The 3D human neural model developed by Hogberg et al. However, the inability of these 2D models to recapitulate in vivo-like cytoarchitectural organization and synaptic connections of the brain has impeded their use in precise disease modeling or drug screening applications.Ī variety of protocols are available for differentiating hPSCs into 3D neural cell aggregates. have developed a 2D neural culture system for producing connections between neurons from two distinct brain regions, the neocortex and midbrain. Notably, the glutamatergic projection neurons were generated in a temporally sensitive manner mimicking in vivo neocortical development, with deep-layer CTIP2 + neurons appearing first, followed by generation of upper-layer SATB2 + neurons. were able to mimic neocortical development in 2D culture conditions to generate both glutamatergic and GABAergic cortical neurons on radial glial scaffolding by employing neocortical trophic factors FGF18, BDNF, and NT3. Through specialized differentiation protocols, these 2D culture models have the ability to produce specified and highly homogeneous cell populations, such as excitatory and inhibitory cortical neurons, midbrain dopaminergic neurons, and motor neurons. In this review, we summarize the current state of using hPSC-derived in vitro 3D models of brain development and neurodegenerative disorders and discuss the advantages and challenges of employing 3D human brain models for drug screening and investigating mechanisms behind these neurological disorders.ĢD neural tube-like rosettes, made up of neural progenitors organized radially around ventricle-like cavities, have previously been generated from hPSCs to study neuronal development. However, the potential of hiPSCs to recapitulate complex human brain disorders remains incompletely exploited. Recent progress in iPSC technology has provided a remarkable alternative for the study of human brain diseases through the scalable, manipulatable production of human neural cells derived directly from patients with diverse neurological diseases. Although the human brain is the ideal model to study human neuropathology, the limited availability of healthy and diseased brain tissue as well as the difficulties with culturing or genetically manipulating the tissue makes this an inopportune model with which to easily elucidate molecular mechanisms underlying these disorders.
Many of them, including autism spectrum disorder (ASD), schizophrenia, Alzheimer’s disease (AD), and Parkinson’s disease (PD), are caused by a heterogeneous combination of variant alleles and have therefore proven difficult to recapitulate in animal models, which are better suited for studying single-gene mutations. In recent years, genomic studies of individuals with developmental or neurodegenerative diseases have tremendously advanced our understanding of the genetics of these disorders.
This review describes the history and current state of 3D brain organoid differentiation strategies, a survey of applications of organoids towards studies of neurodevelopmental and neurodegenerative disorders, and the challenges associated with their use as in vitro models of neurological disorders. Finally, the addition of CRISPR/Cas9 genome editing provides incredible potential for personalized cell replacement therapy with genetically corrected hiPSCs.
Furthermore, the combination of hiPSC technology and small-molecule high-throughput screening (HTS) facilitates the development of novel pharmacotherapeutic strategies, while transcriptome sequencing enables the transcriptional profiling of patient-derived brain organoids. Studies using patient-derived brain organoids have already revealed novel insights into molecular and genetic mechanisms of certain complex human neurological disorders such as microcephaly, autism, and Alzheimer’s disease. Human iPSC (hiPSC) reprogramming methods, combined with 3D brain organoid tools, may allow patient-derived organoids to serve as a preclinical platform to bridge the translational gap between animal models and human clinical trials. Three-dimensional (3D) brain organoids derived from human pluripotent stem cells (hPSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), appear to recapitulate the brain’s 3D cytoarchitectural arrangement and provide new opportunities to explore disease pathogenesis in the human brain.
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