UC San Diego

Myocardial infarction (MI) is one of the leading causes of death in the world. Due to the ischemic damage present in the heart, many people who do survive MI undergo negative left ventricular remodeling, heart failure, and ultimately death. There are no current treatments that directly mitigate molecular cascades following MI and negative remodeling. Using tissue engineering applications, we have investigated the role of both natural and synthetic biomaterials to treat the heart to directly influence a pro-reparative response at the molecular, cellular, and tissue level present in MI. While we have broadly investigated these pro-reparative responses with our naturally derived ECM biomaterials, it is relatively unknown how our biomaterials influence pro-repair on specific cell types, regions of the heart, and per sex. Here, we thus utilize transcriptomic techniques, such as spatial transcriptomics to measure spatial heterogeneity of ECM administration, alongside snRNAseq to measure cellular interactions due to both ECM hydrogel and iECM administration. With the ECM hydrogel and iECM, we measure immunomodulation, cardioprotection, fibroblast activation, vasculature development, and neurogenesis. These tools were once again utilized to investigate whether the iECM elicits pro-repair in a sex-specific manner, where we note that the iECM induces stronger immunomodulatory effects in female rats but maintain pro-repair in male rats. With these pro-reparative findings in mind, we then create a synthetic material, a Keap1 inhibiting PLP, that would elicit immunomodulatory, cardioprotective, and angiogenic effects. We demonstrate in vitro and in vivo efficacy of immunomodulation and cardioprotection of the Keap1i-PLPs in MI. Thus, this research highlights the potential for ECM biomaterials to induce pro-reparative responses in MI, explores sex-specific effects with ECM biomaterial administration, and delineates how a synthetic material can be created and elicit similar reparative effects.