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

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

PROVIDER: PRJNA576785 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10256947_1.fastq.gz	Fastqsanger.gz
	SRR10256947_2.fastq.gz	Fastqsanger.gz
	SRR10256948_1.fastq.gz	Fastqsanger.gz
	SRR10256948_2.fastq.gz	Fastqsanger.gz
	SRR10256949_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

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.

2019-11-25 | GSE138680 | GEO

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.

| S-EPMC6839847 | biostudies-literature

Deciphering the effect of UM171 on human hematopoietic progenitor cell fate through clonal analysis

Project description:Ex vivo expansion of hematopoietic stem cells (HSC) requires the maintenance of a stemness state while cells are proliferating. This can be achieved via exposure to UM171 which leads to the degradation of chromatin modifiers and prevents the loss of key epigenetic marks. However, the chromatin landscape varies across populations within the hematopoietic system and the effect of UM171 on self-renewal and differentiation potential of different hematopoietic progenitor cells is less characterized. To address this, we used the CellTag barcoding approach to track the fate of individual stem and progenitor cells during in vitro expansion. We showed that in addition to its HSC self-renewing property, UM171 specifically modulates cell fate of a precursor common to erythroid, megakaryocytic, and mast cells in favor of self-renewal and a mast-bias differentiation trajectory. This differentiation bias can be driven by pro-inflammatory signaling pathways that are activated downstream of UM171 and resulted in an abundant mast cell population that can be transplanted as part of the graft to populate mice tissues in xenotransplantation studies.

2024-11-12 | GSE264199 | GEO

Expression profiling of fresh, DMSO or UM171 expanded CD34+ cells by high throughput sequencing

Project description:Ex-vivo expansion of hematopoietic stem cells (HSCs) is gaining in importance for cell and gene therapy and requires a shift from dormancy state to activation and cycling. However, abnormal or excessive HSC activation results in reduced self-renewal ability and increased propensity for myeloid-biased differentiation. To date, the threshold of HSC activation that marks “the point of no return” is undetermined. Identifying the molecular determinants that restrain or control HSC activation is essential for preventing accelerated exhaustion of cultured-HSCs. We now report that activation of the E3 ligase complex CRL3KBTBD4 by UM171 not only induces epigenetic changes through CoREST1 degradation but also control chromatin bound MYC levels to prevent excessive activation and maintain lympho-myeloid potential of expanded populations. Furthermore, reconstitution activity and multipotency of UM171-treated HSC is specifically compromised when MYC levels are experimentally increased despite degradation of CoREST1.

2024-10-24 | GSE232227 | GEO

AML5_DMSO vs UM171

Project description:UM171 effect on AML5 cell lines (kinetic)

2019-11-25 | GSE138487 | GEO

UM171 expands distinct types of myeloid and lymphoid progenitors from human pluripotent stem cells.

Project description:Overall, our studies revealed that UM171 differentially enriches specific populations of hematopoietic progenitors, in HSC expansion and lymphoid culture conditions, and that it is a potent small molecule agonist for expansion of granulocytic progenitors and lymphoid progenitors from hPSCs.

2019-05-21 | GSE128295 | GEO

AML5_DMSO vs UM171

Project description:AML5_DMSO vs UM171

| PRJNA591592 | ENA

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

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

Asymmetric Engagement of Dimeric CRL3/KBTBD4 by the Molecular Glue UM171 Licenses Degradation of HDAC1/2 Complexes

Project description:UM171 is a potent agonist of ex vivo human hematopoietic stem cell (HSC) self-renewal1. By co-opting KBTBD4, a substrate receptor of the CULLIN3-RING E3 ubiquitin ligase (CRL3) complex, UM171 promotes the degradation of the LSD1-CoREST corepressor complex, thereby limiting HSC attrition2,3. However, the direct target and mechanism of action of UM171 remain unclear. Here, we reveal that UM171 acts as a molecular glue to induce high-affinity interactions between KBTBD4 and HDAC1/2 to promote corepressor degradation. Through proteomics and chemical inhibitor studies, we discover that the principal target of UM171 is HDAC1/2. Cryo-electron microscopy analysis of dimeric KBTBD4 bound to UM171 and the LSD1-HDAC1-CoREST complex unveils an asymmetric assembly, in which a single UM171 molecule enables a pair of KELCH-repeat propeller domains to recruit the HDAC1 catalytic domain. One KBTBD4 propeller partially masks the rim of the HDAC1 active site, which is exploited by UM171 to extend the E3-neo-substrate interface. The other propeller cooperatively strengthens HDAC1 binding via a distinct interface. The overall CoREST-HDAC1/2-KBTBD4 interaction is further buttressed by an endogenous cofactor, inositol hexakisphosphate, which acts as a second molecular glue. The functional relevance of the quaternary complex interaction surfaces is demonstrated by base editor scanning of KBTBD4 and HDAC1. By delineating the direct target of UM171 and its mechanism of action, we reveal how the cooperativity offered by a dimeric CRL3 E3 can be leveraged by a small molecule degrader.

2024-11-18 | MSV000096456 | MassIVE

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