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ActivinA Induced SMAD1/5 Signaling in an iPSC Derived EC Model of Fibrodysplasia Ossificans Progressiva (FOP) Can Be Rescued by the Drug Candidate Saracatinib

Hildebrandt, Susanne ; Kampfrath, Branka ; Fischer, Kristin ; Hildebrand, Laura ; Haupt, Julia ; Stachelscheid, Harald ; Knaus, Petra

Stem cell reviews, 2021-06, Vol.17 (3), p.1039-1052 [Periódico revisado por pares]

New York: Springer US

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ActivinA Induced SMAD1/5 Signaling in an iPSC Derived EC Model of Fibrodysplasia Ossificans Progressiva (FOP) Can Be Rescued by the Drug Candidate Saracatinib
Autor: Hildebrandt, Susanne ; Kampfrath, Branka ; Fischer, Kristin ; Hildebrand, Laura ; Haupt, Julia ; Stachelscheid, Harald ; Knaus, Petra
Assuntos: Animals ; Benzodioxoles ; Biomedical and Life Sciences ; Biomedical Engineering and Bioengineering ; Cell Biology ; Endothelial cells ; Endothelium ; Gene expression ; Induced Pluripotent Stem Cells ; Life Sciences ; Mice ; Myositis ossificans ; Myositis Ossificans - drug therapy ; Myositis Ossificans - genetics ; Ossification (ectopic) ; Pattern formation ; Phenotypes ; Pluripotency ; Quinazolines ; Regenerative Medicine/Tissue Engineering ; Signal Transduction ; Smad1 Protein - genetics ; Smad5 Protein ; Stem cell transplantation ; Stem Cells ; Transcription ; Transcriptomes ; Vascularization
É parte de: Stem cell reviews, 2021-06, Vol.17 (3), p.1039-1052
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SourceType-Scholarly Journals-1
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Descrição: Balanced signal transduction is crucial in tissue patterning, particularly in the vasculature. Heterotopic ossification (HO) is tightly linked to vascularization with increased vessel number in hereditary forms of HO, such as Fibrodysplasia ossificans progressiva (FOP). FOP is caused by mutations in the BMP type I receptor ACVR1 leading to aberrant SMAD1/5 signaling in response to ActivinA. Whether observed vascular phenotype in human FOP lesions is connected to aberrant ActivinA signaling is unknown. Blocking of ActivinA prevents HO in FOP mice indicating a central role of the ligand in FOP. Here, we established a new FOP endothelial cell model generated from induced pluripotent stem cells (iECs) to study ActivinA signaling. FOP iECs recapitulate pathogenic ActivinA/SMAD1/5 signaling. Whole transcriptome analysis identified ActivinA mediated activation of the BMP/NOTCH pathway exclusively in FOP iECs, which was rescued to WT transcriptional levels by the drug candidate Saracatinib. We propose that ActivinA causes transcriptional pre-patterning of the FOP endothelium, which might contribute to differential vascularity in FOP lesions compared to non-hereditary HO. Graphical abstract
Editor: New York: Springer US
Idioma: Inglês

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ActivinA Induced SMAD1/5 Signaling in an iPSC Derived EC Model of Fibrodysplasia Ossificans Progressiva (FOP) Can Be Rescued by the Drug Candidate Saracatinib

Hildebrandt, Susanne ; Kampfrath, Branka ; Fischer, Kristin ; Hildebrand, Laura ; Haupt, Julia ; Stachelscheid, Harald ; Knaus, Petra

New York: Springer US

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