Abstract
Acute myocardial infarction triggers a strong inflammatory response in the affected cardiac tissue. New therapeutic tools based on stem cell therapy may modulate the unbalanced inflammation in the damaged cardiac tissue, contributing to the resolution of this pathological condition. The main goal of this study was to analyze the immunomodulatory effects of cardiosphere-derived cells (CDCs) and their extracellular vesicles (EV-CDCs), delivered by intrapericardial administration in a clinically relevant animal model, during the initial pro-inflammatory phase of an induced myocardial infarction. This effect was assessed in peripheral blood and pericardial fluid leukocytes from infarcted animals. Additionally, cardiac functional parameters, troponin I, hematological and biochemical components were also analyzed to characterize myocardial infarction-induced changes, as well as the safety aspects of these procedures. Our preclinical study demonstrated a successful myocardial infarction induction in all animals, without any reported adverse effect related to the intrapericardial administration of CDCs or EV-CDCs. Significant changes were observed in biochemical and immunological parameters after myocardial infarction. The analysis of peripheral blood leukocytes revealed an increase of M2 monocytes in the EV-CDCs group, while no differences were reported in other lymphocyte subsets. Moreover, arginase-1 (M2-differentiation marker) was significantly increased in pericardial fluids 24 h after EV-CDCs administration. In summary, we demonstrate that, in our experimental conditions, intrapericardially administered EV-CDCs have an immunomodulatory effect on monocyte polarization, showing a beneficial effect for counteracting an unbalanced inflammatory reaction in the acute phase of myocardial infarction. These M2 monocytes have been defined as “pro-regenerative cells” with a pro-angiogenic and anti-inflammatory activity.
Highlights
Cardiac heart failure is one of the main death causes worldwide [1]
There is extensive literature describing the therapeutic potential of cardiosphere-derived cells (CDCs) in myocardial infarction [28], which has been extended to other diseases such as Duchenne muscular dystrophy [29] and aging [14]
The therapeutic effect of CDCs in aging mouse hearts is a matter of debate [30, 31], it is widely accepted that CDCs attenuate the inflammation during myocardial injury [7, 8, 16]
Summary
In acute myocardial infarction (AMI), the cardiac tissue injury triggers a strong inflammatory process where immune cells and soluble mediators are involved. This inflammatory process has been extensively studied, characterized and sequenced. An initial pro-inflammatory phase occurs at days 1–3 after myocardial infarction, and is followed by an anti-inflammatory phase at days 4–7, to achieve tissue repair [2]. During the pro-inflammatory phase, cell death and tissue injury trigger the release of “danger signals” (i.e. activation of complement cascade, reactive oxygen species production, Toll-like receptor activation), which induce cytokine/ chemokine production for the recruitment of leukocytes, such. The bone marrow initiates the activation of hematopoietic cells and leukocyte production which are mobilized into the blood [3]
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