Engineering a Human Pluripotent Stem Cell-Based in vitro Microphysiological System for Studying the Metformin Response in Aortic Smooth Muscle Cells.

Nan Chen,Shichao Zhu,Sisi Feng,Jun Li,Mieradilijiang Abudupataer,Kai Zhu,Wenrui Ma,Chunsheng Wang,Hao Lai

doi:10.3389/fbioe.2021.627877

Abstract

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 in vitro model is of great demand for successful drug screening. In this study, we induced an in vitro 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 in vitro 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.

Highlights

Aortic aneurysm, which is defined as a pathological dilation of the aorta, presents as a lifethreatening disease due to the potential to develop dissection or rupture (Goldfinger et al, 2014)
As the main component in the middle layer of the aorta, human aortic smooth muscle cells (HASMCs) are stimulated by cyclic stretching in vivo, which cannot be simulated under traditional 2D cell culture
We found that a contractile phenotype of HASMCs was induced by cyclic stretching in our system, which was closer to the native biology of HASMCs than those from traditional 2D cell culture

Summary

Introduction

Aortic aneurysm, which is defined as a pathological dilation of the aorta, presents as a lifethreatening disease due to the potential to develop dissection or rupture (Goldfinger et al, 2014). Great interest in discovering drug therapies that may be positive for reducing continuous dilatation of aortic aneurysms has been shown in many studies (Sweeting et al, 2012). Few efficiencies in reducing aortic aneurysm growth or rupture were associated with these prescribed drugs, including angiotensinconverting enzyme inhibitors, β-blockers, calcium channel blockers and antiplatelet agents (Golledge, 2019). Some clinical studies focusing on the reduction of aortic aneurysm growth in patients receiving metformin prescription were reported (Fujimura et al, 2016; Golledge et al, 2017; Hinchliffe, 2017; Yu et al, 2019). An epidemiological study reported that a non-significantly reduced risk of aortic aneurysm rupture was associated with metformin prescription (Kristensen et al, 2017).

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