Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Myeloid, B, and T lineage regeneration from pluripotent stem cells by defined transcription factors

ABSTRACT: Generating prolonged multi-lineage hematopoiesis from pluripotent stem cells (PSCs), an unlimited cell source, is a crucial aim for regenerative hematology. In this study, we used a gene-edited PSC line and revealed that simultaneous expression of three transcription factors, Runx1, Hoxa9, and Hoxa10, drove robust emergence of induced hematopoietic progenitor cells (iHPCs). The iHPCs engrafted successfully in wild type animals and repopulated abundant and complete myeloid, B, and T lineage mature cells in primary and secondary C57BL/6 recipients. The regenerative multi-lineage hematopoiesis distributed normally in multiple organs, persisted over six months, and eventually declined over time with no leukemogenesis. Transcriptome characterization of regenerative myeloid, B, and T cells at the single cell resolution further projected their identities to natural cell counterparts. Thus, we provide strong genetic evidence that co-expression of exogenous Runx1, Hoxa9, and Hoxa10 simultaneously leads to long-term reconstitution of myeloid, B, and T lineages using PSC-derived iHPCs as cell source.

ORGANISM(S): Mus musculus

PROVIDER: GSE217945 | GEO | 2023/02/14

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Vascular niche induction of hematopoietic progenitors from pluripotent stem cells

Project description:Pluripotent stem cells (PSC) represent an alternative source of hematopoietic stem cells (HSCs). Clinical translation is impeded by limited engraftment of human (h)PSC-multipotent progenitor cells (MPP). This barrier suggests that additional cues are required for definitive hematopoiesis. We hypothesized that vascular niche producing Notch ligands Jagged-1 (JAG1) and Delta-like ligand-4 (DLL4) would drive definitive hematopoiesis. To test our hypothesis, hes2 human embryonic stem cells (hESC) 2 and Macaca nemestrina (Mn) iPSC line-7 were differentiated with cytokines Â± endothelial cells (EC), which express JAG1 and DLL4. EC co-culture supported emergence of 8-fold more CD34+CD45+ cells compared to co-culture with cytokines Â± ECs with JAG1 or DLL4 knockdown. EC-induced cells exhibit Notch activation and express HSC-specific targets of Notch signaling RUNX1 and GATA2. EC-induced PSC-MPP engraft at a higher level in NSG mice compared to cytokine-induced cells (10% >5 months), and selection increased engraftment (30%). Long-term engraftment and the myeloid-to-lymphoid ratio achieved with vascular niche induction is similar to levels achieved for cord blood MPP and up to 20-fold higher than hPSC-MPP engraftment. Our findings identify a previously underappreciated role for endothelial Notch ligands in PSC definitive hematopoiesis and production of long-term engrafting CD34+ cells and suggest they are critical for HSC emergence. Transcriptome sequencing of Macaca nemestrina (Mn) iPSCs

2015-12-31 | E-GEOD-64644 | biostudies-arrayexpress

Hoxa9/meis1-transgenic zebrafish develops acute myeloid leukemia-like disease with rapid onset and high-penetrance

Project description:HOXA9/MEIS1 plays a synergistic causative role and overexpresses frequently in acute myeloid leukemia (AML). Hoxa9/Meis1 transgenic murine results in rapid leukemic transformation of primary bone marrow cells. However, murine model is not suitable to perform a high-throughput phenotypic screen in vivo and identify compounds for AML therapy. A transgenic zebrafish overexpresses hoxa9/meis1 need to generate. We have engineered an inducible transgenic line Tg (drl:hoxa9;hsp70:meis1) harboring hoxa9/meis1 under the draculin (drl) promoter. The downregulation of runx1, c-myb, mpx, mfap4, and gata1 in Tg (drl:hoxa9;hsp70:meis1) embryos indicated enforced hoxa9/meis1 perturbs embryonic hematopoiesis. Importantly, adult Tg (drl:hoxa9;hsp70:meis1) develops malignant myeloid disease with an abundance of myeloid precursor cells, anemia, and high mortality after a latency period (~5-months-aged) with comparable to murine model and human AML patients. Genome-wide transcription changes analysis indicated arrested differentiation genes such as gata2b, notch1b, and gfi1ab are upregulated. Leflunomide, inhibitor of enzyme dihydroorotate dehydrogenase (DHODH) which is a potential option for differentiation therapy of AML, relieves defective hematopoiesis in transgenic embryos and larvae. Collectively, we have identified an inducible malignant myeloid disease transgenic zebrafish model similar to AML and provided a unique opportunity for high-throughput in vivo chemical screening for AML therapy and study the related mechanisms.

2022-09-01 | GSE204744 | GEO

Vascular niche induction of hematopoietic progenitors from pluripotent stem cells

Project description:Pluripotent stem cells (PSC) represent an alternative source of hematopoietic stem cells (HSCs). Clinical translation is impeded by limited engraftment of human (h)PSC-multipotent progenitor cells (MPP). This barrier suggests that additional cues are required for definitive hematopoiesis. We hypothesized that vascular niche producing Notch ligands Jagged-1 (JAG1) and Delta-like ligand-4 (DLL4) would drive definitive hematopoiesis. To test our hypothesis, hes2 human embryonic stem cells (hESC) 2 and Macaca nemestrina (Mn) iPSC line-7 were differentiated with cytokines ± endothelial cells (EC), which express JAG1 and DLL4. EC co-culture supported emergence of 8-fold more CD34+CD45+ cells compared to co-culture with cytokines ± ECs with JAG1 or DLL4 knockdown. EC-induced cells exhibit Notch activation and express HSC-specific targets of Notch signaling RUNX1 and GATA2. EC-induced PSC-MPP engraft at a higher level in NSG mice compared to cytokine-induced cells (10% >5 months), and selection increased engraftment (30%). Long-term engraftment and the myeloid-to-lymphoid ratio achieved with vascular niche induction is similar to levels achieved for cord blood MPP and up to 20-fold higher than hPSC-MPP engraftment. Our findings identify a previously underappreciated role for endothelial Notch ligands in PSC definitive hematopoiesis and production of long-term engrafting CD34+ cells and suggest they are critical for HSC emergence.

2015-12-31 | GSE64644 | GEO

Gene expression data of human chord blood hematopoietic progenior cells subjected to myeloid differentiation and transduced with lncRNA HOXA10-AS

Project description:Long non-coding RNAs (lncRNAs) have emerged as crucial regulators of gene expression and cell fate decisions. We predicted HOXA10-AS as a novel non-coding regulator of hematopoiesis and leukemogenesis We overexpressed HOXA10-AS using a bidirectional vector construct, which resulted in impaired monocytic in vitro differentiation and myeloid colony-formation. In addition, shRNA, sgRNA and LNA-GapmeR mediated downregulation of HOXA10-AS resulted in reduced leukemic growth of KMT2A-r cell lines and patient blasts. (p≤0.05). Here we assess early effects of ectopic HOXA10-AS expression in human HSPC subjected to myeloid differentiation conditions.

2020-01-01 | GSE123694 | GEO

Identification and Characterization of Hoxa9 Binding Sites in Hematopoietic Cells

Project description:The clustered homeobox proteins play crucial roles in development, hematopoiesis and leukemia yet the targets they regulate and their mechanisms of action are poorly understood. Here, we identified the binding sites for Hoxa9 and the Hox cofactor Meis1 on a genome-wide level and profiled their associated epigenetic modifications and transcriptional targets. Hoxa9 and the Hox cofactor Meis1 co-bind at hundreds of highly evolutionarily-conserved sites, most of which are distant from transcription start sites. These sites show high levels of histone H3K4 monomethylation and CBP/P300 binding characteristic of enhancers. Furthermore, a subset of these sites shows enhancer activity in transient transfection assays. Many Hoxa9 and Meis1 binding sites are also bound by PU.1 and other lineage-restricted transcription factors previously implicated in establishment of myeloid enhancers. Conditional Hoxa9 activation is associated with CBP/P300 recruitment, histone acetylation and transcriptional activation of a network of proto-oncogenes including Erg, Flt3, Lmo2, Myb and Sox4. Collectively this work suggests that Hoxa9 regulates transcription by interacting with enhancers of genes important for hematopoiesis and leukemia. To identify the genome-wide binding sites for Hoxa9 and the Hox cofactor Meis1

2011-12-04 | E-GEOD-33509 | biostudies-arrayexpress

Single cell RNA sequencing of CD42+ and CD42- iHPC in RUNX1 haploinsufficiency

Project description:To gain insights into the global and local transcriptomic changes underlying defective production of CD42a+ iHPCs in RUNX1+/-, we performed scRNA SEQ on sorted CD42a- and CD42a+ iHPCs from L1 and L1-C. There were on average 11,328 reads per cell with an average of 2,081 genes expressed. To identify and analyze distinct subpopulations in the control and RUNX1+/- iHPCs, dimension reduction was performed and cell clustering was visualized using uniform manifold approximation and projection (UMAP)

2020-04-23 | GSE149136 | GEO

Transcriptome profiling of hematopoietic cells derived from human pluripotent stem cells

Project description:We performed morphogen-directed differentiation of human PSCs into HE followed by combinatorial screening of 26 candidate HSC-specifying TFs for the potential to promote hematopoietic engraftment in irradiated immune deficient murine hosts. We recovered seven TFs (ERG, HOXA5, HOXA9, HOXA10, LCOR, RUNX1, SPI1) that together were sufficient to convert HE into hematopoietic stem and progenitor cells (HSPCs) that engraft primary and secondary murine recipients.

2017-05-17 | GSE83719 | GEO

inDrop single cell RNA-seq of hematopoietic cells derived from human pluripotent stem cells

2017-05-17 | GSE85111 | GEO

Identification and characterization of regenerative innate lymphoid cells from pluripotent stem cells [WT-CHILP/iR9-CHILP_SmartSeq2]

Project description:We identified that synergistic and inducible expression of Runx1 and Hoxa9 in pluripotent stem cells (PSCs) gave rise to engraftable iHPC capable of developing into common helper innate lymphoid progenitors (CHILPs) in the Rag2-/-Il2rg-/- recipients. To assess the gene-expression pattern of the PSC-derived R9-iCHILPs, we performed single-cell RNA-seq on the regenerative CD45.2+GFP+Lin-CD127+CD135-α4β7+Sca1mid/-CD25- R9-iCHILPs from the bone marrow of Rag2-/-Il2rg-/- recipient mice and the CD45.2+Lin-CD127+CD135-α4β7+Sca1mid/-CD25- WT-CHILPs from the bone marrow of wild type mice (C57BL/6, CD45.2).

2022-09-30 | GSE210861 | GEO

Regeneration of immunocompetent B lymphopoiesis from pluripotent stem cells guided by transcription factors

Project description:We identified that the coordinated expression of exogenous transcription factors(Lhx2, Hoxa9, and Runx1), efficiently guides PSC-derived hematopoietic progenitors (iHPC) preferentially towards B cell lineage commitment, which successfully regenerate B lymphopoiesis in B-cell deficient animals. Of note, the abundancy of in vivo lymphopoiesis includes pro/pre-B progenitors, immature B cells, and all subsets of mature B1a, B1b, FO B and MZ B reconstitution in vivo. We performed single-cell RNA-Seq using the sorted GFP+CD45+ Lin- cells from the bone marrow of recipients at day 7.5 after iHPC transplantation.

2021-12-16 | GSE180319 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data