Abstract
Mesenchymal stromal cell (MSC) transplantation has been investigated as an advanced treatment of heart failure; however, further improvement of the therapeutic efficacy and mechanistic understanding are needed. Our previous study has reported that epicardial placement of fibrin sealant films incorporating rat amniotic membrane-derived (AM)-MSCs (MSC-dressings) could address limitations of traditional transplantation methods. To progress this finding toward clinical translation, this current study aimed to examine the efficacy of MSC-dressings using human AM-MSCs (hAM-MSCs) and the underpinning mechanism for myocardial repair. Echocardiography demonstrated that cardiac function and structure were improved in a rat ischemic cardiomyopathy model after hAM-MSC-dressing therapy. hAM-MSCs survived well in the rat heart, enhanced myocardial expression of reparative genes, and attenuated adverse remodeling. Copy number analysis by qPCR revealed that upregulated reparative genes originated from endogenous rat cells rather than hAM-MSCs. These results suggest hAM-MSC-dressing therapy stimulates a secondary release of paracrine factors from endogenous cells improving myocardial repair (“secondary paracrine effect”), and cardiac M2-like macrophages were identified as a potential cell source of repair. We demonstrated hAM-MSCs increased M2-like macrophages through not only enhancing M2 polarization but also augmenting their proliferation and migration capabilities via PGE2, CCL2, and TGF-β1, resulting in enhanced cardiac function after injury.
Highlights
Myocardial infarction (MI) and post-MI ischemic cardiomyopathy (ICM) is an increasing clinical, social, and financial burden.[1]
We have previously reported that epicardial placement of a rat-derived amniotic membrane-derived (AM)-mesenchymal stromal cell (MSC)-dressing markedly increased donor cell engraftment and enhanced cardiac function in a syngeneic rat ICM model compared to intramyocardial injection.[9]
HAM-MSC-dressing therapy was feasible, safe, and effective to treat ICM in a rat model We characterized hAM-MSC-dressing therapy in a rat post-MI ICM model to progress our development of this emerging technique toward clinical application
Summary
Myocardial infarction (MI) and post-MI ischemic cardiomyopathy (ICM) is an increasing clinical, social, and financial burden.[1]. The inner layer consists of a fibrin-MSC complex that enables its prompt and firm adherence to the heart surface without sutures or extra adhesives and enhances the reparative ability of incorporated MSCs. The outer collagen sponge protects the MSC-fibrin complex from abrasion by the surrounding tissues, improving donor cell retention and survival.[9] As an MSC type, an increasing number of reports propose the advantages of amniotic membrane-derived MSCs (AMMSCs) in terms of mass production as well as immunomodulative and tissue-repair abilities.[2,10,11] We have previously reported that epicardial placement of a rat-derived AM-MSC-dressing markedly increased donor cell engraftment and enhanced cardiac function in a syngeneic rat ICM model compared to intramyocardial injection.[9] For further development of this AM-MSC-dressing therapy toward clinical application, we confirm that human (h)AM-MSC-dressings are feasible, safe, and functional in a rat ICM model. The previously reported observation that MSCs of this cell source survived well without causing significant immunological responses in an immunocompetent rat heart[10] would validate this human-to-rat xenogeneic cell-transplantation model for the purpose of characterizing hAMMSC-dressings
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