Transition from Animal-Based to Human Induced Pluripotent Stem Cells (iPSCs)-Based Models of Neurodevelopmental Disorders: Opportunities and Challenges

Abstract

Neurodevelopmental disorders (NDDs) arise from the disruption of highly coordinated mechanisms underlying brain development, which results in impaired sensory, motor and/or cognitive functions. Although rodent models have offered very relevant insights to the field, the translation of findings to clinics, particularly regarding therapeutic approaches for these diseases, remains challenging. Part of the explanation for this failure may be the genetic differences—some targets not being conserved between species—and, most importantly, the differences in regulation of gene expression. This prompts the use of human-derived models to study NDDS. The generation of human induced pluripotent stem cells (hIPSCs) added a new suitable alternative to overcome species limitations, allowing for the study of human neuronal development while maintaining the genetic background of the donor patient. Several hIPSC models of NDDs already proved their worth by mimicking several pathological phenotypes found in humans. In this review, we highlight the utility of hIPSCs to pave new paths for NDD research and development of new therapeutic tools, summarize the challenges and advances of hIPSC-culture and neuronal differentiation protocols and discuss the best way to take advantage of these models, illustrating this with examples of success for some NDDs.

hPSC-Derived Astrocytes at the Forefront of Translational Applications in Neurological Disorders

“…The at-scale production of hPSC-derived cell types, either manually or via automated platforms, has facilitated the development of high-throughput cell-based assays and in vitro models of disease, providing a valuable tool for translational research in drug discovery and therapeutic development. Due to significant biological differences between species, these human cell-based models have the ability to more closely recapitulate in vivo human physiology when compared to existing animal models [ 121 ]. Moreover, the use of hPSC-derived cell types, including astrocytes, creates an opportunity to realize precision medicine where patient-derived cells can be utilized to develop personalized treatments specifically tailored to an individual’s genetic background ( Figure 3 A–D).…”

Investigating the reliability of the evoked response in human iPSCs-derived neuronal networks coupled to micro-electrode arrays

“…To our current understanding, MEAs have predominantly found application in investigations involving in vitro neuronal networks derived from rodent sources, particularly in cases of localized stimulation ( Massobrio et al , 2015 ). Nevertheless, the results obtained from the studies of rodents-derived in vitro models cannot be directly translated to human-derived networks, which are becoming a standard nowadays ( Lamas et al , 2023 ). Indeed, human-induced pluripotent stem cells (hiPSCs) reproducing structural and functional aspects of the human brain are giving the possibility to obtain networks with the same phenotype of the donor, thus allowing the development of subject-specific networks.…”