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1.
Blood ; 128(12): 1567-77, 2016 09 22.
Artículo en Inglés | MEDLINE | ID: mdl-27421959

RESUMEN

The first definitive hematopoietic stem cells (dHSCs) in the mouse emerge in the dorsal aorta of the embryonic day (E) 10.5 to 11 aorta-gonad-mesonephros (AGM) region. Notch signaling is essential for early HSC development but is dispensable for the maintenance of adult bone marrow HSCs. How Notch signaling regulates HSC formation in the embryo is poorly understood. We demonstrate here that Notch signaling is active in E10.5 HSC precursors and involves both Notch1 and Notch2 receptors, but is gradually downregulated while they progress toward dHSCs at E11.5. This downregulation is accompanied by gradual functional loss of Notch dependency. Thus, as early as at final steps in the AGM region, HSCs begin acquiring the Notch independency characteristic of adult bone marrow HSCs as part of the maturation program. Our data indicate that fine stage-dependent tuning of Notch signaling may be required for the generation of definitive HSCs from pluripotent cells.


Asunto(s)
Aorta/embriología , Embrión de Mamíferos/citología , Gónadas/embriología , Células Madre Hematopoyéticas/citología , Mesonefro/embriología , Receptor Notch2/metabolismo , Células del Estroma/citología , Animales , Aorta/metabolismo , Células Cultivadas , Embrión de Mamíferos/metabolismo , Gónadas/metabolismo , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/metabolismo , Mesonefro/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Transducción de Señal , Células del Estroma/metabolismo
2.
Nat Commun ; 7: 10784, 2016 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-26952187

RESUMEN

During embryonic development, adult haematopoietic stem cells (HSCs) emerge preferentially in the ventral domain of the aorta in the aorta-gonad-mesonephros (AGM) region. Several signalling pathways such as Notch, Wnt, Shh and RA are implicated in this process, yet how these interact to regulate the emergence of HSCs has not previously been described in mammals. Using a combination of ex vivo and in vivo approaches, we report here that stage-specific reciprocal dorso-ventral inductive interactions and lateral input from the urogenital ridges are required to drive HSC development in the aorta. Our study strongly suggests that these inductive interactions in the AGM region are mediated by the interplay between spatially polarized signalling pathways. Specifically, Shh produced in the dorsal region of the AGM, stem cell factor in the ventral and lateral regions, and BMP inhibitory signals in the ventral tissue are integral parts of the regulatory system involved in the development of HSCs.


Asunto(s)
Aorta/metabolismo , Gónadas/metabolismo , Células Madre Hematopoyéticas/metabolismo , Mesonefro/metabolismo , Transducción de Señal , Animales , Aorta/embriología , Proteína Morfogenética Ósea 4/genética , Proteína Morfogenética Ósea 4/metabolismo , Femenino , Gónadas/embriología , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/citología , Masculino , Mesonefro/embriología , Ratones Endogámicos C57BL
3.
PLoS One ; 7(12): e52714, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23300748

RESUMEN

A major challenge for further development of drug screening procedures, cell replacement therapies and developmental studies is the identification of expandable human stem cells able to generate the cell types needed. We have previously reported the generation of an immortalized polyclonal neural stem cell (NSC) line derived from the human fetal ventral mesencephalon (hVM1). This line has been biochemically, genetically, immunocytochemically and electrophysiologically characterized to document its usefulness as a model system for the generation of A9 dopaminergic neurons (DAn). Long-term in vivo transplantation studies in parkinsonian rats showed that the grafts do not mature evenly. We reasoned that diverse clones in the hVM1 line might have different abilities to differentiate. In the present study, we have analyzed 9 hVM1 clones selected on the basis of their TH generation potential and, based on the number of v-myc copies, v-myc down-regulation after in vitro differentiation, in vivo cell cycle exit, TH⁺ neuron generation and expression of a neuronal mature marker (hNSE), we selected two clones for further in vivo PD cell replacement studies. The conclusion is that homogeneity and clonality of characterized NSCs allow transplantation of cells with controlled properties, which should help in the design of long-term in vivo experiments.


Asunto(s)
Neuronas Dopaminérgicas/fisiología , Células-Madre Neurales/fisiología , Enfermedad de Parkinson Secundaria/terapia , Animales , Puntos de Control del Ciclo Celular , Diferenciación Celular , Proliferación Celular , Células Cultivadas , Neuronas Dopaminérgicas/trasplante , Regulación hacia Abajo , Femenino , Dosificación de Gen , Expresión Génica , Humanos , Proteínas de Filamentos Intermediarios/genética , Proteínas de Filamentos Intermediarios/metabolismo , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Mesencéfalo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Nestina , Células-Madre Neurales/trasplante , Proteína Oncogénica p55(v-myc)/genética , Proteína Oncogénica p55(v-myc)/metabolismo , Ratas , Ratas Sprague-Dawley , Investigación con Células Madre
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