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1.
Thromb Haemost ; 118(9): 1586-1599, 2018 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-30103245

RESUMEN

Thromboembolic events are the main cause of mortality in BCR-ABL1-negative myeloproliferative neoplasms (MPNs) but their underlying mechanisms are largely unrecognized. The Janus kinase 2 (JAK2)V617F mutation is the most frequent genetic alteration leading to MPN. Usually found in haematopoietic progenitors and stem cells, this mutation has also been described in endothelial cells (ECs) of MPN patients. In this study, we have questioned the impact of the JAK2V617F mutation on EC phenotype and functions. We developed an induced pluripotent stem cells strategy to compare JAK2 mutant and wild-type ECs. Transcriptomic assays showed that several genes and pathways involved in inflammation, cell adhesion and thrombotic events were over-represented in JAK2V617F ECs and expression levels of von Willebrand factor and P-selectin (CD62P) proteins were increased. Finally, we found that leucocytes from MPN patients adhere more tightly to JAK2V617F ECs. Our results show that JAK2V617F ECs have a pro-inflammatory and pro-thrombotic phenotype and were functionally pro-adherent.


Asunto(s)
Plaquetas/fisiología , Células Endoteliales/fisiología , Células Madre Pluripotentes Inducidas/fisiología , Janus Quinasa 2/genética , Células Progenitoras Mieloides/fisiología , Trastornos Mieloproliferativos/genética , Trombosis/genética , Adhesión Celular/genética , Diferenciación Celular , Células Cultivadas , Proteínas de Fusión bcr-abl/metabolismo , Perfilación de la Expresión Génica , Humanos , Mutación/genética , Transgenes/genética
2.
Stem Cells Transl Med ; 3(6): 686-91, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24736403

RESUMEN

The use of synthetic messenger RNAs to generate human induced pluripotent stem cells (iPSCs) is particularly appealing for potential regenerative medicine applications, because it overcomes the common drawbacks of DNA-based or virus-based reprogramming strategies, including transgene integration in particular. We compared the genomic integrity of mRNA-derived iPSCs with that of retrovirus-derived iPSCs generated in strictly comparable conditions, by single-nucleotide polymorphism (SNP) and copy number variation (CNV) analyses. We showed that mRNA-derived iPSCs do not differ significantly from the parental fibroblasts in SNP analysis, whereas retrovirus-derived iPSCs do. We found that the number of CNVs seemed independent of the reprogramming method, instead appearing to be clone-dependent. Furthermore, differentiation studies indicated that mRNA-derived iPSCs differentiated efficiently into hepatoblasts and that these cells did not load additional CNVs during differentiation. The integration-free hepatoblasts that were generated constitute a new tool for the study of diseased hepatocytes derived from patients' iPSCs and their use in the context of stem cell-derived hepatocyte transplantation. Our findings also highlight the need to conduct careful studies on genome integrity for the selection of iPSC lines before using them for further applications.


Asunto(s)
Reprogramación Celular , Fibroblastos/metabolismo , Vectores Genéticos , Células Madre Pluripotentes Inducidas/metabolismo , ARN Mensajero/metabolismo , Retroviridae/genética , Factores de Transcripción/metabolismo , Transfección/métodos , Diferenciación Celular , Células Cultivadas , Variaciones en el Número de Copia de ADN , Perfilación de la Expresión Génica/métodos , Regulación del Desarrollo de la Expresión Génica , Genotipo , Hepatocitos/metabolismo , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , Fenotipo , Polimorfismo de Nucleótido Simple , Factores de Transcripción/genética
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