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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.

PROVIDER: EGAS00001003756 | EGA |

REPOSITORIES: EGA

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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.

2019-11-19 | GSE125213 | GEO

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.

| EGAD00001005140 | EGA

Human hematopoietic stem cell expansion through modulation of lineage-associated gene expression programs

Project description:Hematopoietic stem cells (HSCs) must balance self-renewal and lineage differentiation to regenerate the hematopoietic system throughout life. HSCs exhibit lineage-associated gene expression that keeps them responsive to demands of mature blood production. However, it is not known whether this process, termed lineage priming, directly influences HSC self-renewal. We investigated the link between stemness and lineage priming by attenuating the early lymphoid transcription factor E47 through ID2 over-expression (OE). Transcriptional profiling of ID2 OE HSCs showed down regulation of B-cell factors including EBF1 and FOXO1 with a concomitant increase in stemness programs and myeloerythroid factors including CEBPA and GATA1. This resulted in myeloid commitment bias from the earliest stages of differentiation. HSC self-renewal was strongly affected by this lineage perturbation resulting in an 11-fold expansion of HSCs. Thus, early lymphoid transcription factors antagonize human HSC self-renewal, providing a direct link between differentiation program priming and the maintenance of stem cell self-renewal. Three independent lineage depleted CB samples were transduced with P-CTRL or P-ID2 and injected into 5 mice (30 mice total). From every group of 5 mice, human lin- cells were isolated and GFP+CD34+CD38-CD45RA- HSPCs were sorted by FACS.

2013-12-01 | E-GEOD-45486 | biostudies-arrayexpress

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

MYCT1 CONTROLS ENVIRONMENTAL SENSING IN HUMAN HEMATOPOIETIC STEM CELLS

Project description:Hematopoietic stem cells (HSC) rely on a unique regulatory machinery that facilitates life-long blood production and enables reconstitution of the entire hematopoietic system upon transplantation. However, the biological processes governing human HSC self-renewal and engraftment ability are poorly understood and challenging to recapitulate ex vivo to facilitate robust human HSC expansion. We discovered a novel HSC regulatory protein, MYCT1 (MYCT target 1), that is selectively expressed in endothelial cells (EC) and undifferentiated human HSPCs but becomes drastically downregulated during HSC culture. Lentiviral knockdown of MYCT1 in human foetal liver and cord blood HSPCs revealed a critical role for MYCT1 in governing human HSPC expansion and engraftment ability. Single cell RNAseq of human CB HSPCs after MYCT1 knockdown and overexpression revealed that MYCT1 governs HSC functional competence and modulates cellular properties essential for HSC stemness, such as low mitochondrial metabolic activity. Indeed, restoring the compromised MYCT1 expression in cultured human CB HSPCs improved ex vivo expansion of the most undifferentiated human HSPCs and enhanced their engraftment ability. We found that MYCT1 is localized in the endosomal membrane and interacts with vesicle trafficking regulators and signalling machinery essential for HSC and EC function. Loss of MYCT1 led to excessive endocytosis and hyperactive signalling responses to cytokines, whereas restoring MYCT1 expression in cultured CB HSPCs balanced the abnormal endocytosis associated with prolonged culture and fine-tuned signalling responses. Our work identifies MYCT1-moderated endocytosis and environmental sensing as an essential regulatory mechanism required to preserve human HSC stemness, and pinpoints silencing of MYCT1 as a critical contributor to the dysfunction of cultured human HSCs that needs to be addressed to improve human HSC culture strategies.

2024-04-15 | PXD042257 | Pride

Microarray analysis of human hematopoietic stem cells (HSC) treated or not with antioxidants and cultured 2 days against uncultured HSC

Project description:HSC endured stress upon culture, that led to decrease their functional properties (i.e. decreased HSC self-renewal potential). Here we study the impact of antioxidants in the maintenance of HSC cultured 2 days in vitro.

2023-09-16 | E-MTAB-12121 | biostudies-arrayexpress

Targeting JNK Pathway Expands Human Hematopoietic Stem Cells

Project description:The limited number of human hematopoietic stem cells (HSCs) has restrained their widespread clinical application. Despite great efforts in recent years, the in vitro expansion of HSCs remains a challenge due to incomplete understanding of the signaling networks underlying HSC self-renewal. Here we show that culturing human cord blood (CB) CD34+ cells with JNK-IN-8, an inhibitor of the JNK signaling pathway, can enhance the self-renewal of HSCs with a 6-fold increase in number. These expanded CD34+ cells repopulated recipient mice for 20 weeks and can form secondary engraftment that lasted for more than 21 weeks. Knockdown of c-Jun, a major downstream target in the JNK pathway, significantly promoted the expansion of hematopoietic stem and progenitor cells (HSPCs). Our findings demonstrate a critical role of JNK pathway in regulating HSC expansion, provide new insights into HSC self-renewal mechanism, and may lead to improved clinical application of HSCs.

2019-01-17 | GSE114524 | GEO

miR-146 modulation in ALS astrocytes

Project description:Regarding astrocytes and microglia, we are looking for pathways related with inflammatory activation, phagocytosis and vesicular/exosome trafficking. Regarding motor neurons, we are searching for pathways related with mitochondrial dynamics, Endoplasmic Reticulum stress, cell death, axonal transport, synaptic vesicles transport and oxidative stress. The general aim is to identify putative hits in ALS that relates with miR-146a expression.

2021-04-06 | PXD024294 | Pride

Young and old HSCs from WT and Lnk-/- mice

Project description:The adaptor protein Lnk is an important negative regulator of HSC homeostasis and self-renewal. This study aims to investigate the role of Lnk in HSC aging. Here we performed expression profiling of bone marrow CD150+CD48-LSK LT-HSCs from young and old WT and Lnk-/- mice. Results identify select Lnk-mediated pathways with potential involvement in HSC self-renewal and aging.

2012-10-03 | GSE39553 | GEO

Zfx controls the self-renewal of embryonic and hematopoietic stem cells

Project description:Stem cells (SC) exhibit a unique capacity for self-renewal in an undifferentiated state. It is unclear whether the self-renewal of pluripotent embryonic SC (ESC) and of tissue-specific adult SC such as hematopoietic SC (HSC) is controlled by common mechanisms. The deletion of transcription factor Zfx impaired the self-renewal but not the differentiation capacity of murine ESC; conversely, Zfx overexpression facilitated ESC self-renewal by opposing differentiation. Furthermore, Zfx deletion abolished the maintenance of adult bone marrow HSC, but did not affect erythromyeloid progenitors or fetal HSC. In both ESC and HSC, Zfx activated a common set of direct target genes. In addition, the loss of Zfx resulted in the induction of immediate-early and/or stress-inducible genes in both SC types but not in their differentiated progeny. These studies identify the first shared transcriptional regulator of ESC and HSC, suggesting a common molecular basis of self-renewal in embryonic and adult SC. Keywords: Global gene expression data analysis in Zfx-deficient murine ESC and HSC

2007-04-20 | GSE7069 | GEO

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