Avances recientes en medicina regenerativa sugieren que será posible transformar cualquier tipo de célula humana en otra de interés terapéutico, sin los desafíos éticos ni los riesgos para los pacientes que implica el empleo de células madres embrionarias.
Cristián Fierro / Fernando Fierro

Santiago / Cultura – Importantes avances científicos han hecho posible el uso de una gran variedad de células, diferentes a las células madre, como opciones terapéuticas en el área de la medicina regenerativa.

En general, los especialistas en biología del desarrollo han considerado que —a diferencia de las plantas— el compromiso de una célula animal con un linaje particular es irreversible. Por ejemplo, cuando una célula madre o progenitora se diferencia y se convierte en una neurona, termina siendo una célula neuronal para siempre: es como si el desarrollo se dirigiera en una sola dirección. Así, la reprogramación de células, es decir, la idea de transformar en otra distinta una célula ya diferenciada y terminal, es una alternativa relativamente nueva.
 
En los años noventa, J. Choi y colaboradores, usando un gen regulador maestro, convirtieron fibroblastos —un tipo de células que forman parte del tejido conectivo del organismo— en células musculares. Posteriormente, también se obtuvieron reguladores maestros para favorecer la transformación (o transdiferenciación) de otros tipos de células, aunque se trató de éxitos discretos y esporádicos. Entre estos, figuraron la transformación de células del oído medio en células receptoras auditivas (que fallan con la edad y desencadenan la sordera) o la transdiferenciación de linfocitos B (células que producen anticuerpos en la sangre) en macrófagos (células del sistema inmunológico que se localizan en los tejidos). Estos avances pueden considerarse discretos porque solo logran un proceso de transformación entre dos tipos celulares muy relacionados entre sí. La familiaridad de estos tipos de células queda de manifiesto en el hecho de que un solo regulador, maestro y general, logra promover estas transformaciones.
 
El campo de reprogramación celular comenzó a cambiar rápidamente en la década siguiente gracias a los estudios de Yamanaka y colaboradores (1), quienes descubrieron la sorprendente posibilidad de “inducir” células madre embrionarias (es decir, pluripotentes) a partir de células ya diferenciadas y adultas, como las células de la piel de un paciente. Increíblemente estos resultados se lograron usando solo cuatro reguladores, o factores de transcripción, como se les conoce técnicamente. El gran avance, al “desdiferenciar”, fue hacer que células de la piel se transformaran y derivaran hacia un estado embrionario inicial, con lo que ahora podrían “diferenciarse” nuevamente hacia otro linaje celular. Cómo se logró este avance es explicado en forma resumida en la siguiente sección.
 
CRUCIAL TRABAJO CON CÉLULAS PLURIPOTENTES INDUCIDAS
 
La posibilidad práctica de “cambiarle los planos” a una célula adulta terminalmente diferenciada, para transformarla en otro tipo de célula, es un desafío de profundo escrutinio científico en la actualidad. En forma esquemática y resumida: una célula puede ser vista como una gran biblioteca (2) con infinidad de planos (compuestos de genes) donde ciertos bibliotecarios —o factores de transcripción— deciden qué casas (proteínas) construir. Dependiendo de los planos que utilizan estos bibliotecarios —trabajando también como arquitectos, es decir, activando y desactivando variedad de genes—, se producirá uno u otro tipo de proteínas y se determinará qué célula resultará finalmente. Sin ir a los detalles, baste señalar que los factores de transcripción son proteínas que regulan la transcripción de genes. Al ser activados, se configura la expresión genética en el núcleo de la célula. Lo revolucionario del trabajo de Yamanaka fue demostrar cómo la introducción de solo cuatro factores de transcripción basta para activar los planos específicos y necesarios para transformar una célula adulta en otra muy similar a una célula madre embrionaria, denominada “célula pluripotente inducida”.
 
Recientemente, capitalizándose el éxito en el uso de varios factores de transcripción para transformar la célula, se ha logrado la inducción directa de una variedad de células adultas hacia otros tipos celulares, sin necesariamente “desdiferenciarlas” completamente hacia un estado embrionario (3). Solo dentro de los últimos meses, acortando el camino y haciéndola “saltar” hacia otro linaje celular, se han logrado grandes avances para evitar la larga y compleja ruta del regreso de una célula a un estado embrionario. Estos procesos están esquemáticamente resumidos en la figura que se presenta en esta página.
 
Hace poco, Leda y Srivastaba (4) lograron reprogramar células de la piel y transformarlas en cardiomiocitos, las células responsables de la palpitación del corazón. Utilizando un protocolo análogo al de Yamanaka, exploraron trabajosamente la combinación de innumerables factores de transcripción y llegaron a la conclusión de que la inclusión de tan solo tres de ellos —Gata4, Mef2c y Tbx5— eran suficientes para generar cardiomiocitos palpitantes a partir de fibroblastos de la piel. Exitosamente demostraron la posibilidad de transformar directamente células de la piel en cardiomiocitos, sin la necesidad de producir células madre embrionarias inducidas como intermediarias (5). La eficiencia de esta transformación fue también significativamente alta, pues más del 20% de las células tratadas se transformaron en cardiomiocitos (como comparación, es importante mencionar que la eficiencia para inducir células madre embrionarias inducidas es menor a 0,1%). Estos resultados traen como consecuencia innovadoras posibilidades para tratar enfermedades. Como ejemplo de los beneficios de estos trabajos, en la sección siguiente presentamos potenciales implicaciones en el tratamiento del corazón.
 
NUEVOS TRATAMIENTOS: EL CORAZÓN
 
El corazón está compuesto por tres tipos de células: los cardiomiocitos, es decir, las células capaces de contraerse espontáneamente; las células vasculares, que forman los vasos sanguíneos del corazón, y los fibroblastos cardíacos, o células que forman el tejido conectivo que constituye el “andamiaje” del corazón. Lo interesante es que más del 50% de las células que forman este órgano son fibroblastos, es decir, células que no contribuyen a las palpitaciones propias de ese órgano. El desarrollo impropio de los cardiomiocitos es una de las principales causas de las malformaciones congénitas del corazón. Por otro lado, es sabido que a consecuencia de un ataque cardíaco muchas de sus células (cardiomiocitos) mueren por falta de irrigación sanguínea, comprometiendo así la salud del paciente y su calidad de vida.
 
Desgraciadamente los cardiomiocitos tienen muy poca o nula capacidad de regeneración. Es aquí donde los resultados de Leda y Srivastaba abren la puerta hacia implicaciones terapéuticas importantes ya que en el futuro el órgano dañado, al ser tratado de esta manera (reprogramación directa de fibroblastos), podría reponer sus cardiomiocitos destruidos. Este nuevo procedimiento acarrea también potenciales ventajas frente a un tratamiento que emplee células madre embrionarias o embrionarias inducidas. Por ejemplo, al evitarse el paso hacia células pluripotentes inducidas, se elimina uno de los riesgos de este proceso, cual es la generación de posibles tumores al inyectar células pluripotentes residuales al paciente. Una segunda ventaja que mencionan los autores consiste en la posibilidad de introducir estos tres factores de transcripción directamente en el corazón del paciente, para de ese modo reprogramar —en el corazón mismo— la población endógena de fibroblastos hacia cardiomiocitos, contribuyendo entonces a la contractibilidad general del corazón.
 
Finalmente, a diferencia de otras alternativas celulares, se utilizarían células provenientes del mismo paciente, evitándose las complicaciones de un rechazo inmunológico. Además, en otro campo importante, se evade el conflicto ético al evitarse la destrucción de células madre embrionarias en el proceso.
 
Similares avances fueron publicados recientemente en un texto que da cuenta de la reprogramación de fibroblastos hacia neuronas (6). Esos resultados abren la posibilidad de tratar males como el Parkinson (donde neuronas dopaminérgicas paulatinamente son destruidas) o daños en el tejido nervioso de la columna vertebral que inhiben severamente —a veces en su totalidad— las posibilidades motoras del individuo. De igual forma, hace pocas semanas, se logró la reprogramación de fibroblastos hacia células progenitoras de la sangre (7). Este último resultado abre las puertas a nuevas terapias para combatir las enfermedades de la sangre.
 
MIRANDO HACIA EL FUTURO
 
La asombrosa velocidad de estos avances sugiere que los logros se expandirán hasta el punto en que podamos transformar cualquier tipo de célula humana, genéticamente manipulable, en otro tipo de célula de interés terapéutico (8). Sin embargo, también quedan importantes aspectos técnicos por resolver para que algún día estas tecnologías puedan ser utilizadas en pacientes. Desde el punto de vista clínico, deben desarrollarse estudios que demuestren que estas alternativas son seguras y eficaces. Desde el punto de vista científico, queda por resolver el mecanismo por el cual este cambio ocurre. Cómo y por qué esta des-diferenciación ocurre en forma natural en plantas (de una simple hoja transplantada, por ejemplo, se puede desarrollar nuevamente un árbol) y en algunos animales (como los platelmintos: de un fragmento de gusano o un pedazo de estrella de mar se puede producir nuevamente un organismo entero) y no en humanos, es un tema que necesita toda la atención del mundo científico.
 
(1) K. Takahashi, S. Yamanaka: “Induction of pluripotente stem cells from Mouse embryonic and adult fibroblast cultures by defined factors” (2006), Cell 126, julio 2006, pp. 663-676.
(2) C. Fierro, F. Fierro: “Un cambio sísmico en la terapia celular”. Revista Mensaje nº 569, junio 2008, p. 40.
(3) C.R. Nicholas, A. R. Kriegstein (2010): “Cell Reprogramming Gets Direct”, Nature 463, pp. 1031-1032.
(4) M. Ieda, J. Fu, P. Delgado-Olguín, V. Vedantham, Y. Hayashi, B. Bruneau, D. Srivastava (2010): “Direct Reprograming of Fibroblasts into Functional Cardiomiocytes by Defined Factors”, Cell 142, pp. 375-386.
(5) R. Passier, C. Mummery (2010) “Getting to the Heart of the Matter: Direct Reprogramming to Cardiomyocytes”, Stem Cell 7, pp. 140-141.
(6) Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Südhof TC, Wernig M. (2010): “Direct conversion of fibroblasts to functional neurons by defined factors”, Nature 463 (7284), pp. 1035-1041.
(7) Szabo E, Rampalli S, Risueño RM, Schnerch A, Mitchell R, Fiebig-Comyn A, Levadoux-Martin M, Bhatia M. (2010): “Direct conversion of human fibroblasts to multilineage blood progenitors”. Nature 468 (7323): pp. 521-526. Epub 2010, nov 7.
(8) D. Sareen, C. N Svendsen (2010): “Stem Cell Biologist play a Mean Pinball”. Nature Biotechnology 28, pp. 323-325.
____________
Cristián Fierro Correa. Doctor en Química / Fernando A. Fierro. Doctor en Biología Celular. Artículo publicado en revista Mensaje, www.mensaje.cl

 
Revista Mirada Global © Copyright 2009
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