The Importance of Non-neuronal Cell Types in hiPSC-Based Disease Modeling and Drug Screening

Abstract

Current applications of human induced pluripotent stem cell (hiPSC) technologies in patient-specific models of neurodegenerative and neuropsychiatric disorders tend to focus on neuronal phenotypes. Here, we review recent efforts toward advancing hiPSCs toward non-neuronal cell types of the central nervous system (CNS) and highlight their potential use for the development of more complex in vitro models of neurodevelopment and disease. We present evidence from previous works in both rodents and humans of the importance of these cell types (oligodendrocytes, microglia, astrocytes) in neurological disease and highlight new hiPSC-based models that have sought to explore these relationships in vitro. Lastly, we summarize efforts toward conducting high-throughput screening experiments with hiPSCs and propose methods by which new screening platforms could be designed to better capture complex relationships between neural cell populations in health and disease.

Astrocyte alterations in neurodegenerative pathologies and their modeling in human induced pluripotent stem cell platforms

“…The iPSC-based models revealing a central role of astrocyte dysfunctions in pathogenesis of neurodegenerative diseases makes them attractive target for drug discovery. Due to complexity of pathophysiological mechanisms, pre-clinical models that adequately reflect this are indispensable for the development of novel pharmacological treatments [ 217 ]. Currently, a number of in vitro models clearly indicate a pivotal role of astrocytes modulating neuronal responses, including their ability to survive environmental stress.…”

The involvement of astrocytes in early‐life adversity induced programming of the brain

“…BOX 2 Human-based iPSC models to study astrocytes in the context of ELA Many studies in recent years proved the power of iPSC technology. IPSC-based models identified a number of cellautonomous deficits underlying SCZ including astrocyte involvement (Gonzalez, Gregory, & Brennand, 2017;Windrem et al, 2017). Taking into account recent GWAS studies for MDD, iPSC-based studies for MDD will soon follow.…”

An Epilepsy-Associated KCNT1 Mutation Enhances Excitability of Human iPSC-Derived Neurons by Increasing Slack KNa Currents

“…hiPSCs surpass heterologous systems because regular, adjunct biology is conserved (Liu et al, 2013;LaMarca et al, 2018). In a wide variety of neurological disorders, hiPSCs have not only advanced understanding of disease mechanisms, but have also provided a more relevant avenue for drug screening (Tidball and Parent, 2016;Csobonyeiova et al, 2017;Gonzalez et al, 2017;Balan et al, 2018).…”