Brain Organoids: A New, Transformative Investigational Tool for Neuroscience Research

Abstract

Brain organoids are self‐assembled, three‐dimensionally structured tissues that are typically derived from pluripotent stem cells. They are multicellular aggregates that more accurately recapitulate the tissue microenvironment compared to the other cell culture systems and can also reproduce organ function. They are promising models for evaluating drug leads, particularly those that target neurodegeneration, since they are genetically and phenotypically stable over prolonged durations of culturing and they reasonably reproduce critical physiological phenomena such as biochemical gradients and responses by the native tissue to stimuli. Beyond drug discovery, the use of brain organoids could also be extended to investigating early brain development and identifying the mechanisms that elicit neurodegeneration. Herein, the current state of the fabrication and use of brain organoids in drug development and medical research is summarized. Although the use of brain organoids represents a quantum leap over existing investigational tools used by the pharmaceutical industry, they are nonetheless imperfect systems that could be greatly improved through bioengineering. To this end, some key scientific challenges that would need to be addressed in order to enhance the relevance of brain organoids as model tissue are listed. Potential solutions to these challenges, including the use of bioprinting, are highlighted thereafter.

Organoid Technology: A Reliable Developmental Biology Tool for Organ-Specific Nanotoxicity Evaluation

“…Various organoids have been developed to mimic either whole-brain or sub-brain regions such as the hypothalamus, adenohypophysis, forebrain, midbrain, cerebral cortex, cerebellum, and hippocampus or even neural organoids ( Suga et al, 2011 ; Lancaster et al, 2013 ; Muguruma et al, 2015 ; Sakaguchi et al, 2015 ; Jo et al, 2016 ; Qian et al, 2016 , 2018 ; Quadrato et al, 2017 ; Zhu et al, 2017 ; Mansour et al, 2018 ; Paşca, 2018 ; Xu et al, 2018a ; Andrews and Nowakowski, 2019 ; Cakir et al, 2019 ; Marton and Paşca, 2019 ; Nascimento et al, 2019 ; Chen et al, 2020 ). The organoids have also facilitated the evaluation of efficacy and toxicity of the drugs having implications over the neuromuscular system ( Vaez Ghaemi et al, 2018 ; Marx, 2020 ; Matsui et al, 2020 ; Shou et al, 2020 ). The human PSC-derived cerebral organoid has been successfully used as a model to study the Zika virus-induced teratogenic effects on the developing brain and the therapeutic effects of the potential candidates which can alleviate those ( Watanabe et al, 2017 ).…”

Improving the Rate of Translation of Tissue Engineering Products

“…Moreover, organoids also offer more mechanical, chemical, and physical control to the experimentalist over competing platforms such as explanted tissues, and can be combined with chip‐based, microfluidic systems to probe a greater range of biochemical and physiological phenomena . Notably, organoids can be employed to systematically probe the symphony of signaling cascades, and the analysis of these data using systems biology to chart the molecular landscape of disease could greatly improve the future productivity of drug discovery and development .…”

“…Numerous technical questions remain to be answered ( Figure ), the foremost of which are effectively inducing vascularization in the engineered tissues, modulating the immune response, and establishing a reliable source of cells by possibly generating universal donor cell lines . Significant methodological advances also need to occur in order to ensure that the engineered tissues faithfully recapitulate the in vivo tissue microenvironment and exhibit appropriate mechanical properties . The community also needs to minimize the gap between current understanding of tissue remodeling and cellular behavior in vivo and how this knowledge is applied to improve the performance and reliability of TE products.…”

The Mechanical Properties of Neurospheres

“…This architectural feature of spheroids makes them particularly insightful models for investigating the mechanisms of tissue formation and responses to physiological and mechanical cues. [ 18–20 ] Importantly, the state‐of‐the‐art for differentiation and maturation of neuronal spheroids or neurospheres from neural progenitor cells (NPCs) is quite advanced. [ 13,21 ] In fact, neurospheres have also been shown to generate neurons and glial cells when they are cultured in specific differentiation media, which make them excellent models for studying differentiation, development, and neurotoxicological mechanisms.…”