Modeling the Human Brain With ex vivo Slices and in vitro Organoids for Translational Neuroscience

Advances in translational neuroscience require experimental models recapitulating the complexity of the human brain. In contrast to conventional 2D cell culture models and animal models, 3D cultures have emerged as auspicious models to recapitulate the human brain structure and function in the laboratory setting (Jorfi et al., 2018). Human-derived 3D brain cultures are likely to recapitulate important human brain features in health and disease better than rodent brains (Humpel, 2015; Paşca, 2018), thus offering an optimal platform to examine pathophysiological mechanisms of diseases and demonstrate proof-of-concept evidence of the efficacy of new discoveries or treatments. As such, human-derived 3D cultures are perfectly positioned to play a critical role in experimental medicine.

Human brain tissue can be obtained from biopsies or through reprogramming technologies, including induced pluripotent stem cells. Recent advances in lab-made brain organoid technologies offer exciting opportunities for learning about neurological and psychiatric disease mechanisms (Quadrato et al., 2016). In addition, access to live brain tissue from patients, with minimal ethical concern, expand prospects for pre-clinical validation of therapeutics using human brain slice cultures (Martinez et al., 2011; Jones et al., 2016; Parker et al., 2017; Horowitz et al., 2020; Almeida et al., 2021). Despite these exciting advances, important drawbacks still limit the use of human-derived organoids and slice cultures. Brain organoids remain artificial and would benefit from more rigorous comparison with human brain tissue directly obtained from biopsies. In this article, we identify limitations and highlight opportunities for expanding the potential contribution of cutting-edge brain organoid technologies and more classical organotypic slices of adult human brain biopsies for translational neuroscience.