Enhanced intramyocardial vascular cell delivery promotes post-myocardial infarction healing by polarizing pro-regenerative neutrophils

The success of vascular progenitor cell transplantation to treat myocardial infarction (MI) is primarily limited by the low engraftment of delivered cells due to a washout effect during myocardium contraction. A clinically applicable biomaterial to improve cell retention is arguably needed to enable optimization of intramyocardial cell delivery. Here, we developed a novel therapeutic cell delivery method for MI treatment based on a photocrosslinkable gelatin methacryloyl (GelMA) hydrogel. A combination of human vascular progenitor cells (endothelial progenitors and mesenchymal stem cells) with the capacity to form functional vasculatures after transplantation, were injected with a rapid in-situ photopolymerization approach into the infarcted zone of mouse hearts. Our approach significantly improved acute cell retention and achieved a long-term beneficial post-MI cardiac healing, including stabilizing cardiac functions, preserving viable myocardium, and preventing cardiac fibrosis. Furthermore, the engrafted vascular cells polarized recruited bone marrow-derived neutrophils toward a non-inflammatory phenotype via TGF{beta} signaling, establishing a pro-regenerative microenvironment. Depletion of neutrophils canceled the therapeutic benefits produced by cell delivery in the ischemic hearts, indicating that the non-inflammatory, pro-regenerative neutrophils were indispensable mediators of cardiac remodeling. In summary, our novel GelMA hydrogel-based intramyocardial vascular cell delivery approach has the potential to improve the treatment of acute MI.