Abstract
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.
Highlights
Traumatic brain injury (TBI) is a head injury caused by a blow, bump, or jolt to the head or body or a penetrating head injury, associated with accidents, contact sports, and military duties that result in disruption of normal brain structure and function [1,2,3]
We found that when cerebral organoids (COs) were generated from IPSCs derived from patients affected by inherited Alzheimer’s disease (AD), the organoids developed over time the main pathological features of AD: Aβ amyloid plaques, Tau neurofibrillary tangles, and neurodegeneration [30]
We have evaluated the mechanical responses of the brain and the different mixtures with two dynamic scenarios
Summary
Traumatic brain injury (TBI) is a head injury caused by a blow, bump, or jolt to the head or body or a penetrating head injury, associated with accidents, contact sports, and military duties that result in disruption of normal brain structure and function [1,2,3]. Stretch and shear-based in vitro culture systems have been developed to model TBI in neurons derived from human induced pluripotent stem cells (iPSCs) [15,16,17] These in vitro platforms do not have the three-dimensional organization and complexity of the brain, nor the adequate extracellular matrix necessary to model the biophysical interactions after the mechanical damage. CCI allows control of relevant parameters related to the impact, such as contact velocity, dwelling time, and depth, to modulate the severity of damage [33] Using this optimized model, we report that COs can recapitulate the primary pathology of TBI, including metabolic changes after neuronal damage, neuronal loss, and astrogliosis
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