Abstract
In zebrafish, the role of matrix metalloproteinases (MMPs) in the inflammatory phase of heart regeneration following cryoinjury remains poorly understood. Here, we demonstrated an increase in MMP enzymatic activity and elevated expression of mmp9 and mmp13 in the injured area (IA) of hearts from as early as 1 day post-cryoinjury (dpc). Treatment with the broad-spectrum MMP inhibitor, GM6001, during the first week after cryoinjury resulted in impaired heart regeneration, as indicated by the larger scar and reduced numbers of proliferating cardiomyocytes. GM6001 also significantly reduced the number of leukocytes to the IA at 0.5 dpc to 4 dpc. Specific inhibition of both MMP-9 and MMP-13 also resulted in impaired regeneration and leukocyte recruitment. However, chemokine rescue with recombinant CXCL8 and CCL2 restored the recruitment of macrophages and the cardiac regenerative capability in GM6001-treated fish. MMP-9 and MMP-13 cleaved zebrafish CXCL8 at the same site, and the truncated form was more chemotactic than the intact form. In contrast, CCL2 did not have an MMP-9 or MMP-13 cleavage site. Together, these data suggest that MMPs might play a key role in the inflammatory phase of heart regeneration in zebrafish, by mediating leukocyte recruitment via the activation of chemokines.
Highlights
Unlike adult mammals, adult zebrafish exhibit an exceptional regenerative capability to replace damaged ventricular tissues with new cardiac muscle cells, and they achieve robust anatomical and functional recovery
Based on various previous reports, it is possible to describe the dynamic series of events that occur during heart regeneration following cryoinjury, as comprising 3 main phases
We investigated if the enzymatic activity of matrix metalloproteinases (MMPs) might be essential for zebrafish heart regeneration following cryoinjury, especially with regards to the inflammatory phase during the first 7 days
Summary
Adult zebrafish exhibit an exceptional regenerative capability to replace damaged ventricular tissues with new cardiac muscle cells, and they achieve robust anatomical and functional recovery. Ventricular resection experiments using the Tg(coro1a:EGFP) line of zebrafish, where leukocytes are labeled with EGFP, demonstrated that these cells first appeared at ~3 days post amputation (dpa), and the numbers peaked at 7 dpa and 14 dpa, after which they gradually disappeared at 19 dpa[24]. While these different studies demonstrate a broad inflammatory response occurring during the first 7 days in different injury models, the dynamics of recruitment, dispersal and peak densities of the neutrophil and macrophage populations need further exploration. We discuss the subtle differences that occur in the MMP cleavage of CCL2, which might help to explain the divergent outcomes following ventricular damage in zebrafish and mammals
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