Reaching into the toolbox: Stem cell models to study neuropsychiatric disorders

Abstract

Recent advances in genetics, molecular biology, and stem cell biology have accelerated our understanding of neuropsychiatric disorders, like autism spectrum disorder (ASD), major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ). This progress highlights the incredible complexity of both the human brain and mental illnesses from the biochemical to the cellular level. Contributing to the complexity of neuropsychiatric disorders are their polygenic nature, cellular and brain region interconnectivity, and dysregulation of human-specific neurodevelopmental processes. Here, we discuss available tools, including CRISPR-Cas9, and the applications of these tools to develop cellbased two-dimensional (2D) models and 3D brain organoid models that better represent and unravel the intricacies of neuropsychiatric disorder pathophysiology.

Analysis of Gene-Environment Interactions Related to Developmental Disorders

“…Advances in genome editing technologies have enabled us to edit any gene of interest in various experimental models, including zebrafish and induced pluripotent stem (iPS) cells generated from human samples ( Adachi et al, 2022 ; Whiteley et al, 2022 ). Public databases focusing on genes, biological samples, and chemicals related to various diseases including DDs, have been expanding ( Al-Jawahiri and Milne, 2017 ; Reilly et al, 2017 ; Lombardo et al, 2019 ; Davis et al, 2021 ).…”

Cognitive impairment in psychiatric diseases: Biomarkers of diagnosis, treatment, and prevention

“…Reprogrammed iPSCs from patient-derived somatic cells contribute significantly to recapitulating the development of neuronal cells with disease-specific genetic backgrounds ( Soliman et al, 2017 ). Modeling techniques for inducing disease in iPSCs, including directed differentiation of neuronal subtypes, glial cells, and 3D brain organoid models, are handy for modeling how complex genetic variation leads to disease pathogenesis ( Wang et al, 2020 ; Whiteley et al, 2022 ). The researchers directly reprogrammed human induced pluripotent stem cells iPSCs from SCZ patients, and then differentiated these disease-specific iPSCs into neurons.…”

“…These concerns make the clinical application of stem cells limited by safety and ethical issues. Even more exciting for us, with innovations in stem cell disease modeling methods, and precise disease-specific therapeutic doses, regimens, and pathways, new technologies pave the way for future personalized medicine research on stem cells and more effective drug discovery processes in cognitive disorders ( Whiteley et al, 2022 ).…”

Advantages of CRISPR-Cas9 combined organoid model in the study of congenital nervous system malformations

“…There are 12 genes related to microcephaly, most of which encode centrosome proteins, which play an essential role in mitosis (Faheem et al, 2015). Among these genes, CDK5RAP2 regulates centriole replication, and the deletion of CDK5RAP2 has been shown to affect the proliferation of neural precursor cells, mainly by delaying chromosome segregation and chromosome instability (Gonzalez-Martinez et al, 2021,2022. However, mice with CDK5RAP2 mutation did not show severe brain volume reduction in human patients (Gonzalez-Martinez et al, 2021).…”