Human Embryonic Stem Cell-derived Cerebral Organoids for Treatment of Mild Traumatic Brain Injury in a Mouse Model

Abstract:Objective: There are no effective treatments for relieving neuronal dysfunction after mild traumatic brain injury (TBI). Here, we evaluated therapeutic efficacy of human embryonic stem cell-derived cerebral organoids (hCOs) in a mild TBI model, in terms of repair of damaged cortical regions, neurogenesis, and improved cognitive function. Methods: Male C57BL/6J mice were randomly divided into sham-operated, mild TBI, and mild TBI with hCO groups. hCOs cultured at 8 weeks were used for transplantation. Mice were sacrificed at 7 and 14 days after transplantation followed by immunofluorescence staining, cytokine profile microarray, and novel object recognition test.Results: 8W-hCOstransplantation significantly reduced neuronal cell death, recovered microvessel density, and promoted neurogenesis in the ipsilateral subventricular zone and dentate gyrus of hippocampus after mild TBI. In addition, increased angiogenesis into the engrafted hCOs was observed. Microarray results of hCOs revealed neuronal differentiation potential and higher expression of early brain development proteins associated with neurogenesis, angiogenesis and extracellular matrix remodeling. Ultimately, 8W-hCOtransplantation resulted in reconstruction of damaged cortex and improvement in cognitive function after mild TBI. Conclusion: hCO transplantation may be feasible for treating mild TBI-related neuronal dysfunction via reconstruction of damaged cortex and neurogenesis in the hippocampus.