Biology subjects

Beisaw, A.

Publications and source records attributed to Beisaw, A..

6 recordsLinked to original sources

bioRxiv2026

Junb acts downstream of the Il-11/Stat3 signaling axis to limit tissue damage induced fibro-inflammation during regeneration

Inflammation is essential for regeneration yet can also drive fibroinflammatory remodeling; what determines these opposing outcomes remains unclear. Comparative transcriptomic analyses revealed that injured mouse hearts activated a broad inflammatory program, whereas zebrafish hearts mounted a restricted response characterized by selective il11 induction. This divergence extended across tissues and species: the non-regenerative mammalian injuries examined shared an inflammatory signature distinct from regenerative vertebrate contexts. We identified the AP-1 transcription factor Junb as an Il-11-Stat3-dependent regulator that restrains inflammation during fin fold regeneration. Combined loss of junba and junbb amplified a mammalian-like inflammatory program, increased neutrophil recruitment and fibroinflammatory gene expression, and reduced proliferation and regenerative outgrowth. Strikingly, dexamethasone or ibuprofen substantially restored regeneration in Junb deficient zebrafish larvae, demonstrating that hyperinflammation is a major determinant of regenerative failure. Thus, the Il-11-Stat3-Junb axis maintains a regeneration permissive inflammatory state preventing a regenerative response from shifting toward mammalian-like fibroinflammation.

immunology↗

bioRxiv2026

Cardiomyocyte autophagy promotes a pro-regenerative immune response during cardiac regeneration

Adult zebrafish possess a remarkable ability to regenerate their heart following cardiac injury. Over the past decades, our understanding of the diverse cell types involved in zebrafish cardiac regeneration has greatly advanced. However, the mechanisms governing their interaction and how heterocellular crosstalk drives regeneration remain poorly understood. Here, we identify cardiomyocyte autophagy as a key link between the cardiomyocyte injury response and heterocellular crosstalk between cardiomyocytes and macrophages. We find that cardiomyocyte autophagy is downstream of AP-1 transcription factors. Using newly generated genetic tools, we find that cardiomyocyte autophagy is an important regulator of cardiomyocyte protrusion into the fibrotic injured tissue and its disruption leads to defects in scar resolution. Notably, we find that blocking cardiomyocyte autophagy has a marked effect on the transcriptomic signatures in cardiac macrophages, shifting gene expression from phagocytic/pro-inflammatory/pro-reparative towards pro-angiogenic and pro-fibrotic states. Altogether, our results uncover autophagy as a mechanism linking cardiomyocyte injury responses to macrophage phenotype and coordinated tissue remodeling during heart regeneration.

cell biology↗

bioRxiv2026

FYCO1 improves postischemic cardiac remodeling via enhanced autophagic flux and attenuation of proinflammatory signaling

Acute myocardial infarction (MI) is associated with severe metabolic and oxidative stress that triggers cardiomyocyte death, pro-inflammatory signaling and progressive structural remodeling frequently culminating in heart failure. Although significant advances in reperfusion therapy improved acute survival in patients, therapeutic strategies that directly target intracellular processes in response to injury remain limited. One key response mechanism, autophagy, is rapidly activated to ameliorate ischemic stress. Yet, defective autophagic flux may exacerbate cardiomyocyte injury and maladaptive tissue remodeling. Here we identify FYCO1 as a cardiomyocyte-enriched key regulator of autophagy that enhances autophagic flux and promotes myocardial resilience following ischemic injury. Using cardiomyocyte-specific FYCO1 transgenic mice subjected to permanent coronary ligation, we demonstrate that FYCO1 overexpression limits infarct expansion, reduces cardiomyocyte injury, and preserves cardiac function during remodeling. In vivo RFP-EGFP-LC3 autophagy reporter analyses reveal that FYCO1 promotes a sustained increase of autophagic flux by coordinating autophagosome formation and efficient autolysosomal clearance. Transcriptomic profiling identifies a cardioprotective gene program in FYCO1-Tg animals subjected to MI, with suppression of proinflammatory, proapoptotic and stress-response pathways. Systemic serum cytokine and chemokine profiling as well as transcriptomic analyses of myocardium confirm reduced inflammatory signaling and subsequent reduction in macrophage recruitment into the infarct border zone. Together these findings position FYCO1 as a key regulator of cardiomyocyte autophagy and reveal a previously unrecognized link between autophagy and inflammation in shaping cardiac remodeling following myocardial infarction. FYCO1-mediated autophagy promotes myocardial preservation and functional recovery, highlighting autophagic flux as a promising target for cardioprotective interventions.

molecular biology↗

bioRxiv2024

BMP signaling promotes heart regeneration via alleviation of replication stress

One hallmark of aging is a decline in tissue regeneration, which can be caused by DNA replication stress. Whether highly regenerative species like zebrafish are immune from such hindrances to replication is unknown. In contrast to most mammals, adult zebrafish achieve complete heart regeneration via cell cycle entry and proliferation of mature cardiomyocytes. We found that cycling cardiomyocytes experience replication stress, which is induced by the demands of regeneration, but does not occur during physiological heart growth. Since zebrafish cardiomyocyte regeneration is remarkably efficient, heart regeneration appears to depend on elevated capabilities to overcome replication stress. Indeed, pharmacological inhibition of ATM and ATR kinases revealed that DNA damage response signaling is essential for heart regeneration. Using inducible overexpression of ligands and inhibitors of the Bone Morphogenetic Protein (BMP)-Smad pathway, combined with analysis of genetic mutants, we found that BMP signaling alleviates cardiomyocyte replication stress. In the absence of BMP signaling, cardiomyocytes become arrested in the S-phase of the cell cycle, which prevents progression to mitosis and results in heart regeneration failure. Interestingly, BMP signaling can also rescue neonatal mouse cardiomyocytes and human fibroblasts from hydroxyurea-induced replication stress. DNA fiber spreading assays in human cancer cells and human hematopoietic stem and progenitor cells (HSPCs) indicate that BMP signaling acts directly on replication dynamics by accelerating DNA replication fork progression and by facilitating their re-start after replication stress-induced stalling. Our results identify the ability to overcome replication stress as key factor for the elevated heart regeneration capacity in zebrafish. Notably, the conserved capability of BMP signaling to promote stress-free DNA replication might unlock new avenues towards anti-aging and pro-regenerative applications in humans.

developmental biology↗

bioRxiv2024

Border-zone cardiomyocytes and macrophages contribute to remodeling of the extracellular matrix to promote cardiomyocyte invasion during zebrafish cardiac regeneration

Despite numerous advances in our understanding of zebrafish cardiac regeneration, an aspect that remains less studied is how regenerating cardiomyocytes invade, and eventually replace, the collagen-containing fibrotic tissue following injury. Here, we provide an in-depth analysis of the process of cardiomyocyte invasion using live-imaging and histological approaches. We observed close interactions between protruding cardiomyocytes and macrophages at the wound border zone, and macrophage-deficient irf8 mutant zebrafish exhibited defects in extracellular matrix (ECM) remodeling and cardiomyocyte protrusion into the injured area. Using a resident macrophage ablation model, we show that defects in ECM remodeling at the border zone and subsequent cardiomyocyte protrusion can be partly attributed to a population of resident macrophages. Single-cell RNA-sequencing analysis of cells at the wound border revealed a population of cardiomyocytes and macrophages with fibroblast-like gene expression signatures, including the expression of genes encoding ECM structural proteins and ECM-remodeling proteins. The expression of mmp14b, which encodes a membrane-anchored matrix metalloproteinase, was restricted to cells in the border zone, including cardiomyocytes, macrophages, fibroblasts, and endocardial/endothelial cells. Genetic deletion of mmp14b led to a decrease in 1) macrophage recruitment to the border zone, 2) collagen degradation at the border zone, and 3) subsequent cardiomyocyte invasion. Furthermore, cardiomyocyte-specific overexpression of mmp14b was sufficient to enhance cardiomyocyte invasion into the injured tissue and along the apical surface of the wound. Altogether, our data shed important insights into the process of cardiomyocyte invasion of the collagen-containing injured tissue during cardiac regeneration. They further suggest that cardiomyocytes and resident macrophages contribute to ECM remodeling at the border zone to promote cardiomyocyte replenishment of the fibrotic injured tissue.

cell biology↗

bioRxiv2018

Genome-wide strategies reveal target genes of Npas4l associated with cardiovascular development in zebrafish

The development of a vascular network is essential to nourish tissues and sustain organ function throughout life. Endothelial cells (ECs) are the building blocks of blood vessels, yet our understanding of EC specification remains incomplete. zebrafish cloche/npas4l mutants have been used broadly as an avascular model, but little is known about the molecular mechanisms of action of the Npas4l transcription factor. Here, to identify its direct and indirect target genes, we combined complementary genome-wide approaches including transcriptome analyses and chromatin immunoprecipitation (ChIP). The cross-analysis of these datasets indicates that Npas4l functions as a master regulator by directly inducing a group of transcription factor genes crucial for hematoendothelial specification such as etv2, tal1 and lmo2. We also identified new targets of Npas4l and investigated the function of a subset of them using the CRISPR/Cas9 technology. Phenotypic characterization of tspan18b mutants reveals a novel player in developmental angiogenesis, confirming the reliability of the datasets generated. Collectively, these data represent a useful resource for future studies aimed to better understand EC fate determination and vascular development.

developmental biology↗