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El ictus es una de las principales causas de discapacidad (incluida la paralisis) y deterioro cognitivo en adultos, y la segunda causa de defuncion a nivel mundial, detras de la cardiopatia isquemica. Se estima que un 25-53 % de los pacientes con ictus presentan, durante al menos 6 meses despues del accidente cerebrovascular, dependencia para la realizacion de al menos una tarea cotidiana, ocasionando incalculables costes personales, familiares y sociales. En la actualidad, no existen terapias eficaces que reparen el tejido cerebral danado y promuevan un grado satisfactorio de recuperacion funcional en los pacientes. Entre los diferentes enfoques experimentales examinados en las ultimas decadas, la terapia celular se ha configurado como una opcion viable para restaurar las areas danadas del cerebro; con la formacion de nuevo tejido cerebral derivado de las celulas exogenas trasplantadas o/y mediante la estimulacion de los mecanismos endogenos de reparacion cerebral. La relevancia de este enfoque se ha visto incrementada en la ultima decada, con una expansion progresiva del numero de ensayos clinicos realizados en pacientes con dano cerebral a los que se han realizado implantes de diversas poblaciones celulares por via sistemica e intra-cerebral. El trasplante combinado de celulas terapeuticas y distintos biomateriales para incrementar la viabilidad de los injertos celulares, constituye una estrategia prometedora en plena fase de expansion. Debido a la peculiar estructura fisico-quimica, asi como a los modulos de rigidez cercanos a los tejidos blandos como el cerebro, los hidrogeles se presentan como un grupo muy versatil e interesante de andamios estructurales para la encapsulacion celular y la reconstruccion cerebral. En el presente trabajo, mostramos un novedoso enfoque terapeutico basado en el implante combinado de celulas madre mesenquimales e hidrogeles de fibroina de la seda como soporte para el tratamiento del accidente cerebrovascular. Por un lado, se ha demostrado la inocuidad y tolerabilidad de este biomaterial con el tejido cerebral y su funcionalidad, asi como su capacidad para favorecer el injerto celular tras el implante cerebral. Por otro lado, en un modelo experimental de accidente cerebrovascular en el raton, se ha demostrado que esta estrategia favorece la neuroproteccion y la remodelacion funcional entre diferentes representaciones corticales, siendo este ultimo mecanismo, sustrato para la neuro-restauracion y la recuperacion funcional post-ictus. ABSTRACT Stroke is a leading cause of adult disability (including paralysis) and cognitive impairment and the second-leading global cause of death behind ischemic heart disease. It is estimated that 25-53% of patients remain dependent for at least one daily task up to 6 months after stroke, globally producing incalculable personal, family and social costs. Currently there are not therapies available to repair the damaged brain tissue and promote a satisfactory degree of functional recovery in patients. In recent decades, a considerable progress has been made in the development of experimental therapies to treat brain disorders. Among the different experimental approaches examined in the last decades, cell therapy has been configured as a viable option for restoring damaged brain areas with new cerebral tissue derived from exogenous implanted cells as well as for stimulating endogenous brain repair mechanisms. The relevance of this approach has been seen in later years, with a progressive expansion of clinical trials that have included patients with cerebral damage transplanted with different cell populations through systemic or intracerebral routes. The combined implantation of cells and different biomaterials to increase the viability of cellular grafts constitutes a very promising strategy in phase of full expansion. Due to its special chemical and physical structure with stiffness modules in the range of soft tissues like the brain, hydrogels appear a versatile and interesting group of architectonic elements for cell encapsulation and brain reconstruction. In this study, we show a novel therapeutic approach based on the combined implantation of mesenchymal stem cells and silk fibroin-based hydrogels as a support for brain stroke treatment. Firstly, we have demonstrated the innocuousness and tolerability of this biomaterial with brain tissue and function as well as its ability to favor cellular engraftment after brain implantation. Secondly, in an experimental stroke model in mice we have shown that this strategy favors neuroprotection and functional remodeling between cortical representations, being this latter, substrate for post-stroke neuro-restoration and functional recovery.

Terapia Celular Asistida por Hidrogeles de Fibroína en un Modelo Experimental de Ictus Cerebral