Inflammation-mediated notch signaling skews fanconi anemia hematopoietic stem cell differentiation.
J Immunol
; 191(5): 2806-17, 2013 Sep 01.
Article
en En
| MEDLINE
| ID: mdl-23926327
ABSTRACT
Hematopoietic stem cells (HSCs) can either self-renew or differentiate into various types of cells of the blood lineage. Signaling pathways that regulate this choice of self-renewal versus differentiation are currently under extensive investigation. In this study, we report that deregulation of Notch signaling skews HSC differentiation in mouse models of Fanconi anemia (FA), a genetic disorder associated with bone marrow failure and progression to leukemia and other cancers. In mice expressing a transgenic Notch reporter, deletion of the Fanca or Fancc gene enhances Notch signaling in multipotential progenitors (MPPs), which is correlated with decreased phenotypic long-term HSCs and increased formation of MPP1 progenitors. Furthermore, we found an inverse correlation between Notch signaling and self-renewal capacity in FA hematopoietic stem and progenitor cells. Significantly, FA deficiency in MPPs deregulates a complex network of genes in the Notch and canonical NF-κB pathways. Genetic ablation or pharmacologic inhibition of NF-κB reduces Notch signaling in FA MPPs to near wild type level, and blocking either NF-κB or Notch signaling partially restores FA HSC quiescence and self-renewal capacity. These results suggest a functional crosstalk between Notch signaling and NF-κB pathway in regulation of HSC differentiation.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Células Madre Hematopoyéticas
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Transducción de Señal
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Diferenciación Celular
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FN-kappa B
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Receptores Notch
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Anemia de Fanconi
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Año:
2013
Tipo del documento:
Article