Synthetic extracellular matrix mimic hydrogel improves efficacy of mesenchymal stromal cell therapy for ischemic cardiomyopathy

Publication date: Available online 16 January 2018
Source:Acta Biomaterialia
Author(s): Maria Chiara Ciuffreda, Giuseppe Malpasso, Cindy Chokoza, Deon Bezuidenhout, Kyle P. Goetsch, Manuela Mura, Federica Pisano, Neil H. Davies, Massimiliano Gnecchi
BackgroundMesenchymal stromal cells (MSC) repair infarcted hearts mainly through paracrine mechanisms. Low cell engraftment limits the release of soluble paracrine factors (SF) over time and, consequently, MSC efficacy. We tested whether a synthetic extracellular matrix mimic, a hydrogel containing heparin (H-HG), could ameliorate MSC engraftment and binding/release of SF, thus improving MSC therapy efficacy.Methods and ResultsIn vitro, rat bone-marrow MSC (rBM-MSC) were seeded and grown into H-HG. Under normoxia, the hydrogel did not affect cell survival (rBM-MSC survival >90% at each time point tested); vice versa, under hypoxia the biomaterial resulted to be protective for the cells (p<0.001 vs rBM-MSC alone).cells were protected from hypoxia. H-HG or control PEG hydrogels (HG) were incubated with VEGF or bFGF for binding/release quantification. Data showed significantly higher amount of VEGF and bFGF bound by H-HG compared with HG (p<0.05) and a constant release over time.In vivomyocardial infarction (MI) was induced in female Sprague Dawley rats by permanent coronary ligation. One week later, saline, rBM-MSC, H-HG or rBM-MSC/H-HG were injected in the infarct zone. The co-injection of rBM-MSC/H-HG into infarcted hearts significantly increased cardiac function. Importantly, we observed a significant gain in MSC engraftment, reduction of ventricular remodeling and stimulation of neo-vasculogenesis. We also documented higher amounts of several pro-angiogenic factors in hearts treated with rBM-MSC/H-HG.ConclusionsOur data show that H-HG increases MSC engraftment, efficiently fine tunes the paracrine MSC actions and improves cardiac function in infarcted rat hearts. Given its efficacy and safety, documented by the absence of immunoreaction, our strategy appears readily translatable to pre-clinical and clinical settings.Statement of significanceTransplantation of mesenchymal stromal cells (MSC) is a promising treatment for ischemic heart disease, but low cell engraftment limits the release of soluble paracrine factors (SF) and, consequently, MSC efficacy. Thus, in this study we developed an enzymatically degradable polyethylene glycol hydrogel containing heparin (H-HG) able to increase MSC retention and to bind and release paracrine soluble factors secreted by the cells. The result was a significant amelioration in cardiac function, neo-vasculogenesis, endogenous cardiac regeneration and a reduction in ventricular remodeling and scarring. The beneficial effects observed in our study are comparable to those obtained using a much greater number of cells, strengthening the efficacy of the biomaterial used in increasing the therapeutic effects of MSC.

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