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Transient inhibition of JNK pathway improves hematopoietic stem cell engraftment

ABSTRACT: Transient inhibition of JNK pathway improves hematopoietic stem cell engraftment

PROVIDER: PRJNA694702 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13523931_1.fastq.gz	Fastqsanger.gz
	SRR13523931_2.fastq.gz	Fastqsanger.gz
	SRR13523932_1.fastq.gz	Fastqsanger.gz
	SRR13523932_2.fastq.gz	Fastqsanger.gz
	SRR13523933_1.fastq.gz	Fastqsanger.gz

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Transient inhibition of JNK pathway improves hematopoietic stem cell engraftment

Project description:We found that transient inhibition of JNK pathway increased short term-HSC frequency in cord blood CD34+ cells by 12.56 folds. Transcriptome analysis shows that inhibition of JNK pathway upregulated HSC-specific and anti-oxidative gene expression, prevented upregulation of cell cycle entry, oxidative phosphorylation and glycolysis related gene expression, and downregulated reactive oxygen species (ROS) active gene expression. Consistently, cell cycle and metabolic analysis show that inhibition of JNK pathway prevented HSC from cell cycle entry, glucose uptake increase and ROS accumulation. Accordingly, transient inhibition of JNK pathway also enhanced long term-HSC recovery during cord blood CD34+ cell collection. Collectively, these findings suggest that transient inhibition of JNK pathway could promote quiescent state of HSCs by preventing cell cycle entry and metabolic activation, thus improving HSC recovery and engraftment ability.

2022-06-29 | GSE165501 | GEO

Stromal Repair via Long-term Engraftment of Primary Bone Marrow Stroma Improves Hematopoietic Stem Cell Transplantation

Project description:Stromal Repair via Long-term Engraftment of Primary Bone Marrow Stroma Improves Hematopoietic Stem Cell Transplantation

2017-07-02 | GSE79091 | GEO

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

Human hematopoietic stem cell engraftment in goat

Project description:Human hematopoietic stem cell engraftment in goat

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Transient Inhibition of the JNK Pathway Promotes Human Hematopoietic Stem Cell Quiescence and Engraftment.

Project description:The widespread clinical application of cord blood (CB) for hematopoietic stem cell (HSC) transplantation is limited mainly by the inadequate number of hematopoietic stem and progenitor cells (HSPCs) in single CB units, which results in unsuccessful or delayed engraftment in recipients. The identification of agents to promote CB HSPC engraftment has significant therapeutic value. Here, we found that transient inhibition of the JNK pathway increased the HSC frequency in CB CD34+ cells to 13.46-fold. Mechanistic studies showed that inhibition of the JNK pathway upregulated the expression of quiescence-associated and stemness genes in HSCs, preventing HSCs from entering the cell cycle, increasing glucose uptake and accumulating reactive oxygen species (ROS). Importantly, transient inhibition of the JNK pathway during CB CD34+ cell collection also enhanced long-term HSC (LT-HSC) recovery and engraftment efficiency. Collectively, these findings suggest that transient inhibition of the JNK pathway could promote a quiescent state in HSCs by preventing cell cycle entry and metabolic activation, thus enhancing the HSC number and engraftment potential. Together, these findings improve the understanding of the regulatory mechanisms governing HSC quiescence and stemness and have the potential to improve HSC collection and transplantation.

| S-EPMC9216500 | biostudies-literature

Targeting JNK Pathway Expands Human Hematopoietic Stem Cells

Project description:Targeting JNK Pathway Expands Human Hematopoietic Stem Cells

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PRC2 inhibition counteracts the culture-associated loss of engraftment potential of human cord blood-derived hematopoietic stem and progenitor cells

Project description:Cord blood hematopoietic stem cells (CB-HSCs) are an outstanding source for transplantation approaches. However, the amount of cells per donor is limited and culture expansion of CB-HSCs is accompanied by a loss of engraftment potential. In order to analyze the molecular mechanisms leading to this impaired potential we profiled global and local epigenotypes during the expansion of human CB hematopoietic stem and progenitor cells (HPSCs). Human CB-derived CD34+ cells were cultured in serum-free medium together with SCF, TPO, FGF, with or without Igfbp2 and Angptl5 (STF/STFIA cocktails). As compared to the STF cocktail, the STFIA cocktail maintains in vivo repopulation capacity of cultured CD34+ cells. Upon expansion, CD34+ cells genome-wide remodel their epigenotype and depending on the cytokine cocktail, cells show different H3K4me3 and H3K27me3 levels. Expanding cells without Igfbp2 and Angptl5 leads to higher global H3K27me3 levels. ChIPseq analyses reveal a cytokine cocktail-dependent redistribution of H3K27me3 profiles. Inhibition of the PRC2 component EZH2 counteracts the culture-associated loss of NOD scid gamma (NSG) engraftment potential. Collectively, our data reveal chromatin dynamics that underlie the culture-associated loss of engraftment potential. We identify PRC2 component EZH2 as being involved in the loss of engraftment potential during the in vitro expansion of HPSCs. 6 samples were hybridized GeneChip Human Gene 1.0 ST Arrays (Affymetrix)

2015-08-07 | E-GEOD-58461 | biostudies-arrayexpress

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

Mllt3 Governs Self-Renewal And Engraftment Of Human Hematopoietic Stem Cells

Project description:Mllt3 Governs Self-Renewal And Engraftment Of Human Hematopoietic Stem Cells

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High-throughput characterization of hematopoietic stem cell engraftment after intravenous and intracerebroventricular dosing

Project description:Hematopoietic stem/progenitor cell gene therapy (HSPC-GT) has shown clear neurological benefit in rare diseases, which is achieved through the engraftment of genetically modified microglia-like cells (MLCs) in the brain. Still, the engraftment dynamics and the nature of engineered MLCs, as well as their potential use in common neurogenerative diseases have remained largely unexplored. Here, we firstly comprehensively characterized how different routes of administration affect the biodistribution of genetically engineered MLCs and other HSPC-derivatives in mice. We then generated a high-resolution single cell transcriptional map of MLCs and discovered that they could clearly be distinguished from macrophages as well as from resident microglia by the expression of a specific gene signature which is reflective of their HSPC ontogeny and irrespective of their long-term engraftment history. Lastly, using murine models of Parkinson’s disease and frontotemporal dementia, we demonstrated that MLCs can deliver therapeutically relevant levels of protein to the brain, thereby opening avenues for the clinical translation of HSPC-GT to the treatment of major neurological diseases.

2022-05-31 | GSE201756 | GEO

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