RESUMO
The mechanisms used by embryos to pattern tissues across their axes has fascinated developmental biologists since the founding of embryology. Here, using single-cell technology, we interrogate complex patterning defects and define a Hedgehog (Hh)-fibroblast growth factor (FGF) signaling axis required for anterior mesoderm lineage development during gastrulation. Single-cell transcriptome analysis of Hh-deficient mesoderm revealed selective deficits in anterior mesoderm populations, culminating in defects to anterior embryonic structures, including the pharyngeal arches, heart, and anterior somites. Transcriptional profiling of Hh-deficient mesoderm during gastrulation revealed disruptions to both transcriptional patterning of the mesoderm and FGF signaling for mesoderm migration. Mesoderm-specific Fgf4/Fgf8 double-mutants recapitulated anterior mesoderm defects and Hh-dependent GLI transcription factors modulated enhancers at FGF gene loci. Cellular migration defects during gastrulation induced by Hh pathway antagonism were mitigated by the addition of FGF4 protein. These findings implicate a multicomponent signaling hierarchy activated by Hh ligands from the embryonic node and executed by FGF signals in nascent mesoderm to control anterior mesoderm patterning.
Assuntos
Fator 4 de Crescimento de Fibroblastos/genética , Fator 8 de Crescimento de Fibroblasto/genética , Gastrulação/genética , Proteína GLI1 em Dedos de Zinco/genética , Animais , Padronização Corporal/genética , Linhagem da Célula/genética , Embrião de Galinha , Fatores de Crescimento de Fibroblastos/genética , Gástrula/crescimento & desenvolvimento , Gástrula/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas Hedgehog/genética , Mesoderma/crescimento & desenvolvimento , Mesoderma/metabolismo , Camundongos , Transdução de Sinais/genética , Análise de Célula Única , Transcriptoma/genéticaRESUMO
Hydrogen sulfide (H2S) is an endogenous, gaseous signaling molecule that plays a critical role in cardiac and vascular biology. H2S regulates vascular tone and oxidant defenses and exerts cytoprotective effects in the heart and circulation. Recent studies indicate that H2S modulates various components of metabolic syndrome, including obesity and glucose metabolism. This review will discuss studies exhibiting H2S -derived cardioprotective signaling in heart failure with reduced ejection fraction (HFrEF). We will also discuss the role of H2S in metabolic syndrome and heart failure with preserved ejection fraction (HFpEF).
RESUMO
A lack of preclinical large animal models of heart failure with preserved ejection fraction (HFpEF) that recapitulate this comorbid-laden syndrome has led to the inability to tease out mechanistic insights and to test novel therapeutic strategies. This study developed a large animal model that integrated multiple comorbid determinants of HFpEF in a miniswine breed that exhibited sensitivity to obesity, metabolic syndrome, and vascular disease with overt clinical signs of heart failure. The combination of a Western diet and 11-deoxycorticosterone acetate salt-induced hypertension in the Göttingen miniswine led to the development of a novel large animal model of HFpEF that exhibited multiorgan involvement and a full spectrum of comorbidities associated with human HFpEF.