Chen Nan, Abudupataer Mieradilijiang, Feng Sisi, Zhu Shichao, Ma Wenrui, Li Jun, Lai Hao, Zhu Kai, Wang Chunsheng
Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
Shanghai Institute of Cardiovascular Diseases, Shanghai, China.
Front Bioeng Biotechnol. 2021 Mar 18;9:627877. doi: 10.3389/fbioe.2021.627877. eCollection 2021.
Aortic aneurysm is a common cardiovascular disease characterised by continuous dilation of the aorta, and this disease places a heavy burden on healthcare worldwide. Few drugs have been suggested to be effective in controlling the progression of aortic aneurysms. Preclinical drug responses from traditional cell culture and animals are usually controversial. An effective model is of great demand for successful drug screening. In this study, we induced an microphysiological system to test metformin, which is a potential drug for the treatment of aortic aneurysms. Human pluripotent stem cell-derived aortic smooth muscle cells (hPSC-HASMCs) were cultured on an microphysiological system, which could replicate the cyclic stretch of the human native aortic wall. By using this system, we found that HASMCs were more likely to present a physiologically contractile phenotype compared to static cell cultures. Moreover, we used hPSC-HASMCs in our microphysiological system to perform metformin drug screening. The results showed that hPSC-HASMCs presented a more contractile phenotype via NOTCH 1 signalling while being treated with metformin. This result indicated that metformin could be utilised to rescue hPSC-HASMCs from phenotype switching during aortic aneurysm progression. This study helps to elucidate potential drug targets for the treatment of aortic aneurysms.
主动脉瘤是一种常见的心血管疾病，其特征是主动脉持续扩张，这种疾病给全球医疗保健带来了沉重负担。很少有药物被认为对控制主动脉瘤的进展有效。传统细胞培养和动物实验的临床前药物反应通常存在争议。成功进行药物筛选非常需要一个有效的模型。在本研究中，我们构建了一个微生理系统来测试二甲双胍，它是一种治疗主动脉瘤的潜在药物。人多能干细胞衍生的主动脉平滑肌细胞（hPSC-HASMCs）在微生理系统上培养，该系统可以模拟人类天然主动脉壁的周期性拉伸。通过使用这个系统，我们发现与静态细胞培养相比，HASMCs更有可能呈现出生理收缩表型。此外，我们在微生理系统中使用hPSC-HASMCs进行二甲双胍药物筛选。结果表明，在使用二甲双胍治疗时，hPSC-HASMCs通过NOTCH 1信号通路呈现出更收缩的表型。这一结果表明，二甲双胍可用于挽救主动脉瘤进展过程中hPSC-HASMCs的表型转换。本研究有助于阐明治疗主动脉瘤的潜在药物靶点。
