Collagen Matrices Enhance Survival of Transplanted Cardiomyoblasts and Contribute to Functional Improvement of Ischemic Rat Hearts

Abstract

Background— Cardiac cell transplantation is limited by poor graft viability. We aimed to enhance the survival of transplanted cardiomyoblasts using growth factor-supplemented collagen matrices. Methods and Results— H9c2 cardiomyoblasts were lentivirally transduced to express firefly luciferase and green fluorescent protein (GFP). Lewis rats underwent ligation of the left anterior descending artery (LAD) ligation to induce an anterior wall myocardial infarction. Hearts (n=9/group) were harvested and restored ex vivo with 1×10 6 genetically labeled H9c2 cells either in (1) saline-suspension, or seeded onto (2) collagen-matrix (Gelfoam [GF];), (3) GF/Matrigel (GF/MG), (4) GF/MG/VEGF (10 μg/mL), or (5) GF/MG/FGF (10 μg/mL). Hearts were then abdominally transplanted into syngeneic recipients (working heart model). Controls (n=6/group) underwent infarction followed by GF implantation or saline injection. Cell survival was evaluated using optical bioluminescence on days 1, 5, 8, 14, and 28 postoperatively. At 4 weeks, fractional shortening and ejection fraction were determined using echocardiography and magnetic resonance imaging, respectively. Graft characteristics were assessed by immunohistology. Bioluminescence signals on days 5, 8, and 14 were higher for GF-based grafts compared with plain H9c2 injections ( P <0.03). Signals were higher for GF/MG grafts compared with GF alone ( P <0.02). GFP-positive, spindle-shaped H9c2 cells were found integrated in the infarct border zones at day 28. Left ventricular (LV) function of hearts implanted with collagen-based grafts was better compared with controls ( P <0.05). Vascular endothelial growth factor or fibroblast growth factor did not further improve graft survival or heart function. Conclusions— Collagen matrices enhance early survival of H9c2 cardiomyoblasts after transplantation into ischemic hearts and lead to improved LV function. Further optimization of the graft design should make restoration of large myocardial infarctions by tissue engineering approaches effective.

Systems approaches to preventing transplanted cell death in cardiac repair

“…Two recent studies have established that successful engraftment of cardiomyocytes is enhanced by co-delivery of the cells with matrix. Kutschka et al demonstrated that grafts were larger and ventricular function was improved in infarcted rats when human embryonic stem cell-derived cardiomyocytes were delivered with collagen matrices, including GelFoam and the basement membrane preparation, Matrigel [72]. As will be discussed below, Laflamme et al found that Matrigel significantly enhanced survival of hESC-derived cardiomyocytes in infarcted hearts of athymic rats [21,22].…”

Physiological function and transplantation of scaffold-free and vascularized human cardiac muscle tissue

“…Delivery of cells in tissue-like structures that preserve cellular attachments could increase cell delivery efficiency and reduce cell death (4). Most heart tissue engineered in vitro to date has focused on creating tissues by seeding neonatal rat or chick cardiomyocytes into polymer or extracellular matrix scaffolds and gels (5)(6)(7)(8)(9)(10)(11). Creation of 3D tissues that are composed only of cells and the matrix they secrete (12)(13)(14)(15), which we refer to as ''scaffoldfree'' tissue engineering, addresses limitations associated with polymer and exogenous matrix-based tissues (e.g., unfavorable host response to biomaterials).…”

Cardiogel supports adhesion, proliferation and differentiation of stem cells with increased oxidative stress protection

“…The cells proliferated, differentiated and even withstood the artificial oxidative stress. This when compared to other biomaterial scaffolds including commercially available ones like Matrigel (BD Biosciences, Franklin Lakes, NJ, USA) could either deliver cells or promote in situ regeneration (Kutschka et al, 2006;Laflamme et al, 2007). The long-term effects including immunogenic response of such materials are yet to be completely understood.…”

“…Attempts have been made to replace infarcted (Heng et al, 2004). Co-delivery of cells with various matrices including collagen matrices, Gel Foam and Matrigel has been successfully carried out (Kutschka et al, 2006;Laflamme et al, 2007). But their long term effects, including immunogenic response in most cases have not been studied well.…”