Human induced pluripotent stem cells for modelling neurodevelopmental disorders

Abstract

Currently, we have a poor understanding of the pathogenesis of neurodevelopmental disorders, owing to the fact that post-mortem and imaging studies are only capable of measuring the postnatal status quo and offer little insight into the processes that give rise to the observed outcomes. Human induced pluripotent stem cells (hiPSCs) in principle should prove powerful in elucidating the pathways that give rise to neurodevelopmental disorders. HiPSCs are embryonic stem cell-like cells that can be derived from somatic cells. They retain the unique genetic signature of the individual from whom they were derived from, and thus allow researchers to recapitulate that individual’s idiosyncratic neural development in a dish. In the case of diseased individuals, we can reenact the disease-altered trajectory of brain development and examine how and why phenotypic and molecular abnormalities arise in these diseased brains. In this paper, we review various aspects of hiPSC biology and experimental design as well as discuss existing hiPSC models of neurodevelopmental disorders. As already shown by some studies discussed in this review, our hope is that iPSCs will illuminate the pathophysiology of developmental disorders of the CNS and lead to therapeutic avenues for the millions that today suffer from neurodevelopmental disorders.

Stem Cells, Genome Editing, and the Path to Translational Medicine

“…Without detailed knowledge of the underlying genetics, patient-derived hiPSCs after in vitro differentiation provide a nearly unlimited supply of disease-relevant somatic cells for in vitro modelling that carry all the genetic elements implicated in disease development. Comparing neurons derived from patients with schizophrenia or autism spectrum disorders to age-matched unaffected individuals (Figure 1B) identified disease-relevant phenotypic changes providing proof-of concept to modeling sporadic diseases (reviewed in (Ardhanareeswaran et al, 2017; Hoffman et al, 2018). While initially surprising, considering the patients’ genetic heterogeneity, such robust disease-associated phenotypes may result from diverse genetic variants that converge on common developmental pathways such as cortical development, synaptic function and epigenetic processes (Hoffman et al, 2018).…”

“…Following in vitro differentiation, patient-derived hiPSCs provide disease-relevant somatic cells, which carry all the genetic elements implicated in the disease reflecting the genetic spectrum of the patient population. While discussing all of these studies is beyond the scope of this work, excellent recent reviews summarize hiPSC diseases models for neurodevelopmental (Ardhanareeswaran et al, 2017), neuropsychiatric (Hoffman et al, 2018) and neurodegenerative diseases including Alzheimer’s disease (Sullivan and Young-Pearse, 2017) and Parkinson’s disease (Shi et al, 2016; Zhang et al, 2017)), motor neuron and Huntington’s disease. The spectrum of phenotypes, which can be assessed in hiPSC-based in vitro models include a wide range of molecular, metabolic, cellular and electrophysiological analysis.…”

“Donating our bodies to science”: A discussion about autopsy and organ donation in Turner syndrome

“…It is still difficult to harvest sufficient numbers of cells from a living donor to create stem cell lines. Creating induced pluripotent stem (iPS) cell lines from adult tissues like skin and blood can allow researchers to recapitulate changes that occur during development and study why development of some tissues does not occur normally in TS (Ardhanareeswaran, Mariani, Coppola, Abyzov, & Vaccarino, 2017). …”

Recent advances in modelling of cerebellar ataxia using induced pluripotent stem cells

“…Dissociated cultures of neurons allow for close monitoring of their individual development throughout differentiation; however, their maturation and survival is limited compared to neurons developing in the embryonic brain, likely due to the lack of appropriate support in in vitro cultures 26,27 . Moreover, disease phenotypes affecting synapse formation, dendritic retraction and neuronal migration 28,29 , which may only arise from interactions between cells and their environment, may be lost in these two-dimensional cultures.…”

“…Indeed, transcriptomic analysis of other iPSC-derived neuronal models has revealed that the generated neurons are still in an embryonic state, despite the fact that individual neurons have been stained for mature markers (reviewed in 29 ). Such immature cells may be beneficial for the study of developmental aspects of disease.…”