Human Neural Organoids for Studying Brain Cancer and Neurodegenerative Diseases

Abstract

The lack of relevant in vitro neural models is an important obstacle on medical progress for neuropathologies. Establishment of relevant cellular models is crucial both to better understand the pathological mechanisms of these diseases and identify new therapeutic targets and strategies. To be pertinent, an in vitro model must reproduce the pathological features of a human disease. However, in the context of neurodegenerative disease, a relevant in vitro model should provide neural cell replacement as a valuable therapeutic opportunity. Such a model would not only allow screening of therapeutic molecules but also can be used to optimize neural protocol differentiation [for example, in the context of transplantation in Parkinson's disease (PD)]. This study describes two in vitro protocols of 1) human glioblastoma development within a human neural organoids (NO) and 2) neuron dopaminergic (DA) differentiation generating a three-dimensional (3D) organoid. For this purpose, a well-standardized protocol was established that allows the production of size-calibrated neurospheres derived from human embryonic stem cell (hESC) differentiation. The first model can be used to reveal molecular and cellular events occurring during in glioblastoma development within the neural organoid, while the DA organoid not only represents a suitable source of DA neurons for cell therapy in Parkinson's disease but also can be used for drug testing.

Practical Review on Preclinical Human 3D Glioblastoma Models: Advances and Challenges for Clinical Translation

“…Most of the 3D models discussed above have been implemented with cells of the microenvironment to generate co-cultures able to overcome the 3D model’s limitations. Co-cultures of spheroids, tumorospheres, organotypic slices and GBM-derived from cerebral organoids have been used to study the relationships between tumor cells and immune or endothelial cells, neurons, astrocytes, microglia, and macrophages [ 25 , 27 , 32 , 33 , 110 , 111 , 112 , 113 , 114 ]. Furthermore, thanks to 3D bioprinting, forms and physical constraints can be applied to biomaterials, which will improve co-cultures experiments.…”

A combined RNA-seq and whole genome sequencing approach for identification of non-coding pathogenic variants in single families

“…Our approach is applicable to any inherited disease, both WGS and RNA-seq techniques are commercially available, gold standards are being established and the analysis tools are readily accessible 47,48,82,[49][50][51][52][53][54][55]81 . Ex vivo organoid models are being developed for a multitude of tissues including brain 83,84 , kidney 85 , liver 86,87 and lung 88 .…”

A combined RNA-seq and whole genome sequencing approach for identification of non-coding pathogenic variants in single families

“…Our approach is applicable to any inherited disease, both WGS and RNA-seq techniques are commercially available, gold standards are being established and the analysis tools are readily accessible 47, 48, 49–55, 81, 82 . Ex vivo organoid models are being developed for a multitude of tissues including brain 83, 84 , kidney 85 , liver 86, 87 and lung 88 .…”