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The innate immune regulator MyD88 dampens fibrosis during zebrafish heart regeneration

ABSTRACT: The innate immune response is triggered rapidly after injury and its spatiotemporal dynamics are critical for regeneration, but many questions remain about its exact role. Here we show that MyD88, a key component of the innate immune response, controls not only the inflammatory but also the fibrotic response during zebrafish cardiac regeneration. We find in cryoinjured myd88-/- ventricles a significant reduction in neutrophil and macrophage numbers as well as the expansion of a collagen-rich endocardial population. Further analyses reveal compromised PI3K/AKT pathway activation in the myd88-/- endocardium and increased myofibroblasts and scarring. Notably, endothelial-specific overexpression of myd88 reverses these neutrophil, fibrotic, and scarring phenotypes. Mechanistically, we identify the endocardial-derived chemokine gene cxcl18b as a target of the MyD88-signaling pathway, and using loss- and gain-of-function tools show that it controls neutrophil recruitment. Altogether, these findings shed light on the pivotal role of MyD88 in modulating inflammation and fibrosis during tissue regeneration.

ORGANISM(S): Danio rerio

PROVIDER: GSE262351 | GEO | 2024/07/29

REPOSITORIES: GEO

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The innate immune regulator MyD88 dampens fibrosis during zebrafish heart regeneration (dst169)

Project description:The innate immune system is triggered rapidly after injury and its spatiotemporal dynamics are critical for successful regeneration. MyD88 is a key component of the innate immune response; however, its role during regeneration remains unclear. Here we show that MyD88 controls not only the inflammatory but also the fibrotic response during zebrafish cardiac regeneration. Our data reveal a significant reduction in pro-inflammatory neutrophil and macrophage populations, as well as the expansion of a collagen-rich endocardial population in cryoinjured myd88-/- ventricles. Consistent with these findings, we observed increased myofibroblasts, fibrin abundance, and scarring in myd88-/- ventricles. Transcriptomic analyses of endocardial cells and immunostaining experiments reveal compromised PI3K/AKT pathway activation in the myd88-/- endocardium. Moreover, loss of MyD88 impairs cardiomyocyte proliferation and protrusive activity towards the injured area. Notably, endothelial-specific overexpression of myd88 reverses the neutrophil, fibrotic, and scarring phenotypes in cryoinjured myd88-/- ventricles. Mechanistically, we identify the endocardial-derived chemokine gene cxcl18b as a transcriptional target of the MyD88-signaling axis and using loss- and gain-of-function tools show that it controls neutrophil recruitment. Altogether, these findings shed light on the pivotal role of MyD88 in modulating inflammation and fibrosis, thereby emphasizing the strong impact of the innate immune response during tissue regeneration.

2024-07-29 | GSE262247 | GEO

The innate immune regulator MyD88 dampens fibrosis during zebrafish heart regeneration

Project description:This SuperSeries is composed of the SubSeries listed below. The innate immune response is triggered rapidly after injury and its spatiotemporal dynamics are critical for regeneration, but many questions remain about its exact role. Here we show that MyD88, a key component of the innate immune response, controls not only the inflammatory but also the fibrotic response during zebrafish cardiac regeneration. We find in cryoinjured myd88-/- ventricles a significant reduction in neutrophil and macrophage numbers as well as the expansion of a collagen-rich endocardial population. Further analyses reveal compromised PI3K/AKT pathway activation in the myd88-/- endocardium and increased myofibroblasts and scarring. Notably, endothelial-specific overexpression of myd88 reverses these neutrophil, fibrotic, and scarring phenotypes. Mechanistically, we identify the endocardial-derived chemokine gene cxcl18b as a target of the MyD88-signaling pathway, and using loss- and gain-of-function tools show that it controls neutrophil recruitment. Altogether, these findings shed light on the pivotal role of MyD88 in modulating inflammation and fibrosis during tissue regeneration.

2024-07-29 | GSE262248 | GEO

The innate immune regulator MyD88 dampens fibrosis during zebrafish heart regeneration (dst139)

Project description:The innate immune response is triggered rapidly after injury and its spatiotemporal dynamics are critical for regeneration, but many questions remain about its exact role. Here we show that MyD88, a key component of the innate immune response, controls not only the inflammatory but also the fibrotic response during zebrafish cardiac regeneration. We find in cryoinjured myd88-/- ventricles a significant reduction in neutrophil and macrophage numbers as well as the expansion of a collagen-rich endocardial population. Further analyses reveal compromised PI3K/AKT pathway activation in the myd88-/- endocardium and increased myofibroblasts and scarring. Notably, endothelial-specific overexpression of myd88 reverses these neutrophil, fibrotic, and scarring phenotypes. Mechanistically, we identify the endocardial-derived chemokine gene cxcl18b as a target of the MyD88-signaling pathway, and using loss- and gain-of-function tools show that it controls neutrophil recruitment. Altogether, these findings shed light on the pivotal role of MyD88 in modulating inflammation and fibrosis during tissue regeneration.

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Injury-activated endocardium plays structural and signalling roles in zebrafish heart regeneration

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flt1 inactivation promotes zebrafish cardiac regeneration by enhancing endothelial activity and limiting the fibrotic response

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2024-11-12 | GSE264406 | GEO

The innate immune regulator MyD88 dampens fibrosis during zebrafish heart regeneration

Project description:The innate immune regulator MyD88 dampens fibrosis during zebrafish heart regeneration

| PRJNA1090894 | ENA

The innate immune regulator MyD88 dampens fibrosis during zebrafish heart regeneration

Project description:The innate immune regulator MyD88 dampens fibrosis during zebrafish heart regeneration

| PRJNA1091566 | ENA

The innate immune regulator MyD88 dampens fibrosis during zebrafish heart regeneration (dst139)

Project description:The innate immune regulator MyD88 dampens fibrosis during zebrafish heart regeneration (dst139)

| PRJNA1090509 | ENA

The innate immune regulator MyD88 dampens fibrosis during zebrafish heart regeneration (dst169)

Project description:The innate immune regulator MyD88 dampens fibrosis during zebrafish heart regeneration (dst169)

| PRJNA1090898 | ENA

Myocardial Differentiation is Dependent upon Endocardial Signalling During Early Cardiogenesis in vitro

Project description:The endocardium interacts with the myocardium to promote proliferation and morphogenesis during the later stages of heart development. However, the role of the endocardium in early cardiac ontogeny remains under-explored. Given the shared origin, subsequent juxtaposition, and essential cell-cell interactions of endocardial and myocardial cells throughout heart development, we hypothesized that paracrine signaling from the endocardium to the myocardium is critical for initiating early differentiation of myocardial cells. To test this, we generated an in vitro, endocardial-specific ablation model using the diphtheria toxin receptor under the regulatory elements of the NFATc1 genomic locus (NFATc1-DTR) Early treatment of NFATc1-DTR embryoid bodies with diphtheria toxin efficiently ablated endocardial cells, which significantly attenuated the percent of beating EBs in culture and expression of early and late myocardial differentiation markers. The addition of Bmp2 during endocardial ablation partially rescued myocyte differentiation, maturation and function. Therefore, we conclude that early stages of myocardial differentiation rely on endocardial paracrine signaling mediated in part by Bmp2. Our findings provide novel insight into early endocardial-myocardial interactions that can be explored to promote early myocardial development and growth.

2019-05-01 | GSE119505 | GEO

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