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Simposio 9 Terapia Celular Simposio 9 Terapia celular Moderadora: Pilar Ortiz. Banc de Sang i Teixits, Barcelona S9-1 Desarrollo de la hemopoyesis en humanos: del embrión al adulto A. Bigas. S9-2 Cellular immunotherapy against infectious agents P. Comoli. S9-3 Optimización de sistemas de producción celular con calidad GMP JJ. Cairó, J. Garcia. Simposio S9-1 Desarrollo de la hemopoyesis en humanos: del embrión al adulto Desarrollo de la hemopoyesis en humanos: del S9-1 embrión al adulto A. Bigas. Grupo de investigación en Células Madre y Cáncer. Programa de investigación en Cancer. IMIM-Hospital del Mar. Parc de Recerca Biomédica de Barcelona (PRBB). Introducción Las células madre hematopoyéticas son las responsables de la formación de células sanguíneas especializadas durante toda la vida. Para ello, estas células deben tener la capaci- dad de auto-renovación, así como de diferenciación hacia los distintos tipos celulares. La capacidad de autorenova- ción indefinida es la que diferencia a estas células de los progenitores multipotentes. Históricamente se han desarro- llado diversas técnicas para caracterizar y distinguir las células madre de otros precursores hematológicos indife- renciados. Actualmente, se considera que una célula madre hematopoyética es aquella que es capaz de reconstitutir la hematopoyesis al ser transplantada a un organismo inmu- nodeprimido1. Estas células residen en la médula ósea de una persona adulta y se perpetúan mediante auto-replica- ción. Sin embargo, en algún momento debe existir un pre- cursor a partir del cual las células madre del adulto se generan. Actualmente hay evidencias de que esta célula precursora existe, al menos, durante la vida embrionaria, ya que se ha demostrado que las células hematopoyéticas de un ratón adulto provienen de un precursor con caracte- rísticas endoteliales (VE-cad+ aunque también Runx+) que se formó durante el desarrollo embrionario y que muy pro- Figura 1 : La gráfica muestra el porcentaje de células hematopoyéticas b-galacto- bablemente coincide con el denominado hemangioblasto2- sidasa+ en un ratón adulto que provienen de unos precursores marcados a dis- 5. Estas investigaciones son muy importantes para demos- tintos días de desarrollo embrionario (eje X, E6.5 a E10.5). Estos estudios demues- tran que células Runx1+ marcadas genéticamente en un embrión de día 9.5 trar que el proceso de la hematopoyesis embrionaria escon- (aproximadamente) son precursoras del 100% de las células sanguíneas que se de las claves para saber generar células madre hematopo- encuentran en el ratón adulto). Publicado por Samokhvalov et al, Nature 2007 yéticas con capacidad de formar todos los tipos de células hematológicas a largo plazo. necesidades iniciales de oxígeno y nutrientes. Hematopoyesis primitiva en el saco vitelino El proceso de la hematopoyesis primitiva, aunque ¿Qué sabemos sobre la hematopoyesis en el embrión muy importante durante el desarrollo, es un proceso humano? Al igual que en el ratón, hay una primera transitorio e independiente del que formará las células etapa embrionaria que se caracteriza por la formación de hematopoyéticas que mantendrán al organismo adulto. algunos tipos de células sanguíneas, mayoritariamente Más adelante, sin embargo, el saco embrionario puede eritrocitos y macrófagos. Este proceso tiene lugar duran- tener capacidad para formar otras células que sean pre- te un corto periodo de tiempo y se conoce como hema- cursores de las células madre adultas. Esta posibilidad topoyesis primitiva. Estas células sanguíneas primitivas está todavía en discusión5,6. se originan en el saco vitelino que es la estructura más externa de origen embrionario, probablemente para faci- litar el acceso del oxígeno a los eritrocitos. Estas células Hematopoyesis definitiva durante el desarro- serán las encargadas de distribuir oxígeno al embrión llo embrionario cuando éste haya crecido suficiente como para que no A partir de día 19 de desarrollo embrionario humano pueda conseguirlo por difusión celular. Esto ocurre a (día 10 en el ratón), en la región caudal de la aorta dor- partir de los 21 días de desarrollo en el embrión huma- sal , donde se localiza la gónada y el mesonefros (AGM), no (día 8.5 en ratón) que es cuando se establece la cir- se observan células hematopoyéticas indiferenciadas culación entre el embrión y el saco vitelino mediante las que, a diferencia de las células hematopoyeticas primi- arterias y venas vitelinas, y al mismo tiempo se observa tivas, tienen la capacidad de regenerar la hematopoye- la conexión entre el embrión y la placenta (mediante las sis de forma permanente al ser transplantadas a un arterias y venas umbilicales). Cuando estas conexiones ratón SCID irradiado7. Esta característica es la que iden- se han establecido, las células hematopoyéticas primiti- tifica a las células madre hematopoyéticas y las prime- vas originadas previamente en el saco embrionario están ras células de este tipo que se detectan en el embrión, disponibles para circular hasta el embrión y cubrir las se generan en esta región de la AGM, asociadas al endo- 20 Congreso Nacional de la SETS 141 A. Bigas. Figura 2: Representación de las distintas fases y nichos hematopoyéticos durante el desarrollo hematopoyético en el embrión de ratón y humano. (a partir de Mikkola et al,(12)) telio de la aorta8. Últimamente se ha descrito que Vías de señalización molecular que regulan simultáneamente se originan células de las mismas la formación de células madre hematopoyéti- características en la placenta y en las arterias vitelinas cas en el embrión y umbilicales, indicando que muy probablemente las Nuestro laboratorio está investigando el papel que algu- condiciones para generar células madre hematopoyéti- nas vías de señalización como Notch y Wnt tienen en el cas se consiguen en diversas estructuras arteriales del proceso de formación de las células madre hematopoyé- embrión9,11. ticas. Como es lógico, los experimentos funcionales El proceso de formación de estas células se ha carac- deben hacerse en ratón para después buscar las compa- terizado en los últimos años gracias en parte al estudio raciones en el caso de células humanas. En estudios de ratones mutantes que presentan alteraciones en las publicados recientemente hemos demostrado que la vía primeras etapas de la hematopoyesis. Así mismo, los de Notch debe activarse para que las células hematopo- embriones mutantes para genes como AML1/Runx1 o yéticas de la aorta puedan formarse. GATA2 entre otros, carecen de células hematopoyéticas Notch es una proteína que se encuentra en la membra- capaces de reconstituir un organismo adulto (13, 14). Se na de muchas células y que interacciona con otras proteí- considera que la expresión de estos genes es parcialmen- nas que se encuentran en células adyacentes (ligandos). te los responsable de la ejecución del programa hemato- Estas interacciones célula-célula tienen como resultado el poyético. procesamiento de Notch y su internacilización al núcleo de Figure 3: A) Embriones de ratón a día 9.5-10 de desarrollo incluidos dentro del saco vitelino (izquierda) o sin el saco vitelino (izquierda). El recuadro señala la región donde se encuentra la AGM. B) sección transversal de una aorta murina donde se observan células que expresan el transgen GFP bajo el promotor Ly6/sca que funciona en HSC (15) C) tinción CD34 en una sección de aorta de un embrión humano. Se observa un cluster de célu- las emergentes que son CD34+16. 142 20 Congreso Nacional de la SETS Simposio S9-1 Desarrollo de la hemopoyesis en humanos: del embrión al adulto Figura 4: Protocolo experimental para analizar las células hematopoyéticas que se originan en la aorta de un embrión de ratón. Estas células una vez obtenidos se dis- gregan mediante incubación en collagenasa y se pueden transplantar a ratones irradiados para estudiar las HSC. la célula dónde funciona como factor de la transcripción. sible pensar en su utilización terapéutica. En resumen, En el caso de la hematopoyesis embrionaria en la aorta, no se ha conseguido generar células madre hematopoyé- sabemos que Notch tiene que interaccionar con Jagged1 ticas de forma reproducible a partir de células madre para que se pueda formar hematopoyesis17. embrionarias. Gran parte de este fracaso es debido a que Otra línea de investigación importante en el labora- no conocemos cómo se generan estas células y para ello torio consiste en identificar la función de la vía de seña- debemos estudiar cómo se hace en el embrión e intentar lización de Wnt que és importante en el este proceso. seguir los mismos pasos en el laboratorio. Aplicaciones de la investigación embrionaria Problemas asociados a la hematopoyesis en la generación de tejido sanguíneo embrionaria: dónde se generan las leucemias? La disponibilidad de células madre hematopoyéticas es Existen células preleucémicas en el embrión? actualmente el punto limitante para el transplante Investigaciones recientes demuestran que existen algunas hematológico de muchos enfermos sin donantes compa- aberraciones cromosómicas asociadas a leucemias que se tibles. En los últimos años y gracias al desarrollo de los originan durante la fase fetal o embrionaria. Se ha obser- bancos de células de cordón umbilical, se ha aumentado vado que si un gemelo monoplacental desarrolla leucemia ligeramente el número de donantes para ciertos tipos a una edad temprana (antes de los 4 años), el otro tiene transplantes. Sin embargo, para mejorar esta situación más posibilidades de padecer ese mismo tipo de leucemia de forma permanente, necesitamos investigar sobre nue- comparado con el resto de la población19. Además altera- vas fuentes de células madre. En este sentido, las célu- ciones genéticas asociadas a leucemias en pacientes que las derivadas de células madre embrionarias (células ES, han desarrollado leucemias, se han encontrado en muestras del inglés Embryonic Stem) representan una nueva de sangre obtenidas al nacer, indicando que estas alteracio- expectativa a la solución de este problema. nes se han originado durante el periodo embrionario o Hoy en día podemos generar muchos tipos celulares fetal. Estos descubrimientos ponen de manifiesto la necesi- a partir de células madre embrionarias.
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