mice and a combined sample of PDGFRa+ Sca+ CD45- lineage- cells from three Prx1-Cre Rosa26Ai9/+ Cxcl12gfp/+ mice were used and analyzed.
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Project description:Hematopoietic stem cells (HSCs) inhabit distinct microenvironments within the adult bone marrow (BM) that govern the delicate balance between HSC quiescence, self-renewal, and differentiation. It has been suggested that quiescent HSCs localize adjacent to BM arteriole endothelial cells in a significant and non-random distribution. This data suggests that the arteriole BM vascular niche may be the primary HSC niche. Because the BM arteriole niche is composed of tightly-associated pericytes, including smooth muscle actin+, LepR+, Nestin+, NG2+, and nonmyelinating Schwann cells, we sought to begin to uncouple the arteriole BM EC niche by examining its capacity to support the maintenance and expansion of HSCs ex vivo and in vivo. We developed a method to isolate and culture BM arteriole endothelial cells in serum-/growth factor-free conditions, allowing for a non-biased approach to examining their instructive function. Utilizing our protocol, we demonstrate that BM endothelial cells, but not BM stromal cells, have the capacity to expand long-term repopulating, multi-lineage HSCs in lieu of complex serum and cytokine supplementation. In addition, transplantation of arteriole endothelial cells promoted rapid hematopoietic recovery and protected HSCs following an LD50 dose of myeloablative irradiation. These data demonstrate that arteriole-derived BM endothelial cells are endowed with the necessary signals to support the self-renewal and regenerative capacity of LT-HSCs and that transplantation of arteriole BM endothelial cells could be used as a therapeutic means to decrease pancytopenias associated with myeloablative treatments to treat a wide array of disease states. Transcriptome sequencing of bone marrow endothelial cells and bone marrow stroma, in vitro and in vivo, with and without HSC co-culture.
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2013-12-31 | E-GEOD-39835 | biostudies-arrayexpress
Project description:Hematopoietic stem cells (HSCs) primarily reside in the bone marrow where signals generated by stromal cells regulate their self-renewal, proliferation, and trafficking. Endosteal osteoblasts and perivascular stromal cells including endothelial cells3, CXCL12-abundant reticular (CAR) cells, leptin-receptor positive stromal cells, and nestin-GFP positive mesenchymal progenitors have all been implicated in HSC maintenance. However, it is unclear if specific hematopoietic progenitor cell (HPC) subsets reside in distinct niches defined by the surrounding stromal cells and the regulatory molecules they produce. CXCL12 (stromal-derived factor-1, SDF-1) regulates both HSCs and lymphoid progenitors and is expressed by all of these stromal cell populations. Here, we selectively deleted Cxcl12 from candidate niche stromal cell populations and characterized the effect on HPCs. Deletion of Cxcl12 from mineralizing osteoblasts has no effect on HSCs or lymphoid progenitors. Deletion of Cxcl12 from osterix-expressing stromal cells, which includes CAR cells and osteoblasts, results in constitutive HPC mobilization and a loss of B lymphoid progenitors, but HSC function is normal. Cxcl12 deletion in endothelial cells results in a modest loss of long-term repopulating activity. Strikingly, deletion of Cxcl12 in nestin-negative mesenchymal progenitors using Prx1-Cre is associated with a marked loss of HSCs, long-term repopulating activity, HSC quiescence, and common lymphoid progenitors. These data suggest that osterix-expressing stromal cells comprise a distinct niche that supports B lymphoid progenitors and retains HPC in the bone marrow, while expression of CXCL12 from stromal cells in the perivascular region, including endothelial cells and mesenchymal progenitors, support HSCs.
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