The Effect Of Myocardial Inflammation On Stem Cell Effectiveness As �Renvironmental Protection Agencyir Cell� Therapy

Project Summary: The effect of myocardial inflammation on stem cell effectiveness as �rEnvironmental Protection Agencyir cell�therapy Cardiovascular disease including myocardial infarction (MI) is the leading cause of death in the westernworld. Following MI, myocardial inflammation plays a crucial role in the pathogenesis of MI injury andmacrophages are among the key cells activated during the initial phases of the host response regulating thehealing process. Macrophages undergo phenotypic changes from pro-inflammatory (M1) towards an anti-inflammatory and wound healing phenotype (M2) through mechanisms that are not yet fully elucidated. Whilemacrophages emerged as attractive effectors in tissue injury and rEnvironmental Protection Agencyir, the contribution of specificmacrophage subsets on cardiac cell function and survival in the steady state as well as in the diseased state isnot fully understood. A better understanding of the role of myocardial inflammation post-MI is especiallyimportant for stem cell-based therapy, as most of the transplanted cells do not endure the inflammatoryresponse and functionally couple with the resident cells in an ischemic environment. There are currently no appropriate in vitro experimental models to study the role of myocardialinflammation and macrophages, as existing models focus almost exclusively on mimicking the healthy cardiacmicroenvironment with the goal of providing a living surgical replacement. Thus, this proposal aims toinvestigate the role of macrophage subsets and the effect of myocardial inflammation on residentcardiomyocytes as well as on transplanted stem cells using both in vitro and in vivo models. A well-controlledin vitro diseased tissue model that can serve as a powerful tool to evaluate the heterocellular cross-talk duringpost-MI rEnvironmental Protection Agencyir process will be developed. To complement and translate the findings from the in vitro diseasedmodel, mouse MI models exhibiting either enhanced or suppressed inflammation will be utilized. Detailed andmore mechanistic insights into macrophage interaction with the resident cells as well as transplanted stemcells as �rEnvironmental Protection Agencyir cell� during multi-phase rEnvironmental Protection Agencyir process opens the possibility of exploring macrophagemodulation as new therapeutic strategy. The results from this study will provide the basis for approaches toenhance acute retention and survival of the transplanted cells in the diseased tissue, which can ultimately leadto enhancing the efficacy of a cell-based therapy.