Ex vivo cultured mouse LT-HSCs RNA-seq
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ABSTRACT:
PROVIDER: PRJNA815304 | ENA |
REPOSITORIES: ENA
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Project description:Mouse LT-HSCs were co-cultured with polymer nanospheres for ex vivo expansion
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Project description:Transplantation with low numbers of hematopoietic stem cells (HSCs), found in many of the publically accessible cryopreserved umbilical cord blood (UCB) units, leads to delayed time to engraftment, high graft failure rates, and early mortality in many patients. A chemical screen in zebrafish identified the prostaglandin compound, 16,16 dimethyl prostaglandin E2 (dmPGE2), to be a critical regulator of hematopoietic stem cell homeostasis. We hypothesized that an ex vivo modulation with dmPGE2 prior to transplantation would lead to enhanced engraftment by increasing the “effective” dose of hematopoietic stem cells (HSCs) in cord blood. A phase I trial of reduced-intensity double UCB transplantation was performed to evaluate safety, rates of engraftment and fractional chimerism of dmPGE2 enhanced UCB units. To explore potential causes of the lack of enhanced efficacy in the first cohort, we characterized HSCs to determine whether the prostaglandin pathway was being activated under the ex vivo incubation conditions (4°C, 10µM dmPGE2, 60 minutes). Incubation conditions were identified (37°C, 10µM dmPGE2, 120 minutes) that maximize the activation of the prostaglandin pathway by dmPGE2 in human CD34+ cells. Isolated human CD34+ from umbilical cord blood were incubated ex vivo in Stem Span media with 10uM 16,16-dmPGE2 or DMSO. Two treatment conditions were evaluated (4 deg C for 1 hour, 37 deg C for 2 hours) with either 3 or 7 biological replicates at each condition. Total RNA was isolated post incubation and analyzed on Affymetrix microarrays for pathway activation.
2012-04-15 | E-GEOD-36547 | biostudies-arrayexpress
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
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.
2013-07-17 | GSE48539 | GEO
Project description:To investigate how ex vivo culture affects chromatin accessibility in cultured HSC, we performed the Assay for Transposase Accessible Chromatin with high-throughput sequencing (ATAC-Seq) on cLT (CD34+CD90+CD45RA-) and cST populations purified from 8 day cultured lineage depleted cord blood (lin- CB) cells treated with 3-Factor (4HPR+UM171+SR1), U+S or 4HPR as well as untreated and vehicle-treated (DMSO) control populations. The subsequent ATAC-seq data was compared to chromatin accessibility signatures generated from uncultured hematopoietic stem and progenitor populations (Takayama, et al.). We found that ex vivo culture shifted cLT and cST cells isolated from control or untreated samples to a chromatin accessibility profiles not found in LT-HSC, suggesting some loss of a stem-cell associated chromatin state. By contrast, 4HPR-treated, to some extent, and 3-Factor-treated HSC maintained chromatin accessibility features of uncultured LT-HSC.
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Project description:We performed tagmentation-based whole-genome bisulfite sequencing on young and aged LT-HSCs.
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Project description:Transplantation with low numbers of hematopoietic stem cells (HSCs), found in many of the publically accessible cryopreserved umbilical cord blood (UCB) units, leads to delayed time to engraftment, high graft failure rates, and early mortality in many patients. A chemical screen in zebrafish identified the prostaglandin compound, 16,16 dimethyl prostaglandin E2 (dmPGE2), to be a critical regulator of hematopoietic stem cell homeostasis. We hypothesized that an ex vivo modulation with dmPGE2 prior to transplantation would lead to enhanced engraftment by increasing the “effective” dose of hematopoietic stem cells (HSCs) in cord blood. A phase I trial of reduced-intensity double UCB transplantation was performed to evaluate safety, rates of engraftment and fractional chimerism of dmPGE2 enhanced UCB units. To explore potential causes of the lack of enhanced efficacy in the first cohort, we characterized HSCs to determine whether the prostaglandin pathway was being activated under the ex vivo incubation conditions (4°C, 10µM dmPGE2, 60 minutes). Incubation conditions were identified (37°C, 10µM dmPGE2, 120 minutes) that maximize the activation of the prostaglandin pathway by dmPGE2 in human CD34+ cells.
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Project description:We report differences in gene expression between WT and Fam122a KO LT-HSCs.
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Project description:Investigation of circular RNAs that have a higher expression level in LT-HSCs
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Project description:Loss of Phf6 prevents the functional decline and immunophenotypic changes associated with age-related, long-term repopulating hematopoietic stem cell (LT-HSC) exhaustion. To identify the underlying molecular mechanisms that account for these differences, we performed RNA-seq profiling of LT-HSCs isolated from the bone marrow of Phf6 wild-type and knock-out, young (16-week-old) and aged (24-month-old) C57BL/6 mice. Our analysis revealed that LT-HSCs isolated from 24-month-old, Phf6 knockout mice retained the molecular signatures associated with young LT-HSCs whereas LT-HSCs isolated from aged, Phf6 wild-type mice acquired signatures consistent with HSC exhaustion. Mechanistically, these data revealed important roles for key metabolic pathways including glutathione metabolism and sterol biosynthesis, as well as cell-cell interaction and signaling pathways such as the interferon and TGF-beta responses.
2022-11-01 | GSE165695 | GEO