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Single-cell reconstitution reveals persistence of clonal heterogeneity in the murine hematopoietic system [RNA-seq]

ABSTRACT: We transplanted a single HSC into irradiated mice, creating a clonal hematopoietic system. Using RNA-Seq on the cDNA of the peripheral compartments (T cells, B cells), we studied mitotically stable transcriptional states of the alleles of the entire transcriptome on the differentiating HSC.

ORGANISM(S): Mus musculus

PROVIDER: GSE174038 | GEO | 2022/05/20

REPOSITORIES: GEO

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Single-cell reconstitution reveals persistence of clonal heterogeneity in the murine hematopoietic system [WES]

Project description:We transplanted a single HSC into irradiated mice, creating a clonal hematopoietic system. This allowed us to study mitotically stable allelic imbalances at peripheral compartments (T cells, B cells).

2022-05-20 | GSE174039 | GEO

Label-free quantitative proteomics analysis of bone marrow cells of MK-LCM WT versus KO mice

Project description:High ploidy large cytoplasmic megakaryocytes (LCM) are critical negative regulators of hematopoietic stem cells (HSC) and are responsible for platelet formation. Using a mouse knockout model with normal megakaryocyte numbers but essentially devoid of LCM (MK-LCM KO), we demonstrated a pronounced increase in bone marrow HSC concurrent with endogenous mobilization and extramedullary hematopoiesis. When HSC isolated from a MK-LCM KO microenvironment were transplanted in lethally irradiated mice, the absence of LCM increased HSC in BM, blood and spleen. Severe thrombocytopenia was observed in animals with diminished LCM, although there was no change in megakaryocyte ploidy distribution. In contrast, WT HSC-generated LCM regulated a normal HSC pool and prevented thrombocytopenia. The present label-free quantitative LC-MSMS data was used to determine proteins that are differentially expressed in bone marrow cells of MK-LCM WT versus MK-LCM KO mice.

2023-05-10 | PXD040423 | Pride

Longâterm engraftment of primary bone marrow stroma promotes hematopoietic reconstitution after transplantation

Project description:Restoration of hematopoiesis upon bone marrow (BM) transplantation relies on the engraftment, expansion and function of transplanted hematopoietic stem cells (HSC). However, the number of donorâderived HSC typically remain much below that present in normal individuals and this likely limits and delays hematopoietic recovery. HSC depend on supportive stromal niches, however, whether the preâconditioning required for BM transplantation damages this stromal niche has not been evaluated extensively. Using mouse models, we now find that that BM stroma cells (BMSC) are severely and permanently damaged by preâconditioning. Transplantation of primary but not cultured BMSC quantitatively reconstitutes stroma function in vivo, which is mediated by a multipotent CD73+ CD105â Sca1+ BMSC subpopulation. BMSC coâtransplantation significantly ameliorates clinical side effects of BM transplantation and doubles expansion of functional, donorâ derived HSC, demonstrating the potential of stroma transplantation to improve HSC transplantation. Purified CD45âTer119âCD73+ CD105â and CD45âTer119âCD73+ CD105+ cells were directly sorted on lysis buffer with FACS Aria 2 in triplicate.

2016-09-01 | E-GEOD-79091 | biostudies-arrayexpress

RNA seq of CD45.2+ Neo1 deficient or wildtype Hematopoietic stem cells, 4 or 15 month after stem cell transplantation

Project description:To study the role of the receptor Neo1 in Hematopoietic stem cells (HSC) we transplanted Neo1 deficient bone marrow and wildtype controls on a CD45.2 background into lethally irradiated CD45.1 recipients. Either 4 or 15 months after transplantation we isolated HSC (Lineage -, Sca-1+, c-Kit+, Cd150+, CD48-, CD34-, CD45.2+) to identify molecular differences due to Neo1 deficiency and found a loss of HSC quiescence and signatures associated with decreased stem cell function.

2020-07-22 | E-MTAB-7902 | biostudies-arrayexpress

Single-cell reconstitution reveals persistence of clonal heterogeneity in the murine hematopoietic system

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-05-20 | GSE174040 | GEO

Gene expression profiling of HOXB4-transduced murine hematopoietic stem cells

Project description:Overexpression of HOXB4 in hematopoietic stem cells (HSCs) leads to increased self-renewal without causing hematopoietic malignancies in transplanted mice. The molecular basis of HOXB4-mediated benign HSC expansion in vivo is not well understood. To gain further insight into the molecular events underlying HOXB4-mediated HSC expansion, we analyzed gene expression changes at multiple time points in Lin-Sca1+c-kit+ (LSK) cells from mice transplanted with bone marrow (BM) cells transduced with a MSCV-HOXB4-ires-YFP vector. A distinct HOXB4 transcriptional program was reproducibly induced and stabilized by 12 weeks after transplant. Dynamic expression changes were observed in genes critical for HSC self-renewal as well as genes involved in myeloid and B cell differentiation. Prdm16, a transcription factor associated with human acute myeloid leukemia (AML), was markedly repressed by HOXB4 but upregulated by HOXA9 and HOXA10, suggesting that Prdm16 downregulation was involved in preventing leukemia in HOXB4 transplanted mice. Functional evidence to support this mechanism was obtained by enforcing co-expression of sPrdm16 and HOXB4, which led to enhanced self-renewal, myeloid expansion, and leukemia. Altogether, these studies define the transcriptional pathways involved in HOXB4 HSC expansion in vivo and identify repression of Prdm16 transcription as a mechanism by which expanding HSCs avoid leukemic transformation. 5-FU treated bone marrow cells from female C57Bl/6L mice were transduced with concentrated supernatant from GPE+86-derived producer cells containing MSCV-HOXB4-ires-YFP or MSCV-ires-GFP retroviral vectors. Transduced cells were transplanted into lethally irradiated C57Bl/6L mice. HOXB4-YFP or GFP expressing LSK cells were sorted from transplanted mice at 6, 12 and 24 weeks post transplantation, of which RNA was extracted for microarray.

2014-10-01 | E-GEOD-59804 | biostudies-arrayexpress

TRACE-Seq Reveals Clonal Reconstitution Dynamics of Gene Targeted Human Hematopoietic Stem Cells

Project description:We present Tracking Recombination Alleles in Clonal Engraftment using sequencing (TRACE-Seq), a novel methodology that utilizes barcoded rAAV6 donor template libraries, carrying either in-frame silent mutations or semi-randomized nucleotide sequences outside the coding region, to track the in vivo lineage contribution of gene targeted HSPC clones. By targeting the HBB gene with a rAAV6 donor template library consisting of ~20,000 possible unique exon 1 in-frame silent mutations, we track the hematopoietic reconstitution of HBB targeted myeloid-only, lymphoid-only, and multi-lineage repopulating human HSPC clones in immunodeficient mice.

2020-08-09 | GSE155910 | GEO

PDGFB-expressing MSCs improve human hematopoietic stem cell engraftment in immunodeficient mice

Project description:The bone marrow (BM) niche regulates multiple HSC processes. Clinical treatment for hematological malignancies, by HSC transplantation often requires preconditioning total body irradiation, which severely and irreversibly impairs the BM niche and HSC regeneration. Novel strategies to enhance HSC regeneration in irradiated BM are needed. We compared the effects of niche factors EGF, FGF2 and PDGFB on HSC hematopoietic regeneration using human MSCs that were transduced with these factors via lentiviral vectors. Among above niche factors tested, PDGFB-MSCs most significantly improved human hematopoietic cell engraftment in immunodeficient mice. PDGFB-MSC-treated BM more efficiently enhanced transplanted human HSC self-renewal in secondary transplantations from primary recipients. Although PDGFB-MSCs did not directly increase HSC expansion in vitro, GSEA revealed anti-apoptotic signaling being increased in PDGFB-MSCs versus GFP-MSCs. PDGFB-MSCs had enhanced survival and expansion after transplantation, leading to an enlarged humanized niche cell pool. Our study demonstrates the efficacy of MSC-mediated niche factors in clinical HSC transplantation for patients.

2020-06-22 | GSE113857 | GEO

global gene expression profiling experiments of HSC cultured in cysteine or valine deficient medium by RNA-sequencing analysis

Project description:We investigated the role of amino acid to maintain HSC function. To identify essential amino acids for HSCs, CD34-KSL cells were cultured in single amino acids deficient medium. And cultured cells were transplanted into lethally irradiated mice. Then, the donor chimerism and lineage contribution was estimated. Surprisingly, HSC proliferation was prevented in valine and cysteine deficient medium in vitro. Donor cells cultured in these medium were also not engrafted. To elucidate the effects and influences of cysteine and valine in HSCs, we performed global gene expression profiling experiments by RNA-sequencing analysis. Gene sets categorized with cell cycle, mitosis, cell division or DNA replication were strongly down-regulated in both valine- or cysteine-depleted conditions These results imply distinctive amino-acid metabolism involved in HSC division.

2016-06-26 | GSE70307 | GEO

Global methylation alterations in Dnmt3aKO derived malignancies

Project description:To test the long-term effects of lack of Dnmt3a on mouse HSCs, we established a cohort of lethally irradiated mice transplanted with Dnmt3a-KO or WT HSC control cells. Dnmt3a deletion in purified HSCs transplanted alone leads to an array of hematologic disorders that models the spectrum of disorders seen in human malignancies. We investigated DNA methylation alterations in disease and control mice by RRBS. We generated an average of 23.81 million reads per sample (18.97 - 31.67 million) of which an average of 18.07 million could be mapped to the mm9 genome (2.78 - 26.42 million). We achieved an average CpG coverage depth of 31.79-fold (8.09 - 47.44-fold) and average bisulfite conversion efficiency of 99.91% (99.87 - 99.95%). Reduced representation bisulfite sequencing of cells using Illumina HiSeq 2000 and 2500

2014-12-08 | E-GEOD-60264 | biostudies-arrayexpress

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