From Neuronal Differentiation of iPSCs to 3D Neural Organoids: Modeling of Neurodegenerative Diseases

Abstract

In the last decade, the finding that somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) leads to a great improvement of research involving the use of differentiated stem cells as model of diseases. In the field of neurodegeneration, iPSC technology allowed to culture in vitro all the types of patient-specific neurons, not only helping the discovery of diseases' etiopathology but also testing new drugs with a personalized medicine approach. Moreover, iPSCs can be combined with the 3D bioprinting technology, allowing physiological cell-to-cell interactions, given by a combination of several biomaterials, scaffolds, and cells. This technology combines bioplotter and biomaterials which can encapsulate several types of cells, e.g., iPSCs or differentiated neurons, to develop an innovative cellular model. iPSCs and 3D cell cultures' technologies represent the first step to obtain a more reliable model, like an organoid to facilitate neurodegenerative diseases' investigation.

From Neuronal Differentiation of iPSCs to 3D Neuro-Organoids: Modelling and Therapy of Neurodegenerative Diseases

“…In the last few years, advances have been made to move on from a 2D to a 3D approach in order to gain further insights into the cytoarchitecture of the brain and into the disease mechanisms that may take place in the central nervous system. Both methods present with advantages and disadvantages: while 2D models with directed monolayer differentiation may provide an easier substrate for imaging assays and morphological studies such as dendrite complexity, 3D cultures can result in a large diversity of cell types and allow the study of cell-cell interactions between different populations [45,46]. 3D human brain cultures are usually obtained with the differentiation of iPSCs into either neural cell aggregates or into more complex brain organoids.…”

Three-Dimensional Human Neural Stem Cell Models to Mimic Heparan Sulfate Proteoglycans and the Neural Niche

“…Pioneered by Takahashi and Yamanaka 36 in 2006, the discovery of highly expressed transcription factors OCT3/4, c-MYC, KLF4 and Sox2, allowed mouse fibroblasts to be induced to become pluripotent via retrovirus-mediated transduction. 37,38 This technique has been further refined, and it is now routine to reprogram somatic cells using viral and nonviral constructs. This allows for less invasive and potentially negates the need for harvesting of stem cells including the opportunity to develop disease derived iPSCs as potential autologous treatments.…”

“…2B). 32,37,40,43,49,[51][52][53] The highly customizable nature of hydrogels allows researchers to examine many different aspects of the neural microenvironment, as well as develop disease-based models, to study cellular interactions specific to pathologies in 3D. As an example, a recent study conducted by Papadimitriou et al utilized star-shaped poly (ethylene glycol; starPEG) GAG heparin semisynthetic hydrogels to develop a neural ECM microenvironment to study neural plasticity in an model of Alzheimer's disease (AD).…”

From Zero to Neuro-Reprogramming: Innovations in Translational Neuroregenerative Medicine

“…Since iNSCs can be directed to a specific developmental lineage from embryonic to adult, appropriate models for neurodevelopment and neurogenesis can be generated (Figure 2) (2,29,30). Furthermore, patient-derived iNSCs can be generated which recapitulate characteristic hallmarks of the associated disease including amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's, Parkinson's, and Huntington's disease (30)(31)(32)(33)(34)(35)(36). For example, iNSC-derived neurons from Alzheimer's patients display the typical pathological features in vitro including elevated amyloid beta plaques and phosphorylated tau proteins (2,32).…”

“…Similarly, neurons derived from Parkinson's patients posses higher than normal levels of both oxidative stress and alpha-synuclein impairing neuronal survival and function (37,38). Subsequent interventions using molecular or genetic techniques can then be applied to rescue pathological phenotypes in patient cells or induced in control cells which do not bear the original disease phenotype (2,30,31,39,40). Therefore, iNSCs represent a new platform for which studies can be designed to better understand human specific disease mechanisms and facilitate the development of therapeutic targets.…”