Transplantation of adipose-derived stem cells combined with neuregulin-microparticles promotes efficient cardiac repair in a rat myocardial infarction model

Tissue engineering is a promising strategy to promote heart regeneration after amyocardial infarction (MI). In this study, we investigated the reparative potential of a system that combines adipose-derived stem cells (ADSCs) withmicroparticles (MPs) loaded with neuregulin (NRG), named ADSC-NRG-MPs, on a rat MI model. First, cells were attached to the surface of MPs encapsulating NRG and coated with a 1:1 mixture of collagen and poly-D-lysine. Oneweek after in vivo administration, the systemfavored the shift ofmacrophage expression froma pro-inflammatory to a regenerative phenotype.At long-term, the adhesion ofADSCs toMPs resulted in an increased cell engraftment,with cells being detectable inthe tissue up to threemonths. In consonance, better tis- sue repairwas observed in the animals treatedwith cells attached toMPs,which presented thicker left ventricles than the animals treatedwith ADSCs alone.Moreover, the presence ofNRGin the systempromoted amore com- plete regeneration, reducing the infarct size and stimulating cardiomyocyte proliferation. Regarding vasculogenesis, the presence of ADSCs and NRG-MPs alone stimulated vessel formation when compared to the control group, but the combination of both induced the largest vasculogenic effect, promoting the formation of both arterioles and capillaries. Importantly, onlywhen ADSCswere administered adhered toMPs, theywere in- corporated into newly formed vessels. Collectively, these findings demonstrate that the combination of ADSCs, MPs and NRG favored a synergy for inducing a greater and more complete improvement in heart regeneration and provided strong evidence tomove forward with preclinical studieswith this strategy.