Induced Pluripotent Stem Cell (iPSC)-Based Neurodegenerative Disease Models for Phenotype Recapitulation and Drug Screening

Abstract

Neurodegenerative diseases represent a significant unmet medical need in our aging society. There are no effective treatments for most of these diseases, and we know comparatively little regarding pathogenic mechanisms. Among the challenges faced by those involved in developing therapeutic drugs for neurodegenerative diseases, the syndromes are often complex, and small animal models do not fully recapitulate the unique features of the human nervous system. Human induced pluripotent stem cells (iPSCs) are a novel technology that ideally would permit us to generate neuronal cells from individual patients, thereby eliminating the problem of species-specificity inherent when using animal models. Specific phenotypes of iPSC-derived cells may permit researchers to identify sub-types and to distinguish among unique clusters and groups. Recently, iPSCs were used for drug screening and testing for neurologic disorders including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), spinocerebellar atrophy (SCA), and Zika virus infection. However, there remain many challenges still ahead, including how one might effectively recapitulate sporadic disease phenotypes and the selection of ideal phenotypes and for large-scale drug screening. Fortunately, quite a few novel strategies have been developed that might be combined with an iPSC-based model to solve these challenges, including organoid technology, single-cell RNA sequencing, genome editing, and deep learning artificial intelligence. Here, we will review current applications and potential future directions for iPSC-based neurodegenerative disease models for critical drug screening.

Regenerative Stem Cell Therapy for Neurodegenerative Diseases: An Overview

“…iPSCs are a type of pluripotent stem cells that are artificially derived from non-pluripotent, adult somatic cells, including fibroblasts, hepatocytes, circulating T cells, and keratinocytes, by forcing the expression of genes and transcription factors that maintain embryonic stem cells [ 15 ]. These reprogrammed cells now provide a promising strategy for producing unlimited autologous neurons for transplantation in neurodegenerative patients [ 2 ]. iPSCs can be converted into mature functional neural lineages using an optimized differentiation method, which widens the scope of its potential applications in the studies of the mechanisms underlying various neurodegenerative disorders and the screening of novel therapeutic targets [ 16 , 17 ].…”

“…Although current medications have proven helpful in alleviating the symptoms, they cannot reverse the significant loss of dopaminergic neurons over time as the disease progresses. On the other hand, several different factors, including protein folding and dysfunction of the ubiquitin-proteasome pathway, mitochondrial dysfunction, and oxidative stress, have been discovered to contribute to the onset and progression of the disease [ 2 , 58 ]. Thus, the heterogeneity in pathology and underlying causes of PD makes its treatment challenging.…”

“…Unfortunately, the currently available treatment options are insufficient in arresting the neurodegenerative processes [ 1 ]. The complexity of the mechanisms associated with neuronal loss and the contradicting physiological causes of these diseases significantly hinder our understanding of the pathogenic processes and the consequential development of effective treatments [ 2 ]. Moreover, difficulty in targeting the widespread neuronal cell death, coupled with the lack of robust regenerative capacity of the central nervous system (CNS) and the enormous limitations for the vast majority of drugs (98% of small-molecule drugs and 100% of large-molecule drugs) regarding crossing the blood–brain barrier (BBB) further adds to the difficulty of treating these diseases [ 3 , 4 , 5 , 6 , 7 ].…”

Where and Why Modeling Amyotrophic Lateral Sclerosis

“…A great improvement in ALS cellular research was then provided by the exploitation of human-induced pluripotent stem cells (iPSCs) [ 83 ] that introduced the advantage of generating cells directly from individual patients with familial or sporadic ALS mutations [ 84 , 85 ]. In addition to motor neurons, iPSCs can also mimic other cell types associated with ALS such as astrocytes, microglia and oligodendrocytes, well known to be directly involved in the disease.…”

NEUROD1 Intrinsically Initiates Differentiation of Induced Pluripotent Stem Cells into Neural Progenitor Cells

“…The need for iPSC is especially high in disease modelling given the difficulties in isolating cells from patients and obtaining the optimal number of cells for experiments. Among different cell lineages from iPSC, neuronal lineage which can be matured to functional neuron is of special clinical interest, and iPSC-derived neuronal differentiation models are already in use in analysis of neurodegenerative disease such as Alzheimer's disease, Parkinson's disease, Huntington's disease and motor neuron diseases (Chang et al, 2020;Wu et al, 2019). Although iPSC-derived NPC model has been well studied in terms of defining cellular phenotype and neuronal function according to gene expression, the mechanism of gene regulation is still elusive (Kang et al, 2017;Zhang et al, 2013).…”