Investigating scaffold designs for progenitor cells-based cell therapy for cardiac repair

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Bhutani, Srishti
Davis, Michael E.
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Cell therapy for congestive heart failure has shown promising results in preclinical studies, but results of clinical trials suggest the need for this modality to be optimized. C-kit+ cardiac progenitor cells (CPCs) are adult stem cells that have been shown to differentiate toward lineages of the heart and exert beneficial paracrine effects. Their injection in humans resulted in moderate but insufficient improvements in cardiac function after myocardial infarction. In this project, we studied two strategies for enhancing CPC based-cell therapy using tunable maleimide-crosslinked poly(ethylene glycol) (PEG-MAL) hydrogels. In the first strategy, CPCs were encapsulated in PEG-MAL hydrogels presenting vascular endothelial growth factor (VEGF). Although activation of ERK signaling was observed in CPCs encapsulated in VEGF presenting PEG gels, this strategy failed to induce endothelial differentiation or modulate paracrine effects of CPCs in vitro. Different growth factor doses, cell populations and biomaterial density and degradation rates were tested. In the second strategy, CPCs were encapsulated in integrin-specific hydrogels. α2β1-specific hydrogels induced cardiomyocyte differentiation of CPCs accompanied by a reduction in expression of secreted factors in vitro. Interestingly, following injection in rats undergoing ischemia-reperfusion, treatment with CPCs encapsulated in non-adhesive hydrogels resulted in the greatest preservation of cardiac contractility and attenuation of post-infarct remodeling. Overall, this work adds to our knowledge of CPC behavior in presence of stimuli relevant to pragmatic design of regenerative therapies, as well as broadens our understanding of design principles that may be used to augment effects of cell therapy for myocardial repair.
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