RESUMEN
The microbiome research field has rapidly evolved over the last few decades, becoming a major topic of scientific and public interest. The gut microbiota (GM) is the microbial population living in the gut. The GM has many functions, such as maintaining gut homeostasis and host health, providing defense against enteric pathogens, and involvement in immune system development. Several studies have shown that GM is implicated in dysbiosis and is presumed to contribute to neurodegeneration. This review focuses mainly on describing the connection between the intestinal microbiome alterations (dysbiosis) and the onset of neurodegenerative diseases to explore the mechanisms that link the GM to nervous system health, such as the gut-brain axis, as well as the mitochondrial, the adaptive humoral immunity, and the microvesicular pathways. The gut-brain communication depends on a continuous bidirectional flow of molecular signals exchanged through the neural and the systemic circulation. These pathways represent a possible new therapeutic target against neuroinflammation and neurodegeneration. Progress in this context is desperately needed, considering the severity of most neurodegenerative diseases and the current lack of effective treatments.
RESUMEN
We generated human induced pluripotent stem cells (hiPSCs) from dermal fibroblasts of a 40 years old female patient homozygous for the mutation c.535 G > A p.G179S on the KCNQ1 gene, causing a severe form of autosomal recessive Long QT Syndrome type 1 (AR-LQT1). The hiPSCs, generated using classical approach of the four retroviruses enconding the reprogramming factors OCT4, SOX2, cMYC and KLF4, display pluripotent stem cell characteristics, and differentiate into cell lineages of all three germ layers: endoderm, mesoderm and ectoderm.
Asunto(s)
Células Madre Pluripotentes Inducidas/metabolismo , Síndrome de QT Prolongado/genética , Adulto , Diferenciación Celular , Línea Celular , Femenino , Humanos , Factor 4 Similar a KruppelRESUMEN
We generated PSMi001-A and PSMi008-A hiPSC lines from two individuals belonging to a South African (SA) founder population in which the malignant KCNQ1-A341V mutation cosegregates with the Long QT Syndrome (LQTS) phenotype. PSMi001-A was derived from an asymptomatic KCNQ1-A341V mutation carrier, whereas PSMi008-A was derived from a healthy non-mutation carrier, heterozygous for the minor variant rs16847548 on the NOS1AP gene, associated with QT prolongation in the general population, and with a greater risk for cardiac arrest in the affected members of the SA founder population. The hiPSCs, generated using the Yamanaka's retroviruses, display pluripotent stem cell features and trilineage differentiation potential.
Asunto(s)
Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Síndrome de QT Prolongado/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Paro Cardíaco/genética , Paro Cardíaco/metabolismo , Humanos , Inmunohistoquímica , Cariotipificación , Mutación/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Piel/citología , SudáfricaRESUMEN
We generated human induced pluripotent stem cells (hiPSCs) from dermal fibroblasts of a woman carrier of the heterozygous mutation c.568Câ¯>â¯T p.R190W on the KCNQ1 gene. hiPSCs, obtained using four retroviruses enconding the reprogramming factors OCT4, SOX2, cMYC and KLF4, display pluripotent stem cell characteristics, and can be differentiated into spontaneously beating cardiomyocytes (hiPSC-CMs).
Asunto(s)
Diferenciación Celular , Reprogramación Celular , Fibroblastos/patología , Células Madre Pluripotentes Inducidas/patología , Canal de Potasio KCNQ1/genética , Mutación , Síndrome de Romano-Ward/genética , Adulto , Células Cultivadas , Femenino , Fibroblastos/metabolismo , Heterocigoto , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Factor 4 Similar a Kruppel , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Fenotipo , Síndrome de Romano-Ward/patologíaRESUMEN
We generated human induced pluripotent stem cells (hiPSCs) from dermal fibroblasts of a male carrier of the heterozygous mutation c.1781â¯Gâ¯>â¯A p.R594Q on the KCNQ1 gene. hiPSCs, generated using four retroviruses each encoding for OCT4, SOX2, KLF4 and cMYC, display pluripotent stem cell characteristics, and can be differentiated into spontaneously beating cardiomyocytes (hiPSC-CMs).
Asunto(s)
Diferenciación Celular , Fibroblastos/patología , Células Madre Pluripotentes Inducidas/patología , Canal de Potasio KCNQ1/genética , Mutación , Miocitos Cardíacos/patología , Síndrome de Romano-Ward/genética , Adulto , Células Cultivadas , Reprogramación Celular , Fibroblastos/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Factor 4 Similar a Kruppel , Masculino , Miocitos Cardíacos/metabolismo , Fenotipo , Síndrome de Romano-Ward/patologíaRESUMEN
We generated human induced pluripotent stem cells (hiPSCs) from a symptomatic Long QT Syndrome (LQTS) type 1 patient, belonging to a South African (SA) founder population segregating the heterozygous mutation c.1022Câ¯>â¯T p.A341V on the KCNQ1 gene. The patient is also homozygous for the two minor variants rs4657139 and rs16847548 on the NOS1AP gene, associated with greater risk for cardiac arrest and sudden death in LQTS mutation carriers of the founder population. hiPSCs, obtained using four retroviruses encoding the reprogramming factors OCT4, SOX2, cMYC and KLF4, display pluripotent stem cell characteristics, and can be differentiated into spontaneously beating cardiomyocytes (hiPSC-CMs).
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Línea Celular , Células Madre Pluripotentes Inducidas , Canal de Potasio KCNQ1/genética , Síndrome de Romano-Ward/genética , Diferenciación Celular , Técnicas de Reprogramación Celular , Análisis Mutacional de ADN , Femenino , Heterocigoto , Homocigoto , Humanos , Cariotipo , Factor 4 Similar a Kruppel , Persona de Mediana EdadRESUMEN
Mesenchymal stromal cells are excellent candidates for regenerative medicine since they are multipotent, easy to isolate, can be expanded to obtain clinically relevant numbers and are immunoprivileged. Stable genetic modification with viral vectors can improve mesenchymal stromal cell function and enhance their therapeutic potential. However, standard viral vectors achieve sub-optimal transduction efficiency with a single infection. On the other hand, multiple transduction cycles or antibiotic-based selection methods may alter the stem cell phenotype. We hypothesized that the use of lentiviral vectors containing specific regulatory sequences may result in improved transduction efficiency. Thus, we compared two types of third generation lentiviral vectors, one of which, the pLenti7.3 vector, contains the optimized sequences for Polypurine Tract and Woodchuck Post-transcriptional Regulatory Element. We demonstrated that with the pLenti7.3 it is possible to efficiently transduce human mesenchymal stromal cells with a single transduction cycle. Additionally, we successfully showed that by using the pLenti7.3 vector it is possible to efficiently over-express different growth factors, particularly relevant for cardiac protection and differentiation, in human mesenchymal stromal cells.
