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Using organoids to evaluate safety and potency of cell therapies

B Fernandez-Muñoz(1,2) A B Garcia-Delgado(1,2,3) C Casado(1,2) R Campos-Cuerva(1,2,4) C Rosell-Valle(1,2) M Martin-Lopez(1,2,4) R Aguilar-Quesada(5) P Catalina(5) M Rivero-Garvia(4,6) J Marquez-Rivas(4,6) R Sanchez-Pernaute(2)

1:Unidad de Producción y Reprogramación Celular (UPRC), Sevilla, Spain; 2:Red Andaluza de Diseño y Traslación de Terapias Avanzadas (RADyTTA), Sevilla, Spain; 3:Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain; 4:IBiS, Instituto de Biomedicina de Sevilla, Sevilla, Spain; 5:Biobanco del Sistema Sanitario Público de Andalucía, Granada, Spain; 6:Departamento de Neurocirugía, Hospital Virgen del Rocío, Sevilla, Spain

Animal models currently used to test the efficacy and safety of cell therapies, mainly murine models, have important limitations as the underlying molecular and cellular mechanisms are often inherently different in humans, especially in the brain. Therefore, for translation to the clinic, the development of more complex and predictive models based on human cells may be crucial. Here, we have developed an in vitro model based on human forebrain organoids to study the differentiation potential of neural stem cells (NSC) and their safety and efficacy profiles as cell therapeutics. We generated brain organoids from iPSC lines and identified the formation of different cerebral tissues and cell types at different time points by the expression of typical markers from ventricular zone, ependyma, choroid plexus, cerebral cortex, microglia, oligodendrocyte precursors, astrocytes and neurons. After 4 months of culture, we transplanted different NSC lines transduced with EGFP into organoids. Live imaging of NSC-EGFP injected into organoids showed that cells integrated and migrated within the human tissue. We studied the differentiation potential, comparing these data with transplantation studies in the brain of NOD-SCID-γ mice. We found that NSC differentiate mostly into neuron and oligodendrocyte precursors both in mice and human organoid models although the number of neuroblasts were higher in mice models. Our results suggest that brain organoids can be used in the evaluation of cell therapies, complementing the information obtained from animal models and increasing the predictability for future treatments, since it is a human model.

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