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RNA-seq of cultured human hematopoietic stem and progenitor cells from umblical cord blood in cytokine-rich ex vivo culture conditions following sphingolipid modulation

ABSTRACT: To elucidate the biological pathways altered by sphingolipid modulation with N-(4-hydroxyphenyl) retinamide (4HPR) treatment in human HSPC that may contribute to the restraint in proliferation while promoting persistence of HSC self-renewal as well as determine the mechanism of synergy in enhancement of HSC self-renewal with CB CD34+ agonists UM171 and StemRegenin 1 (SR1), we performed RNA-sequencing (RNA-Seq) of 3 pools of lin-CB cells following 2 or 4 days with DMSO, 4HPR, UM171+SR1 or 3-Factor (4HPR+UM171+SR1). We identified modulation of sphingolipid metabolism regulates self-renewal through activating coordinated stress pathways that coalesce on endoplasmic reticulum stress and autophagy programs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE125213 | GEO | 2019/11/19

REPOSITORIES: GEO

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RNA-seq of cultured human hematopoietic stem and progenitor cells from umblical cord blood in cytokine-rich ex vivo culture conditions following sphingolipid modulation

Project description:To elucidate the biological pathways altered by sphingolipid modulation with N-(4-hydroxyphenyl) retinamide (4HPR) treatment in human HSPC that may contribute to the restraint in proliferation while promoting persistence of HSC self-renewal as well as determine the mechanism of synergy in enhancement of HSC self-renewal with CB CD34+ agonists UM171 and StemRegenin 1 (SR1), we performed RNA-sequencing (RNA-Seq) of 3 pools of lin-CB cells following 2 or 4 days with DMSO, 4HPR, UM171+SR1 or 3-Factor (4HPR+UM171+SR1). We identified modulation of sphingolipid metabolism regulates self-renewal through activating coordinated stress pathways that coalesce on endoplasmic reticulum stress and autophagy programs.

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ena-DATASET-UHN-12-07-2019-21:18:48:905-1513 - samples

Project description:In order to elucidate the biological pathways altered by sphingolipid modulation with N-(4-hydroxyphenyl) retinamide (4HPR) treatment in human HSPC that may contribute to the restraint in proliferation while promoting persistence of HSC self-renewal, as well as determine the mechanism of synergy in enhancement of HSC self-renewal with CB CD34+ agonists UM171 and StemRegenin 1 (SR1), we performed RNA-sequencing (RNA-Seq) of 3 pools of lin-CB cells following 2 or 4 days with DMSO, 4HPR, UM171+SR1 or 3-Factor (4HPR+UM171+SR1). We identified modulation of sphingolipid metabolism regulates self-renewal through activating coordinated stress pathways that coalesce on endoplasmic reticulum stress and autophagy programs.

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RNA expression profiling of human mPB or CB-derived CD34+ cells treated with UM171 at different doses

Project description:RNASeq data for mPB or CB-derived CD34+ exposed to UM171 human mobilized peripheral blood or cord blood-derived CD34(+) cells were cultured for 16 hours with vehicle (DMSO), dose response of UM171 [11.9nM, 19nM, 30.5nM, 48.8nM, 78.1nM and 125nM], SR1 [500nM] and combination of( UM171 [48.8nM]+SR1 [500nM])

2014-10-21 | E-GEOD-57561 | biostudies-arrayexpress

Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells

Project description:Although practiced clinically for more than 40 years, the use of hematopoietic stem cell (HSC) transplants remains limited by the ability to expand these cells ex vivo. An unbiased screen with primary human HSCs identified a purine derivative, StemRegenin 1 (SR1), that promotes the ex vivo expansion of CD34+ cells. Culture of HSCs with SR1 led to a 50-fold increase in cells expressing CD34 and a 17-fold increase in cells that retain the ability to engraft immunodeficient mice. Mechanistic studies show that SR1 acts by antagonizing the aryl hydrocarbon receptor (AHR). The identification of SR1 and AHR modulation as a means to induce ex vivo HSC expansion should facilitate the clinical use of HSC therapy. LGC006, a less potent SR1 analog, was also examined. KEYWORDS: two compounds, multiple doses, one time point two compounds, multiple doses, one time point

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ATAC-seq of immunophenotypic LT-HSC and ST-HSC from umblical cord blood in cytokine-rich ex vivo culture conditions following sphingolipid modulation

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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Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells

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UM171 induces a homeostatic inflammatory-detoxification response supporting human HSC self-renewal

Project description:Elucidation of the molecular cues required to balance adult stem cell self-renewal and differentiation is critical for advancing cellular therapies. Herein, we report that the hematopoietic stem cell (HSC) self-renewal agonist UM171 triggers a balanced pro- and anti-inflammatory/detoxification network that relies on NFKB activation and protein C receptor-dependent ROS detoxification, respectively. We demonstrate that within this network, EPCR serves as a critical protective component as its deletion hypersensitizes primitive hematopoietic cells to pro-inflammatory signals and ROS accumulation resulting in compromised stem cell function. Conversely, abrogation of the pro-inflammatory activity of UM171 through treatment with dexamethasone, cAMP elevating agents or NFKB inhibitors abolishes EPCR upregulation and HSC expansion. Together, these results show that UM171 stimulates ex vivo HSC expansion by establishing a critical balance between key pro- and anti-inflammatory mediators of self-renewal.

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Transcriptome data of CD34+ human cord blood-derived cell treated with UM171, SR1 or both

Project description:mRNA profiling of CD34+ human cord blood-derived cell treated with UM171, SR1 or both mRNA profiles of CD34+ human cord blood-derived cell treated with DMSO (control), SR1 [500nM], UM171 [35nM] or combination SR1 [500nM]+ UM171 [35nM] for 30min, 3hr, 12hr, 24hr, 48hr, 72hr were generated by deep sequencing

2014-10-21 | E-GEOD-57299 | biostudies-arrayexpress

Gene Expression data human HSCs with 2-LSD1 inhibitors

Project description:Human CB HSC enriched fractions were treated with LSD1 inhibitor 2-PCPA and UM171 to identify differntially regulated genes by these compounds.

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miR-125a Confers Multi-Lineage Long-Term Repopulating Stem Cell Activity to Murine and Human Hematopoietic Progenitors

Project description:Umbilical cord blood (CB) is a non-invasive, convenient and broadly used source of hematopoietic stem cells (HSCs) for allogeneic stem cell transplantation. However, limiting numbers of HSCs remain a major constraint for its clinical application. One feasible option would be to expand HSCs to improve therapeutic outcome, however available protocols and the molecular mechanisms governing the self-renewal of HSC are unclear. Here we show that ectopic expression of a single miRNA, miR-125a, in purified murine and human multipotent progenitors (MPP) resulted in increased self-renewal and robust long-term multi-lineage repopulation in transplanted recipient mice. Using quantitative proteomics and Western blot analysis, we identified a restricted set of miR-125a targets which revealed the involvement of the MAP kinase signaling pathway in conferring long-term repopulating capacity to multipotent progenitors in human and mice. Our findings offer the innovative potential to use MPP with enhanced self-renewal activity to augment limited sources of HSC to improve clinical protocols.

2017-01-11 | PXD003931 | Pride

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