Abstract
Myocardial injury, such as myocardial infarction (MI), can lead to drastic heart damage. Zebrafish have the extraordinary ability to regenerate their heart after a severe injury. Upon ventricle resection, fibrin clots seal the wound and serve as a matrix for recruiting myeloid-derived phagocytes. Accumulated neutrophils and macrophages not only reduce the risk of infection but also secrete cytokines and growth factors to promote tissue repair. However, the underlying cellular and molecular mechanisms for how immune responses are regulated during the early stages of cardiac repair are still unclear. We investigated the role and programming of early immune responses during zebrafish heart regeneration. We found that zebrafish treated with an anti-inflammatory glucocorticoid had significantly reduced heart regenerative capacities, consistent with findings in other higher vertebrates. Moreover, inhibiting the inflammatory response led to excessive collagen deposition. A microarray approach was used to assess the differential expression profiles between zebrafish hearts with normal or impaired healing. Combining cytokine profiling and immune-staining, our data revealed that impaired heart regeneration could be due to reduced phagocyte recruitment, leading to diminished angiogenesis and cell proliferation post-cardiac injury. Despite their robust regenerative ability, our study revealed that glucocorticoid treatment could effectively hinder cardiac repair in adult zebrafish by interfering with the inflammatory response. Our findings may help to clarify the initiation of cardiac repair, which could be used to develop a therapeutic intervention that may enhance cardiac repair in humans to compensate for the loss of cardiomyocytes after an MI.
Highlights
Cardiovascular diseases have long been the leading cause of morbidity and mortality worldwide [1], in which myocardial infarction (MI) is associated with the highest risk of death and complications [2]
Using transgenic labeling and immunostaining assays, we further demonstrated that impaired cardiac repair in zebrafish could be related to diminished phagocytes recruitment, angiogenesis and cell proliferation
Myeloid-derived phagocytes recruitment has been observed during cardiac repair [18]; MPX, which is a lysosomal enzyme expressed by neutrophils and commonly denoted as an indicator of inflammation [19]
Summary
Cardiovascular diseases have long been the leading cause of morbidity and mortality worldwide [1], in which myocardial infarction (MI) is associated with the highest risk of death and complications [2]. Fibrotic scar tissue disrupts previously synchronized ventricular contraction, leading to pathological cardiac remodeling, heart failure and eventual death. Zebrafish have an astounding ability to regenerate many vital organs, including the heart [6] and central nervous system [7], which are difficult for fully grown mammals to repair after traumatic injuries [8]. Numerous studies have demonstrated that the adult zebrafish can fully repair its damaged heart from up to a 20% ventricular resection within two months. A murine genetic fate tracking study demonstrated that the mammalian myocardium can partially be regenerated after cardiac injury [10]. Such regenerative ability cannot compensate the loss of cardiomyocytes in conditions like MI occurred in adult mammals
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