Abstract
Although cardiac mesenchymal cell (CMC) therapy mitigates post-infarct cardiac dysfunction, the underlying mechanisms remain unidentified. It is acknowledged that donor cells are neither appreciably retained nor meaningfully contribute to tissue regeneration—suggesting a paracrine-mediated mechanism of action. As the immune system is inextricably linked to wound healing/remodeling in the ischemically injured heart, the reparative actions of CMCs may be attributed to their immunoregulatory properties. The current study evaluated the consequences of CMC administration on post myocardial infarction (MI) immune responses in vivo and paracrine-mediated immune cell function in vitro. CMC administration preferentially elicited the recruitment of cell types associated with innate immunity (e.g., monocytes/macrophages and neutrophils). CMC paracrine signaling assays revealed enhancement in innate immune cell chemoattraction, survival, and phagocytosis, and diminished pro-inflammatory immune cell activation; data that identifies and catalogues fundamental immunomodulatory properties of CMCs, which have broad implications regarding the mechanism of action of CMCs in cardiac repair.
Highlights
Cardiac mesenchymal cell (CMC) therapy mitigates post-infarct cardiac dysfunction, the underlying mechanisms remain unidentified
We found a low number of neutrophils in shamoperated mice (29.9 ± 7.7 cells per mg of tissue), but this number increased markedly in hearts after I/R injury (740.8 ± 96.2 cells per mg of tissue, P < 0.01)
We found that compared with sham operation both Ly6Chigh and Ly6Clow monocyte subpopulations were increased after myocardial infarction (MI) (Ly6Chigh: 12.9 ± 5.5 vs 210.5 ± 62.7 cells per mg of tissue, respectively, P < 0.05; Ly6Clow: 18.5 ± 1.0 vs 105.9 ± 22.6 cells per mg of tissue, P < 0.05)
Summary
Cardiac mesenchymal cell (CMC) therapy mitigates post-infarct cardiac dysfunction, the underlying mechanisms remain unidentified. CMC paracrine signaling assays revealed enhancement in innate immune cell chemoattraction, survival, and phagocytosis, and diminished pro-inflammatory immune cell activation; data that identifies and catalogues fundamental immunomodulatory properties of CMCs, which have broad implications regarding the mechanism of action of CMCs in cardiac repair. The immune system is a necessary component of myocardial repair, it is unknown whether the improvement in cardiac function after cell therapy is due to immunoregulatory actions of CMCs. the purpose of this study was to determine whether administration of CMCs soon after MI regulates the reparative immune response. In vitro data demonstrated that the secretome of CMCs exerts chemotactic activity towards neutrophils and monocytes/macrophages, enhances survival of neutrophils and macrophages, enhances phagocytosis, and inhibits pro-inflammatory activation of macrophages These observations suggest that CMCs have immunomodulatory properties that could contribute to CMC-induced myocardial repair. Identification of reparative immune pathways enhanced by cell therapy would advance our understanding of the mechanism of action of cell therapy and may provide a new therapeutic target for improving myocardial repair without administration of cell products
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