RESUMO
The choroid plexus (CP) is a key regulator of the central nervous system (CNS) homeostasis through its secretory, immunological and barrier properties. Accumulating evidence suggests that the CP plays a pivotal role in the pathogenesis of multiple sclerosis (MS), but the underlying mechanisms remain largely elusive. To get a comprehensive view on the role of the CP in MS, we studied transcriptomic alterations of the human CP in progressive MS and non-neurological disease controls using RNA sequencing. We identified 17 genes with significantly higher expression in progressive MS patients relative to that in controls. Among them is the newly described long non-coding RNA HIF1A-AS3. Next to that, we uncovered disease-affected pathways related to hypoxia, secretion and neuroprotection, while only subtle immunological and no barrier alterations were observed. In an ex vivo CP explant model, a subset of the upregulated genes responded in a similar way to hypoxic conditions. Our results suggest a deregulation of the Hypoxia-Inducible Factor (HIF)-1 pathway in progressive MS CP. Importantly, cerebrospinal fluid levels of the hypoxia-responsive secreted peptide PAI-1 were higher in MS patients with high disability relative to those with low disability. These findings provide for the first time a complete overview of the CP transcriptome in health and disease, and suggest that the CP environment becomes hypoxic in progressive MS patients, highlighting the altered secretory and neuroprotective properties of the CP under neuropathological conditions. Together, these findings provide novel insights to target the CP and promote the secretion of neuroprotective factors into the CNS of progressive MS patients.
Assuntos
Plexo Corióideo/metabolismo , Hipóxia/genética , Esclerose Múltipla Crônica Progressiva/genética , Esclerose Múltipla Recidivante-Remitente/genética , Neuroproteção/genética , Neurossecreção/genética , Adrenomedulina/líquido cefalorraquidiano , Adrenomedulina/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Perfilação da Expressão Gênica , Ontologia Genética , Glicoproteínas/líquido cefalorraquidiano , Glicoproteínas/genética , Humanos , Fator 1 Induzível por Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Peptídeos e Proteínas de Sinalização Intercelular/líquido cefalorraquidiano , Peptídeos e Proteínas de Sinalização Intercelular/genética , Ventrículos Laterais , Masculino , Metalotioneína/genética , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/líquido cefalorraquidiano , Esclerose Múltipla Recidivante-Remitente/líquido cefalorraquidiano , Inibidor 1 de Ativador de Plasminogênio/líquido cefalorraquidiano , Inibidor 1 de Ativador de Plasminogênio/genética , RNA Antissenso/genética , RNA Longo não Codificante , RNA-SeqRESUMO
During heart regeneration in the zebrafish, fibrotic tissue is replaced by newly formed cardiomyocytes derived from preexisting ones. It is unclear whether the heart is composed of several cardiomyocyte populations bearing different capacity to replace lost myocardium. Here, using sox10 genetic fate mapping, we identify a subset of preexistent cardiomyocytes in the adult zebrafish heart with a distinct gene expression profile that expanded after cryoinjury. Genetic ablation of sox10+ cardiomyocytes impairs cardiac regeneration, revealing that these cells play a role in heart regeneration.