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Identification of Novel Regulators of Transcription in Ipsc-Derived Cardiovascular Progenitors

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Identification of Novel Regulators of Transcription in Ipsc-Derived Cardiovascular Progenitors Facultad de Ciencias IDENTIFICATION OF NOVEL REGULATORS OF TRANSCRIPTION IN IPSC-DERIVED CARDIOVASCULAR PROGENITORS Javier Linares Acosta PhD Thesis Pamplona, June 2019 Facultad de Ciencias IDENTIFICATION OF NOVEL REGULATORS OF TRANSCRIPTION IN IPSC-DERIVED CARDIOVASCULAR PROGENITORS Javier Linares Acosta Facultad de Ciencias Identification of novel regulators of transcription in iPSC-derived cardiovascular progenitors Memoria presentada por D. Javier Linares Acosta para aspirar al grado de Doctor por la Universidad de Navarra. El presente trabajo ha sido realizado bajo nuestra dirección en el Departamento de Terapia Celular y Medicina Regenerativa y autorizamos su presentación ante el Tribunal que lo ha de juzgar. Pamplona, 8 de mayo de 2019 Dr. Felipe Prósper Cardoso Dra. Xonia Carvajal-Vergara (Director de la Tesis Doctoral) (Co-Directora de la Tesis Doctoral) This work has been supported by the Spanish Government, ‘Promoción del Talento y su Empleabilidad’ State Program, under a MINECO BES-2014-069226 grant co-financed by European Social Fund (ESF), associated to ‘Retos de la Sociedad’ State Program, FEDER/MICIU/AIE/SAF2013-46142-R. Agradecimientos Quiero expresar mi agradecimiento al CIMA, a la CUN y a la Universidad de Navarra por haberme brindado unas condiciones únicas para desarrollarme tanto profesional como personalmente. Gracias al MINECO, por la ayuda concedida que ha permitido que este trabajo se haya podido llevar a cabo. Es complicado encontrar las palabras más justas, las más adecuadas, para describir el profundo agradecimiento que debo a todas las personas que me habéis acompañado a lo largo de esta historia, así que me serviré de la sensación de inmensa alegría y satisfacción por el desarrollo de esta idea, de este proyecto, que se ha llevado a cabo gracias a la colaboración e implicación que de una manera u otra habéis tenido todos los que me habéis acompañado. Quiero dar las gracias de manera especial a mis directores de tesis. Felipe, gracias por tu confianza y por permitirme comenzar esta historia en este laboratorio. Xonia, muchísimas gracias por tu apoyo y tus consejos incondicionales, por ser un ejemplo de lucha constante y por alentarme a cada momento; gracias por ser una gran maestra en este viaje. Quiero expresar mi más profundo agradecimiento al grupo Cardiac Reprogramming por ser un aporte activo para el desarrollo de esta tesis. Gracias Esti, por ser mi mejor apoyo tanto en la poyata como fuera de ella, por todo lo compartido contigo y por permitirme trabajar de una manera tan cómoda. Gracias Leyre por tu trabajo y tu ayuda constantes, por tu ilusión y tu perseverancia. Gracias Félix, porque pese a tu breve paso por el grupo, lo impregnaste de frescura. Si hay algo que he aprendido en este grupo es que el trabajo en equipo siempre multiplica esfuerzos. Infinitas gracias a todos. Muchas gracias a la enorme familia de Terapia Celular y Oncohematología. Es un placer trabajar en un grupo con tanta gente que día a día crea un ambiente tan dinámico, distendido y enriquecedor. Gracias a todos y cada uno de vosotros por hacer del esfuerzo y del trabajo diario algo tan cómodo y motivador. Gracias a Silvia y a Isa por vuestros consejos y generosidad, por vuestro apoyo constante. Gracias a Saray, Rebeca, Miriam, por estar siempre disponibles a ayudar y hacerlo siempre con una buena carga de humor. Gracias a Arantxa C. y Arantxa B., tan diferentes en carácter a pesar del nombre, pero tan parecidas en cuanto a la calidez y las ganas de ayudar. Gracias a Eva, Edu, Teresa, Óscar, Elena Iglesias y Giulia por vuestra cercanía y generosidad. Gracias a Miranda, Leire y Edurnen por estar siempre disponibles, por vuestros consejos y apoyo. Gracias a Jose, Juan Antonio, Paula R., Pilar, María, Ángel, Laura A., Íñigo, Marta, Ana Cris, Laura V., Ane y Naroa por vuestra ayuda, motivación y entusiasmo. Gracias a Manu, Juanro, Aranguren, Adri, Froi, Bea, Ana Pérez, Elena, Xabi, Borja, Ana Pardo, de los que se puede aprender tanto. Gracias por vuestro apoyo y energía. Gracias a todos los que habéis pasado por el laboratorio: Zapata, Andoni, Aguado, Emma, Mentxu, Marién, es un lujo y un placer haber compartido experiencias con vosotros. Quiero dar las gracias de manera especial a mis dos mellizas, Raquel y Paula, por haber recorrido juntos este camino. Gracias por todas las experiencias que hemos vivido juntos tanto dentro como fuera del laboratorio. Por la cercanía y por el apoyo, por la conexión. Sois un gran ejemplo de superación y de esfuerzo. Gracias por ser parte fundamental en el desarrollo de esta tesis. Gracias a todos los que forman parte de los laboratorios de Biología Celular y Molecular de la CUN y de Ortopedia. Gracias a Tania y a Adriana, por los buenos momentos, las charlas y las inyecciones de energía constantes. Gracias a Quique, Gloria, Ascen, Susana, Goretti, Leti, María, Rebeca, Marga y Pury, por todos los momentos compartidos. Gracias a todos aquellos de los programas de Oncohematología, Terapia Celular, Genómica Avanzada e Inmunología que en algún momento me han bridado ayuda, me han regalado momentos únicos o me han alentado con hechos, con palabras o con abrazos. Gracias Amaia, Sarai Sarvide, Marta Lasa, Irene, Patricia Maiso, Erika, Aintzane, por estar siempre pendientes y hacer más fácil el camino. Gracias al servicio de Citometría. En especial, quiero agradecer a Diego su ayuda y su paciencia infinitas, a Idoia por alegrarme las visitas al citómetro, y a Sonia por su ayuda. Gracias a los servicios de Genómica, Imagen, Morfología y Bioinformática. Gracias infinitas a Elizabeth Guruceaga por su paciencia, su apoyo y su constante disponibilidad. Gracias a María Eugenia Fernández, Andreu M. Climent y Dung-Fang Lee, por vuestro apoyo y colaboraciones. Gracias a los servicios de Genética de la Policlínica Gipuzkoa, y de Citogenética del CNIO. Gracias a Sylvie, a Leyre Arbeloa y a Ander, por tantos momentos de risas y distensión. Gracias a Marisol Ripa y Carolina Matute por vuestra ayuda constante y vuestra cercanía. Gracias a Mari y Ana del CIMA, y a Asun, Vanesa, María y Ana, de la CUN, por regalarme tantas sonrisas. Gracias al departamento de Bioquímica y Genética de la UNAV. Gracias a Silvia Cenoz y a Íñigo por estar pendientes siempre del más mínimo detalle y por estar siempre dispuestos a ayudar. Quiero expresar mi agradecimiento a Guillermo Zalba y a Ujué por la comodidad que generan y todo lo aprendido con ellos. Gracias a Marisol Aymerich y a Ana Rouzaut por su atención y generosidad. Gracias a Lola Odero, por estar siempre pendiente y transmitirme tanto ánimo. No puedo olvidarme de expresar mi agradecimiento a Teresa Portolés y a María José Feito por brindarme la oportunidad de iniciarme en el mundo de la investigación e instigarme a seguir siempre adelante. Muchas gracias a las personas con las que compartí trabajo y experiencias en el grupo de Interacciones Célula-Biomaterial: Conchita, Ceci, Carmen, Isa, Ana. Gracias al departamento de Bioquímica y Biología Molecular I de la UCM. Gracias a mis amigos que, a pesar de la distancia y el tiempo que muchas veces nos ha separado, siempre estáis conmigo. Es un placer contar con gente como vosotros. Gracias a Vicky. Gracias a Elena y Aingeru, y a Unai. Gracias a Jonathan, Alicia y a Lucía, que tanta ilusión ha puesto en ellos. Gracias a Desy, Mariola y Nerea porque a pesar de la distancia física que nos ha marcado el camino, es un lujo seguir conectando a la perfección cuando nos vemos como si no pasara el tiempo. Gracias a Jorge, Eva, Carra, Leti, Helena y Alban, por los buenos momentos compartidos. Gracias a Lizz y Manu por su alegría. Gracias a Dany, por ser mi pilar fundamental. Por hacerme y dejarme hacerte tan feliz sin censura, y por descubrírmelo con una simple sonrisa. Y como diría Salinas, gracias por brindarme la alegría tan alta de vivir en los pronombres: gracias por ser tú, porque sin apenas proponértelo me permites ser mi mejor yo, y por aunar todo eso en un nosotros. Gracias a Andrea, Juan, Gemma, David, Juanjo, Elena, Nobelita, Juanan, Lucía, Noa, Álvaro y Mario. Sois geniales y es un placer poder contar siempre con vosotros. Muchísimas gracias a mi familia, mi principal motor y apoyo. Mamá, gracias por tu confianza y tu aliento constantes; eres el mejor ejemplo que se puede seguir. Gracias por colmarte con los sueños compartidos de tu gente, por regalarnos la capacidad para asombrarnos y por ser una constante fuente de inspiración y valores. Papá, ojalá estuvieras aquí sentado para poder disfrutar juntos de estas sensaciones que seguro te habrían encantado. David, gracias por tu bondad y tu atención constantes. Erika, eres un ejemplo de superación; gracias por ser tan especial. Beto, gracias por estar lleno de sensibilidad y locura a partes iguales. Gracias a Raquel, por tu apoyo. Infinitas gracias a Miguel y David, por aportar tanto en nuestras vidas, por vuestra ilusión y vuestros sueños, que no dejan de ser los míos. Gracias por recordarme el verdadero valor de las cosas. La tesis es un camino largo, y recorrerlo sería mucho más complicado, si no imposible, sin todos aquellos que habéis estado, que estáis y que estaréis. Muchas gracias a todos. “Ten siempre a Ítaca en tu mente. Llegar allí es tu destino. Mas no apresures nunca el viaje. Mejor que dure muchos años y atracar, viejo ya, en la isla, enriquecido de cuanto ganaste en el camino sin aguantar a que Ítaca te enriquezca”. (Kavafis) Abbreviations AHF (aSHF): anterior heart field (anterior second heart field). AHF-CVP: cardiovascular progenitor derived from AHFiPSCs. AHFiPSCs: induced pluripotent stem cells derived from Ai6-Mef2c-AHF-Cre mice. AHFiPS-D0: undifferentiated AHFiPSCs.
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