RESUMEN
The roles of microRNAs (miRNAs) and the miRNA processing machinery in the regulation of stem cell biology are not well understood. Here, we show that the p53 family member and p63 isoform, ΔNp63, is a transcriptional activator of a cofactor critical for miRNA processing (DGCR8). This regulation gives rise to a unique miRNA signature resulting in reprogramming cells to multipotency. Strikingly, ΔNp63(-/-) epidermal cells display profound defects in terminal differentiation and express a subset of markers and miRNAs present in embryonic stem cells and fibroblasts induced to pluripotency using Yamanaka factors. Moreover, ΔNp63(-/-) epidermal cells transduced with an inducible DGCR8 plasmid can differentiate into multiple cell fates in vitro and in vivo. We found that human primary keratinocytes depleted of ΔNp63 or DGCR8 can be reprogrammed in 6 d and express a unique miRNA and gene expression signature that is similar but not identical to human induced pluripotent stem cells. Our data reveal a role for ΔNp63 in the transcriptional regulation of DGCR8 to reprogram adult somatic cells into multipotent stem cells.
Asunto(s)
Regulación hacia Abajo/genética , Queratinocitos/metabolismo , Células Madre Multipotentes/citología , Fosfoproteínas/genética , Proteínas/genética , Proteínas de Unión al ARN/genética , Transactivadores/genética , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética , Adulto , Animales , Diferenciación Celular , Línea Celular , Linaje de la Célula , Proliferación Celular , Quimera , Embrión de Mamíferos/citología , Células Epidérmicas , Perfilación de la Expresión Génica , Proteínas de Homeodominio/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Queratinocitos/citología , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Células Madre Multipotentes/metabolismo , Proteína Homeótica Nanog , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Fosfoproteínas/deficiencia , Fosfoproteínas/metabolismo , Proteínas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/metabolismo , Factores de Transcripción SOXB1/metabolismo , Transactivadores/deficiencia , Transactivadores/metabolismo , Factores de Transcripción/deficiencia , Factores de Transcripción/metabolismo , Transcripción Genética , Proteínas Supresoras de Tumor/deficiencia , Proteínas Supresoras de Tumor/metabolismoRESUMEN
We report the case of a MS patient on subcutaneous ofatumumab who became infected with SARS-CoV-2 and remained asymptomatic while developing antiviral IgM and IgG antibodies. The patient was B-cell depleted with normal serum immunoglobulin levels. Anti-SARS-CoV-2 IgG antibodies remained positive three months after the initial infection. These findings suggest that a MS patient treated with ofatumumab may be able to mount an effective humoral response to SARS-CoV-2 infection and probably to COVID-19 vaccines as well. Further research will be necessary to evaluate the humoral response of MS patients on ofatumumab to SARS-CoV-2 infection and COVID-19 vaccines.