Patient-derived microphysiological model identifies the therapeutic potential of metformin for thoracic aortic aneurysm
Wenrui Ma,
Jingjing Zhang,
Shaowen Liu,
Shiqiang Yan,
Kehua Xu,
Yu Shrike Zhang,
Mieradilijiang Abudupataer,
Yang Ming,
Shichao Zhu,
Bitao Xiang,
Xiaonan Zhou,
Shaman Luo,
Hui Huang,
Yuyi Tang,
Shan Zhang,
Zhuxin Xie,
Nan Chen,
Xiaoning Sun,
Jun Li,
Hao Lai,
Chunsheng Wang,
Kai Zhu,
Weijia Zhang
Affiliations
Wenrui Ma
Department of Cardiac Surgery, Zhongshan Hospital Fudan University, Institutes of Biomedical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai 200032, China
Jingjing Zhang
Department of Cardiac Surgery, Zhongshan Hospital Fudan University, Institutes of Biomedical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai 200032, China; The State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai 200438, China
Shaowen Liu
Department of Cardiac Surgery, Zhongshan Hospital Fudan University, Institutes of Biomedical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai 200032, China
Shiqiang Yan
Department of Cardiac Surgery, Zhongshan Hospital Fudan University, Institutes of Biomedical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai 200032, China
Kehua Xu
Department of Cardiac Surgery, Zhongshan Hospital Fudan University, Institutes of Biomedical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai 200032, China
Yu Shrike Zhang
Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, Massachusetts 02139, United States
Mieradilijiang Abudupataer
Department of Cardiac Surgery, Zhongshan Hospital Fudan University, Institutes of Biomedical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai 200032, China
Yang Ming
Department of Cardiac Surgery, Zhongshan Hospital Fudan University, Institutes of Biomedical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai 200032, China
Shichao Zhu
Department of Cardiac Surgery, Zhongshan Hospital Fudan University, Institutes of Biomedical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai 200032, China
Bitao Xiang
Department of Cardiac Surgery, Zhongshan Hospital Fudan University, Institutes of Biomedical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai 200032, China
Xiaonan Zhou
Department of Cardiac Surgery, Zhongshan Hospital Fudan University, Institutes of Biomedical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai 200032, China
Shaman Luo
Department of Cardiac Surgery, Zhongshan Hospital Fudan University, Institutes of Biomedical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai 200032, China; The State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai 200438, China
Hui Huang
Department of Cardiac Surgery, Zhongshan Hospital Fudan University, Institutes of Biomedical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai 200032, China
Yuyi Tang
Cardiovascular Research Laboratory, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China
Shan Zhang
Department of Cardiac Surgery, Zhongshan Hospital Fudan University, Institutes of Biomedical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai 200032, China
Zhuxin Xie
Department of Cardiac Surgery, Zhongshan Hospital Fudan University, Institutes of Biomedical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai 200032, China
Nan Chen
Department of Cardiac Surgery, Zhongshan Hospital Fudan University, Institutes of Biomedical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai 200032, China
Xiaoning Sun
Department of Cardiac Surgery, Zhongshan Hospital Fudan University, Institutes of Biomedical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai 200032, China
Jun Li
Department of Cardiac Surgery, Zhongshan Hospital Fudan University, Institutes of Biomedical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai 200032, China
Hao Lai
Department of Cardiac Surgery, Zhongshan Hospital Fudan University, Institutes of Biomedical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai 200032, China
Chunsheng Wang
Department of Cardiac Surgery, Zhongshan Hospital Fudan University, Institutes of Biomedical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai 200032, China; Corresponding authors.
Kai Zhu
Department of Cardiac Surgery, Zhongshan Hospital Fudan University, Institutes of Biomedical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai 200032, China; Corresponding authors.
Weijia Zhang
Department of Cardiac Surgery, Zhongshan Hospital Fudan University, Institutes of Biomedical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai 200032, China; The State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai 200438, China; The Shanghai Key Laboratory of Medical Imaging Computing and Computer Assisted Intervention, Shanghai Medical College of Fudan University, Shanghai 200433, China; Corresponding authors.
Summary: Background: Thoracic aortic aneurysm (TAA) is the permanent dilation of the thoracic aortic wall that predisposes patients to lethal events such as aortic dissection or rupture, for which effective medical therapy remains scarce. Human-relevant microphysiological models serve as a promising tool in drug screening and discovery. Methods: We developed a dynamic, rhythmically stretching, three-dimensional microphysiological model. Using patient-derived human aortic smooth muscle cells (HAoSMCs), we tested the biological features of the model and compared them with native aortic tissues. Drug testing was performed on the individualized TAA models, and the potentially effective drug was further tested using β-aminopropionitrile-treated mice and retrospective clinical data. Findings: The HAoSMCs on the model recapitulated the expressions of many TAA-related genes in tissue. Phenotypic switching and mitochondrial dysfunction, two disease hallmarks of TAA, were highlighted on the microphysiological model: the TAA-derived HAoSMCs exhibited lower alpha-smooth muscle actin expression, lower mitochondrial membrane potential, lower oxygen consumption rate and higher superoxide accumulation than control cells, while these differences were not evidently reflected in two-dimensional culture flasks. Model-based drug testing demonstrated that metformin partially recovered contractile phenotype and mitochondrial function in TAA patients’ cells. Mouse experiment and clinical investigations also demonstrated better preserved aortic microstructure, higher nicotinamide adenine dinucleotide level and lower aortic diameter with metformin treatment. Interpretation: These findings support the application of this human-relevant microphysiological model in studying personalized disease characteristics and facilitating drug discovery for TAA. Metformin may regulate contractile phenotypes and metabolic dysfunctions in diseased HAoSMCs and limit aortic dilation. Funding: This work was supported by grants from National Key R&D Program of China (2018YFC1005002), National Natural Science Foundation of China (82070482, 81771971, 81772007, 51927805, and 21734003), the Science and Technology Commission of Shanghai Municipality (20ZR1411700, 18ZR1407000, 17JC1400200, and 20YF1406900), Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), and Shanghai Municipal Education Commission (Innovation Program 2017-01-07-00-07-E00027). Y.S.Z. was not supported by any of these funds; instead, the Brigham Research Institute is acknowledged.
