3D in vitro Model of Vascular Medial Thickening in Pulmonary Arterial Hypertension
3D in vitro Model of Vascular Medial Thickening in Pulmonary Arterial Hypertension
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DOI：
10.3389/fbioe.2020.00482
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发表时间：
2020-05-20
影响因子：
5.7
通讯作者：
Ogawa, Aiko
中科院分区：
文献类型：
--
作者：
Morii, Chiharu;Tanaka, Hiroyoshi Y.;Ogawa, Aiko
在肺动脉高压（PAH）中，肺动脉平滑肌细胞（PASMC）过度增殖导致血管中层增厚。内侧增厚是肺血管重塑的组织病理学标志，肺血管重塑是驱动 PAH 进展的核心疾病过程。肺血管重塑导致小肺动脉狭窄和/或阻塞。这导致肺血管阻力增加、肺动脉压升高，最终导致右心衰竭。为了提高 PAH 患者的生存率（诊断后 3 年仍保持在约 60%），需要开发新型 PAH 靶向药物。为此，有必要详细了解 PASMC 过度增殖和随之而来的内侧增厚的机制。然而，缺乏概括内侧增厚的体外模型阻碍了我们对所涉及的发病机制的更深入理解。在本研究中，我们应用 3 维 (3D) 细胞培养技术，利用人 PAH 患者来源的 PASMC 开发了一种新型肺动脉中层体外模型。添加血小板衍生生长因子 (PDGF)-BB（一种已知可促进 PAH 中 PASMC 过度增殖的有丝分裂原）会导致 3D-PAH 介质组织厚度增加。相反，使用 PDGF 受体抑制剂伊马替尼或其他临床 PAH 药物会抑制 PDGF-BB 的这种内侧增厚诱导作用。总之，通过使用 3D 细胞培养技术，我们报告了 PAH 中层增厚的体外模型的生成，迄今为止尚未在体外成功建模。该模型对于评估候选 PAH 药物抑制内侧增厚的能力可能有用。
In pulmonary arterial hypertension (PAH), excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) causes vascular medial thickening. Medial thickening is a histopathological hallmark of pulmonary vascular remodeling, the central disease process driving PAH progression. Pulmonary vascular remodeling causes stenosis and/or obstruction of small pulmonary arteries. This leads to increased pulmonary vascular resistance, elevated pulmonary arterial pressure, and ultimately right heart failure. To improve the survival of PAH patients, which remains at approximately 60% at 3 years after diagnosis, the development of novel PAH-targeted drugs is desired. To this end, a detailed understanding of the mechanisms underlying excessive PASMC proliferation and the medial thickening that ensues is necessary. However, a lack of in vitro models that recapitulate medial thickening impedes our deeper understanding of the pathogenetic mechanisms involved. In the present study, we applied 3-dimensional (3D) cell culture technology to develop a novel in vitro model of the pulmonary artery medial layer using human PAH patient-derived PASMCs. The addition of platelet-derived growth factor (PDGF)-BB, a mitogen known to promote excessive PASMC proliferation in PAH, resulted in increased thickness of the 3D-PAH media tissues. Conversely, administration of the PDGF receptor inhibitor imatinib or other clinical PAH drugs inhibited this medial thickening-inducing effect of PDGF-BB. Altogether, by using 3D cell culture technology, we report the generation of an in vitro model of medial thickening in PAH, which had hitherto not been successfully modeled in vitro. This model is potentially useful for assessing the ability of candidate PAH drugs to suppress medial thickening.