title: Paracrine Effects of Adipose-Derived Stem Cells on Matrix Stiffness-Induced Cardiac Myofibroblast Differentiation via Angiotensin II Type 1 Receptor and Smad7.
abstract: Human mesenchymal stem cells (hMSCs) hold great promise in cardiac fibrosis therapy, due to their potential ability of inhibiting cardiac myofibroblast differentiation (a hallmark of cardiac fibrosis). However, the mechanism involved in their effects remains elusive. To explore this, it is necessary to develop an in vitro cardiac fibrosis model that incorporates pore size and native tissue-mimicking matrix stiffness, which may regulate cardiac myofibroblast differentiation. In the present study, collagen coated polyacrylamide hydrogel substrates were fabricated, in which the pore size was adjusted without altering the matrix stiffness. Stiffness is shown to regulate cardiac myofibroblast differentiation independently of pore size. Substrate at a stiffness of 30 kPa, which mimics the stiffness of native fibrotic cardiac tissue, was found to induce cardiac myofibroblast differentiation to create in vitro cardiac fibrosis model. Conditioned medium of hMSCs was applied to the model to determine its role and inhibitory mechanism on cardiac myofibroblast differentiation. It was found that hMSCs secrete hepatocyte growth factor (HGF) to inhibit cardiac myofibroblast differentiation via downregulation of angiotensin II type 1 receptor (AT1R) and upregulation of Smad7. These findings would aid in establishment of the therapeutic use of hMSCs in cardiac fibrosis therapy in future.
authors.affiliation: The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P.R. China.|Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an 710049, P.R. China.|Department of Biomedical Engineering, Faculty of Engineering, University of Malaya, Kuala Lumpur 50603, Malaysia.
authors.forename: Kar Wey
authors.initials: KW
authors.lastname: Yong
authors.affiliation: The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P.R. China.|Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an 710049, P.R. China.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Li
authors.affiliation: The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P.R. China.|Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an 710049, P.R. China.
authors.forename: Fusheng
authors.initials: F
authors.lastname: Liu
authors.affiliation: The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P.R. China.|Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an 710049, P.R. China.|Department of Endocrinology and Metabolism, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, P.R. China.
authors.lastname: Bin Gao
authors.affiliation: Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an 710049, P.R. China.
authors.forename: Tian Jian
authors.initials: TJ
authors.lastname: Lu
authors.affiliation: Department of Biomedical Engineering, Faculty of Engineering, University of Malaya, Kuala Lumpur 50603, Malaysia.
authors.forename: Wan Abu Bakar
authors.initials: WA
authors.lastname: Wan Abas
authors.affiliation: Department of Biomedical Engineering, Faculty of Engineering, University of Malaya, Kuala Lumpur 50603, Malaysia.
authors.forename: Wan Kamarul Zaman
authors.initials: WK
authors.lastname: Wan Safwani
authors.affiliation: Department of Biomedical Engineering, Faculty of Engineering, University of Malaya, Kuala Lumpur 50603, Malaysia.
authors.forename: Belinda
authors.initials: B
authors.lastname: Pingguan-Murphy
authors.affiliation: The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P.R. China.|Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an 710049, P.R. China.
authors.forename: Yufei
authors.initials: Y
authors.lastname: Ma
authors.affiliation: The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P.R. China.|Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an 710049, P.R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.affiliation: The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P.R. China.|Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an 710049, P.R. China.
authors.forename: Guoyou
authors.initials: G
authors.lastname: Huang
mesh_terms: D000273:Adipose Tissue / Q000166:cytology* / Q000378:metabolism; D000328:Adult; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D058628:Myofibroblasts / Q000166:cytology* / Q000473:pathology; D019899:Paracrine Communication; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D051906:Smad7 Protein / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; C066855:HGF protein, human; D044140:Receptor, Angiotensin, Type 1; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D017228:Hepatocyte Growth Factor