title: Myocyte-depleted engineered cardiac tissues support therapeutic potential of mesenchymal stem cells.
abstract: The therapeutic potential of mesenchymal stem cells (MSCs) for restoring cardiac function after cardiomyocyte loss remains controversial. Engineered cardiac tissues (ECTs) offer a simplified three-dimensional in vitro model system to evaluate stem cell therapies. We hypothesized that contractile properties of dysfunctional ECTs would be enhanced by MSC treatment. ECTs were created from neonatal rat cardiomyocytes with and without bone marrow-derived adult rat MSCs in a type-I collagen and Matrigel scaffold using custom elastomer molds with integrated cantilever force sensors. Three experimental groups included the following: (1) baseline condition ECT consisting only of myocytes, (2) 50% myocyte-depleted ECT, modeling a dysfunctional state, and (3) 50% myocyte-depleted ECT plus 10% MSC, modeling dysfunctional myocardium with intervention. Developed stress (DS) and pacing threshold voltage (VT) were measured using 2-Hz field stimulation at 37°C on culture days 5, 10, 15, and 20. By day 5, DS of myocyte-depleted ECTs was significantly lower than baseline, and VT was elevated. In MSC-supplemented ECTs, DS and VT were significantly better than myocyte-depleted values, approaching baseline ECTs. Findings were similar through culture day 15, but lost significance at day 20. Trends in DS were partly explained by changes in the cell number and alignment with time. Thus, supplementing myocyte-depleted ECTs with MSCs transiently improved contractile function and compensated for a 50% loss of cardiomyocytes, mimicking recent animal studies and clinical trials and supporting the potential of MSCs for myocardial therapy.
authors.affiliation: Cardiovascular Cell and Tissue Engineering Laboratory, Cardiovascular Research Center, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA. kevin.costa@mssm.edu
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Serrao
authors.forename: Irene C
authors.initials: IC
authors.lastname: Turnbull
authors.forename: Damian
authors.initials: D
authors.lastname: Ancukiewicz
authors.forename: Do Eun
authors.initials: DE
authors.lastname: Kim
authors.forename: Evan
authors.initials: E
authors.lastname: Kao
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Cashman
authors.forename: Lahouaria
authors.initials: L
authors.lastname: Hadri
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Costa
mesh_terms: D000818:Animals; D002452:Cell Count; D020405:Dermis / Q000166:cytology; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D005455:Fluorescent Antibody Technique; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D032342:Muscle Cells / Q000166:cytology*; D009206:Myocardium / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013314:Stress, Mechanical; D013997:Time Factors; D023822:Tissue Engineering / Q000379:methods*