<EM>IN VIVO</EM> ORGANOIDS AS A NEW MODEL FOR TRAUMATIC BRAIN INJURY

Traumatic brain injury is a major cause of death and disability in adults, yet available treatment options to improve prognosis after trauma are limited. Pre-clinical research in this field is mostly based on animal models of brain injury, but experimental results often fail to translate to human. Consequently, clinical trials of candidate treatments have had a high failure rate. Cerebral organoids are extremely useful as models of human pathologies but have intrinsic limitations that hinder their use in trauma research. In recent years, organoid transplantation in rodents has emerged as a promising tool to study human cerebral tissue in a complex living system. Exploiting our experience in organoid development and animal models of trauma, we aim to establish organoid transplantation as a model to study traumatic brain injury.
In our protocol, forebrain organoids are grown in vitro for 49-60 days, after which they are transplanted in the motor cortex of pharmacologically immunosuppressed rats. The organoid cells continue to differentiate in vivo and integrate with the host tissue; neuronal and synaptic markers can be detected throughout the human tissue. Approximately 11 weeks after transplantation, the animals are subjected to a penetrating traumatic brain injury; the focus of the injury is positioned in the proximity of the transplant site. Animals are sacrificed at different time points after surgery and the injury response in the transplanted organoids is studied at histological and transcriptional level. Our results will potentially individuate novel pathways of interest for targeted treatment.