Origin and function of activated fibroblast states during zebrafish heart regeneration

Hu, Bo; Lelek, S.; Spanjaard, Bastiaan; El-Sammak, Hadil; Simões, Mário; Mintcheva, Janita; Aliee, Hananeh; Schäfer, Ronny; Meyer, Alexander M; Theis, Fabian J.; Stainier, Didier Y. R.; Panàkovà, Daniela; Junker, Jan Philipp

doi:10.1038/s41588-022-01129-5

Cited by 48 publications

(71 citation statements)

References 84 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Following cardiac injury in adult zebrafish, epicardial cells are activated to turn on embryonic genes, proliferate, and migrate to repopulate the wound site. In addition to supplying supporting cell types, epicardial cells provide paracrine signals and extracellular matrix (ECM) components for CM division and coronary angiogenesis [5][6][7]12 . Recent studies have highlighted the vital roles of the epicardium in zebrafish heart regeneration [13][14][15] , and the mobilization of epicardial cells has been reported to improve mammalian heart repair 16,17 .…”

mentioning

confidence: 99%

Activation of a transient progenitor state in the epicardium is required for zebrafish heart regeneration

et al. 2022

View full text Add to dashboard Cite

The epicardium, a mesothelial cell tissue that encompasses vertebrate hearts, supports heart regeneration after injury through paracrine effects and as a source of multipotent progenitors. However, the progenitor state in the adult epicardium has yet to be defined. Through single-cell RNA-sequencing of isolated epicardial cells from uninjured and regenerating adult zebrafish hearts, we define the epithelial and mesenchymal subsets of the epicardium. We further identify a transiently activated epicardial progenitor cell (aEPC) subpopulation marked by ptx3a and col12a1b expression. Upon cardiac injury, aEPCs emerge from the epithelial epicardium, migrate to enclose the wound, undergo epithelial-mesenchymal transition (EMT), and differentiate into mural cells and pdgfra+hapln1a+ mesenchymal epicardial cells. These EMT and differentiation processes are regulated by the Tgfβ pathway. Conditional ablation of aEPCs blocks heart regeneration through reduced nrg1 expression and mesenchymal cell number. Our findings identify a transient progenitor population of the adult epicardium that is indispensable for heart regeneration and highlight it as a potential target for enhancing cardiac repair.

show abstract

mentioning

confidence: 99%

Activation of a transient progenitor state in the epicardium is required for zebrafish heart regeneration

et al. 2022

View full text Add to dashboard Cite

show abstract

“…RUNX1 is a transcription factor with important roles in inflammatory responses and hematological cancers 51, 52 . Studies performed in zebrafish suggest a role in fibroblast activation 53, 54 . To explore a relationship between RUNX1 in macrophages and fibroblasts in cardiac recovery, we applied a deep learning approach 55, 56 and found that RUNX1 target gene expression measured at the time of LVAD implantation predicts acquisition of recovered versus non-recovered states in both cell populations.…”

Section: Discussionmentioning

confidence: 99%

Defining Cardiac Recovery at Single Cell Resolution

Amrute

Lai

et al. 2022

Preprint

View full text Add to dashboard Cite

Recovery of cardiac function is the ultimate goal of heart failure therapy. Unfortunately, cardiac recovery remains a rare and poorly understood phemomenon. Herein, we performed single nucleus RNA-sequencing (snRNA-seq) from non-diseased donors and heart failure patients. By comparing patients who recovered LV systolic function following LV assist device implantation to those who did not recover and donors, we defined the cellular and transcriptional landscape and predictors of cardiac recovery. We sequenced 40 hearts and recovered 185,881 nuclei with 13 distinct cell types. Using pseudobulk differential expression analysis to detangle cell specific signatures of cardiac recovery, we observed that recovered cardiomyocytes do not revert to a normal state, and instead, retain transcriptional signatures observed in heart failure. Macrophages and fibroblasts displayed the strongest signatures of recovery. While some evidence of reversion to a normal state was observed, many heart failure associated genes remained elevated and recovery signatures were predominately indicative of a biological state that was unique from donor and heart failure conditions. Acquisition of recovery states was associated with improved LV systolic function. Pro-inflammatory macrophages and inflammatory signaling in fibroblasts were identified as negative predictors of recovery. We identified downregulation of RUNX1 transcriptional activity in macrophages and fibroblasts as a central event associated with and predictive of cardiac recovery. In silico perturbation of RUNX1 in macrophages and fibroblasts recapitulated the transcriptional state of cardiac recovery. This prediction was corroborated in a mouse model of cardiac recovery mediated by BRD4 inhibition where we observed a decrease in macrophage and fibroblast Runx1 expression, diminished chromatin accessibility within peaks linked to the Runx1 locus, and acquisition of recovery signatures. These findings suggest that cardiac recovery is a unique biological state and identify RUNX1 as a possible therapeutic target to facilitate cardiac recovery.

show abstract

“…73 Additionally, several transient cell states with fibroblast characteristics were observed following heart injury in zebrafish, Wnt/β-catenin signaling inhibition led to a significant delay in heart regeneration of the endocardial fibroblast response. 74 So, the related signaling pathways become of great interest in heart regeneration in animal models.…”

Section: Senescence and Regenerationmentioning

confidence: 99%

Pez cebra: modelado de senescencia en el contexto de la enfermedad y la regeneración

Carrillo-Rosas¹,

Ríos-Pérez²,

Zampedri³

2022

Investigación en Discapacidad

View full text Add to dashboard Cite

Cellular senescence is a natural biological process characterized by a permanent and irreversible state of cellular arrest, mitochondrial alteration, and secretion of senescence-associated phenotype (SASP) components. Several factors can induce senescence, including but not limited to DNA damage, oxidative stress, and neuroinflammation, these factors have also been linked to several disorders such as Alzheimer's, Parkinson's, cancer, among others. The increased presence of senescent cells among different diseases suggests the importance of senescence in the pathophysiology of a great number of disorders, thus the need for different models that could help deepen our understanding of the molecular mechanisms of senescence, identify possible targets for therapeutic interventions, and arising challenges. In addition to in vitro models, most senescent research has come from classical model species, i.e., mouse (Mus musculus) and rat (Rattus norvegicus). However, senescence is highly conserved; different studies have shown that senescent cells seem to accumulate in all vertebrate organisms and that several associated genes show similar expression patterns, opening the door to new vertebrate models. The zebrafish has become a strong emerging model for different diseases, such as cancer, inflammation, neurodegeneration, among others; it shares multiple advantages with classical models, such as well-established genome editing tools and a fully sequenced genome. Additionally, zebrafish exhibit multiple advantages, including high fecundity for robust statistical analysis, external fertilization, and optical transparency that enables powerful imaging capabilities and makes it a versatile model for experimental manipulation and structural visualization. Here we present the zebrafish as a model that can contribute significantly to our understanding of the processes involved in senescence and age-related diseases. ResumenLa senescencia celular es un proceso biológico natural caracterizado por un estado permanente e irreversible de arresto celular, alteraciones mitocondriales y secreción de componentes del fenotipo asociado a la senescencia (SASP). Varios factores pueden inducir la senescencia, incluidos el daño al ADN, estrés oxidante y neuroinflamación; estos factores también se han relacionado con varios trastornos como el Alzheimer, el Parkinson, el cáncer, entre otros. La mayor presencia de células senescentes entre diferentes enfermedades sugiere la importancia de la senescencia en la fisiopatología de un gran número de trastornos, por lo tanto, la necesidad de diferentes modelos que podrían ayudar a profundizar nuestra comprensión de los mecanismos moleculares de la senescencia, identificar posibles objetivos para intervenciones terapéuticas y los desafíos que surgen. Además de los modelos in vitro, la mayoría de las investigaciones senescentes provienen de especies modelo clásicas, es decir, ratón (Mus musculus) y rata (Rattus norvegicus). Sin embargo, la senescencia está muy conservada;

show abstract

Origin and function of activated fibroblast states during zebrafish heart regeneration

Cited by 48 publications

References 84 publications

Activation of a transient progenitor state in the epicardium is required for zebrafish heart regeneration

Activation of a transient progenitor state in the epicardium is required for zebrafish heart regeneration

Defining Cardiac Recovery at Single Cell Resolution

Pez cebra: modelado de senescencia en el contexto de la enfermedad y la regeneración

Contact Info

Product

Resources

About