title: A Tissue-Engineered Chondrocyte Cell Sheet Induces Extracellular Matrix Modification to Enhance Ventricular Biomechanics and Attenuate Myocardial Stiffness in Ischemic Cardiomyopathy.
abstract: There exists a substantial body of work describing cardiac support devices to mechanically support the left ventricle (LV); however, these devices lack biological effects. To remedy this, we implemented a cell sheet engineering approach utilizing chondrocytes, which in their natural environment produce a relatively elastic extracellular matrix (ECM) for a cushioning effect. Therefore, we hypothesized that a chondrocyte cell sheet applied to infarcted and borderzone myocardium will biologically enhance the ventricular ECM and increase elasticity to augment cardiac function in a model of ischemic cardiomyopathy (ICM). Primary articular cartilage chondrocytes of Wistar rats were isolated and cultured on temperature-responsive culture dishes to generate cell sheets. A rodent ICM model was created by ligating the left anterior descending coronary artery. Rats were divided into two groups: cell sheet transplantation (1.0 × 10(7) cells/dish) and no treatment. The cell sheet was placed onto the surface of the heart covering the infarct and borderzone areas. At 4 weeks following treatment, the decreased fibrotic extension and increased elastic microfiber networks in the infarct and borderzone areas correlated with this technology's potential to stimulate ECM formation. The enhanced ventricular elasticity was further confirmed by the axial stretch test, which revealed that the cell sheet tended to attenuate tensile modulus, a parameter of stiffness. This translated to increased wall thickness in the infarct area, decreased LV volume, wall stress, mass, and improvement of LV function. Thus, the chondrocyte cell sheet strengthens the ventricular biomechanical properties by inducing the formation of elastic microfiber networks in ICM, resulting in attenuated myocardial stiffness and improved myocardial function.
authors.affiliation: 1 Department of Cardiothoracic Surgery, Stanford University School of Medicine , Stanford, California.|4 Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine , Osaka, Japan .
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shudo
authors.affiliation: 1 Department of Cardiothoracic Surgery, Stanford University School of Medicine , Stanford, California.|2 Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania School of Medicine , Philadelphia, Pennsylvania.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Cohen
authors.affiliation: 1 Department of Cardiothoracic Surgery, Stanford University School of Medicine , Stanford, California.|2 Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania School of Medicine , Philadelphia, Pennsylvania.
authors.forename: John W
authors.initials: JW
authors.lastname: MacArthur
authors.affiliation: 1 Department of Cardiothoracic Surgery, Stanford University School of Medicine , Stanford, California.|2 Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania School of Medicine , Philadelphia, Pennsylvania.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Goldstone
authors.affiliation: 3 Center for Childhood Cancer and Blood Diseases, The Research Institute , Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Satoru
authors.initials: S
authors.lastname: Otsuru
authors.affiliation: 2 Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania School of Medicine , Philadelphia, Pennsylvania.
authors.forename: Alen
authors.initials: A
authors.lastname: Trubelja
authors.affiliation: 1 Department of Cardiothoracic Surgery, Stanford University School of Medicine , Stanford, California.
authors.forename: Jay
authors.initials: J
authors.lastname: Patel
authors.affiliation: 1 Department of Cardiothoracic Surgery, Stanford University School of Medicine , Stanford, California.
authors.forename: Bryan B
authors.initials: BB
authors.lastname: Edwards
authors.affiliation: 2 Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania School of Medicine , Philadelphia, Pennsylvania.
authors.forename: George
authors.initials: G
authors.lastname: Hung
authors.affiliation: 2 Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania School of Medicine , Philadelphia, Pennsylvania.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Fairman
authors.affiliation: 2 Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania School of Medicine , Philadelphia, Pennsylvania.
authors.forename: Christopher
authors.initials: C
authors.lastname: Brusalis
authors.affiliation: 2 Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania School of Medicine , Philadelphia, Pennsylvania.
authors.forename: William
authors.initials: W
authors.lastname: Hiesinger
authors.affiliation: 2 Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania School of Medicine , Philadelphia, Pennsylvania.
authors.forename: Pavan
authors.initials: P
authors.lastname: Atluri
authors.affiliation: 2 Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania School of Medicine , Philadelphia, Pennsylvania.
authors.forename: Arudo
authors.initials: A
authors.lastname: Hiraoka
authors.affiliation: 4 Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine , Osaka, Japan .
authors.forename: Shigeru
authors.initials: S
authors.lastname: Miyagawa
authors.affiliation: 4 Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine , Osaka, Japan .
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sawa
authors.affiliation: 1 Department of Cardiothoracic Surgery, Stanford University School of Medicine , Stanford, California.
authors.forename: Y Joseph
authors.initials: YJ
authors.lastname: Woo
mesh_terms: D000818:Animals; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000378:metabolism; D019902:Chondrocytes / Q000166:cytology*; D007150:Immunohistochemistry; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D023822:Tissue Engineering / Q000379:methods*