Prolonged neutrophil retention in the wound impairs zebrafish heart regeneration after cryoinjury

Xu, Shisan; Xie, Fangjing; Tian, Li; Manno, Sinai H. C.; Manno, Francis A. M.; Cheng, Shuk Han

doi:10.1016/j.fsi.2019.09.030

Cited by 21 publications

(18 citation statements)

References 44 publications

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“…Their finding that replicating the regenerative immune response in a scarring model improved regeneration post-injury suggests that targeting macrophage and neutrophil dynamics could be a novel therapeutic strategy. Since this study, many groups have investigated the tight regulation of spatiotemporal leukocyte dynamics post-MI [20,21] and have shown that dysregulation inhibits regeneration and leads to fibrotic scar deposition [22][23][24]. Further characterisation of the differences in the immune response between regenerative and non-regenerative species and understanding how leukocytes regulate regeneration will be critical in developing an effective immunomodulatory therapy.…”

Section: What We Can Learn From a Closely Related Teleost Fish: Medaka (Oryzias Latipes)-one Of The Few Documented Non-regenerative Fishmentioning

confidence: 91%

Unlocking the Secrets of the Regenerating Fish Heart: Comparing Regenerative Models to Shed Light on Successful Regeneration

Potts

Stockdale

Mommersteeg

2021

JCDD

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The adult human heart cannot repair itself after injury and, instead, forms a permanent fibrotic scar that impairs cardiac function and can lead to incurable heart failure. The zebrafish, amongst other organisms, has been extensively studied for its innate capacity to repair its heart after injury. Understanding the signals that govern successful regeneration in models such as the zebrafish will lead to the development of effective therapies that can stimulate endogenous repair in humans. To date, many studies have investigated cardiac regeneration using a reverse genetics candidate gene approach. However, this approach is limited in its ability to unbiasedly identify novel genes and signalling pathways that are essential to successful regeneration. In contrast, drawing comparisons between different models of regeneration enables unbiased screens to be performed, identifying signals that have not previously been linked to regeneration. Here, we will review in detail what has been learnt from the comparative approach, highlighting the techniques used and how these studies have influenced the field. We will also discuss what further comparisons would enhance our knowledge of successful regeneration and scarring. Finally, we focus on the Astyanax mexicanus, an intraspecies comparative fish model that holds great promise for revealing the secrets of the regenerating heart.

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Section: What We Can Learn From a Closely Related Teleost Fish: Medaka (Oryzias Latipes)-one Of The Few Documented Non-regenerative Fishmentioning

confidence: 91%

Unlocking the Secrets of the Regenerating Fish Heart: Comparing Regenerative Models to Shed Light on Successful Regeneration

Potts

Stockdale

Mommersteeg

2021

JCDD

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“…The study of many different in vivo models of cardiovascular disease and injury is helping researchers look beyond CMs to the myriad of cells and processes that co-activate, co-ordinate and co-regulate regeneration of the heart. These processes include signalling mechanisms for cell recruitment (reviewed by Sanz-Morejón and Mercader 2020 ), phagocytic immune cell removal of debris (de Preux Charles et al 2016 ; Lai et al 2017 ; Bevan et al 2020 ), fibroblasts laying down ECM (Simões et al 2020 ) and MMP breakdown of ECM to permit the infiltration of new vasculature (Bellayr et al 2009 ; Marín-Juez et al 2016 ; Xu et al 2019 ), which ultimately provide a supportive architecture for the invasion of new CMs. Further study of this complex interplay will be key to our understanding of the regenerative process as a whole.…”

Section: Cardiomyocyte Proliferationmentioning

confidence: 99%

“…This has shown the direct parallels that exist between zebrafish and mammalian cardiac repair, with timely induction and resolution of the inflammatory response being essential to achieve normal regeneration in the zebrafish heart and to regulate many other aspects of repair, including revascularisation, CM proliferation and scar deposition and resolution (Bevan et al 2020 ; Simões et al 2020 ). Recent observations have also illustrated that without tight regulation of the inflammatory response, excessive immune cell accumulation is inhibitory to regeneration, regardless of the presence of proliferating cells and the ECM (Xu et al 2019 ). This demonstrates that inflammatory cells have critical roles in coupling CM proliferation and scar resolution, both of which are central to an efficient regenerative outcome.…”

Section: Emerging Roles For Inflammatory Populationsmentioning

confidence: 99%

“…However, the release of ROS by neutrophils, as well as infiltrating monocytes, can cause further tissue necrosis and scarring (Bonaventura et al 2019 ). Neutrophil retention has been shown to prolong the inflammatory period leading to delayed scar regression and reduced CM proliferation in heart injury models (Robertson et al 2014 ; Lai et al 2017 ; Xu et al 2019 ), therefore, timely cessation of the neutrophil response is essential for the regenerative outcome observed in zebrafish.…”

Section: Emerging Roles For Inflammatory Populationsmentioning

confidence: 99%

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Zebrafish cardiac regeneration—looking beyond cardiomyocytes to a complex microenvironment

Ryan

Moyse

Richardson

2020

Histochem Cell Biol

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The study of heart repair post-myocardial infarction has historically focused on the importance of cardiomyocyte proliferation as the major factor limiting adult mammalian heart regeneration. However, there is mounting evidence that a narrow focus on this one cell type discounts the importance of a complex cascade of cell–cell communication involving a whole host of different cell types. A major difficulty in the study of heart regeneration is the rarity of this process in adult animals, meaning a mammalian template for how this can be achieved is lacking. Here, we review the adult zebrafish as an ideal and unique model in which to study the underlying mechanisms and cell types required to attain complete heart regeneration following cardiac injury. We provide an introduction to the role of the cardiac microenvironment in the complex regenerative process and discuss some of the key advances using this in vivo vertebrate model that have recently increased our understanding of the vital roles of multiple different cell types. Due to the sheer number of exciting studies describing new and unexpected roles for inflammatory cell populations in cardiac regeneration, this review will pay particular attention to these important microenvironment participants.

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“…Inhibition of inflammation leads to decreased cell proliferation, impaired angiogenesis and thus incomplete regeneration (De Preux Charles et al, 2016;Huang et al, 2013). Additionally, delayed immune response is associated with impaired vascularization and resolution of the scar tissue (Lai et al, 2017), whereas long retention of neutrophils in the wound promotes revascularization (Xu et al, 2019).…”

Section: Zebrafish Heart Regenerationmentioning

confidence: 99%

Study of Midkine-a and Caveolin-1 in zebrafish heart regeneration

Grivas¹

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Zebrafish have the ability to regenerate cardiac tissue after injury in contrast to mammals.Cryoinjury of the heart triggers a regenerative program that includes inflammatory response, cell proliferation and formation of a transient scar that eventually lead to complete tissue regeneration. This thesis focused on understanding the molecular and mechanical properties governing zebrafish heart regeneration. In particular, we studied the role of midkine-a (mdka) and caveolin-1 (cav1), two genes that were upregulated in a microarray analysis of regenerating hearts performed in the laboratory. Additionally, we studied the epigenetic regulation of mdka and tested in vivo different mdka cis-regulatory elements with the goal to identify the minimum regulatory regions that drive mdka expression in development and after injury.Midkine-a (Mdka) is a neurite-growth factor that is involved in the formation of the media floor plate in zebrafish. Here, we show that mdka expression was strongly induced after heart injury, although it was not expressed in intact hearts. In injured hearts, the onset of mdka expression was one-day post cryoinjury (dpci) in all the epicardial layer, whereas by 7dpci the expression became restricted to the epicardial cells covering the injured area. To study the role of Mdka in heart regeneration, we generated mdka-knock out (KO) zebrafish strains. In injured heart, mdka depletion did not trigger upregulation of mdkb and ptn, the two other members of the midkine gene family, which might compensate for the loss of Mdka. Analysis of 90dpci hearts showed that mdka deletion resulted in impaired heart regeneration, with the injured area enriched in collagen deposition.However, the proliferation ratio of cardiomyocytes (CM) and epicardial cells was not affected.Analysis of extracellular matrix turnover, immune cells infiltration in the injured area and revascularization of the regenerating tissue will clarify the reasons for the impaired cardiac regeneration in mdka-KO hearts.During development, mdka is expressed in neural tissues such us neural tube and brain, and is not detected neither in developing hearts nor in adult intact hearts. However, mdka expression was activated upon heart injury, having dynamic expression pattern. To investigate such a change in the expression pattern, we used available ChIP-seq and ATAC-seq data to analyse the epigenetic landscape of mdka. In mdka locus, there are three intronic enhancer sequences and two additional enhancers located upstream of mdka. We tested these enhancers and the mdka promoter linked to GFP reporter and studied their expression patterns in our transgenic lines. We found that the promoter of mdka and the intronic enhancers were responsible for the spatio-temporal expression pattern of mdka during development, in adult tissues and after injury of the heart and the fin.Caveolin-1 (Cav1) is the structural protein of caveolae, small membrane invaginations that are involved in signal transduction and mechanoprotection. Our expression analysis showed that Cav1...

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Prolonged neutrophil retention in the wound impairs zebrafish heart regeneration after cryoinjury

Cited by 21 publications

References 44 publications

Unlocking the Secrets of the Regenerating Fish Heart: Comparing Regenerative Models to Shed Light on Successful Regeneration

Unlocking the Secrets of the Regenerating Fish Heart: Comparing Regenerative Models to Shed Light on Successful Regeneration

Zebrafish cardiac regeneration—looking beyond cardiomyocytes to a complex microenvironment

Study of Midkine-a and Caveolin-1 in zebrafish heart regeneration

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