Abstract
The complex development of the human nervous system has been traditionally studied using a combination of animal models, human post-mortem brain tissue, and human genetics studies. However, there has been a lack of experimental human cellular models that would allow for a more precise elucidation of the intricate dynamics of early human brain development. The development of stem cell technologies, both embryonic and induced pluripotent stem cells (iPSCs), has given neuroscientists access to the previously inaccessible early stages of human brain development. In particular, the recent development of three-dimensional culturing methodologies provides a platform to study the differentiation of stem cells in both normal development and disease states in a more in vivo like context. Three-dimensional neural models or cerebral organoids possess an innate advantage over two-dimensional neural cultures as they can recapitulate tissue organization and cell type diversity that resemble the developing brain. Brain organoids also provide the exciting opportunity to model the integration of different brain regions in vitro. Furthermore, recent advances in the differentiation of non-neuronal tissue from stem cells provides the opportunity to study the interaction between the developing nervous system and other non-neuronal systems that impact neuronal function. In this review, we discuss the potential and limitations of the organoid system to study in vitro neurological diseases that arise in the neuroendocrine and the enteric nervous system or from interactions with the immune system.
Highlights
The formation of the complex nervous system is a fascinating and crucial series of events that occurs during human development
The development of 3D stem cell derived neural model systems has revolutionized how we study the development of the cerebral cortex (Quadrato and Arlotta, 2017; Pasca, 2018b). 3D neural models or brain organoids resemble the multicellular and three-dimensional nature of the structures present in the CNS and can replicate the early stages of brain development (Lancaster et al, 2013; Lancaster and Knoblich, 2014a; Quadrato et al, 2017; Renner et al, 2017)
Subsequent transplantation of rat sarcoma tissue into mouse skin, muscle, and brain parenchyma showed that shortly after transplantations only the rat tissue transplanted into the CNS was protected from immunological attack (Shirai, 1921). These results suggested that the brain and spinal cord are in a state of immunological privilege and are devoid of infectious pathogens present in blood and lymph due to the presence of a blood-brain-barrier (BBB)
Summary
The formation of the complex nervous system is a fascinating and crucial series of events that occurs during human development. Recent work from Song et al (2019) demonstrated that the fusion of cortical neuronal progenitor spheroids with endothelial spheroids and mesenchymal stem cells lead to the formation of a hybrid neurovascular organoid that develops a structure akin to a rudimentary BBB that expressed markers for tight junctions, like ZO1, which are hallmarks of endothelial barrier tissue While these models allow us to study the role of the neurovasculature in development and disease they are still at their infancy and further research is needed to identify the specific cell types within the BBB necessary for viral entry and the cognate receptors necessary for proinflammatory cytokine entry into the developing fetal CNS. The ENS is the largest sensory organ in the body and is formed by a network of neural cells resident in the GI tract
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