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1.
Cell ; 176(5): 1128-1142.e18, 2019 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-30686582

RESUMEN

Collateral arteries are an uncommon vessel subtype that can provide alternate blood flow to preserve tissue following vascular occlusion. Some patients with heart disease develop collateral coronary arteries, and this correlates with increased survival. However, it is not known how these collaterals develop or how to stimulate them. We demonstrate that neonatal mouse hearts use a novel mechanism to build collateral arteries in response to injury. Arterial endothelial cells (ECs) migrated away from arteries along existing capillaries and reassembled into collateral arteries, which we termed "artery reassembly". Artery ECs expressed CXCR4, and following injury, capillary ECs induced its ligand, CXCL12. CXCL12 or CXCR4 deletion impaired collateral artery formation and neonatal heart regeneration. Artery reassembly was nearly absent in adults but was induced by exogenous CXCL12. Thus, understanding neonatal regenerative mechanisms can identify pathways that restore these processes in adults and identify potentially translatable therapeutic strategies for ischemic heart disease.


Asunto(s)
Circulación Colateral/fisiología , Corazón/crecimiento & desarrollo , Regeneración/fisiología , Animales , Animales Recién Nacidos/crecimiento & desarrollo , Quimiocina CXCL12/metabolismo , Vasos Coronarios/crecimiento & desarrollo , Células Endoteliales/metabolismo , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Neovascularización Fisiológica/fisiología , Receptores CXCR4/metabolismo , Transducción de Señal
2.
Exp Eye Res ; 193: 107957, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32032627

RESUMEN

Vision loss is a devastating consequence of systemic hypoxia, but the cellular mechanisms are unclear. We investigated the impact of acute hypoxia in the retina and optic nerve. We induced systemic hypoxia (10% O2) in 6-8w mice for 48 h and performed in vivo imaging using optical coherence tomography (OCT) at baseline and after 48 h to analyze structural changes in the retina and optic nerve. We analyzed glial cellular and molecular changes by histology and immunofluorescence and the impact of pretreatment with 4-phenylbutyric acid (4-PBA) in oligodendroglia survival. After 48 h hypoxia, we found no change in ganglion cell complex thickness and no loss of retinal ganglion cells. Despite this, there was significantly increased expression of CCAAT-enhancer-binding protein homologous protein (CHOP), a marker of endoplasmic reticulum stress, in the retina and optic nerve. In addition, hypoxia induced obvious increase of GFAP expression in the anterior optic nerve, where it co-localized with CHOP, and significant loss of Olig2+ oligodendrocytes. Pretreatment with 4-PBA, which has been shown to reduce endoplasmic reticulum stress, rescued total Olig2+ oligodendrocytes and increased the pool of mature (CC-1+) but not of immature (PDGFRa+) oligodendrocytes. Consistent with a selective vulnerability of the retina and optic nerve in hypoxia, the most striking changes in the 48 h murine model of hypoxia were in glial cells in the optic nerve, including increased CHOP expression in the astrocytes and loss of oligodendrocytes. Our data support a model where glial dysfunction is among the earliest events in systemic hypoxia - suggesting that glia may be a novel target in treatment of hypoxia.


Asunto(s)
Hipoxia/complicaciones , Neuroglía/patología , Enfermedades del Nervio Óptico/diagnóstico , Nervio Óptico/patología , Animales , Supervivencia Celular , Modelos Animales de Enfermedad , Femenino , Hipoxia/diagnóstico , Etiquetado Corte-Fin in Situ , Ratones , Ratones Endogámicos C57BL , Enfermedades del Nervio Óptico/etiología , Células Ganglionares de la Retina/patología , Tomografía de Coherencia Óptica/métodos
3.
Elife ; 82019 10 11.
Artículo en Inglés | MEDLINE | ID: mdl-31603425

RESUMEN

IL-10-producing Tr1 cells promote tolerance but their contributions to tolerogenic memory are unclear. Using 10BiT mice that carry a Foxp3-eGFP reporter and stably express CD90.1 following IL-10 production, we characterized the spatiotemporal dynamics of Tr1 cells in a house dust mite model of allergic airway inflammation. CD90.1+Foxp3-IL-10+ Tr1 cells arise from memory cells and rejoin the tissue-resident memory T-cell pool after cessation of IL-10 production. Persistent antigenic stimulation is necessary to sustain IL-10 production and Irf1 and Batf expression distinguishes CD90.1+Foxp3-IL-10+ Tr1 cells from CD90.1+Foxp3-IL-10- 'former' Tr1. Depletion of Tr1-like cells after primary sensitization exacerbates allergic airway inflammation. However, neither transfer nor depletion of former Tr1 cells influences either Tr1 numbers or the inflammatory response during subsequent allergen memory re-challenge weeks later. Together these data suggest that naturally-arising Tr1 cells do not necessarily give rise to more Tr1 upon allergen re-challenge or contribute to tolerogenic memory. This phenotypic instability may limit efforts to re-establish tolerance by expanding Tr1 in vivo.


Asunto(s)
Asma/patología , Tolerancia Inmunológica , Memoria Inmunológica , Linfocitos T Reguladores/inmunología , Alérgenos/inmunología , Animales , Modelos Animales de Enfermedad , Ratones , Pyroglyphidae/inmunología
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