Human embryonic stem cell-derived motor neurons expressing SOD1 mutants exhibit typical signs of motor neuron degeneration linked to ALS

Saravanan, Konda Mani; Kelly, Theresa K.; Paucar, Andres A.; Roe, Anne; Umbach, Joy A.; Charles, Andrew; Goldman, Steven A.; Kornblum, Harley I.; Wiedau‐Pazos, Martina

doi:10.1242/dmm.002113

Cited by 45 publications

(46 citation statements)

References 38 publications

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“…With the development of culture systems to efficiently generate neural lineage and functional neurons from human pluripotent stem cells, these systems have been used to model neurogenetic disorders through the manipulation of disease-determining genes in hESCs or the generation of patient-specific iPSCs [26,[40][41][42][43][44]. To be an ideal disease model, the culture system should be able to generate the target neurons efficiently and to recapitulate the in vivo pathological process in these target neurons.…”

Section: Discussionmentioning

confidence: 99%

Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy

Wang

Zhang

2012

Cell Res

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Establishing human cell models of spinal muscular atrophy (SMA) to mimic motor neuron-specific phenotypes holds the key to understanding the pathogenesis of this devastating disease. Here, we developed a closely representative cell model of SMA by knocking down the disease-determining gene, survival motor neuron (SMN), in human embryonic stem cells (hESCs). Our study with this cell model demonstrated that knocking down of SMN does not interfere with neural induction or the initial specification of spinal motor neurons. Notably, the axonal outgrowth of spinal motor neurons was significantly impaired and these disease-mimicking neurons subsequently degenerated. Furthermore, these disease phenotypes were caused by SMN-full length (SMN-FL) but not SMN-∆7 (lacking exon 7) knockdown, and were specific to spinal motor neurons. Restoring the expression of SMN-FL completely ameliorated all of the disease phenotypes, including specific axonal defects and motor neuron loss. Finally, knockdown of SMN-FL led to excessive mitochondrial oxidative stress in human motor neuron progenitors. The involvement of oxidative stress in the degeneration of spinal motor neurons in the SMA cell model was further confirmed by the administration of N-acetylcysteine, a potent antioxidant, which prevented disease-related apoptosis and subsequent motor neuron death. Thus, we report here the successful establishment of an hESC-based SMA model, which exhibits disease gene isoform specificity, cell type specificity, and phenotype reversibility. Our model provides a unique paradigm for studying how motor neurons specifically degenerate and highlights the potential importance of antioxidants for the treatment of SMA.

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Section: Discussionmentioning

confidence: 99%

Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy

Wang

Zhang

2012

Cell Res

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“…The cells organize into neural tube-like rosettes and, after 7-8 days in culture, sonic hedgehog (Shh) and cyclic adenosine monophosphate (cAMP) are added to the culture media for one additional week [34]. Alternatively, the human EBs can be held as suspension cultures in the absence of bFGF for 6 days, followed by cell plating on laminin-coated dishes in N2 medium [24,35]. After 6 days, RA is added and the cells differentiate for 3 days until columnar cells form [24,35].…”

Section: Neuroepithelial Cells Achievementmentioning

confidence: 99%

“…Alternatively, the human EBs can be held as suspension cultures in the absence of bFGF for 6 days, followed by cell plating on laminin-coated dishes in N2 medium [24,35]. After 6 days, RA is added and the cells differentiate for 3 days until columnar cells form [24,35]. Medium consisting of F12/DMEM, N2 supplement with heparin (2 g/ml), Shh, RA and cAMP with or without FGF2 can be used for 15 days [36,37].…”

Section: Neuroepithelial Cells Achievementmentioning

confidence: 99%

Human motor neuron generation from embryonic stem cells and induced pluripotent stem cells

Nizzardo

Simone

Falcone

et al. 2010

Cell. Mol. Life Sci.

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Motor neuron diseases (MNDs) are a group of neurological disorders that selectively affect motor neurons. There are currently no cures or efficacious treatments for these diseases. In recent years, significant developments in stem cell research have been applied to MNDs, particularly regarding neuroprotection and cell replacement. However, a consistent source of motor neurons for cell replacement is required. Human embryonic stem cells (hESCs) could provide an inexhaustible supply of differentiated cell types, including motor neurons that could be used for MND therapies. Recently, it has been demonstrated that induced pluripotent stem (iPS) cells may serve as an alternative source of motor neurons, since they share ES characteristics, self-renewal, and the potential to differentiate into any somatic cell type. In this review, we discuss several reproducible methods by which hESCs or iPS cells are efficiently isolated and differentiated into functional motor neurons, and possible clinical applications.

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“…Human ESCs were also used to study the cell-autonomous mechanisms involved in motor neuron degeneration. In 2009 a human embryonic stem cell line was used to generate motor neurons that were then transfected with different constructs containing SOD1 mutations (35). In line with the study performed in SOD1 G93A mESC-derived motor neurons, the authors observed a reduction in neurite length and reduced cell survival.…”

Section: Human Escs and Ipscsmentioning

confidence: 86%

New In Vitro Models to Study Amyotrophic Lateral Sclerosis

Myszczynska

Ferraiuolo

2016

Brain Pathology

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Amyotrophic Lateral Sclerosis (ALS) is a complex multifactorial disorder, characterized by motor neuron loss with involvement of several other cell types, including astrocytes, oligodendrocytes and microglia. Studies in vivo and in in vitro models have highlighted that the contribution of nonneuronal cells to the disease is a primary event and ALS pathogenesis is driven by both cell-autonomous and non-cell autonomous mechanisms. The advancements in genetics and in vitro modeling of the past 10 years have dramatically changed the way we investigate the pathogenic mechanisms involved in ALS. The identification of mutations in transactive response DNA-binding protein gene (TARDBP), fused in sarcoma (FUS) and, more recently, a GGGGCC-hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) and their link with familial ALS have provided new avenues of investigation and hypotheses on the pathophysiology of this devastating disease. In the same years, from 2007 to present, in vitro technologies to model neurological disorders have also undergone impressive developments. The advent of induced pluripotent stem cells (iPSCs) gave the field of ALS the opportunity to finally model in vitro not only familial, but also the larger part of ALS cases affected by sporadic disease. Since 2008, when the first human iPS-derived motor neurons from patients were cultured in a petri dish, several different techniques have been developed to produce iPSC lines through genetic reprogramming and multiple direct conversion methods have been optimised. In this review we will give an overview of how human in vitro models have been used so far, what discoveries they have led to since 2007, and how the recent advances in technology combined with the genetic discoveries, have tremendously widened the horizon of ALS research.

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Human embryonic stem cell-derived motor neurons expressing SOD1 mutants exhibit typical signs of motor neuron degeneration linked to ALS

Cited by 45 publications

References 38 publications

Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy

Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy

Human motor neuron generation from embryonic stem cells and induced pluripotent stem cells

New In Vitro Models to Study Amyotrophic Lateral Sclerosis

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