Caracterización del rol de ALIX y CD9 en la ruta de biogénesis de vesículas extracelulares en un modelo celular de linaje mesenquimal humano

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dc.contributor.advisorSalguero López, Gustavo Andrésspa
dc.contributor.advisorCadavid Gutiérrez, Luis Fernandospa
dc.contributor.authorHernández Mejía, David Guillermospa
dc.contributor.cvlacHernández Mejía, David Guillermo [0001471126]spa
dc.contributor.googlescholarHernández Mejía, David Guillermo [David Hernández Mejía]spa
dc.contributor.orcidHernández Mejía, David Guillermo [0000000330437089]spa
dc.contributor.scopusHernández Mejía, David Guillemro [56389657100]spa
dc.date.accessioned2025-02-17T16:47:02Z
dc.date.available2025-02-17T16:47:02Z
dc.date.issued2024
dc.descriptionilustraciones, diagramas, fotografíasspa
dc.description.abstractLas vesículas extracelulares (VEs) son microestructuras esféricas liberadas por las células como un mecanismo de comunicación celular, tanto a nivel local como sistémico. Estas vesículas desempeñan un papel esencial en la regulación de la homeostasis celular y están implicadas en diversas patologías, incluyendo el cáncer, enfermedades neurodegenerativas y autoinmunes. Su baja inmunogenicidad, toxicidad reducida y presencia en distintos fluidos corporales han despertado un creciente interés en su estudio, especialmente en aplicaciones diagnósticas y terapéuticas. Investigaciones recientes han profundizado en los mecanismos de biogénesis de las VEs, destacando el papel de complejos proteicos como ESCRT, así como de proteínas auxiliares como ALIX o estructurales como CD9, en su formación, selección y empaquetamiento de biomoléculas. Sin embargo, aún no se comprende completamente cómo las alteraciones en la expresión de estas proteínas podrían modificar las interacciones con el complejo ESCRT durante la biogénesis de VE, lo que podría cambiar las características estructurales, de producción, de contenido o funcionales. Resolver esta cuestión es crucial para optimizar la aplicación de VEs en la biomedicina y la biotecnología. Los modelos celulares basados en células de linaje mesenquimal (CLM), como la línea celular MRC-5, ofrecen una plataforma ideal para estudiar procesos de inmunomodulación en ambientes in vitro de inflamación. A partir de VEs derivadas de estas células de linaje mesenquimal humano se puede evaluar la funcionalidad de las VEs después de generar cambios en la expresión de ALIX y CD9, siguiendo los cambios en la inmunomodulación de células del sistema inmune en modelos in vitro de inflamación. Con base en lo anterior, el objetivo principal de esta investigación consistió en dilucidar el rol de las proteínas ALIX y CD9 durante la biogénesis de VEs derivadas de células de linaje mesenquimal humano a través de alteraciones en la expresión de estas proteínas y el impacto generado las características estructurales, concentración, selección de contenido y funcionales de las VEs en un modelo biológico de inmunomodulación. Los resultados conseguidos en la tesis evidenciaron que ALIX y CD9 cumplen funciones fundamentales y complementarias durante la biogénesis de las VEs. Las modificaciones genéticas llevadas a cabo en la línea celular de linaje mesenquimal humano, MRC-5, demostraron la importancia de ALIX y CD9 como reguladores esenciales de la maquinaria del complejo X ESCRT, participando en la selección de biomoléculas y en la escisión y posterior liberación de las VEs (Texto tomado de la fuente).spa
dc.description.abstractAbstract Extracellular vesicles (EVs) are spherical microstructures released by cells as a mechanism of cellular communication at both local and systemic levels. These vesicles play a crucial role in regulating cellular homeostasis and are involved in various pathologies, including cancer, neurodegenerative diseases, and autoimmune disorders. Their low immunogenicity, reduced toxicity, and presence in different bodily fluids have generated increasing interest in their study, particularly for diagnostic and therapeutic applications. Recent research has deepened our understanding of EV biogenesis mechanisms, highlighting the role of protein complexes such as ESCRT, as well as auxiliary proteins like ALIX and structural proteins like CD9, in their formation, selection, and packaging of biomolecules. However, the extent to which alterations in the expression of these proteins may modify their interactions with the ESCRT complex during EV biogenesis remains incompletely understood, potentially affecting structural characteristics, production, content, or functional properties. Addressing this question is crucial for optimizing the application of EVs in biomedicine and biotechnology. Cell models based on mesenchymal lineage cells (MLCs), such as the MRC-5 cell line, provide an ideal platform for studying immunomodulatory processes in in vitro inflammation environments. EVs derived from these human mesenchymal lineage cells can be used to evaluate their functionality after inducing changes in ALIX and CD9 expression, thereby assessing subsequent immunomodulatory effects on immune system cells in in vitro inflammation models. Based on these premises, the main objective of this research was to elucidate the role of ALIX and CD9 proteins during the biogenesis of EVs derived from human mesenchymal lineage cells by altering their expression and analyzing the impact on the structural characteristics, concentration, content selection, and functional properties of EVs in a biological immunomodulation model. The findings of this study demonstrated that ALIX and CD9 play fundamental and complementary roles in EV biogenesis. Genetic modifications performed in the human mesenchymal lineage cell line MRC-5 underscored the importance of ALIX and CD9 as essential regulators of the ESCRT complex machinery, participating in biomolecule selection as well as in membrane scission and subsequent EV release.eng
dc.description.degreelevelMaestríaspa
dc.description.degreenameMagíster en Genética Humanaspa
dc.description.methodsPara cumplir los objetivos planteados en el trabajo se dividió la metodología en cuatro fases: El silenciamiento de un gen facilita la comprensión de su papel en una vía de biogénesis al analizar las repercusiones de su falta en los procesos específicos de la célula. Al limitar su expresión, es posible examinar qué fases del proceso se ven modificadas o interrumpidas, lo que ofrece indicios esenciales acerca de su función, ya sea en la formación, liberación o composición de estructuras como las vesículas extracelulares. Por tal motivo, en una primera fase se generaron varias de líneas celulares MRC-5 silenciadas para el gen ALIX del complejo ESCRT y se determinó el nivel de silenciamiento o reducción de la expresión de este gen con el fin de cumplir la primera parte del objetivo. Para obtener las líneas celulares MRC-5 silenciadas parcialmente (Knockdown) o totalmente (Knock out) para el gen ALIX se utilizaron dos metodologías de transfección distintas. En el primer método de transfección se realizó una nucleofección de un plásmido de expresión del sistema CRISPR-Cas9 asociado a un gen de resistencia a la puromicina para su selección (pSpCas9(BB)-2A-Puro_ pX459 v2.0). El vector seleccionado tiene un sitio de inserción de los sgARN, que previamente fueron seleccionados bioinformáticamente, y clonados en el vector. Las sgARN diseñas van dirigidas a secuencias en los exones 1 y 5 del gen ALIX. Para la clonación en el vector, se realizó la hibridación de ambas hebras, su clonación en el plásmido y se confirmaron tanto por PCR convencional como por secuenciación Sanger. La endonucleasa Cas9 se expresa en conjunto con la ARN guías dentro de las células MRC-5 nucleofectadas para que generen un corte en la región codificante y mediante una reparación de unión de extremos no homólogos (NHEJ) introducir indels para que generen una mutación “frameshift” o de desplazamiento de marco de lectura y finalmente, un codón de parada prematuro y tener un knock out para ALIX. Para la selección de solo las células modificas, posterior a la nucleofección se colocaron las células MRC-5 en cultivo con el antibiótico puromicina, que a altas concentraciones es letal para las células eucariotas. Para evaluar el silenciamiento obtenido por este método se realizaron varias pruebas: (i) Una marcación intracelular de una cola de histidinas DYKDDDDK (Flag) que también se expresa el plásmido nucleofectado por citometría de flujo, (ii) una cuantificación relativa de la expresión de génica de ALIX y Beta 2 microglobulina (B2M) por RT-qPCR, (iii) también se realizó inmunotransferencia o Western Blot para evaluar expresión a nivel de proteína de ALIX frente a la proteína GAPDH como control y (iv) por último, se confirmó por secuenciación Sanger si las células seleccionada contenía algún indel en los exones.spa
dc.description.researchareaTerapia celular y génicaspa
dc.format.extent215 páginasspa
dc.format.mimetypeapplication/pdfspa
dc.identifier.instnameUniversidad Nacional de Colombiaspa
dc.identifier.reponameRepositorio Institucional Universidad Nacional de Colombiaspa
dc.identifier.repourlhttps://repositorio.unal.edu.co/spa
dc.identifier.urihttps://repositorio.unal.edu.co/handle/unal/87503
dc.language.isospaspa
dc.publisherUniversidad Nacional de Colombiaspa
dc.publisher.branchUniversidad Nacional de Colombia - Sede Bogotáspa
dc.publisher.facultyFacultad de Medicinaspa
dc.publisher.placeBogotá, Colombiaspa
dc.publisher.programBogotá - Medicina - Maestría en Genética Humanaspa
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dc.rights.accessrightsinfo:eu-repo/semantics/openAccessspa
dc.rights.licenseAtribución-NoComercial 4.0 Internacionalspa
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/spa
dc.subject.ddcAutoimmune Diseasesspa
dc.subject.ddc570 - Biología::576 - Genética y evoluciónspa
dc.subject.ddc570 - Biología::571 - Fisiología y temas relacionadosspa
dc.subject.ddc610 - Medicina y salud::612 - Fisiología humanaspa
dc.subject.ddc610 - Medicina y salud::616 - Enfermedadesspa
dc.subject.decsVesículas Extracelularesspa
dc.subject.decsExtracellular Vesicleseng
dc.subject.decsComunicación Celularspa
dc.subject.decsCell Communicationeng
dc.subject.decsHomeostasisspa
dc.subject.decsHomeostasiseng
dc.subject.decsEnfermedades neurodegenerativasspa
dc.subject.decsNeurodegenerative Diseaseseng
dc.subject.decsEnfermedades Autoinmunesspa
dc.subject.decsBiogénesis de Organelosspa
dc.subject.decsOrganelle Biogenesiseng
dc.subject.decsSistema Inmunológicospa
dc.subject.decsImmune Systemeng
dc.subject.decsAutoimmune Diseaseseng
dc.subject.proposalCélulas de linajes mesenquimalspa
dc.subject.proposalExosomasspa
dc.subject.proposalMicrovesículasspa
dc.subject.proposalNucleofecciónspa
dc.subject.proposalPartículas lentiviralesspa
dc.subject.proposalModificación genéticaspa
dc.subject.proposalSilenciamiento génicospa
dc.subject.proposalInmunomodulaciónspa
dc.subject.proposalMesenchymal lineage cellseng
dc.subject.proposalExosomeseng
dc.subject.proposalMicrovesicleseng
dc.subject.proposalNucleofectioneng
dc.subject.proposalLentiviral particleseng
dc.subject.proposalGenetic modificationeng
dc.subject.proposalGene silencingeng
dc.subject.proposalImmunomodulationeng
dc.titleCaracterización del rol de ALIX y CD9 en la ruta de biogénesis de vesículas extracelulares en un modelo celular de linaje mesenquimal humanospa
dc.title.translatedCharacterization of the role of ALIX and CD9 in the biogenesis pathway of extracellular vesicles in a human mesenchymal lineage cell modeleng
dc.typeTrabajo de grado - Maestríaspa
dc.type.coarhttp://purl.org/coar/resource_type/c_bdccspa
dc.type.coarversionhttp://purl.org/coar/version/c_ab4af688f83e57aaspa
dc.type.contentTextspa
dc.type.driverinfo:eu-repo/semantics/masterThesisspa
dc.type.redcolhttp://purl.org/redcol/resource_type/TMspa
dc.type.versioninfo:eu-repo/semantics/acceptedVersionspa
dcterms.audience.professionaldevelopmentEstudiantesspa
dcterms.audience.professionaldevelopmentInvestigadoresspa
dcterms.audience.professionaldevelopmentMaestrosspa
dcterms.audience.professionaldevelopmentPúblico generalspa
oaire.accessrightshttp://purl.org/coar/access_right/c_abf2spa

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