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Induced Pluripotent Stem Cells in Neurodegenerative Diseases: Application for Therapy and Disease Modeling

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Stem Cells".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 40520

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Special Issue Editors

Dr. Claudio Soto

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Guest Editor

Department of Neurology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
Interests: protein misfolding diseases; neurodegenerative diseases; prions; Alzheimer’s disease; Parkinson’s disease; biomarkers; stem cells; cerebral organoids

Dr. Abhisek Mukherjee

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Guest Editor

Special Issue Information

Dear Colleagues,

Neurodegenerative diseases (NDs) are a group of age-associated debilitating disorders that progressively destroy cognitive abilities, including memory, reasoning, judgment skills, and motor coordination, causing social seclusion and complete dependence on caregivers. The aged population is increasing globally. Currently, none of the major NDs have a disease-modifying therapy, and without a cure or effective treatment NDs are expected to impose a severe socioeconomic burden on society. The brain is an organ with low regeneration capacity, and when the clinical symptoms of NDs are manifested, a large number of neurons are already dead. For this reason, the development of effective treatments is a difficult task. In recent years, stem cells have received growing attention as a potential regenerative therapy for brain disorders. Some success with stem cell therapies has been reported, but a major problem with using heterologous stem cells is immune rejection, hindering the use of allogenic human cells for transplant. This is especially complicated in the case of NDs, in which the inflammatory processes underlying these disorders can present an intrinsically hostile environment to any allogenic graft. Patient-specific stem cells are now possible thanks to the generation of induced pluripotent stem cells (iPSCs) from patient somatic cells, which has been suggested as a new revolutionary step towards personalized medicine.

Another problem in the development of efficient therapies for NDs is the lack of highly predictable models to study the diseases and test the effect of potential therapies. Rodent models, currently used in NDs research, do not develop pathology naturally. Although transgenic mouse models over-expressing one or a few disease-associated human gene variants reproduce some aspects of the pathology, they are insufficient to reproduce the complete spectrum of human ND pathology. The methodology to reprogram terminally differentiated human cells into iPSCs and differentiate them into brain cells including neurons and glia has provided us a remarkable opportunity to understand disease pathology in human cells with the patient’s genetic makeup and develop regenerative therapies to recover brain damage. The recent development of methodology to generate 3D human brain-like tissue (brain organoids) from patient-derived iPSCs is beginning to revolutionize our understanding of human brain development and diseases.

In this Special Issue we will focus on the use of iPSCs as a new strategy for regenerative cellular therapy for NDs and on the production of 2D and 3D models of NDs.

Prof. Dr. Claudio Soto
Dr. Abhisek Mukherjee
Guest Editors

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Keywords

induced pluripotent stem cells (iPSCs)
cerebral organoids
neurodegenerative diseases
cellular therapy
disease modeling

Published Papers (6 papers)

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Research

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14 pages, 6523 KiB

Open AccessArticle

Induced Pluripotent Stem Cell-Derived Dopaminergic Neurons from Familial Parkinson’s Disease Patients Display α-Synuclein Pathology and Abnormal Mitochondrial Morphology

by Xiaojun Diao, Fei Wang, Andrea Becerra-Calixto, Claudio Soto and Abhisek Mukherjee

Cells 2021, 10(9), 2402; https://doi.org/10.3390/cells10092402 - 13 Sep 2021

Cited by 6 | Viewed by 3355

Abstract

Accumulation of α-synuclein (α-syn) into Lewy bodies (LBs) and mitochondrial abnormalities are the two cardinal pathobiological features of Parkinson’s disease (PD), which are associated with the loss of dopaminergic neurons. Although α-syn accumulates in many different cellular and mouse models, these models generally lack LB features. Here, we generated midbrain dopaminergic (mDA) neuronal cultures from induced pluripotent stem cells (iPSCs) derived from familial PD (fPD) patients and healthy controls. We show that mDA neuronal cultures from fPD patients with A53T mutation and α-syn gene (SNCA) triplication display pathological α-syn deposits, which spatially and morphologically resemble LBs. Importantly, we did not find any apparent accumulation of pathological α-syn in mDA neuronal culture derived from a healthy donor. Furthermore, we show that there are morphological abnormalities in the mitochondrial network in mDA neuronal cultures from fPD patients. Consequently, these cells were more susceptible to mitochondrial damage compared with healthy donor-derived mDA neuronal cultures. Our results indicate that the iPSC-derived mDA neuronal culture platform can be used to investigate the spatiotemporal appearance of LBs, as well as their composition, architecture, and relationship with mitochondrial abnormalities. Full article

(This article belongs to the Special Issue Induced Pluripotent Stem Cells in Neurodegenerative Diseases: Application for Therapy and Disease Modeling)

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16 pages, 2359 KiB

Open AccessArticle

Induced Pluripotent Stem Cells to Understand Mucopolysaccharidosis. I: Demonstration of a Migration Defect in Neural Precursors

by Silvin Lito, Adama Sidibe, Sten Ilmjarv, Patricie Burda, Matthias Baumgartner, Bernhard Wehrle-Haller, Karl-Heinz Krause and Antoine Marteyn

Cells 2020, 9(12), 2593; https://doi.org/10.3390/cells9122593 - 3 Dec 2020

Cited by 4 | Viewed by 2086

Abstract

Background: Mucopolysaccharidosis type I-Hurler (MPS1-H) is a severe genetic lysosomal storage disorder due to loss-of-function mutations in the IDUA gene. The subsequent complete deficiency of alpha l-iduronidase enzyme is directly responsible of a progressive accumulation of glycosaminoglycans (GAG) in lysosomes which affects the functions of many tissues. Consequently, MPS1 is characterized by systemic symptoms (multiorgan dysfunction) including respiratory and cardiac dysfunctions, skeletal abnormalities and early fatal neurodegeneration. Methods: To understand mechanisms underlying MPS1 neuropathology, we generated induced pluripotent stem cells (iPSC) from a MPS1-H patient with loss-of-function mutations in both IDUA alleles. To avoid variability due to different genetic background of iPSC, we established an isogenic control iPSC line by rescuing IDUA expression by a lentivectoral approach. Results: Marked differences between MPS1-H and IDUA-corrected isogenic controls were observed upon neural differentiation. A scratch assay revealed a strong migration defect of MPS1-H cells. Also, there was a massive impact of IDUA deficiency on gene expression (340 genes with an FDR < 0.05). Conclusions: Our results demonstrate a hitherto unknown connection between lysosomal degradation, gene expression and neural motility, which might account at least in part for the phenotype of MPS1-H patients. Full article

(This article belongs to the Special Issue Induced Pluripotent Stem Cells in Neurodegenerative Diseases: Application for Therapy and Disease Modeling)

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17 pages, 3289 KiB

Open AccessArticle

A Simple Differentiation Protocol for Generation of Induced Pluripotent Stem Cell-Derived Basal Forebrain-Like Cholinergic Neurons for Alzheimer’s Disease and Frontotemporal Dementia Disease Modeling

by Sonia Sanz Muñoz, Martin Engel, Rachelle Balez, Dzung Do-Ha, Mauricio Castro Cabral-da-Silva, Damian Hernández, Tracey Berg, Jennifer A. Fifita, Natalie Grima, Shu Yang, Ian P. Blair, Garth Nicholson, Anthony L. Cook, Alex W. Hewitt, Alice Pébay and Lezanne Ooi

Cells 2020, 9(9), 2018; https://doi.org/10.3390/cells9092018 - 2 Sep 2020

Cited by 25 | Viewed by 6165

Abstract

The study of neurodegenerative diseases using pluripotent stem cells requires new methods to assess neurodevelopment and neurodegeneration of specific neuronal subtypes. The cholinergic system, characterized by its use of the neurotransmitter acetylcholine, is one of the first to degenerate in Alzheimer’s disease and is also affected in frontotemporal dementia. We developed a differentiation protocol to generate basal forebrain-like cholinergic neurons (BFCNs) from induced pluripotent stem cells (iPSCs) aided by the use of small molecule inhibitors and growth factors. Ten iPSC lines were successfully differentiated into BFCNs using this protocol. The neuronal cultures were characterised through RNA and protein expression, and functional analysis of neurons was confirmed by whole-cell patch clamp. We have developed a reliable protocol using only small molecule inhibitors and growth factors, while avoiding transfection or cell sorting methods, to achieve a BFCN culture that expresses the characteristic markers of cholinergic neurons. Full article

(This article belongs to the Special Issue Induced Pluripotent Stem Cells in Neurodegenerative Diseases: Application for Therapy and Disease Modeling)

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22 pages, 28472 KiB

Open AccessArticle

Establishment of an in Vitro Human Blood-Brain Barrier Model Derived from Induced Pluripotent Stem Cells and Comparison to a Porcine Cell-Based System

by Annalise Di Marco, Domenico Vignone, Odalys Gonzalez Paz, Ivan Fini, Maria Rosaria Battista, Antonella Cellucci, Elena Bracacel, Giulio Auciello, Maria Veneziano, Vinod Khetarpal, Mark Rose, Alessandro Rosa, Isabelle Gloaguen, Edith Monteagudo, Todd Herbst, Celia Dominguez and Ignacio Muñoz-Sanjuán

Cells 2020, 9(4), 994; https://doi.org/10.3390/cells9040994 - 16 Apr 2020

Cited by 27 | Viewed by 5417

Abstract

The blood-brain barrier (BBB) is responsible for the homeostasis between the cerebral vasculature and the brain and it has a key role in regulating the influx and efflux of substances, in healthy and diseased states. Stem cell technology offers the opportunity to use human brain-specific cells to establish in vitro BBB models. Here, we describe the establishment of a human BBB model in a two-dimensional monolayer culture, derived from human induced pluripotent stem cells (hiPSCs). This model was characterized by a transendothelial electrical resistance (TEER) higher than 2000 Ω∙cm² and associated with negligible paracellular transport. The hiPSC-derived BBB model maintained the functionality of major endothelial transporter proteins and receptors. Some proprietary molecules from our central nervous system (CNS) programs were evaluated revealing comparable permeability in the human model and in the model from primary porcine brain endothelial cells (PBECs). Full article

(This article belongs to the Special Issue Induced Pluripotent Stem Cells in Neurodegenerative Diseases: Application for Therapy and Disease Modeling)

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Review

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34 pages, 2199 KiB

Open AccessReview

Human Pluripotent Stem Cells-Based Therapies for Neurodegenerative Diseases: Current Status and Challenges

by Elizabeth Ford, Jodie Pearlman, Travis Ruan, John Manion, Matthew Waller, Gregory G. Neely and Leslie Caron

Cells 2020, 9(11), 2517; https://doi.org/10.3390/cells9112517 - 20 Nov 2020

Cited by 41 | Viewed by 8382

Abstract

Neurodegenerative diseases are characterized by irreversible cell damage, loss of neuronal cells and limited regeneration potential of the adult nervous system. Pluripotent stem cells are capable of differentiating into the multitude of cell types that compose the central and peripheral nervous systems and so have become the major focus of cell replacement therapies for the treatment of neurological disorders. Human embryonic stem cell (hESC) and human induced pluripotent stem cell (hiPSC)-derived cells have both been extensively studied as cell therapies in a wide range of neurodegenerative disease models in rodents and non-human primates, including Parkinson’s disease, stroke, epilepsy, spinal cord injury, Alzheimer’s disease, multiple sclerosis and pain. In this review, we discuss the latest progress made with stem cell therapies targeting these pathologies. We also evaluate the challenges in clinical application of human pluripotent stem cell (hPSC)-based therapies including risk of oncogenesis and tumor formation, immune rejection and difficulty in regeneration of the heterogeneous cell types composing the central nervous system. Full article

(This article belongs to the Special Issue Induced Pluripotent Stem Cells in Neurodegenerative Diseases: Application for Therapy and Disease Modeling)

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Graphical abstract

25 pages, 2509 KiB

Open AccessReview

Development and Differentiation of Midbrain Dopaminergic Neuron: From Bench to Bedside

by Mengmeng Wang, King-Hwa Ling, Jun Jie Tan and Cheng-Biao Lu

Cells 2020, 9(6), 1489; https://doi.org/10.3390/cells9061489 - 18 Jun 2020

Cited by 28 | Viewed by 14233

Abstract

Parkinson’s Disease (PD) is a neurodegenerative disorder affecting the motor system. It is primarily due to substantial loss of midbrain dopamine (mDA) neurons in the substantia nigra pars compacta and to decreased innervation to the striatum. Although existing drug therapy available can relieve the symptoms in early-stage PD patients, it cannot reverse the pathogenic progression of PD. Thus, regenerating functional mDA neurons in PD patients may be a cure to the disease. The proof-of-principle clinical trials showed that human fetal graft-derived mDA neurons could restore the release of dopamine neurotransmitters, could reinnervate the striatum, and could alleviate clinical symptoms in PD patients. The invention of human-induced pluripotent stem cells (hiPSCs), autologous source of neural progenitors with less ethical consideration, and risk of graft rejection can now be generated in vitro. This advancement also prompts extensive research to decipher important developmental signaling in differentiation, which is key to successful in vitro production of functional mDA neurons and the enabler of mass manufacturing of the cells required for clinical applications. In this review, we summarize the biology and signaling involved in the development of mDA neurons and the current progress and methodology in driving efficient mDA neuron differentiation from pluripotent stem cells. Full article

(This article belongs to the Special Issue Induced Pluripotent Stem Cells in Neurodegenerative Diseases: Application for Therapy and Disease Modeling)

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