hiPSCs for predictive modelling of neurodegenerative diseases: dreaming the possible

Abstract

Human induced pluripotent stem cells (hiPSCs) were first generated in 2007, but the full translational potential of this valuable tool has yet to be realized. The potential applications of hiPSCs are especially relevant to neurology, as brain cells from patients are rarely available for research. hiPSCs from individuals with neuropsychiatric or neurodegenerative diseases have facilitated biological and multi-omics studies as well as large-scale screening of chemical libraries. However, researchers are struggling to improve the scalability, reproducibility and quality of this descriptive disease modelling. Addressing these limitations will be the first step towards a new era in hiPSC research — that of predictive disease modelling — involving the correlation and integration of in vitro experimental data with longitudinal clinical data. This approach is a key element of the emerging precision medicine paradigm, in which hiPSCs could become a powerful diagnostic and prognostic tool. Here, we consider the steps necessary to achieve predictive modelling of neurodegenerative disease with hiPSCs, using Huntington disease as an example.

Proteomic Alterations and Novel Markers of Neurotoxic Reactive Astrocytes in Human Induced Pluripotent Stem Cell Models

“…Human iPSC modeling has quickly become a critical complementary tool to animal models for understanding complex CNS disorders ( Preman et al, 2021 ; Rivetti di Val Cervo et al, 2021 ). Efficient protocols to generate the main CNS cell types (neurons, microglia, astrocytes, oligodendrocytes, etc.)…”

Perspectives on Mechanisms Supporting Neuronal Polarity From Small Animals to Humans

“…Moreover, the implementation of 3D culture brain organoids from patient-derived hiPSC will unravel the complexity and pathophysiological relevance of cell–cell interactions in brain diseases. A broad range of applications have been already assessed including drug discovery and development, toxicology and virology ( Rivetti di Val Cervo et al, 2021 ). However, and with some exceptions, only a few studies focus on central questions about the biology of neural development including the establishment and maintenance of neuronal polarity.…”

Huntington's Disease Gene Hunters: An Expanding Tale

“…The discovery of the gene also enabled the generation of genetically accurate models in cells and animals. Models have been generated in species from yeast through to large animals and many of these models have offered useful insights into the pathophysiology of HD 21–24 . Most widely used have been mouse models, the first of which, the R6 series, were generated by Gillian Bates 25 .…”

“…Models have been generated in species from yeast through to large animals and many of these models have offered useful insights into the pathophysiology of HD. 21 , 22 , 23 , 24 Most widely used have been mouse models, the first of which, the R6 series, were generated by Gillian Bates. 25 Her models provided the seminal observation that the HTT protein containing an expanded polyglutamine tract formed the characteristic pathological hallmark of insoluble cellular aggregates in mouse brain, leading to their detection in human brain 26 —although in fact these had been previously observed in human HD brain without their importance being understood.…”