1. Characterising differences between the regenerative and non-regenerative immune response in the Astyanax mexicanus
- Author
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Potts, Helen, Mommersteeg, Mathilda, and Choudhury, Robin
- Subjects
Myocardial infarction ,Muscles--Regeneration ,Immunology, Comparative ,Heart failure - Abstract
The human heart cannot regenerate following myocardial infarction and instead forms a fibrotic scar that impairs cardiac function and can lead to heart failure. Cardiac regeneration aims to treat the injured heart by stimulating the heart to repair itself. The Astyanax mexicanus is a uniquely suited model of cardiac regeneration as it comprises two closely related populations: (1) the 'regenerative' surface (SF) population and (2) the 'non-regenerative' Pachόn (PF) cave population. The immune response to injury is known to be a key regulator of successful regeneration. However, how this response differs between SF and PF populations is unknown. To fully characterise the A. mexicanus immune response, single cell RNA-sequencing, differential gene expression analysis, histological staining and in situ hybridisation were used to determine the immune cell populations present in the heart at 1-, 3-, 7-, 14- and 30 days post-cryoinjury (dpci). Pharmacological perturbations of the A. mexicanus immune response were then used to explore whether identified differences in the regenerative and scarring immune responses to cardiac injury were exerting control on regenerative capacity. Striking spatiotemporal differences were found in the dynamics of both myeloid and lymphoid populations in the PF and SF. Immediately after injury, the non-regenerative PF showed a stronger response to injury with a significantly greater influx of neutrophils into the wound (1dpci p=0.0156; 3dpci p=0.0075). By 7dpci, this inflammatory response was resolved, and differential gene expression analysis showed that PF neutrophils had returned to the uninjured state. In contrast, the regenerative SF showed a greater immune response at the late stages of cardiac healing (7-, 14- and 30dpci). Specifically, at 7- and 14dpci, a transcriptionally unique population of neutrophils was observed in the SF that remained activated and upregulated TNFα-NFκB signalling. Furthermore, a stark contrast in the B cell response was observed: SF displayed a significant influx of B cells at 14- and 30dpci that was absent in the PF (p<0.005). Inhibition of the SF immune response using 7-14dpci Dexamethasone treatment did not impair the regenerative capacity of the SF but did significantly disrupt scar organisation, resulting in scars that closely resembled time-matched PF scars. This research represents a significant leap forward in our understanding of how the immune response differs between successful regeneration (SF) and scarring (PF). However, further studies will be required to determine the role of late-stage SF neutrophils and B cells in successful regeneration before novel therapeutic targets can be identified for immunomodulation in heart attack patients.
- Published
- 2022