Abstract
BackgroundA major hurdle in the use of exogenous stems cells for therapeutic regeneration of injured myocardium remains the poor survival of implanted cells. To date, the delivery of stem cells into myocardium has largely focused on implantation of cell suspensions.Methodology and Principal FindingsWe hypothesize that delivering progenitor cells in an aggregate form would serve to mimic the endogenous state with proper cell-cell contact, and may aid the survival of implanted cells. Microwell methodologies allow for the culture of homogenous 3D cell aggregates, thereby allowing cell-cell contact. In this study, we find that the culture of cardiac progenitor cells in a 3D cell aggregate augments cell survival and protects against cellular toxins and stressors, including hydrogen peroxide and anoxia/reoxygenation induced cell death. Moreover, using a murine model of cardiac ischemia-reperfusion injury, we find that delivery of cardiac progenitor cells in the form of 3D aggregates improved in vivo survival of implanted cells.ConclusionCollectively, our data support the notion that growth in 3D cellular systems and maintenance of cell-cell contact improves exogenous cell survival following delivery into myocardium. These approaches may serve as a strategy to improve cardiovascular cell-based therapies.
Highlights
Heart failure is a clinical condition arising from the progressive loss of functional muscle cells following cardiac injury [1]
Collectively, our data support the notion that growth in 3D cellular systems and maintenance of cell-cell contact improves exogenous cell survival following delivery into myocardium
In this study, utilizing our recently established microwell array methodology, we demonstrated that cardiac side population (CSP) progenitor cells [28,29], when delivered in 3D cell aggregates exhibit enhanced survival against stressors and toxins in vitro, as well as improved survival following implantation in vivo in a murine model of cardiac injury
Summary
Heart failure is a clinical condition arising from the progressive loss of functional muscle cells following cardiac injury [1]. Stem-cell based therapies have been explored as a means for regeneration of heart tissue [4], with functional differentiation of implanted stem cells into mature cardiomyocytes [5,6,7,8]. Different populations of adult stem cells have been examined following implantation in animal models of and humans with heart disease [9,10,11,12,13]. A major obstacle to realizing therapeutic regeneration is the very poor survival of implanted cells [14,15,16,17]. A major hurdle in the use of exogenous stems cells for therapeutic regeneration of injured myocardium remains the poor survival of implanted cells. The delivery of stem cells into myocardium has largely focused on implantation of cell suspensions
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