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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE213579 | GEO | 2022/09/20

REPOSITORIES: GEO

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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

Variable signaling activity by FOP ACVR1 mutations.

Project description: Not available

| S-EPMC5866189 | biostudies-literature

Oxidative phosphorylation is a pivotal therapeutic target of fibrodysplasia ossificans progressiva

Project description:Heterotopic ossification (HO) is a non-physiological process of bone formation in which progenitor cells in soft tissues differentiate into chondrogenic cells. In the case of fibrodysplasia ossificans progressiva (FOP), a rare genetic disease characterized by progressive and systemic HO, the Activin A/mutated-ACVR1/mTORC1 cascade induces HO in progenitors, one of which is the fibro/adipogenic progenitors (FAPs) in muscle tissues. The relevant biological processes aberrantly regulated by activated mTORC1 remain unclear, however. RNA sequencing analyses revealed the enrichment of genes involved in oxidative phosphorylation (OXPHOS) during Activin A-induced chondrogenesis of mesenchymal stem cells derived from induced pluripotent stem cells (iPSCs) of FOP patients. Functional analyses showed a metabolic transition from glycolysis to OXPHOS during chondrogenesis, in conjunction with an upregulation of mitochondrial biogenesis. mTORC1 inhibition by rapamycin suppressed OXPHOS, and IACS-010759, an inhibitor of OXPHOS, inhibited cartilage matrix formation in vitro, indicating that OXPHOS is principally involved in mTORC1-induced chondrogenesis. Furthermore, IACS-010759 inhibited the muscle injury-induced enrichment of FAP genes and HO in transgenic mice carrying the mutated human ACVR1. These data indicated that OXPHOS is a critical downstream mediator of mTORC1 signaling in chondrogenesis and therefore is a potential FOP therapeutic target.

2024-02-16 | GSE221128 | GEO

Oxidative phosphorylation is a pivotal therapeutic target of fibrodysplasia ossificans progressiva

2024-02-16 | GSE220725 | GEO

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