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1.
Front Cell Dev Biol ; 12: 1388378, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38699159

RESUMO

In heart disease patients, myocyte loss or malfunction invariably leads to fibrosis, involving the activation and accumulation of cardiac fibroblasts that deposit large amounts of extracellular matrix. Apart from the vital replacement fibrosis that follows myocardial infarction, ensuring structural integrity of the heart, cardiac fibrosis is largely considered to be maladaptive. Much work has focused on signaling pathways driving the fibrotic response, including TGF-ß signaling and biomechanical strain. However, currently there are very limited options for reducing cardiac fibrosis, with most patients suffering from chronic fibrosis. The adult heart has very limited regenerative capacity. However, cardiac regeneration has been reported in humans perinatally, and reproduced experimentally in neonatal mice. Furthermore, model organisms such as the zebrafish are able to fully regenerate their hearts following massive cardiac damage into adulthood. Increasing evidence points to a transient immuno-fibrotic response as being key for cardiac regeneration to occur. The mechanisms at play in this context are changing our views on fibrosis, and could be leveraged to promote beneficial remodeling in heart failure patients. This review summarizes our current knowledge of fibroblast properties associated with the healthy, failing or regenerating heart. Furthermore, we explore how cardiac fibroblast activity could be targeted to assist future therapeutic approaches.

2.
Int J Mol Sci ; 24(21)2023 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-37958548

RESUMO

Cornelia de Lange Syndrome (CdLS) patients, who frequently carry a mutation in NIPBL, present an increased incidence of outflow tract (OFT)-related congenital heart defects (CHDs). Nipbl+/- mice recapitulate a number of phenotypic traits of CdLS patients, including a small body size and cardiac defects, but no study has specifically focused on the valves. Here, we show that adult Nipbl+/- mice present aortic valve thickening, a condition that has been associated with stenosis. During development, we observed that OFT septation and neural crest cell condensation was delayed in Nipbl+/- embryos. However, we did not observe defects in the deployment of the main lineages contributing to the semilunar valves. Indeed, endocardial endothelial-to-mesenchymal transition (EndMT), analysed via outflow tract explants, and neural crest migration, analysed via genetic lineage tracing, did not significantly differ in Nipbl+/- mice and their wild-type littermates. Our study provides the first direct evidence for valve formation defects in Nipbl+/- mice and points to specific developmental defects as an origin for valve disease in patients.


Assuntos
Proteínas de Ciclo Celular , Síndrome de Cornélia de Lange , Cardiopatias Congênitas , Animais , Humanos , Camundongos , Valva Aórtica , Proteínas de Ciclo Celular/genética , Síndrome de Cornélia de Lange/genética , Haploinsuficiência , Cardiopatias Congênitas/genética , Mutação
3.
J Mol Cell Biol ; 14(10)2023 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-36271843

RESUMO

Understanding how certain animals are capable of regenerating their hearts will provide much needed insights into how this process can be induced in humans in order to reverse the damage caused by myocardial infarction. Currently, it is becoming increasingly evident that cardiac interstitial cells play crucial roles during cardiac regeneration. To understand how interstitial cells behave during this process, we performed single-cell RNA sequencing of regenerating zebrafish hearts. Using a combination of immunohistochemistry, chemical inhibition, and novel transgenic animals, we were able to investigate the role of cell type-specific mechanisms during cardiac regeneration. This approach allowed us to identify a number of important regenerative processes within the interstitial cell populations. Here, we provide detailed insight into how interstitial cells behave during cardiac regeneration, which will serve to increase our understanding of how this process could eventually be induced in humans.


Assuntos
Infarto do Miocárdio , Miócitos Cardíacos , Animais , Humanos , Peixe-Zebra , Animais Geneticamente Modificados , Proliferação de Células
4.
Front Immunol ; 11: 1537, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32793210

RESUMO

Acute graft-vs.-host disease (aGvHD) is one of the most frequent causes of transplant-related mortality (TRM) after allogeneic hematopoietic cell transplantation (alloHCT). Its treatment is complex and costly. The aim of this study was to retrospectively analyze the impact of country-specific socioeconomic factors on outcome of patients who experience severe aGvHD. Adults with hematological malignancies receiving alloHCT from either HLA-matched siblings (n = 1,328) or unrelated donors (n = 2,824) developing grade 3 or 4 aGvHD were included. In univariate analysis, the probability of TRM at 2 years was increased for countries with lower current Health Care Expenditure (HCE, p = 0.04), lower HCE as % of Gross Domestic Product per capita (p = 0.003) and lower values of the Human Development Index (p = 0.02). In a multivariate model, the risk of TRM was most strongly predicted by current HCE (HR = 0.76, p = 0.006). HCE >median was also associated with reduced risk of the overall mortality (HR 0.73, p = 0.0006) and reduced risk of treatment failure (either relapse or TRM; HR 0.77, p = 0.004). We conclude that country-specific socioeconomic factors, in particular current HCE, are strongly associated with survival of patients who experience severe aGvHD.


Assuntos
Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Aguda , Adolescente , Adulto , Idoso , Progressão da Doença , Europa (Continente)/epidemiologia , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Custos de Cuidados de Saúde , Pesquisas sobre Atenção à Saúde , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Mortalidade , Prognóstico , Sistema de Registros , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Fatores Socioeconômicos , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
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