Abstract
Rationale: Cortical-bone derived stem cells (CBSCs) improve cardiac pump function and reduce scar size after myocardial infarction (MI) compared to Cardiac-Derived and Mesenchymal Stem Cells. However, the mechanism for these improved outcomes is not known. Recent data in a swine model of MI has demonstrated acute changes to the immune response elicited by MI in CBSC treated animals compared to vehicle controls, suggesting that CBSCs may improve post-MI remodeling by modulation of the immune response. Objective: Identify the changes in the immune response of CBSC-treated animals and determine the role of these changes in cardiac healing and wound repair. Methods and Results: Using multi-color flow cytometry, we found that murine bone marrow-derived macrophages (BMDMs) cultured and exposed to CBSC conditioned culture medium in vitro express higher levels of the mannose receptor CD206 than controls, indicating alternative “M2” activation. In addition, CD86 expression on BMDMs exposed to the classical (M1) activators interferon-γ (INF-γ) and lipopolysaccharide (LPS) in conditioned CBSC media was significantly lower than cells treated only with INF-γ and LPS. Blocking the IL-4 receptor on the BMDMs with a monoclonal antibody in conditioned media decreased CD206 expression, increased CD86 expression, and failed to mitigate the activation elicited by INF-γ and LPS. Exposing the BMDMs to conditioned media also increased the amount of the anti-inflammatory cytokine IL-1 receptor antagonist (IL1-RA) released compared to controls, matching previous data from a swine-model of MI that showed increased IL-1RA blood levels in CBSC-treated swine 72 hours post-MI. Together these data implicate IL-4 as a possible mechanism through which CBSCs influence the inflammatory response raised to MI. Conclusion: Soluble factors secreted by CBSCs change the phenotype of immune cells in vitro and in vivo . A possible mechanism for the beneficial effects of CBSCs on cardiac wound healing after MI may come from their ability to modulate the monocyte/macrophage response to preserve cardiac structure and function.
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