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

中文翻译：

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候选药物 Saracatinib 可挽救 iPSC 衍生的骨化性纤维发育不良（FOP）EC 模型中 ActivinA 诱导的 SMAD1/5 信号传导

平衡的信号转导在组织模式中至关重要，尤其是在脉管系统中。异位骨化 (H2O) 与血管形成密切相关，在 H2O 的遗传形式中，血管数量增加，例如进行性骨化性纤维发育不良(FOP)。FOP 是由 BMP I 型受体ACVR1的突变引起的导致响应 ActivinA 的异常 SMAD1/5 信号传导。在人类 FOP 病变中观察到的血管表型是否与异常的 ActivinA 信号传导有关尚不清楚。阻断 ActivinA 可防止 FOP 小鼠中的 H2O，表明配体在 FOP 中的核心作用。在这里，我们建立了一种由诱导多能干细胞 (iECs) 生成的新 FOP 内皮细胞模型，以研究 ActivinA 信号传导。FOP iEC 概括了致病性 ActivinA/SMAD1/5 信号。全转录组分析确定了 ActivinA 介导的 BMP/NOTCH 通路仅在 FOP iECs 中激活，候选药物 Saracatinib 将其恢复到 WT 转录水平。我们建议 ActivinA 引起 FOP 内皮的转录预模式，与非遗传性 H2O 相比，这可能导致 FOP 病变中的不同血管分布。

图形概要