Journal articles: 'IPSC-derived neurons'

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Allison, Reilly L., Jacob W. Adelman, Jenica Abrudan, Raul A. Urrutia, Michael T. Zimmermann, Angela J. Mathison, and Allison D. Ebert. "Microglia Influence Neurofilament Deposition in ALS iPSC-Derived Motor Neurons." Genes 13, no. 2 (January 27, 2022): 241. http://dx.doi.org/10.3390/genes13020241.

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which upper and lower motor neuron loss is the primary phenotype, leading to muscle weakness and wasting, respiratory failure, and death. Although a portion of ALS cases are linked to one of over 50 unique genes, the vast majority of cases are sporadic in nature. However, the mechanisms underlying the motor neuron loss in either familial or sporadic ALS are not entirely clear. Here, we used induced pluripotent stem cells derived from a set of identical twin brothers discordant for ALS to assess the role of astrocytes and microglia on the expression and accumulation of neurofilament proteins in motor neurons. We found that motor neurons derived from the affected twin which exhibited increased transcript levels of all three neurofilament isoforms and increased expression of phosphorylated neurofilament puncta. We further found that treatment of the motor neurons with astrocyte-conditioned medium and microglial-conditioned medium significantly impacted neurofilament deposition. Together, these data suggest that glial-secreted factors can alter neurofilament pathology in ALS iPSC-derived motor neurons.

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Matsui, Toshikatsu, Norimasa Miyamoto, Fumiyo Saito, and Tadahiro Shinozawa. "Molecular Profiling of Human Induced Pluripotent Stem Cell-Derived Cells and their Application for Drug Safety Study." Current Pharmaceutical Biotechnology 21, no. 9 (June 9, 2020): 807–28. http://dx.doi.org/10.2174/1389201021666200422090952.

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Drug-induced toxicity remains one of the leading causes of discontinuation of the drug candidate and post-marketing withdrawal. Thus, early identification of the drug candidates with the potential for toxicity is crucial in the drug development process. With the recent discovery of human- Induced Pluripotent Stem Cells (iPSC) and the establishment of the differentiation protocol of human iPSC into the cell types of interest, the differentiated cells from human iPSC have garnered much attention because of their potential applicability in toxicity evaluation as well as drug screening, disease modeling and cell therapy. In this review, we expanded on current information regarding the feasibility of human iPSC-derived cells for the evaluation of drug-induced toxicity with a focus on human iPSCderived hepatocyte (iPSC-Hep), cardiomyocyte (iPSC-CMs) and neurons (iPSC-Neurons). Further, we CSAHi, Consortium for Safety Assessment using Human iPS Cells, reported our gene expression profiling data with DNA microarray using commercially available human iPSC-derived cells (iPSC-Hep, iPSC-CMs, iPSC-Neurons), their relevant human tissues and primary cultured human cells to discuss the future direction of the three types of human iPSC-derived cells.

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Avazzadeh, Sahar, Jara Maria Baena, Cameron Keighron, Yajaira Feller-Sanchez, and Leo R. Quinlan. "Modelling Parkinson’s Disease: iPSCs towards Better Understanding of Human Pathology." Brain Sciences 11, no. 3 (March 14, 2021): 373. http://dx.doi.org/10.3390/brainsci11030373.

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Parkinson’s Disease (PD) is a chronic neurodegenerative disorder characterized by motor and non-motor symptoms, among which are bradykinesia, rigidity, tremor as well as mental symptoms such as dementia. The underlying cause of Parkinson disease is degeneration of dopaminergic neurons. It has been challenging to develop an efficient animal model to accurately represent the complex phenotypes found with PD. However, it has become possible to recapitulate the myriad of phenotypes underlying the PD pathology by using human induced pluripotent stem cell (iPSC) technology. Patient-specific iPSC-derived dopaminergic neurons are available and present an opportunity to study many aspects of the PD phenotypes in a dish. In this review, we report the available data on iPSC-derived neurons derived from PD patients with identified gene mutations. Specifically, we will report on the key phenotypes of the generated iPSC-derived neurons from PD patients with different genetic background. Furthermore, we discuss the relationship these cellular phenotypes have to PD pathology and future challenges and prospects for iPSC modelling and understanding of the pathogenesis of PD.

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Guyett, Paul, Mike Hendrickson, and Kurt Laha. "CNS Drug Discovery Using iPSC-Derived Neurons." Genetic Engineering & Biotechnology News 38, no. 20 (November 15, 2018): 14–15. http://dx.doi.org/10.1089/gen.38.20.08.

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Ichise, Eisuke, Tomohiro Chiyonobu, Mitsuru Ishikawa, Yasuyoshi Tanaka, Mami Shibata, Takenori Tozawa, Yoshihiro Taura, et al. "Impaired neuronal activity and differential gene expression in STXBP1 encephalopathy patient iPSC-derived GABAergic neurons." Human Molecular Genetics 30, no. 14 (May 7, 2021): 1337–48. http://dx.doi.org/10.1093/hmg/ddab113.

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Abstract Syntaxin-binding protein 1 (STXBP1; also called MUNC18–1), encoded by STXBP1, is an essential component of the molecular machinery that controls synaptic vesicle docking and fusion. De novo pathogenic variants of STXBP1 cause a complex set of neurological disturbances, namely STXBP1 encephalopathy (STXBP1-E) that includes epilepsy, neurodevelopmental disorders and neurodegeneration. Several animal studies have suggested the contribution of GABAergic dysfunction in STXBP1-E pathogenesis. However, the pathophysiological changes in GABAergic neurons of these patients are still poorly understood. Here, we exclusively generated GABAergic neurons from STXBP1-E patient-derived induced pluripotent stem cells (iPSCs) by transient expression of the transcription factors ASCL1 and DLX2. We also generated CRISPR/Cas9-edited isogenic iPSC-derived GABAergic (iPSC GABA) neurons as controls. We demonstrated that the reduction in STXBP1 protein levels in patient-derived iPSC GABA neurons was slight (approximately 20%) compared to the control neurons, despite a 50% reduction in STXBP1 mRNA levels. Using a microelectrode array–based assay, we found that patient-derived iPSC GABA neurons exhibited dysfunctional maturation with reduced numbers of spontaneous spikes and bursts. These findings reinforce the idea that GABAergic dysfunction is a crucial contributor to STXBP1-E pathogenesis. Moreover, gene expression analysis revealed specific dysregulation of genes previously implicated in epilepsy, neurodevelopment and neurodegeneration in patient-derived iPSC GABA neurons, namely KCNH1, KCNH5, CNN3, RASGRF1, SEMA3A, SIAH3 and INPP5F. Thus, our study provides new insights for understanding the biological processes underlying the widespread neuropathological features of STXBP1-E.

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Hedegaard, Anne, Jimena Monzón-Sandoval, Sarah E. Newey, Emma S. Whiteley, Caleb Webber, and Colin J. Akerman. "Pro-maturational Effects of Human iPSC-Derived Cortical Astrocytes upon iPSC-Derived Cortical Neurons." Stem Cell Reports 15, no. 1 (July 2020): 38–51. http://dx.doi.org/10.1016/j.stemcr.2020.05.003.

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Miletta, Maria Consolata, and Tamas L. Horvath. "Patient-Derived iPSC-Hypothamic Neurons: The Ultimate Protocol." Cell Stem Cell 22, no. 5 (May 2018): 615–16. http://dx.doi.org/10.1016/j.stem.2018.04.019.

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Lee, Sebum, and Eric J. Huang. "Modeling ALS and FTD with iPSC-derived neurons." Brain Research 1656 (February 2017): 88–97. http://dx.doi.org/10.1016/j.brainres.2015.10.003.

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Vangeel, Laura. "TRP Channel Function in iPSC-Derived Sensory Neurons." Biophysical Journal 112, no. 3 (February 2017): 135a. http://dx.doi.org/10.1016/j.bpj.2016.11.750.

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Pierson, Tyler M., Yogesh K. Kushwaha, Hiral Oza, and Maria G. Otero. "Modeling CLN6 with IPSC-derived neurons and glia." Molecular Genetics and Metabolism 138, no. 2 (February 2023): 107269. http://dx.doi.org/10.1016/j.ymgme.2022.107269.

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Cordella, Federica, Laura Ferrucci, Chiara D’Antoni, Silvia Ghirga, Carlo Brighi, Alessandro Soloperto, Ylenia Gigante, Davide Ragozzino, Paola Bezzi, and Silvia Di Angelantonio. "Human iPSC-Derived Cortical Neurons Display Homeostatic Plasticity." Life 12, no. 11 (November 14, 2022): 1884. http://dx.doi.org/10.3390/life12111884.

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Maintaining the excitability of neurons and circuits is fundamental for healthy brain functions. The global compensatory increase in excitatory synaptic strength, in response to decreased activity, is one of the main homeostatic mechanisms responsible for such regulation. This type of plasticity has been extensively characterized in rodents in vivo and in vitro, but few data exist on human neurons maturation. We have generated an in vitro cortical model system, based on differentiated human-induced pluripotent stem cells, chronically treated with tetrodotoxin, to investigate homeostatic plasticity at different developmental stages. Our findings highlight the presence of homeostatic plasticity in human cortical networks and show that the changes in synaptic strength are due to both pre- and post-synaptic mechanisms. Pre-synaptic plasticity involves the potentiation of neurotransmitter release machinery, associated to an increase in synaptic vesicle proteins expression. At the post-synaptic level, we report an increase in the expression of post-synaptic density proteins, involved in glutamatergic receptor anchoring. These results extend our understanding of neuronal homeostasis and reveal the developmental regulation of its expression in human cortical networks. Since induced pluripotent stem cell-derived neurons can be obtained from patients with neurodevelopmental and neurodegenerative diseases, our platform offers a versatile model for assessing human neural plasticity under physiological and pathological conditions.

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Imran, Saima Jalil, Barbora Vagaska, Jan Kriska, Miroslava Anderova, Mario Bortolozzi, Gino Gerosa, Patrizia Ferretti, and Radim Vrzal. "Aryl Hydrocarbon Receptor (AhR)-Mediated Signaling in iPSC-Derived Human Motor Neurons." Pharmaceuticals 15, no. 7 (July 4, 2022): 828. http://dx.doi.org/10.3390/ph15070828.

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Exposure to environmental pollutants and endogenous metabolites that induce aryl hydrocarbon receptor (AhR) expression has been suggested to affect cognitive development and, particularly in boys, also motor function. As current knowledge is based on epidemiological and animal studies, in vitro models are needed to better understand the effects of these compounds in the human nervous system at the molecular level. Here, we investigated expression of AhR pathway components and how they are regulated by AhR ligands in human motor neurons. Motor neurons generated from human induced pluripotent stem cells (hiPSCs) were characterized at the molecular level and by electrophysiology. mRNA levels of AhR target genes, CYP1A1 and CYP1B1 (cytochromes P450 1A1/1B1), and AhR signaling components were monitored in hiPSCs and in differentiated neurons following treatment with AhR ligands, 2,3,7,8,-tetrachlodibenzo-p-dioxin (TCDD), L-kynurenine (L-Kyn), and kynurenic acid (KA), by RT-qPCR. Changes in AhR cellular localization and CYP1A1 activity in neurons treated with AhR ligands were also assessed. The neurons we generated express motor neuron-specific markers and are functional. Transcript levels of CYP1B1, AhR nuclear translocators (ARNT1 and ARNT2) and the AhR repressor (AhRR) change with neuronal differentiation, being significantly higher in neurons than hiPSCs. In contrast, CYP1A1 and AhR transcript levels are slightly lower in neurons than in hiPSCs. The response to TCDD treatment differs in hiPSCs and neurons, with only the latter showing significant CYP1A1 up-regulation. In contrast, TCDD slightly up-regulates CYP1B1 mRNA in hiPSCs, but downregulates it in neurons. Comparison of the effects of different AhR ligands on AhR and some of its target genes in neurons shows that L-Kyn and KA, but not TCDD, regulate AhR expression and differently affect CYP1A1 and CYP1B1 expression. Finally, although TCDD does not significantly affect AhR transcript levels, it induces AhR protein translocation to the nucleus and increases CYP1A1 activity. This is in contrast to L-Kyn and KA, which either do not affect or reduce, respectively, CYP1A1 activity. Expression of components of the AhR signaling pathway are regulated with neuronal differentiation and are differently affected by TCDD, suggesting that pluripotent stem cells might be less sensitive to this toxin than neurons. Crucially, AhR signaling is affected differently by TCDD and other AhR ligands in human motor neurons, suggesting that they can provide a valuable tool for assessing the impact of environmental pollutants.

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Imamura, Keiko, Yuishin Izumi, Akira Watanabe, Kayoko Tsukita, Knut Woltjen, Takuya Yamamoto, Akitsu Hotta, et al. "The Src/c-Abl pathway is a potential therapeutic target in amyotrophic lateral sclerosis." Science Translational Medicine 9, no. 391 (May 24, 2017): eaaf3962. http://dx.doi.org/10.1126/scitranslmed.aaf3962.

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Amyotrophic lateral sclerosis (ALS), a fatal disease causing progressive loss of motor neurons, still has no effective treatment. We developed a phenotypic screen to repurpose existing drugs using ALS motor neuron survival as readout. Motor neurons were generated from induced pluripotent stem cells (iPSCs) derived from an ALS patient with a mutation in superoxide dismutase 1 (SOD1). Results of the screen showed that more than half of the hits targeted the Src/c-Abl signaling pathway. Src/c-Abl inhibitors increased survival of ALS iPSC-derived motor neurons in vitro. Knockdown of Src or c-Abl with small interfering RNAs (siRNAs) also rescued ALS motor neuron degeneration. One of the hits, bosutinib, boosted autophagy, reduced the amount of misfolded mutant SOD1 protein, and attenuated altered expression of mitochondrial genes. Bosutinib also increased survival in vitro of ALS iPSC-derived motor neurons from patients with sporadic ALS or other forms of familial ALS caused by mutations in TAR DNA binding protein (TDP-43) or repeat expansions in C9orf72. Furthermore, bosutinib treatment modestly extended survival of a mouse model of ALS with an SOD1 mutation, suggesting that Src/c-Abl may be a potentially useful target for developing new drugs to treat ALS.

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Mortensen, Christina, Nanna Elman Andersen, and Tore Bjerregaard Stage. "Bridging the Translational Gap in Chemotherapy-Induced Peripheral Neuropathy with iPSC-Based Modeling." Cancers 14, no. 16 (August 15, 2022): 3939. http://dx.doi.org/10.3390/cancers14163939.

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Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially serious adverse effect of a wide range of chemotherapeutics. The lack of understanding of the molecular mechanisms underlying CIPN limits the efficacy of chemotherapy and development of therapeutics for treatment and prevention of CIPN. Human induced pluripotent stem cells (iPSCs) have become an important tool to generate the cell types associated with CIPN symptoms in cancer patients. We reviewed the literature for iPSC-derived models that assessed neurotoxicity among chemotherapeutics associated with CIPN. Furthermore, we discuss the gaps in our current knowledge and provide guidance for selecting clinically relevant concentrations of chemotherapy for in vitro studies. Studies in iPSC-derived neurons revealed differential sensitivity towards mechanistically diverse chemotherapeutics associated with CIPN. Additionally, the sensitivity to chemotherapy was determined by donor background and whether the neurons had a central or peripheral nervous system identity. We propose to utilize clinically relevant concentrations that reflect the free, unbound fraction of chemotherapeutics in plasma in future studies. In conclusion, iPSC-derived sensory neurons are a valuable model to assess CIPN; however, studies in Schwann cells and motor neurons are warranted. The inclusion of multiple iPSC donors and concentrations of chemotherapy known to be achievable in patients can potentially improve translational success.

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Leventoux, Nicolas, Satoru Morimoto, Kent Imaizumi, Yuta Sato, Shinichi Takahashi, Kyoko Mashima, Mitsuru Ishikawa, et al. "Human Astrocytes Model Derived from Induced Pluripotent Stem Cells." Cells 9, no. 12 (December 13, 2020): 2680. http://dx.doi.org/10.3390/cells9122680.

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Induced pluripotent stem cell (iPSC)-based disease modeling has a great potential for uncovering the mechanisms of pathogenesis, especially in the case of neurodegenerative diseases where disease-susceptible cells can usually not be obtained from patients. So far, the iPSC-based modeling of neurodegenerative diseases has mainly focused on neurons because the protocols for generating astrocytes from iPSCs have not been fully established. The growing evidence of astrocytes’ contribution to neurodegenerative diseases has underscored the lack of iPSC-derived astrocyte models. In the present study, we established a protocol to efficiently generate iPSC-derived astrocytes (iPasts), which were further characterized by RNA and protein expression profiles as well as functional assays. iPasts exhibited calcium dynamics and glutamate uptake activity comparable to human primary astrocytes. Moreover, when co-cultured with neurons, iPasts enhanced neuronal synaptic maturation. Our protocol can be used for modeling astrocyte-related disease phenotypes in vitro and further exploring the contribution of astrocytes to neurodegenerative diseases.

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Bachmann, Sarah, Jenice Linde, Michael Bell, Marc Spehr, Hans Zempel, and Geraldine Zimmer-Bensch. "DNA Methyltransferase 1 (DNMT1) Shapes Neuronal Activity of Human iPSC-Derived Glutamatergic Cortical Neurons." International Journal of Molecular Sciences 22, no. 4 (February 18, 2021): 2034. http://dx.doi.org/10.3390/ijms22042034.

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Epigenetic mechanisms are emerging key players for the regulation of brain function, synaptic activity, and the formation of neuronal engrams in health and disease. As one important epigenetic mechanism of transcriptional control, DNA methylation was reported to distinctively modulate synaptic activity in excitatory and inhibitory cortical neurons in mice. Since DNA methylation signatures are responsive to neuronal activity, DNA methylation seems to contribute to the neuron’s capacity to adapt to and integrate changing activity patterns, being crucial for the plasticity and functionality of neuronal circuits. Since most studies addressing the role of DNA methylation in the regulation of synaptic function were conducted in mice or murine neurons, we here asked whether this functional implication applies to human neurons as well. To this end, we performed calcium imaging in human induced pluripotent stem cell (iPSC)-derived excitatory cortical neurons forming synaptic contacts and neuronal networks in vitro. Treatment with DNMT1 siRNA that diminishs the expression of the DNA (cytosine-5)-methyltransferase 1 (DNMT1) was conducted to investigate the functional relevance of DNMT1 as one of the main enzymes executing DNA methylations in the context of neuronal activity modulation. We observed a lowered proportion of actively firing neurons upon DNMT1-knockdown in these iPSC-derived excitatory neurons, pointing to a correlation of DNMT1-activity and synaptic transmission. Thus, our experiments suggest that DNMT1 decreases synaptic activity of human glutamatergic neurons and underline the relevance of epigenetic regulation of synaptic function also in human excitatory neurons.

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McCready, Fraser P., Sara Gordillo-Sampedro, Kartik Pradeepan, Julio Martinez-Trujillo, and James Ellis. "Multielectrode Arrays for Functional Phenotyping of Neurons from Induced Pluripotent Stem Cell Models of Neurodevelopmental Disorders." Biology 11, no. 2 (February 16, 2022): 316. http://dx.doi.org/10.3390/biology11020316.

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In vitro multielectrode array (MEA) systems are increasingly used as higher-throughput platforms for functional phenotyping studies of neurons in induced pluripotent stem cell (iPSC) disease models. While MEA systems generate large amounts of spatiotemporal activity data from networks of iPSC-derived neurons, the downstream analysis and interpretation of such high-dimensional data often pose a significant challenge to researchers. In this review, we examine how MEA technology is currently deployed in iPSC modeling studies of neurodevelopmental disorders. We first highlight the strengths of in vitro MEA technology by reviewing the history of its development and the original scientific questions MEAs were intended to answer. Methods of generating patient iPSC-derived neurons and astrocytes for MEA co-cultures are summarized. We then discuss challenges associated with MEA data analysis in a disease modeling context, and present novel computational methods used to better interpret network phenotyping data. We end by suggesting best practices for presenting MEA data in research publications, and propose that the creation of a public MEA data repository to enable collaborative data sharing would be of great benefit to the iPSC disease modeling community.

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Verheyen, An, Annick Diels, Joyce Dijkmans, Tutu Oyelami, Giulia Meneghello, Liesbeth Mertens, Sofie Versweyveld, et al. "Using Human iPSC-Derived Neurons to Model TAU Aggregation." PLOS ONE 10, no. 12 (December 31, 2015): e0146127. http://dx.doi.org/10.1371/journal.pone.0146127.

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Liu, Jing, Katarzyna A. Kościelska, Zhengyu Cao, Susan Hulsizer, Natalie Grace, Gaela Mitchell, Catherine Nacey, et al. "Signaling defects in iPSC-derived fragile X premutation neurons." Human Molecular Genetics 21, no. 17 (May 28, 2012): 3795–805. http://dx.doi.org/10.1093/hmg/dds207.

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Fyfe, Ian. "Mutation-specific amyloid-β processing in iPSC-derived neurons." Nature Reviews Neurology 15, no. 6 (April 29, 2019): 310. http://dx.doi.org/10.1038/s41582-019-0195-z.

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Schwartzentruber, Jeremy, Stefanie Foskolou, Helena Kilpinen, Julia Rodrigues, Kaur Alasoo, Andrew J. Knights, Minal Patel, et al. "Molecular and functional variation in iPSC-derived sensory neurons." Nature Genetics 50, no. 1 (December 11, 2017): 54–61. http://dx.doi.org/10.1038/s41588-017-0005-8.

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Halliwell, Robert F., Hamed Salmanzadeh, Leanne Coyne, and William S. Cao. "An Electrophysiological and Pharmacological Study of the Properties of Human iPSC-Derived Neurons for Drug Discovery." Cells 10, no. 8 (July 31, 2021): 1953. http://dx.doi.org/10.3390/cells10081953.

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Human stem cell-derived neurons are increasingly considered powerful models in drug discovery and disease modeling, despite limited characterization of their molecular properties. Here, we have conducted a detailed study of the properties of a commercial human induced Pluripotent Stem Cell (iPSC)-derived neuron line, iCell [GABA] neurons, maintained for up to 3 months in vitro. We confirmed that iCell neurons display neurite outgrowth within 24 h of plating and label for the pan-neuronal marker, βIII tubulin within the first week. Our multi-electrode array (MEA) recordings clearly showed neurons generated spontaneous, spike-like activity within 2 days of plating, which peaked at one week, and rapidly decreased over the second week to remain at low levels up to one month. Extracellularly recorded spikes were reversibly inhibited by tetrodotoxin. Patch-clamp experiments showed that iCell neurons generated spontaneous action potentials and expressed voltage-gated Na and K channels with membrane capacitances, resistances and membrane potentials that are consistent with native neurons. Our single neuron recordings revealed that reduced spiking observed in the MEA after the first week results from development of a dominant inhibitory tone from GABAergic neuron circuit maturation. GABA evoked concentration-dependent currents that were inhibited by the convulsants, bicuculline and picrotoxin, and potentiated by the positive allosteric modulators, diazepam, chlordiazepoxide, phenobarbital, allopregnanolone and mefenamic acid, consistent with native neuronal GABAA receptors. We also show that glycine evoked robust concentration-dependent currents that were inhibited by the neurotoxin, strychnine. Glutamate, AMPA, Kainate and NMDA each evoked concentration-dependent currents in iCell neurons that were blocked by their selective antagonists, consistent with the expression of ionotropic glutamate receptors. The NMDA currents required the presence of the co-agonist glycine and were blocked in a highly voltage-dependent manner by Mg2+ consistent with the properties of native neuronal NMDA receptors. Together, our data suggest that such human iPSC-derived neurons may have significant value in drug discovery and development and may eventually largely replace the need for animal tissues in human biomedical research.

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Kaifer, Kevin A., Eric Villalón, Benjamin S. O'Brien, Samantha L. Sison, Caley E. Smith, Madeline E. Simon, Jose Marquez, et al. "AAV9-mediated delivery of miR-23a reduces disease severity in Smn2B/−SMA model mice." Human Molecular Genetics 28, no. 19 (May 20, 2019): 3199–210. http://dx.doi.org/10.1093/hmg/ddz142.

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Abstract Spinal muscular atrophy (SMA) is a neuromuscular disease caused by deletions or mutations in survival motor neuron 1 (SMN1). The molecular mechanisms underlying motor neuron degeneration in SMA remain elusive, as global cellular dysfunction obscures the identification and characterization of disease-relevant pathways and potential therapeutic targets. Recent reports have implicated microRNA (miRNA) dysregulation as a potential contributor to the pathological mechanism in SMA. To characterize miRNAs that are differentially regulated in SMA, we profiled miRNA levels in SMA induced pluripotent stem cell (iPSC)-derived motor neurons. From this array, miR-23a downregulation was identified selectively in SMA motor neurons, consistent with previous reports where miR-23a functioned in neuroprotective and muscle atrophy-antagonizing roles. Reintroduction of miR-23a expression in SMA patient iPSC-derived motor neurons protected against degeneration, suggesting a potential miR-23a-specific disease-modifying effect. To assess this activity in vivo, miR-23a was expressed using a self-complementary adeno-associated virus serotype 9 (scAAV9) viral vector in the Smn2B/− SMA mouse model. scAAV9-miR-23a significantly reduced the pathology in SMA mice, including increased motor neuron size, reduced neuromuscular junction pathology, increased muscle fiber area, and extended survival. These experiments demonstrate that miR-23a is a novel protective modifier of SMA, warranting further characterization of miRNA dysfunction in SMA.

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Smethurst, Phillip, Emmanuel Risse, Giulia E. Tyzack, Jamie S. Mitchell, Doaa M. Taha, Yun-Ru Chen, Jia Newcombe, John Collinge, Katie Sidle, and Rickie Patani. "Distinct responses of neurons and astrocytes to TDP-43 proteinopathy in amyotrophic lateral sclerosis." Brain 143, no. 2 (February 1, 2020): 430–40. http://dx.doi.org/10.1093/brain/awz419.

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Abstract Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease caused by motor neuron loss, resulting in muscle wasting, paralysis and eventual death. A key pathological feature of ALS is cytoplasmically mislocalized and aggregated TDP-43 protein in >95% of cases, which is considered to have prion-like properties. Historical studies have predominantly focused on genetic forms of ALS, which represent ∼10% of cases, leaving the remaining 90% of sporadic ALS relatively understudied. Additionally, the role of astrocytes in ALS and their relationship with TDP-43 pathology is also not currently well understood. We have therefore used highly enriched human induced pluripotent stem cell (iPSC)-derived motor neurons and astrocytes to model early cell type-specific features of sporadic ALS. We first demonstrate seeded aggregation of TDP-43 by exposing human iPSC-derived motor neurons to serially passaged sporadic ALS post-mortem tissue (spALS) extracts. Next, we show that human iPSC-derived motor neurons are more vulnerable to TDP-43 aggregation and toxicity compared with their astrocyte counterparts. We demonstrate that these TDP-43 aggregates can more readily propagate from motor neurons into astrocytes in co-culture paradigms. We next found that astrocytes are neuroprotective to seeded aggregation within motor neurons by reducing (mislocalized) cytoplasmic TDP-43, TDP-43 aggregation and cell toxicity. Furthermore, we detected TDP-43 oligomers in these spALS spinal cord extracts, and as such demonstrated that highly purified recombinant TDP-43 oligomers can reproduce this observed cell-type specific toxicity, providing further support to a protein oligomer-mediated toxicity hypothesis in ALS. In summary, we have developed a human, clinically relevant, and cell-type specific modelling platform that recapitulates key aspects of sporadic ALS and uncovers both an initial neuroprotective role for astrocytes and the cell type-specific toxic effect of TDP-43 oligomers.

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VanHook, Annalisa M. "Cholesterol and Alzheimer’s disease." Science Signaling 12, no. 575 (April 2, 2019): eaax4932. http://dx.doi.org/10.1126/scisignal.aax4932.

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Hiramatsu, Satoe, Asuka Morizane, Tetsuhiro Kikuchi, Daisuke Doi, Kenji Yoshida, and Jun Takahashi. "Cryopreservation of Induced Pluripotent Stem Cell-Derived Dopaminergic Neurospheres for Clinical Application." Journal of Parkinson's Disease 12, no. 3 (April 5, 2022): 871–84. http://dx.doi.org/10.3233/jpd-212934.

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Background: Pluripotent stem cell (PSC)-derived dopaminergic (DA) neurons are an expected source of cell therapy for Parkinson’s disease. The transplantation of cell aggregates or neurospheres, instead of a single cell suspension has several advantages, such as keeping the 3D structure of the donor cells and ease of handling. For this PSC-based therapy to become a widely available treatment, cryopreservation of the final product is critical in the manufacturing process. However, cryopreserving cell aggregates is more complicated than cryopreserving single cell suspensions. Previous studies showed poor survival of the DA neurons after the transplantation of cryopreserved fetal ventral-mesencephalic tissues. Objective: To achieve the cryopreservation of induced pluripotent stem cell (iPSC)-derived DA neurospheres toward clinical application. Methods: We cryopreserved iPSC-derived DA neurospheres in various clinically applicable cryopreservation media and freezing protocols and assessed viability and neurite extension. We evaluated the population and neuronal function of cryopreserved cells by the selected method in vitro. We also injected the cells into 6-hydroxydopamine (6-OHDA) lesioned rats, and assessed their survival, maturation and function in vivo. Results: The iPSC-derived DA neurospheres cryopreserved by Proton Freezer in the cryopreservation medium Bambanker hRM (BBK) showed favorable viability after thawing and had equivalent expression of DA-specific markers, dopamine secretion, and electrophysiological activity as fresh spheres. When transplanted into 6-OHDA-lesioned rats, the cryopreserved cells survived and differentiated into mature DA neurons, resulting in improved abnormal rotational behavior. Conclusion: These results show that the combination of BBK and Proton Freezer is suitable for the cryopreservation of iPSC-derived DA neurospheres.

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Voronkov, Dmitry N., Alla V. Stavrovskaya, Anastasia S. Guschina, Artyom S. Olshansky, Olga S. Lebedeva, Artyom V. Eremeev, and Maria A. Lagarkova. "Morphological Characterization of Astrocytes in a Xenograft of Human iPSC-Derived Neural Precursor Cells." Acta Naturae 14, no. 3 (October 29, 2022): 100–108. http://dx.doi.org/10.32607/actanaturae.11710.

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Transplantation of a mixed astrocyte and neuron culture is of interest in the development of cell therapies for neurodegenerative diseases. In this case, an assessment of engraftment requires a detailed morphological characterization, in particular an analysis of the neuronal and glial populations. In the experiment performed, human iPSC-derived neural progenitors transplanted into a rat striatum produced a mixed neuron and astrocyte population in vivo by the sixth month after transplantation. The morphological characteristics and neurochemical profile of the xenografted astrocytes were similar to those of mature human astroglia. Unlike neurons, astrocytes migrated to the surrounding structures and the density and pattern of their distribution in the striatum and cerebral cortex differed, which indicates that the microenvironment affects human glia integration. The graft was characterized by the zonal features of glial cell morphology, which was a reflection of cell maturation in the central area, glial shaft formation around the transplanted neurons, and migration to the surrounding structures.

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Zhao, Helen, Guy Perkins, Hang Yao, David Callacondo, Otto Appenzeller, Mark Ellisman, Albert R. La Spada, and Gabriel G. Haddad. "Mitochondrial dysfunction in iPSC-derived neurons of subjects with chronic mountain sickness." Journal of Applied Physiology 125, no. 3 (September 1, 2018): 832–40. http://dx.doi.org/10.1152/japplphysiol.00689.2017.

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Patients with chronic mountain sickness (CMS) suffer from hypoxemia, erythrocytosis, and numerous neurologic deficits. Here we used induced pluripotent stem cell (iPSC)-derived neurons from both CMS and non-CMS subjects to study CMS neuropathology. Using transmission electron microscopy, we report that CMS neurons have a decreased mitochondrial volume density, length, and less cristae membrane surface area. Real-time PCR confirmed a decreased mitochondrial fusion gene optic atrophy 1 (OPA1) expression. Immunoblot analysis showed an accumulation of the short isoform of OPA1 (S-OPA1) in CMS neurons, which have reduced ATP levels under normoxia and increased lactate dehydrogenase (LDH) release and caspase 3 activation after hypoxia. Improving the balance between the long isoform of OPA1 and S-OPA1 in CMS neurons increased the ATP levels and attenuated LDH release under hypoxia. Our data provide initial evidence for altered mitochondrial morphology and function in CMS neurons, and reveal increased cell death under hypoxia due in part to altered mitochondrial dynamics. NEW & NOTEWORTHY Induced pluripotent stem cell-derived neurons from chronic mountain sickness (CMS) subjects have altered mitochondrial morphology and dynamics, and increased sensitivity to hypoxic stress. Modification of OPA1 can attenuate cell death after hypoxic treatment, providing evidence that altered mitochondrial dynamics play an important role in increased vulnerability under stress in CMS neurons.

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Rakovic, Aleksandar, Philip Seibler, and Christine Klein. "iPS models of Parkin and PINK1." Biochemical Society Transactions 43, no. 2 (April 1, 2015): 302–7. http://dx.doi.org/10.1042/bst20150010.

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Parkinson disease (PD) is a degenerative disorder of the central nervous system resulting from depletion of dopaminergic neurons and currently remains incurable despite enormous international research efforts. The development of induced pluripotent stem cell (iPSC) technology opened up the unique possibility of studying disease mechanisms in human tissue that was otherwise not accessible, such as the brain. Of particular interest are the monogenetic forms of PD as they closely resemble the more common ‘idiopathic’ PD and, through the mutated protein, provide a clear research target in iPSC-derived neurons. Recessively inherited Parkin and PTEN-induced putative kinase 1 (PINK1) mutations have been investigated in this context and the present review describes the first insights gained from studies in iPSC-derived dopaminergic neurons, which comprise abnormalities in mitochondrial and dopamine homoeostasis, microtubular stability and axonal outgrowth. These new models of PD have a high translational potential that includes the identification of druggable targets, testing of known and novel therapeutic agents in the disease-relevant tissue using well-defined read-outs and potential regenerative approaches.

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Kathuria, Annie, Bradley Watmuff, Kara Lopez-Lengowski, Donna McPhie, Bruce Cohen, and Rakesh Karmacharya. "Dendritic Spine Differences in iPSC-Derived Cortical Neurons in Schizophrenia." Biological Psychiatry 89, no. 9 (May 2021): S33—S34. http://dx.doi.org/10.1016/j.biopsych.2021.02.102.

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Carvalhas-Almeida, C., L. Pereira de Almeida, C. Cavadas, P. Perdigão, and A. R. Álvaro. "Insomnia patient-derived iPSC neurons with potential for disease modeling." Sleep Medicine 100 (December 2022): S124—S125. http://dx.doi.org/10.1016/j.sleep.2022.05.343.

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Nakazawa, Takanobu. "Pharmacological studies using iPSC-derived neurons from patients with schizophrenia." Folia Pharmacologica Japonica 156, no. 4 (2021): 220–23. http://dx.doi.org/10.1254/fpj.21003.

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Saavedra, Lorena, Thomas Portman, Daniel Haag, Jonathan Davila, Timothy J. Shafer, Kathleen Wallace, Theresa Freudenrich, and Hui Liu. "In vitro neurotoxicity testing using functional human iPSC-derived neurons." Journal of Pharmacological and Toxicological Methods 111 (September 2021): 106976. http://dx.doi.org/10.1016/j.vascn.2021.106976.

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Negraes, P. D., F. R. Cugola, R. H. Herai, C. A. Trujillo, A. S. Cristino, T. Chailangkarn, A. R. Muotri, and V. Duvvuri. "Modeling anorexia nervosa: transcriptional insights from human iPSC-derived neurons." Translational Psychiatry 7, no. 3 (March 2017): e1060-e1060. http://dx.doi.org/10.1038/tp.2017.37.

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Girardin, Sophie, Blandine Clément, Stephan J. Ihle, Sean Weaver, Jana B. Petr, José C. Mateus, Jens Duru, et al. "Topologically controlled circuits of human iPSC-derived neurons for electrophysiology recordings." Lab on a Chip 22, no. 7 (2022): 1386–403. http://dx.doi.org/10.1039/d1lc01110c.

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We present a method to build microcircuits of human induced pluripotent stem cell (iPSC)-derived neurons with a controlled topology. The circuits are compatible with imaging and microelectrode array experiments.

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Wong, Ching-On, and Kartik Venkatachalam. "Motor neurons from ALS patients with mutations in C9ORF72 and SOD1 exhibit distinct transcriptional landscapes." Human Molecular Genetics 28, no. 16 (May 20, 2019): 2799–810. http://dx.doi.org/10.1093/hmg/ddz104.

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Abstract Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that culminates in paralysis and death. Here, we present our analyses of publicly available multiOMIC data sets generated using motor neurons from ALS patients and control cohorts. Functional annotation of differentially expressed genes in induced pluripotent stem cell (iPSC)-derived motor neurons generated from patients with mutations in C9ORF72 (C9-ALS) suggests elevated expression of genes that pertain to extracellular matrix (ECM) and cell adhesion, inflammation and TGFβ targets. On the other end of the continuum, we detected diminished expression of genes repressed by quiescence-promoting E2F4/DREAM complex. Proteins whose abundance was significantly altered in C9-ALS neurons faithfully recapitulated the transcriptional aberrations. Importantly, patterns of gene expression in spinal motor neurons dissected from C9-ALS or sporadic ALS patients were highly concordant with each other and with the C9-ALS iPSC neurons. In contrast, motor neurons from patients with mutations in SOD1 exhibited dramatically different signatures. Elevated expression of gene sets such as ECM and cell adhesion genes occurs in C9 and sporadic ALS but not SOD1-ALS. These analyses indicate that despite the similarities in outward manifestations, transcriptional and proteomic signatures in ALS motor neurons can vary significantly depending on the identity of the causal mutations.

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Behne, Robert, Julian Teinert, Miriam Wimmer, Angelica D’Amore, Alexandra K. Davies, Joseph M. Scarrott, Kathrin Eberhardt, et al. "Adaptor protein complex 4 deficiency: a paradigm of childhood-onset hereditary spastic paraplegia caused by defective protein trafficking." Human Molecular Genetics 29, no. 2 (January 9, 2020): 320–34. http://dx.doi.org/10.1093/hmg/ddz310.

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Abstract Deficiency of the adaptor protein complex 4 (AP-4) leads to childhood-onset hereditary spastic paraplegia (AP-4-HSP): SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). This study aims to evaluate the impact of loss-of-function variants in AP-4 subunits on intracellular protein trafficking using patient-derived cells. We investigated 15 patient-derived fibroblast lines and generated six lines of induced pluripotent stem cell (iPSC)-derived neurons covering a wide range of AP-4 variants. All patient-derived fibroblasts showed reduced levels of the AP4E1 subunit, a surrogate for levels of the AP-4 complex. The autophagy protein ATG9A accumulated in the trans-Golgi network and was depleted from peripheral compartments. Western blot analysis demonstrated a 3–5-fold increase in ATG9A expression in patient lines. ATG9A was redistributed upon re-expression of AP4B1 arguing that mistrafficking of ATG9A is AP-4-dependent. Examining the downstream effects of ATG9A mislocalization, we found that autophagic flux was intact in patient-derived fibroblasts both under nutrient-rich conditions and when autophagy is stimulated. Mitochondrial metabolism and intracellular iron content remained unchanged. In iPSC-derived cortical neurons from patients with AP4B1-associated SPG47, AP-4 subunit levels were reduced while ATG9A accumulated in the trans-Golgi network. Levels of the autophagy marker LC3-II were reduced, suggesting a neuron-specific alteration in autophagosome turnover. Neurite outgrowth and branching were reduced in AP-4-HSP neurons pointing to a role of AP-4-mediated protein trafficking in neuronal development. Collectively, our results establish ATG9A mislocalization as a key marker of AP-4 deficiency in patient-derived cells, including the first human neuron model of AP-4-HSP, which will aid diagnostic and therapeutic studies.

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Chen, I.-Cheng, Kuo-Hsuan Chang, Yi-Jing Chen, Yi-Chun Chen, Guey-Jen Lee-Chen, and Chiung-Mei Chen. "Pueraria lobata and Daidzein Reduce Cytotoxicity by Enhancing Ubiquitin-Proteasome System Function in SCA3-iPSC-Derived Neurons." Oxidative Medicine and Cellular Longevity 2019 (October 7, 2019): 1–18. http://dx.doi.org/10.1155/2019/8130481.

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Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion within the ATXN3/MJD1 gene. The expanded CAG repeats encode a polyglutamine (polyQ) tract at the C-terminus of the ATXN3 protein. ATXN3 containing expanded polyQ forms aggregates, leading to subsequent cellular dysfunctions including an impaired ubiquitin-proteasome system (UPS). To investigate the pathogenesis of SCA3 and develop potential therapeutic strategies, we established induced pluripotent stem cell (iPSC) lines from SCA3 patients (SCA3-iPSC). Neurons derived from SCA3-iPSCs formed aggregates that are positive to the polyQ marker 1C2. Treatment with the proteasome inhibitor, MG132, on SCA3-iPSC-derived neurons downregulated proteasome activity, increased production of radical oxygen species (ROS), and upregulated the cleaved caspase 3 level and caspase 3 activity. This increased susceptibility to the proteasome inhibitor can be rescued by a Chinese herbal medicine (CHM) extract NH037 (from Pueraria lobata) and its constituent daidzein via upregulating proteasome activity and reducing protein ubiquitination, oxidative stress, cleaved caspase 3 level, and caspase 3 activity. Our results successfully recapitulate the key phenotypes of the neurons derived from SCA3 patients, as well as indicate the potential of NH037 and daidzein in the treatment for SCA3 patients.

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Oakley, Derek H., Mirra Chung, Naomi Klickstein, Caitlin Commins, Bradley T. Hyman, and Matthew P. Frosch. "The Alzheimer Disease-Causing Presenilin-1 L435F Mutation Causes Increased Production of Soluble Aβ43 Species in Patient-Derived iPSC-Neurons, Closely Mimicking Matched Patient Brain Tissue." Journal of Neuropathology & Experimental Neurology 79, no. 6 (April 4, 2020): 592–604. http://dx.doi.org/10.1093/jnen/nlaa025.

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Abstract Familial Alzheimer disease-causing mutations in Presenilin 1 (PSEN1) are generally thought to shift the processing of APP toward longer, more amyloidogenic Aβ fragments. However, certain PSEN1 mutations cause severe reduction in gamma secretase function when expressed in the homozygous state, thus challenging the amyloid hypothesis. We sought to evaluate the effects of one such mutation, PSEN1 L435F, in more physiologic conditions and genetic contexts by using human induced pluripotent stem cell (iPSC)-derived neurons from an individual with familial AD (fAD) linked to the PSEN1 L435F mutation, and compared the biochemical phenotype of the iPS-derived neurons with brain tissue obtained at autopsy from the same patient. Our results demonstrate that in the endogenous heterozygous state, the PSEN1 L435F mutation causes a large increase in soluble Aβ43 but does not change the overall levels of soluble Aβ40 or Aβ42 when compared with control iPSC-neurons. Increased pathologically phosphorylated tau species were also observed in PSEN1-mutant iPSC-neurons. Concordant changes in Aβ species were present in autopsy brain tissue from the same patient. Finally, the feasibility of using Aβ43 immunohistochemistry of brain tissue to identify fAD cases was evaluated in a limited autopsy case series with the finding that strong Aβ43 staining occurred only in fAD cases.

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Alari, Valentina, Paolo Scalmani, Paola Francesca Ajmone, Sara Perego, Sabrina Avignone, Ilaria Catusi, Paola Adele Lonati, et al. "Histone Deacetylase Inhibitors Ameliorate Morphological Defects and Hypoexcitability of iPSC-Neurons from Rubinstein-Taybi Patients." International Journal of Molecular Sciences 22, no. 11 (May 28, 2021): 5777. http://dx.doi.org/10.3390/ijms22115777.

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Rubinstein-Taybi syndrome (RSTS) is a rare neurodevelopmental disorder caused by mutations in CREBBP or EP300 genes encoding CBP/p300 lysine acetyltransferases. We investigated the efficacy of the histone deacetylase inhibitor (HDACi) Trichostatin A (TSA) in ameliorating morphological abnormalities of iPSC-derived young neurons from P149 and P34 CREBBP-mutated patients and hypoexcitability of mature neurons from P149. Neural progenitors from both patients’ iPSC lines were cultured one week with TSA 20 nM and, only P149, for 6 weeks with TSA 0.2 nM, in parallel to neural progenitors from controls. Immunofluorescence of MAP2/TUJ1 positive cells using the Skeletonize Image J plugin evidenced that TSA partially rescued reduced nuclear area, and decreased branch length and abnormal end points number of both 45 days patients’ neurons, but did not influence the diminished percentage of their neurons with respect to controls. Patch clamp recordings of TSA-treated post-mitotic P149 neurons showed complete/partial rescue of sodium/potassium currents and significant enhancement of neuron excitability compared to untreated replicas. Correction of abnormalities of P149 young neurons was also affected by valproic acid 1 mM for 72 h, with some variation, with respect to TSA, on the morphological parameter. These findings hold promise for development of an epigenetic therapy to attenuate RSTS patients cognitive impairment.

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Brot, Sébastien, Nabila Pyrenina Thamrin, Marie-Laure Bonnet, Maureen Francheteau, Maëlig Patrigeon, Laure Belnoue, and Afsaneh Gaillard. "Long-Term Evaluation of Intranigral Transplantation of Human iPSC-Derived Dopamine Neurons in a Parkinson’s Disease Mouse Model." Cells 11, no. 10 (May 10, 2022): 1596. http://dx.doi.org/10.3390/cells11101596.

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Parkinson’s disease (PD) is a neurodegenerative disorder associated with loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). One strategy for treating PD is transplantation of DA neuroblasts. Significant advances have been made in generating midbrain DA neurons from human pluripotent stem cells. Before these cells can be routinely used in clinical trials, extensive preclinical safety studies are required. One of the main issues to be addressed is the long-term therapeutic effectiveness of these cells. In most transplantation studies using human cells, the maturation of DA neurons has been analyzed over a relatively short period not exceeding 6 months. In present study, we generated midbrain DA neurons from human induced pluripotent stem cells (hiPSCs) and grafted these neurons into the SNpc in an animal model of PD. Graft survival and maturation were analyzed from 1 to 12 months post-transplantation (mpt). We observed long-term survival and functionality of the grafted neurons. However, at 12 mpt, we observed a decrease in the proportion of SNpc DA neuron subtype compared with that at 6 mpt. In addition, at 12 mpt, grafts still contained immature neurons. Our results suggest that longer-term evaluation of the maturation of neurons derived from human stem cells is mandatory for the safe application of cell therapy for PD.

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Chao, Chuan-Chuan, Po-Wen Shen, Tsai-Yu Tzeng, Hsing-Jien Kung, Ting-Fen Tsai, and Yu-Hui Wong. "Human iPSC-Derived Neurons as A Platform for Deciphering the Mechanisms behind Brain Aging." Biomedicines 9, no. 11 (November 7, 2021): 1635. http://dx.doi.org/10.3390/biomedicines9111635.

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With an increased life expectancy among humans, aging has recently emerged as a major focus in biomedical research. The lack of in vitro aging models—especially for neurological disorders, where access to human brain tissues is limited—has hampered the progress in studies on human brain aging and various age-associated neurodegenerative diseases at the cellular and molecular level. In this review, we provide an overview of age-related changes in the transcriptome, in signaling pathways, and in relation to epigenetic factors that occur in senescent neurons. Moreover, we explore the current cell models used to study neuronal aging in vitro, including immortalized cell lines, primary neuronal culture, neurons directly converted from fibroblasts (Fib-iNs), and iPSC-derived neurons (iPSC-iNs); we also discuss the advantages and limitations of these models. In addition, the key phenotypes associated with cellular senescence that have been observed by these models are compared. Finally, we focus on the potential of combining human iPSC-iNs with genome editing technology in order to further our understanding of brain aging and neurodegenerative diseases, and discuss the future directions and challenges in the field.

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Huang, Hsiang-Po, Wei Chiang, Lee Stone, Chun-Kai Kang, Ching-Yu Chuang, and Hung-Chih Kuo. "Using human Pompe disease-induced pluripotent stem cell-derived neural cells to identify compounds with therapeutic potential." Human Molecular Genetics 28, no. 23 (September 13, 2019): 3880–94. http://dx.doi.org/10.1093/hmg/ddz218.

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Abstract Pompe disease (OMIM # 232300) is a glycogen storage disease caused by autosomal recessive mutations of the gene encoding alpha-1,4-glucosidase (GAA; EC 3.2.1.20). Despite the relatively effective employment of enzyme replacement therapy, some critical medical issues still exist in patients with this disease, including the persistence of abnormalities in the central nervous system (CNS), probably because of the inability of the recombinant GAA to pass through the blood–brain barrier. To address this issue, identification of more therapeutic agents that target the CNS of patients with Pompe disease may be required. In this study, we derived neuronal cells from Pompe disease-induced pluripotent stem cells (Pom-iPSCs) and proved that they are able to recapitulate the hallmark cellular and biochemical phenotypes of Pompe disease. Using the Pom-iPSC-derived neurons as an in vitro drug-testing model, we then identified three compounds, ebselen, wortmannin and PX-866, with therapeutic potential to alleviate Pompe disease-associated pathological phenotypes in the neurons derived from Pom-iPSCs. We confirmed that all three compounds were able to enhance the GAA activity in the Pom-iPSC-derived neurons. Moreover, they were able to enhance the GAA activity in several important internal organs of GAA-deficient mice when co-injected with recombinant human GAA, and we found that intraperitoneal injection of ebselen was able to promote the GAA activity of the GAA-heterozygous mouse brain. Our results prove the usefulness of Pom-iPSC-derived neuronal populations for identifying new compounds with therapeutic potential.

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Ranjan, Vivek Damodar, Lifeng Qiu, Jolene Wei-Ling Lee, Xuelong Chen, Se Eun Jang, Chou Chai, Kah-Leong Lim, et al. "A microfiber scaffold-based 3D in vitro human neuronal culture model of Alzheimer's disease." Biomaterials Science 8, no. 17 (2020): 4861–74. http://dx.doi.org/10.1039/d0bm00833h.

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Highly efficient neurogenic differentiation, maturation as well as spontaneous amplification of pathogenic amyloid-beta 42 (Aβ42) and phospho-tau expression were achieved on interfacing iPSC-derived neurons with 3D PLGA microfiber scaffolds.

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Burman, Richard J., Lauren M. Watson, Danielle C. Smith, Joseph V. Raimondo, Robea Ballo, Janine Scholefield, Sally A. Cowley, Matthew J. A. Wood, Susan H. Kidson, and Leslie J. Greenberg. "Molecular and electrophysiological features of spinocerebellar ataxia type seven in induced pluripotent stem cells." PLOS ONE 16, no. 2 (February 24, 2021): e0247434. http://dx.doi.org/10.1371/journal.pone.0247434.

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Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disease caused by a polyglutamine repeat expansion in the ATXN7 gene. Patients with this disease suffer from a degeneration of their cerebellar Purkinje neurons and retinal photoreceptors that result in a progressive ataxia and loss of vision. As with many neurodegenerative diseases, studies of pathogenesis have been hindered by a lack of disease-relevant models. To this end, we have generated induced pluripotent stem cells (iPSCs) from a cohort of SCA7 patients in South Africa. First, we differentiated the SCA7 affected iPSCs into neurons which showed evidence of a transcriptional phenotype affecting components of STAGA (ATXN7 and KAT2A) and the heat shock protein pathway (DNAJA1 and HSP70). We then performed electrophysiology on the SCA7 iPSC-derived neurons and found that these cells show features of functional aberrations. Lastly, we were able to differentiate the SCA7 iPSCs into retinal photoreceptors that also showed similar transcriptional aberrations to the SCA7 neurons. Our findings give technical insights on how iPSC-derived neurons and photoreceptors can be derived from SCA7 patients and demonstrate that these cells express molecular and electrophysiological differences that may be indicative of impaired neuronal health. We hope that these findings will contribute towards the ongoing efforts to establish the cell-derived models of neurodegenerative diseases that are needed to develop patient-specific treatments.

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Ellerby, Lisa, Sicheng Song, Sean Mooney, Stephen Scheeler, and Swati Naphade. "GENOMIC ANALYSIS OF HUMAN ISOGENIC APOE IPSC-DERIVED INHIBITORY GABAERGIC NEURONS." Innovation in Aging 3, Supplement_1 (November 2019): S621. http://dx.doi.org/10.1093/geroni/igz038.2315.

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Abstract Isoforms of ApoE modify the risk for Alzheimer’s disease (AD), cardiovascular disease and are also associated with exceptional longevity. Specifically, the ApoE E2 allele is associated with lower risk of AD-related neurodegeneration and with exceptional longevity, while the E4 allele is a major risk factor for AD and is associated with higher levels of Abeta deposition in the brain. The mechanisms modulating extended lifespan/healthspan mediated by E2 compared to E3 and E4 genotypes are not clear. One hypothesis is that the E2 allele is neuroprotective and compensates for neuronal dysfunction induced by misfolded protein expression in aging and disease. To understand the molecular basis of the protective effect of the E2 allele we performed transcriptomic analysis of isogenic iPSCs with E2E2 and E4E4 genotypes differentiated into inhibitory GABAergic neurons. Our analysis revealed that ApoE2 inhibitory GABAergic neurons regulate genes involved in nuclear division, DNA integrity and DNA damage checkpoint.

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Bai, Xiaowen. "Stem Cell-Based Disease Modeling and Cell Therapy." Cells 9, no. 10 (September 29, 2020): 2193. http://dx.doi.org/10.3390/cells9102193.

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Stem cell science is among the fastest moving fields in biology, with many highly promising directions for translatability. To centralize and contextualize some of the latest developments, this Special Issue presents state-of-the-art research of adult stem cells, induced pluripotent stem cells (iPSCs), and embryonic stem cells as well as cancer stem cells. The studies we include describe efficient differentiation protocols of generation of chondrocytes, adipocytes, and neurons, maturation of iPSC-derived cardiomyocytes and neurons, dynamic characterization of iPSC-derived 3D cerebral organoids, CRISPR/Cas9 genome editing, and non-viral minicircle vector-based gene modification of stem cells. Different applications of stem cells in disease modeling are described as well. This volume also highlights the most recent developments and applications of stem cells in basic science research and disease treatments.

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Oakley, Derek H., Naomi Klickstein, Caitlin Commins, Mirra Chung, Simon Dujardin, Rachel E. Bennett, Bradley T. Hyman, and Matthew P. Frosch. "Continuous Monitoring of Tau-Induced Neurotoxicity in Patient-Derived iPSC-Neurons." Journal of Neuroscience 41, no. 19 (April 23, 2021): 4335–48. http://dx.doi.org/10.1523/jneurosci.2590-20.2021.

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Lickfett, Selene, Carmen Menacho, Annika Zink, Narasimha Swamy Telugu, Mathias Beller, Sebastian Diecke, Sidney Cambridge, and Alessandro Prigione. "High-content analysis of neuronal morphology in human iPSC-derived neurons." STAR Protocols 3, no. 3 (September 2022): 101567. http://dx.doi.org/10.1016/j.xpro.2022.101567.

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Mooree, Travis, Poulomee Bose, Jill Wood, Thomas Durcan, and Alexey Pshezhetsky. "iPSC derived neurons of mucopolysaccharidosis III patients show pronounced synaptic defects." Molecular Genetics and Metabolism 135, no. 2 (February 2022): S85. http://dx.doi.org/10.1016/j.ymgme.2021.11.219.

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Journal articles on the topic 'IPSC-derived neurons'

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