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RNA data of human FOP patients-derived iPSCs treated with ACVR1 R206H mutant-targeting AAVs

ABSTRACT: RNA data of human FOP patients-derived iPSCs treated with ACVR1 R206H mutant-targeting AAVs

PROVIDER: PRJNA881398 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21613548.fastq.gz	Fastqsanger.gz
	SRR21613549.fastq.gz	Fastqsanger.gz
	SRR21613550.fastq.gz	Fastqsanger.gz
	SRR21613551.fastq.gz	Fastqsanger.gz
	SRR21613552.fastq.gz	Fastqsanger.gz

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RNA data of human FOP patients-derived iPSCs treated with ACVR1 R206H mutant-targeting AAVs

Project description:We found that both A9 (amiR-RH6) and A10 (amiR-RH7)-AAVs significantly decrease osteogenic differentiation of FOP-iPSCs. We also observed that A9 and A10-AAVs treatment changed the ratio of R206H mutant to wildtype of ACVR1 in FOP-iPSCs. To identify off-target effect of A9 or A10-AAVs, we compared RNA expression of FOP-iPSCs treated with control, A9, or A10-AAVs.

2022-09-20 | GSE213579 | GEO

Recapitulation of the pro-inflammatory signature of monocytes with ACVR1 mutation using FOP patient-derived iPSCs

Project description:Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by progressive heterotopic ossification (HO) in soft tissues due to a heterozygous mutation of the ACVR1A/ALK2 gene (FOP-ACVR1A), which erroneously transduces the BMP signal by Activin-A. Although inflammation is known to trigger HO in FOP, the role of FOP-ACVR1A on inflammatory cells remains to be elucidated. Here we investigated this issue using immortalized monocytic cell lines from FOP-iPSCs (FOP-ML) and mutation-rescued iPSCs (resFOP-ML). Without any stimulation, FOP-ML showed the pro-inflammatory signature of CD16+ monocytes with an up-regulation of INHBA gene, and treatment of resFOP-ML with Activin-A induced an expression profile consistent with FOP-ML at baseline. Treatment of FOP-ML with Activin-A further induced the inflammatory profile with the up-regulation of inflammation-associated genes, some of which were suppressed by corticosteroid. Experiments using an inhibitor for TGFβ or BMP signals demonstrated that Activin-A-induced genes, such as CD16 and CCL7, were regulated by both signals, indicating Activin-A transduced dual signals in FOP-ML. A comparison with resFOP-ML identified several down-regulated genes in FOP-ML, including LYVE-1, which is known to suppress matrix-formation in vivo. The down-regulation of LYVE-1 in HO tissues was confirmed in FOP model mice, verifying the in vitro experiments. These results indicate that FOP-ML faithfully recapitulated the phenotype of primary monocytes in FOP and its combination with resFOP-ML is useful for investigating the molecular events at the initial inflammation stage of HO in FOP.

2022-05-12 | GSE183525 | GEO

Recapitulation of the pro-inflammatory signature of monocytes with ACVR1 mutation using FOP patient-derived iPSCs

Project description:Recapitulation of the pro-inflammatory signature of monocytes with ACVR1 mutation using FOP patient-derived iPSCs

| PRJNA761120 | ENA

Control and FOP Human iPSC derived myogenic cell single cell RNA sequencing

Project description:We compared the transcriptome of sorted muscle stem/progenitor cells differentiated from control and FOP (ACVR1 R206H (c.617>A)) human induced pluripotent stem cells.

2021-12-29 | GSE151918 | GEO

Concurrent progress of reprogramming and gene-correction to overcome limitation of gene therapy of ALK2 mutant iPSCs

Project description:To ameliorate the cumbersome processes of reprogramming and subsequent gene-editing in vulnerable iPSCs, we have developed a greatly simplified one-step procedure, simultaneously introducing reprogramming and gene-editing components into human fibroblast cells. This not only serves to save time, labor, and costs, but opens up a new arena of research that is beyond the current application of gene-editing methodologies due to restrictive reprogramming concerns, inhibitory pluripotency maintenance requirements, and vulnerability of single-cell dissociated iPSCs. We generated iPSCs (mALK2-iPSCs) derived from Fibrodysplasia ossificans progressiva (FOP)-fibroblast cells carrying the ACVR1 p.R206H mutation and gene-corrected ALK2-iPSCs (cALK2-iPSCs). To identify gene-correction effects on global gene expression, gene expression profiling was measured in cALK2-iPSCs and mALK2-iPSCs, calibrated to WT-iPSCs with duplication.

2015-05-12 | E-GEOD-68766 | biostudies-arrayexpress

Expression data from neural crest cells and neural crest cell-derived MSCs from human pluripotent stem cells of FOP patients and controls

Project description:NCCs and NCC-derived MSCs were induced from FOP-iPSCs and control iPSCs, and their expresion profiles were compared. Comparison of gene expressions among hiPSCs, hESCs, hNCCs and hNC-MSCs from FOP-iPSCs and control-iPSCs.

2015-09-17 | E-GEOD-61510 | biostudies-arrayexpress

Expression data from neural crest cells and neural crest cell-derived MSCs from human pluripotent stem cells of FOP patients and controls

Project description:NCCs and NCC-derived MSCs were induced from FOP-iPSCs and control iPSCs, and their expresion profiles were compared.

2015-09-17 | GSE61510 | GEO

RNAseq of nestin-expressing murine brainstem progenitors infected with ACVR1 WT or R206H ACVR1 with and without H3.1K27M

Project description:Diffuse intrinsic pontine glioma (DIPG) is an incurable pediatric brain tumor, resulting in the death of 200-300 children each year in the United States. Recently it was discovered that approximately 25% of all DIPG cases harbor activating mutations in ACVR1, a gene that encodes Activin A receptor (ALK2), a receptor in the bone morphogenetic protein (BMP) pathway, and that DIPGs with ALK2 mutations commonly harbor an H3.1K27M mutation. Herein, we used the RCAS/TVA retroviral system to study the effects of ACVR1 mutations and H3.1K27M on DIPG pathogenesis. In vitro expression of R206H ACVR1 with and without H3.1K27M in nestin-expressing brainstem progenitors resulted in upregulation of mesenchymal markers and gene set enrichment analysis (GSEA) revealed Stat3 pathway activation. Neonatal expression of ACVR1 R206H or G328V in combination with H3.1K27M and p53 deletion in nestin-expressing brainstem progenitors induced glioma-like lesions expressing mesenchymal markers with Stat3 activation but was not sufficient for full gliomagenesis. In combination with platelet-derived growth factor A (PDGFA) signaling, ACVR1 R206H and H3.1K27M significantly decreased survival and increased tumor incidence. We demonstrate that targeting the BMP signaling pathway may be an effective therapeutic strategy to treat ACVR1 R206H mutant DIPGs. Exogenous Noggin expression at tumor initiation significantly increased tumor latency and treatment of ACVR1 R206H mutant murine DIPGs with LDN212854, an ACVR1 inhibitor, significantly prolonged their survival. We confirm relevance of our model to the human disease as human DIPG models with ACVR1 mutations were also sensitive to treatment with LDN212854 in vitro. Altogether, our studies demonstrate that ACVR1 R206H and H3.1K27M promote tumor initiation, accelerate gliomagenesis, promote a mesenchymal profile in part due to Stat3 activation, and identify LDN212854 as a promising compound to treat children with DIPG.

2019-01-25 | GSE125627 | GEO

Anti-ACVR1 antibodies exacerbate heterotopic ossification in fibrodysplasia ossificans progressiva (FOP) by activating FOP-mutant ACVR1.

Project description:Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder whose most debilitating pathology is progressive and cumulative heterotopic ossification (HO) of skeletal muscles, ligaments, tendons, and fascia. FOP is caused by mutations in the type I BMP receptor gene ACVR1, which enable ACVR1 to utilize its natural antagonist, activin A, as an agonistic ligand. The physiological relevance of this property is underscored by the fact that HO in FOP is exquisitely dependent on activation of FOP-mutant ACVR1 by activin A, an effect countered by inhibition of anti-activin A via monoclonal antibody treatment. Hence, we surmised that anti-ACVR1 antibodies that block activation of ACVR1 by ligands should also inhibit HO in FOP and provide an additional therapeutic option for this condition. Therefore, we generated anti-ACVR1 monoclonal antibodies that block ACVR1's activation by its ligands. Surprisingly, in vivo, these anti-ACVR1 antibodies stimulated HO and activated signaling of FOP-mutant ACVR1. This property was restricted to FOP-mutant ACVR1 and resulted from anti-ACVR1 antibody-mediated dimerization of ACVR1. Conversely, wild-type ACVR1 was inhibited by anti-ACVR1 antibodies. These results uncover an additional property of FOP-mutant ACVR1 and indicate that anti-ACVR1 antibodies should not be considered as therapeutics for FOP.

| S-EPMC9197526 | biostudies-literature

Variable signaling activity by FOP ACVR1 mutations.

Project description:Most patients with fibrodysplasia ossificans progressiva (FOP), a rare genetic disorder of heterotopic ossification, have the same causative mutation in ACVR1, R206H. However, additional mutations within the ACVR1 BMP type I receptor have been identified in a small number of FOP cases, often in patients with disease of lesser or greater severity than occurs with R206H mutations. Genotype-phenotype correlations have been suggested in patients, resulting in classification of FOP mutations based on location within different receptor domains and structural modeling. However while each of the mutations induces increased signaling through the BMP-pSmad1/5/8 pathway, the molecular mechanisms underlying functional differences of these FOP variant receptors remained undetermined. We now demonstrate that FOP mutations within the ACVR1 receptor kinase domain are more sensitive to low levels of BMP than mutations in the ACVR1 GS domain. Our data additionally confirm responsiveness of cells with FOP ACVR1 mutations to both BMP and Activin A ligands. We also have determined that constructs with FOP ACVR1 mutations that are engineered without the ligand-binding domain retain increased BMP-pSmad1/5/8 pathway activation relative to wild-type ACVR1, supporting that the mutant receptors can function through ligand-independent mechanisms either directly through mutant ACVR1 or through indirect mechanisms.

| S-EPMC5866189 | biostudies-literature

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