RESUMEN
The structure of the mammalian lung controls the flow of air through the airways and into the distal alveolar region where gas exchange occurs. Specialized cells in the lung mesenchyme produce the extracellular matrix (ECM) and growth factors required for lung structure. Historically, characterizing the mesenchymal cell subtypes was challenging due to their ambiguous morphology, overlapping expression of protein markers, and limited cell-surface molecules needed for isolation. The recent development of single-cell RNA sequencing (scRNA-seq) complemented with genetic mouse models demonstrated that the lung mesenchyme comprises transcriptionally and functionally heterogeneous cell-types. Bioengineering approaches that model tissue structure clarify the function and regulation of mesenchymal cell types. These experimental approaches demonstrate the unique abilities of fibroblasts in mechanosignaling, mechanical force generation, ECM production, and tissue regeneration. This chapter will review the cell biology of the lung mesenchyme and experimental approaches to study their function.
Asunto(s)
Matriz Extracelular , Pulmón , Ratones , Animales , Pulmón/metabolismo , Matriz Extracelular/fisiología , Fibroblastos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Mesodermo/metabolismo , MamíferosRESUMEN
Lithium salts have been in the therapeutic toolbox for better or worse since the 19th century, with purported benefit in gout, hangover, insomnia, and early suggestions that lithium improved psychiatric disorders. However, the remarkable effects of lithium reported by John Cade and subsequently by Mogens Schou revolutionized the treatment of bipolar disorder. The known molecular targets of lithium are surprisingly few and include the signaling kinase glycogen synthase kinase-3 (GSK-3), a group of structurally related phosphomonoesterases that includes inositol monophosphatases, and phosphoglucomutase. Here we present a brief history of the therapeutic uses of lithium and then focus on GSK-3 as a therapeutic target in diverse diseases, including bipolar disorder, cancer, and coronavirus infections.
Asunto(s)
Antimaníacos/uso terapéutico , Trastorno Bipolar/tratamiento farmacológico , Compuestos de Litio/uso terapéutico , Neoplasias/tratamiento farmacológico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Síndrome Respiratorio Agudo Grave/tratamiento farmacológico , Animales , Antimaníacos/farmacología , Trastorno Bipolar/metabolismo , Coronavirus/efectos de los fármacos , Glucógeno Sintasa Quinasa 3/metabolismo , Humanos , Compuestos de Litio/farmacología , Neoplasias/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Monoéster Fosfórico Hidrolasas/metabolismo , Síndrome Respiratorio Agudo Grave/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Chronic lithium treatment stimulates adult hippocampal neurogenesis, but whether increased neurogenesis contributes to its therapeutic mechanism remains unclear. We use a genetic model of neural progenitor cell (NPC) ablation to test whether a lithium-sensitive behavior requires hippocampal neurogenesis. NPC-ablated mice were treated with lithium and assessed in the forced swim test (FST). Lithium reduced time immobile in the FST in NPC-ablated and control mice but had no effect on activity in the open field, a control for the locomotion-based FST. These findings show that hippocampal NPCs that proliferate in response to chronic lithium are not necessary for the behavioral response to lithium in the FST. We further show that 4-6 week old immature hippocampal neurons are not required for this response. These data suggest that increased hippocampal neurogenesis does not contribute to the response to lithium in the forced swim test and may not be an essential component of its therapeutic mechanism.
Asunto(s)
Hipocampo/efectos de los fármacos , Compuestos de Litio/farmacología , Células-Madre Neurales/efectos de los fármacos , Neuronas/efectos de los fármacos , Animales , Proliferación Celular/efectos de los fármacos , Femenino , Hipocampo/citología , Hipocampo/fisiología , Masculino , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Células-Madre Neurales/citología , Neurogénesis/efectos de los fármacos , Neuronas/citología , Neuronas/fisiología , NataciónRESUMEN
The commitment and differentiation of the alveolar type I (AT1) cell lineage is a critical step for the formation of distal lung saccules, which are the primitive alveolar units required for postnatal respiration. How AT1 cells arise from the distal lung epithelial progenitor cells prior to birth and whether this process depends on a developmental niche instructed by mesenchymal cells is poorly understood. We show that mice lacking histone deacetylase 3 specifically in the developing lung mesenchyme display lung hypoplasia including decreased mesenchymal proliferation and a severe impairment of AT1 cell differentiation. This is correlated with a decrease in Wnt/ß-catenin signaling in the lung epithelium. We demonstrate that inhibition of Wnt signaling causes defective AT1 cell lineage differentiation ex vivo. Importantly, systemic activation of Wnt signaling at specific stages of lung development can partially rescue the AT1 cell differentiation defect in vivo. These studies show that histone deacetylase 3 expression generates an important developmental niche in the lung mesenchyme through regulation of Wnt signaling, which is required for proper AT1 cell differentiation and lung sacculation.
Asunto(s)
Células Epiteliales Alveolares/fisiología , Histona Desacetilasas/fisiología , Alveolos Pulmonares/embriología , Nicho de Células Madre/fisiología , Vía de Señalización Wnt/fisiología , Animales , Diferenciación Celular , Endodermo/citología , Genes Letales , Histona Desacetilasas/deficiencia , Histona Desacetilasas/genética , Cloruro de Litio/farmacología , Mesodermo/citología , Ratones , Ratones Endogámicos C57BL , Alveolos Pulmonares/anomalías , Vía de Señalización Wnt/efectos de los fármacosRESUMEN
The development of the lung epithelium is regulated in a stepwise fashion to generate numerous differentiated and stem cell lineages in the adult lung. How these different lineages are generated in a spatially and temporally restricted fashion remains poorly understood, although epigenetic regulation probably plays an important role. We show that the Polycomb repressive complex 2 component Ezh2 is highly expressed in early lung development but is gradually downregulated by late gestation. Deletion of Ezh2 in early lung endoderm progenitors leads to the ectopic and premature appearance of Trp63+ basal cells that extend the entire length of the airway. Loss of Ezh2 also leads to reduced secretory cell differentiation. In their place, morphologically similar cells develop that express a subset of basal cell genes, including keratin 5, but no longer express high levels of either Trp63 or of standard secretory cell markers. This suggests that Ezh2 regulates the phenotypic switch between basal cells and secretory cells. Together, these findings show that Ezh2 restricts the basal cell lineage during normal lung endoderm development to allow the proper patterning of epithelial lineages during lung formation.
Asunto(s)
Linaje de la Célula , Endodermo/citología , Endodermo/embriología , Pulmón/citología , Pulmón/embriología , Complejo Represivo Polycomb 2/metabolismo , Animales , Biomarcadores/metabolismo , Diferenciación Celular/genética , Linaje de la Célula/genética , Proliferación Celular , Proteína Potenciadora del Homólogo Zeste 2 , Células Epiteliales/citología , Células Epiteliales/metabolismo , Epitelio/embriología , Epitelio/metabolismo , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Ontología de Genes , Células Caliciformes/citología , Células Caliciformes/metabolismo , Proteínas Hedgehog/metabolismo , Queratina-5/metabolismo , Pulmón/metabolismo , Ratones , Mutación/genética , Células Neuroendocrinas/citología , Células Neuroendocrinas/metabolismo , Proteínas Nucleares/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Fosfoproteínas/metabolismo , Programas Informáticos , Factor Nuclear Tiroideo 1 , Transactivadores/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Macrophages show endoplasmic reticulum (ER) stress when exposed to lipotoxic signals associated with atherosclerosis, although the pathophysiological importance and the underlying mechanisms of this phenomenon remain unknown. Here we show that mitigation of ER stress with a chemical chaperone results in marked protection against lipotoxic death in macrophages and prevents macrophage fatty acid-binding protein-4 (aP2) expression. Using genetic and chemical models, we show that aP2 is the predominant regulator of lipid-induced macrophage ER stress. The absence of lipid chaperones incites an increase in the production of phospholipids rich in monounsaturated fatty acids and bioactive lipids that render macrophages resistant to lipid-induced ER stress. Furthermore, the impact of aP2 on macrophage lipid metabolism and the ER stress response is mediated by upregulation of key lipogenic enzymes by the liver X receptor. Our results demonstrate the central role for lipid chaperones in regulating ER homeostasis in macrophages in atherosclerosis and show that ER responses can be modified, genetically or chemically, to protect the organism against the deleterious effects of hyperlipidemia.