Similar Datasets
Project description:We have used a conditional mouse model to investigate the role of Smchd1 specifically in hematopoiesis. We found that Smchd1-deleted mice have an altered hematopoietic stem and progenitor cell (HSPC) compartment with reduced repopulating capacity in competitive bone marrow transplantation assays and the gradual loss of adult hematopoietic stem cells (HSCs) with age, suggesting a role for Smchd1 in the maintenance of long-term adult HSCs. The phenotype was more pronounced in female Smchd1-deleted mice, which showed a more severe reduction in HSCs with age, as well as depleted numbers of B cell lymphocytes. Gene expression profiling of Smchd1 deficient HSCs and B cells revealed several known and novel Smchd1-sensitive genes, a significant disruption to X-linked gene expression, although this was not widespread upregulation of X-linked genes in female cells. These data show Smchd1 as a new regulator of long-term HSCs whose effects are more profound in females.
2022-06-20 | GSE188685 | GEO
Project description:We have used a conditional mouse model to investigate the role of Smchd1 specifically in hematopoiesis. We found that Smchd1-deleted mice have an altered hematopoietic stem and progenitor cell (HSPC) compartment with reduced repopulating capacity in competitive bone marrow transplantation assays and the gradual loss of adult hematopoietic stem cells (HSCs) with age, suggesting a role for Smchd1 in the maintenance of long-term adult HSCs. The phenotype was more pronounced in female Smchd1-deleted mice, which showed a more severe reduction in HSCs with age, as well as depleted numbers of B cell lymphocytes. Gene expression profiling of Smchd1 deficient HSCs and B cells revealed several known and novel Smchd1-sensitive genes, a significant disruption to X-linked gene expression, although this was not widespread upregulation of X-linked genes in female cells. These data show Smchd1 as a new regulator of long-term HSCs whose effects are more profound in females.
2022-06-20 | GSE188517 | GEO
Project description:Epigenetic modifier Smchd1 maintains a normal pool of long-term repopulating hematopoietic stem cells in mice
| PRJNA779937 | ENA
Project description:Epigenetic modifier Smchd1 maintains a normal pool of long-term repopulating hematopoietic stem cells in mice II
| PRJNA779954 | ENA
Project description:Epigenetic modifier Smchd1 maintains a normal pool of long-term repopulating hematopoietic stem cells in mice I
| PRJNA779245 | ENA
Project description:Gene therapy for hematological disorders relies on the genetic modification of CD34(+) cells, a heterogeneous cell population containing about 0.01% long-term repopulating cells. Here, we show that the lentiviral vector CD133-LV, which uses a surface marker on human primitive hematopoietic stem cells (HSCs) as entry receptor, transfers genes preferentially into cells with high engraftment capability. Transduction of unstimulated CD34(+) cells with CD133-LV resulted in gene marking of cells with competitive proliferative advantage in vitro and in immunodeficient mice. The CD133-LV-transduced population contained significantly more cells with repopulating capacity than cells transduced with vesicular stomatitis virus (VSV)-LV, a lentiviral vector pseudotyped with the vesicular stomatitis virus G protein. Upon transfer of a barcode library, CD133-LV-transduced cells sustained gene marking in vivo for a prolonged period of time with a 6.7-fold higher recovery of barcodes compared to transduced control cells. Moreover, CD133-LV-transduced cells were capable of repopulating secondary recipients. Lastly, we show that this targeting strategy can be used for transfer of a therapeutic gene into CD34(+) cells obtained from patients suffering of X-linked chronic granulomatous disease. In conclusion, direct gene transfer into CD133(+) cells allows for sustained long-term engraftment of gene corrected cells.
| S-EPMC4426797 | biostudies-other
Project description:The myelodysplastic syndromes (MDS) comprise a group of premalignant hematologic disorders characterized by ineffective hematopoiesis, dysplasia, and transformation to acute myeloid leukemia (AML). Although it is well established that many malignancies can be transplanted, there is little evidence to demonstrate that a premalignant disease entity, such as MDS or colonic polyps, can be transplanted and subsequently undergo malignant transformation in vivo. Using mice that express a NUP98-HOXD13 (NHD13) transgene in hematopoietic tissues, we show that a MDS can be transplanted to WT recipients. Recipients of the MDS bone marrow displayed all of the critical features of MDS, including peripheral blood cytopenias, dysplasia, and transformation to AML. Even when transplanted with a 10-fold excess of WT cells, the NHD13 cells outcompeted the WT cells over a 38-week period. Limiting-dilution experiments demonstrated that the frequency of the cell that could transmit the disease was approximately 1/6,000-1/16,000 and that the MDS was also transferable to secondary recipients as a premalignant condition. Transformation to AML in primary transplant recipients was generally delayed (46-49 weeks after transplant); however, 6 of 10 secondary transplant recipients developed AML. These findings demonstrate that MDS originates in a transplantable, premalignant, long-term repopulating, MDS-initiating cell.
| S-EPMC2544583 | biostudies-literature
Project description:E-proteins are widely expressed basic helix-loop-helix (HLH) transcription factors that regulate differentiation in many cell lineages, including lymphoid, muscle, and neuronal cells. E-protein function is controlled by HLH inhibitors such as Id and SCL/TAL1 proteins, which recently have been suggested to play a role in hematopoietic stem cell (HSC) differentiation. However, the precise stages when these proteins are expressed and their specific functions are not entirely clear. Using a knock-in mouse model where the sequence for the enhanced green fluorescent protein (GFP) was inserted downstream of the Id1 promoter, we were able to track Id1 expression on an individual cell basis and detected Id1 expression in long-term repopulating HSCs (LT-HSCs). Functional assays showed that the Id1/GFP(+)Lin(-)Sca1(+)c-kit(Hi) population was highly enriched for LT-HSCs. Consistent with this expression pattern, Id1 deficiency led to a 2-fold reduction in the number of LT-HSCs defined as Lin(-)Sca1(+)c-kit(Hi)CD48(-)CD150(+). Primary bone marrow transplantation studies revealed that Id1 is dispensable for short-term engraftment. In contrast, both Id1(-/-) whole bone marrow and Lin(-)Sca1(+)c-kit(Hi)Thy1.1(Lo)-enriched HSCs, but not Id3(-/-) marrow, displayed impaired engraftment relative to wild-type controls in secondary transplantation assays. These findings suggest a unique role for Id1 in LT-HSC maintenance and hematopoietic development.
| S-EPMC1988946 | biostudies-literature
Project description:Hematopoietic stem progenitor cells (HSPCs) mobilized to peripheral blood, rather than those remaining in the bone marrow (BM), are commonly used as stem cell source in the clinic. As reactive oxygen species (ROS) are suggested as mediator of HSPC mobilization, we examined the impacts of glucose oxidase (GO) on peripheral mobilization of BM HSPCs and the associated mechanisms. Intravenous injection of GO induced HSPC mobilization even by single treatment, and the GO-mobilized cells maintained their long-term reconstituting and differentiating potentials in conditioned recipients. GO-injected mice lived a normal life without adverse effects such as stem cell senescence, hematopoietic disorders, and blood parameter alteration. The mobilization effect of GO was even evident in animal models showing poor mobilization, such as old, 5-fluorouracil-treated, or alendronate-treated mice. Importantly, combined injection of GO with granulocyte colony-stimulating factor (G-CSF) and/or AMD3100 enhanced more greatly HSPC mobilization than did G-CSF, AMD3100, or both. The GO-stimulated HSPC mobilization was almost completely attenuated by N-acetyl-L-cysteine treatment. Collectively, our results not only highlight the potential role of GO in HSPC mobilization via ROS signaling, but also provide a GO-based new strategy to improve HSPC mobilization in poorly mobilizing allogeneic or autologous donors via combination with G-CSF and/or AMD3100.
| S-EPMC8459634 | biostudies-literature
Project description:Hematopoietic stem progenitor cells (HSPCs) are present in very small numbers in the circulating blood in steady-state conditions. In response to stress or injury, HSPCs are primed to migrate out of their niche to peripheral blood. Mobilized HSPCs are now commonly used as stem cell sources due to faster engraftment and reduced risk of posttransplant infection. In this study, we demonstrated that a nucleotide sugar, UDP-glucose, which is released into extracellular fluids in response to stress, mediates HSPC mobilization. UDP-glucose-mobilized cells possessed the capacity to achieve long-term repopulation in lethally irradiated animals and the ability to differentiate into multi-lineage blood cells. Compared with G-CSF-mobilized cells, UDP-glucose-mobilized cells preferentially supported long-term repopulation and exhibited lymphoid-biased differentiation, suggesting that UDP-glucose triggers the mobilization of functionally distinct subsets of HSPCs. Furthermore, co-administration of UDP-glucose and G-CSF led to greater HSPC mobilization than G-CSF alone. Administration of the antioxidant agent NAC significantly reduced UDP-glucose-induced mobilization, coinciding with a reduction in RANKL and osteoclastogenesis. These findings provide direct evidence demonstrating a potential role for UDP-glucose in HSPC mobilization and may provide an attractive strategy to improve the yield of stem cells in poor-mobilizing allogeneic or autologous donors.
| S-EPMC3726149 | biostudies-other