Clonally selected primitive endothelial cells promote occlusive pulmonary arteriopathy and severe pulmonary hypertension in rats exposed to chronic hypoxia
Clonally selected primitive endothelial cells promote occlusive pulmonary arteriopathy and severe pulmonary hypertension in rats exposed to chronic hypoxia
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DOI：
10.1038/s41598-020-58083-7
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发表时间：
2020-01-24
影响因子：
4.6
通讯作者：
Farkas, Laszlo
中科院分区：
文献类型：
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作者：
Bhagwani, Aneel R.;Farkas, Daniela;Farkas, Laszlo
当前的一种概念表明，内皮细胞 (EC) 克隆选择前体的不受控制的增殖会导致严重的肺动脉高压 (PAH)。我们假设克隆选择的表达祖细胞标记 CD117 的 EC 会促进严重的闭塞性肺动脉高压 (PH)。 PAH患者的重塑肺动脉含有CD117(+) ECs。大鼠肺CD117(+) EC经过四代克隆扩增以富集过度增殖的EC。通过体外和体内血管生成测定测量，所得克隆富集的 EC 表现得与 EC 相似。相同的原始内皮细胞表现出有限的间充质谱系分化能力。通过阻断 TGF-β 信号传导、促进骨形态发生蛋白 (BMP) 信号传导增强内皮分化和功能。 EC克隆的移植导致暴露于慢性缺氧的大鼠动脉闭塞性PH。这些 EC 克隆植入肺动脉中。然而，慢性缺氧的停止促进了肺细胞凋亡和血管病变的消退。总之，据我们所知，这是第一份关于克隆富集的原始 EC 促进闭塞性肺动脉病和严重肺动脉高压的报告。这些原始 EC 克隆在 BMP 和 TGF-β 信号传导的指导下进一步产生内皮和间充质谱系的细胞。
One current concept suggests that unchecked proliferation of clonally selected precursors of endothelial cells (ECs) contribute to severe pulmonary arterial hypertension (PAH). We hypothesized that clonally selected ECs expressing the progenitor marker CD117 promote severe occlusive pulmonary hypertension (PH). The remodelled pulmonary arteries of PAH patients harboured CD117(+) ECs. Rat lung CD117(+) ECs underwent four generations of clonal expansion to enrich hyperproliferative ECs. The resulting clonally enriched ECs behaved like ECs, as measured by in vitro and in vivo angiogenesis assays. The same primitive ECs showed a limited ability for mesenchymal lineage differentiation. Endothelial differentiation and function were enhanced by blocking TGF-beta signalling, promoting bone morphogenic protein (BMP) signalling. The transplantation of the EC clones caused arterio-occlusive PH in rats exposed to chronic hypoxia. These EC clones engrafted in the pulmonary arteries. Yet cessation of chronic hypoxia promoted lung cell apoptosis and resolution of vascular lesions. In conclusion, this is to the best of our knowledge, the first report that clonally enriched primitive ECs promote occlusive pulmonary arteriopathy and severe PH. These primitive EC clones further give rise to cells of endothelial and mesenchymal lineage as directed by BMP and TGF-beta signaling.