Dissecting a regenerative role of il11a as a mitogenic and pro-fibrotic factor in the adult zebrafish heart
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ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE233833 | GEO | 2024/10/01
REPOSITORIES: GEO
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Project description:Dissecting a regenerative role of il11a as a mitogenic and pro-fibrotic factor in the adult zebrafish heart
| PRJNA978068 | ENA
Project description:Adult mammalian skin wounds heal by forming fibrotic scars. We report that full-thickness injuries of reindeer antler skin (velvet) regenerate, whereas back skin forms fibrotic scar. Single-cell multi-omics reveal that uninjured velvet fibroblasts resemble human fetal fibroblasts, whereas back skin fibroblasts express inflammatory mediators mimicking pro-fibrotic adult human and rodent fibroblasts. Consequently, injury elicits site-specific immune responses: back skin fibroblasts amplify myeloid infiltration and maturation during repair, whereas velvet fibroblasts adopt an immunosuppressive phenotype that restricts leukocyte recruitment and hastens immune resolution. Ectopic transplantation of velvet to scar-forming back skin is initially regenerative, but progressively transitions to a fibrotic phenotype akin to the scarless fetal-to-scar-forming transition reported in humans. Skin regeneration is diminished by intensifying, or enhanced by neutralizing, these pathologic fibroblast-immune interactions. Reindeer represent a powerful comparative model for interrogating divergent wound healing outcomes, and our results nominate decoupling of fibroblast-immune interactions as a promising approach to mitigate scar.
| S-EPMC9888357 | biostudies-literature
Project description:After injury, a cascade of events repairs the damaged tissue, including expansion and differentiation of the progenitor pool and redeposition of matrix. To guide future wound regeneration strategies, we compared single-cell sequencing of regenerative (third phalangeal element [P3]) and fibrotic (second phalangeal element [P2]) digit tip amputation (DTA) models as well as traumatic heterotopic ossification (HO; aberrant). Analyses point to a common initial response to injury, including expansion of progenitors, redeposition of matrix, and activation of transforming growth factor β (TGF-β) and WNT pathways. Surprisingly, fibrotic P2 DTA showed greater transcriptional similarity to HO than to regenerative P3 DTA, suggesting that gene expression more strongly correlates with healing outcome than with injury type or cell origin. Differential analysis and immunostaining revealed altered activation of inflammatory pathways, such as the complement pathway, in the progenitor cells. These data suggests that common pathways are activated in response to damage but are fine tuned within each injury. Modulating these pathways may shift the balance toward regenerative outcomes.
| S-EPMC9561541 | biostudies-literature
Project description:AimsIn the adult heart, Notch signalling regulates the response to injury. Notch inhibition leads to increased cardiomyocyte apoptosis, and exacerbates the development of cardiac hypertrophy and fibrosis. The role of Notch in the mesenchymal stromal cell fraction, which contains cardiac fibroblasts and cardiac precursor cells, is, however, largely unknown. In the present study, we evaluate, therefore, whether forced activation of the Notch pathway in mesenchymal stromal cells regulates pathological cardiac remodelling.Methods and resultsWe generated transgenic mice overexpressing the Notch ligand Jagged1 on the surface of cardiomyocytes to activate Notch signalling in adjacent myocyte and non-myocyte cells. In neonatal transgenic mice, activated Notch sustained cardiac precursor and myocyte proliferation after birth, and led to increased numbers of cardiac myocytes in adult mice. In the adult heart under pressure overload, Notch inhibited the development of cardiomyocyte hypertrophy and transforming growth factor-β/connective tissue growth factor-mediated cardiac fibrosis. Most importantly, Notch activation in the stressed adult heart reduced the proliferation of myofibroblasts and stimulated the expansion of stem cell antigen-1-positive cells, and in particular of Nkx2.5-positive cardiac precursor cells.ConclusionsWe conclude that Notch is pivotal in the healing process of the injured heart. Specifically, Notch regulates key cellular mechanisms in the mesenchymal stromal cell population, and thereby controls the balance between fibrotic and regenerative repair in the adult heart. Altogether, these findings indicate that Notch represents a unique therapeutic target for inducing regeneration in the adult heart via mobilization of cardiac precursor cells.
| S-EPMC4139705 | biostudies-literature
Project description:Heart regeneration is an unmet clinical need, hampered by limited renewal of adult cardiomyocytes and fibrotic scarring. Pluripotent stem cell-based strategies are emerging, but unravelling cellular dynamics of host-graft crosstalk remains elusive. Here, by combining lineage tracing and single-cell transcriptomics in injured non-human primate heart biomimics, we uncover the coordinated action modes of human progenitor-mediated muscle repair. Chemoattraction via CXCL12/CXCR4 directs cellular migration to injury sites. Activated fibroblast repulsion targets fibrosis by SLIT2/ROBO1 guidance in organizing cytoskeletal dynamics. Ultimately, differentiation and electromechanical integration lead to functional restoration of damaged heart muscle. In vivo transplantation into acutely and chronically injured porcine hearts illustrated CXCR4-dependent homing, de novo formation of heart muscle, scar-volume reduction and prevention of heart failure progression. Concurrent endothelial differentiation contributed to graft neovascularization. Our study demonstrates that inherent developmental programmes within cardiac progenitors are sequentially activated in disease, enabling the cells to sense and counteract acute and chronic injury.
| S-EPMC9106586 | biostudies-literature
Project description:Objectives: Interleukin 11 (IL11) is highly upregulated in skin and lung fibroblasts from patients with systemic sclerosis (SSc). Here we tested whether IL11 is mechanistically linked with human dermal fibroblast (HDF) activation. Methods: We measured serum IL11 levels in healthy volunteers and patients with early diffuse SSc and manipulated IL11 signalling in HDFs using gain- and loss-of-function approaches. Results: In patients with SSc, serum IL11 levels are elevated as compared to healthy controls. Transforming growth factor beta (TGFβ) isoforms 1, 2 or 3 induced IL11 secretion from HDFs, which highly express IL11RA and the gp130 co-receptor, suggestive of an autocrine loop of IL11 activity in HDFs. IL11 consistently and robustly stimulated ERK activation in HDFs and resulted in HDF-to-myofibroblast transformation. IL11 induced STAT phosphorylation to a lesser extent than ERK and only at high IL11 concentrations. IL11-stimulated ERK activation and fibrosis phenotypes were absent in skin fibroblasts from patients with homozygous loss-of-function mutation in IL11RA. Inhibition of IL11 signaling using either a neutralizing antibody against IL11 or siRNA against IL11RA reduced TGFβ-induced HDF proliferation, matrix production and cell migration, which was phenocopied by pharmacologic inhibition of ERK activity. Conclusions: These data reveal an important contribution of IL11-related ERK activity for TGFβ-stimulated fibrosis phenotypes in HDFs and suggest IL11 as a potential therapeutic target in SSc.
2021-02-22 | GSE162966 | GEO
Project description:To date, the cell and molecular mechanisms regulating tendon healing are poorly understood. Here, we establish a novel model of tendon regeneration using neonatal mice and show that neonates heal via formation of a 'neo-tendon' that differentiates along the tendon specific lineage with functional restoration of gait and mechanical properties. In contrast, adults heal via fibrovascular scar, aberrant differentiation toward cartilage and bone, with persistently impaired function. Lineage tracing identified intrinsic recruitment of Scx-lineage cells as a key cellular mechanism of neonatal healing that is absent in adults. Instead, adult Scx-lineage tenocytes are not recruited into the defect but transdifferentiate into ectopic cartilage; in the absence of tenogenic cells, extrinsic αSMA-expressing cells persist to form a permanent scar. Collectively, these results establish an exciting model of tendon regeneration and uncover a novel cellular mechanism underlying regenerative vs non-regenerative tendon healing.
| S-EPMC5362908 | biostudies-literature
Project description:Background: Cardiac fibrosis is a common pathological process in heart disease and represents a therapeutic target. TGFβ is the canonical driver of cardiac fibrosis and was recently shown to be dependent on IL11 for its profibrotic effects in fibroblasts. In the opposite direction, recombinant human IL11 has been reported as anti-fibrotic and also anti-inflammatory in the mouse heart. Objectives: In this study, we determined the effects of IL11 expression in cardiomyocytes on cardiac pathobiology and function. Methods: We used the Cre-loxP system to generate a tamoxifen-inducible mouse with cardiomyocyte-restricted murine Il11 expression. Using protein assays, bulk RNA-sequencing and in vivo imaging we analysed the effects of IL11 on myocardial fibrosis, inflammation and cardiac function and challenge previous reports suggesting cardioprotective potential of IL11. Results: TGFβ stimulation of cardiomyocytes caused Il11 upregulation. As compared to wild-type controls, Il11 expressing hearts demonstrated severe cardiac fibrosis and inflammation that was associated with the upregulation of cytokines, chemokines, complement factors and increased inflammatory cells. IL11 expression also activated a programme of endothelial-to-mesenchymal transition and resulted in left ventricular dysfunction. Conclusion: Our data define species-matched IL11 as strongly profibrotic and proinflammatory when secreted from cardiomyocytes and further establish IL11 as a disease factor.
2023-08-21 | GSE236854 | GEO
Project description:The kidney has large regenerative capacity that is impeded when injured renal tubular epithelial cells (TECs) undergo SNAI1-driven partial epithelial mesenchymal transition (pEMT). Here we investigate the role of IL11 in TEC pEMT and kidney repair. Wild-type mice with acute kidney injury (AKI) upregulate IL11 in TECs triggering an ERK/P90RSK/GSK3β axis of SNAI1 expression leading to impaired renal function, which is abrogated in Il11 null mice. In mouse models of AKI, a neutralizing IL11 antibody promotes kidney regeneration, while attenuating pEMT, fibrosis and kidney dysfunction. In TECs, TGFβ1 induces autocrine IL11/ERK-dependent pEMT leading to paracrine, IL11-mediated fibroblast activation. Mice with TEC-specific deletion of Il11ra1 are protected from pEMT, inflammation, fibrosis and renal failure. In a mouse model of chronic kidney disease, administration of anti-IL11 reverses fibrosis, regenerates kidney parenchyma and restores renal function. Therapeutic inhibition of IL11 signaling appears permissive for promoting kidney regeneration and improving kidney function.
2022-11-17 | GSE199080 | GEO
Project description:SP promotes decidualization of eSF from women with and without inflammatory disorders (polycystic ovarian syndrome (PCOS), endometriosis) in a manner that is not mediated through semen amyloids and that is associated with a potent transcriptional response including induction of IL11, a cytokine important for SP-induced decidualization.
2020-03-09 | GSE135640 | GEO