Modeling Traumatic Brain Injury in Human Cerebral Organoids.
Santiago Ramirez, Abhisek Mukherjee, Sofia Sepulveda, Andrea Becerra-Calixto, Nicolas Bravo-Vasquez, Camila Gherardelli, Melissa Chavez, Claudio Soto
Author Information
Santiago Ramirez: Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, University of Texas Health Science at Houston, Houston, TX 77030, USA. ORCID
Abhisek Mukherjee: Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, University of Texas Health Science at Houston, Houston, TX 77030, USA.
Sofia Sepulveda: Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, University of Texas Health Science at Houston, Houston, TX 77030, USA.
Andrea Becerra-Calixto: Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, University of Texas Health Science at Houston, Houston, TX 77030, USA.
Nicolas Bravo-Vasquez: Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, University of Texas Health Science at Houston, Houston, TX 77030, USA. ORCID
Camila Gherardelli: Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, University of Texas Health Science at Houston, Houston, TX 77030, USA.
Melissa Chavez: Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, University of Texas Health Science at Houston, Houston, TX 77030, USA.
Claudio Soto: Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, University of Texas Health Science at Houston, Houston, TX 77030, USA.
Traumatic brain injury (TBI) is a head injury that disrupts the normal brain structure and function. TBI has been extensively studied using various in vitro and in vivo models. Most of the studies have been done with rodent models, which may respond differently to TBI than human nerve cells. Taking advantage of the recent development of cerebral organoids (COs) derived from human induced pluripotent stem cells (iPSCs), which resemble the architecture of specific human brain regions, here, we adapted the controlled cortical impact (CCI) model to induce TBI in human COs as a novel in vitro platform. To adapt the CCI procedure into COs, we have developed a phantom brain matrix, matching the mechanical characteristics of the brain, altogether with an empty mouse skull as a platform to allow the use of the stereotactic CCI equipment on COs. After the CCI procedure, COs were histologically prepared to evaluate neurons and astrocyte populations using the microtubule-associated protein 2 (MAP2) and the glial fibrillary acidic protein (GFAP). Moreover, a marker of metabolic response, the neuron-specific enolase (NSE), and cellular death using cleaved caspase 3 were also analyzed. Our results show that human COs recapitulate the primary pathological changes of TBI, including metabolic alterations related to neuronal damage, neuronal loss, and astrogliosis. This novel approach using human COs to model TBI in vitro holds great potential and opens new alternatives for understanding brain abnormalities produced by TBI, and for the development and testing of new therapeutic approaches.
