Academic literature on the topic 'IPSC-derived MN'
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Journal articles on the topic "IPSC-derived MN"
1
Castellanos-Montiel, María José, Mathilde Chaineau, Anna Kristyna Franco-Flores, Ghazal Haghi, Dulce Carrillo-Valenzuela, Wolfgang E. Reintsch, Carol X. Q. Chen, and Thomas M. Durcan. "An Optimized Workflow to Generate and Characterize iPSC-Derived Motor Neuron (MN) Spheroids." Cells 12, no. 4 (February 8, 2023): 545. http://dx.doi.org/10.3390/cells12040545.
Full textAbstract:
A multitude of in vitro models based on induced pluripotent stem cell (iPSC)-derived motor neurons (MNs) have been developed to investigate the underlying causes of selective MN degeneration in motor neuron diseases (MNDs). For instance, spheroids are simple 3D models that have the potential to be generated in large numbers that can be used across different assays. In this study, we generated MN spheroids and developed a workflow to analyze them. To start, the morphological profiling of the spheroids was achieved by developing a pipeline to obtain measurements of their size and shape. Next, we confirmed the expression of different MN markers at the transcript and protein levels by qPCR and immunocytochemistry of tissue-cleared samples, respectively. Finally, we assessed the capacity of the MN spheroids to display functional activity in the form of action potentials and bursts using a microelectrode array approach. Although most of the cells displayed an MN identity, we also characterized the presence of other cell types, namely interneurons and oligodendrocytes, which share the same neural progenitor pool with MNs. In summary, we successfully developed an MN 3D model, and we optimized a workflow that can be applied to perform its morphological, gene expression, protein, and functional profiling over time.
2
Zhang, Yiti, Baitao Zeng, Ao Gu, Qinyu Kang, Mingri Zhao, Guangnan Peng, Miaojin Zhou, et al. "Damaged DNA Is an Early Event of Neurodegeneration in Induced Pluripotent Stem Cell-Derived Motoneurons with UBQLN2P497H Mutation." International Journal of Molecular Sciences 23, no. 19 (September 26, 2022): 11333. http://dx.doi.org/10.3390/ijms231911333.
Full textAbstract:
Ubiquilin-2 (UBQLN2) mutations lead to familial amyotrophic lateral sclerosis (FALS)/and frontotemporal dementia (FTLD) through unknown mechanisms. The combination of iPSC technology and CRISPR-mediated genome editing technology can generate an iPSC-derived motor neuron (iPSC-MN) model with disease-relevant mutations, which results in increased opportunities for disease mechanism research and drug screening. In this study, we introduced a UBQLN2-P497H mutation into a healthy control iPSC line using CRISPR/Cas9, and differentiated into MNs to study the pathology of UBQLN2-related ALS. Our in vitro MN model faithfully recapitulated specific aspects of the disease, including MN apoptosis. Under sodium arsenite (SA) treatment, we found differences in the number and the size of UBQLN2+ inclusions in UBQLN2P497H MNs and wild-type (WT) MNs. We also observed cytoplasmic TAR DNA-binding protein (TARDBP, also known as TDP-43) aggregates in UBQLN2P497H MNs, but not in WT MNs, as well as the recruitment of TDP-43 into stress granules (SGs) upon SA treatment. We noted that UBQLN2-P497H mutation induced MNs DNA damage, which is an early event in UBQLN2-ALS. Additionally, DNA damage led to an increase in compensation for FUS, whereas UBQLN2-P497H mutation impaired this function. Therefore, FUS may be involved in DNA damage repair signaling.
3
Gori, Jennifer L., Devikha Chandrasekaran, John P. Kowalski, Jennifer E. Adair, Brian C. Beard, Sunita L. D'Souza, and Hans-Peter Kiem. "Efficient generation, purification, and expansion of CD34+ hematopoietic progenitor cells from nonhuman primate–induced pluripotent stem cells." Blood 120, no. 13 (September 27, 2012): e35-e44. http://dx.doi.org/10.1182/blood-2012-05-433797.
Full textAbstract:
AbstractInduced pluripotent stem cell (iPSC) therapeutics are a promising treatment for genetic and infectious diseases. To assess engraftment, risk of neoplastic formation, and therapeutic benefit in an autologous setting, testing iPSC therapeutics in an appropriate model, such as the pigtail macaque (Macaca nemestrina; Mn), is crucial. Here, we developed a chemically defined, scalable, and reproducible specification protocol with bone morphogenetic protein 4, prostaglandin-E2 (PGE2), and StemRegenin 1 (SR1) for hematopoietic differentiation of Mn iPSCs. Sequential coculture with bone morphogenetic protein 4, PGE2, and SR1 led to robust Mn iPSC hematopoietic progenitor cell formation. The combination of PGE2 and SR1 increased CD34+CD38−Thy1+CD45RA−CD49f+ cell yield by 6-fold. CD34+CD38−Thy1+CD45RA−CD49f+ cells isolated on the basis of CD34 expression and cultured in SR1 expanded 3-fold and maintained this long-term repopulating HSC phenotype. Purified CD34high cells exhibited 4-fold greater hematopoietic colony-forming potential compared with unsorted hematopoietic progenitors and had bilineage differentiation potential. On the basis of these studies, we calculated the cell yields that must be achieved at each stage to meet a threshold CD34+ cell dose that is required for engraftment in the pigtail macaque. Our protocol will support scale-up and testing of iPSC-derived CD34high cell therapies in a clinically relevant nonhuman primate model.
4
Thiry, Louise, Jean-Pierre Clément, Rainer Haag, Timothy E. Kennedy, and Stefano Stifani. "Optimization of Long-Term Human iPSC-Derived Spinal Motor Neuron Culture Using a Dendritic Polyglycerol Amine-Based Substrate." ASN Neuro 14 (January 2022): 175909142110733. http://dx.doi.org/10.1177/17590914211073381.
Full textAbstract:
Human induced pluripotent stem cells (hiPSCs) derived from healthy and diseased individuals can give rise to many cell types, facilitating the study of mechanisms of development, human disease modeling, and early drug target validation. In this context, experimental model systems based on hiPSC-derived motor neurons (MNs) have been used to study MN diseases such as spinal muscular atrophy and amyotrophic lateral sclerosis. Modeling MN disease using hiPSC-based approaches requires culture conditions that can recapitulate in a dish the events underlying differentiation, maturation, aging, and death of MNs. Current hiPSC-derived MN-based applications are often hampered by limitations in our ability to monitor MN morphology, survival, and other functional properties over a prolonged timeframe, underscoring the need for improved long-term culture conditions. Here we describe a cytocompatible dendritic polyglycerol amine (dPGA) substrate-based method for prolonged culture of hiPSC-derived MNs. We provide evidence that MNs cultured on dPGA-coated dishes are more amenable to long-term study of cell viability, molecular identity, and spontaneous network electrophysiological activity. The present study has the potential to improve hiPSC-based studies of human MN biology and disease. We describe the use of a new coating substrate providing improved conditions for long-term cultures of human iPSC-derived motor neurons, thus allowing evaluation of cell viability, molecular identity, spontaneous network electrophysiological activity, and single-cell RNA sequencing of mature motor neurons.
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Johns, Alexandra E., and Nicholas J. Maragakis. "Exploring Motor Neuron Diseases Using iPSC Platforms." Stem Cells 40, no. 1 (January 1, 2022): 2–13. http://dx.doi.org/10.1093/stmcls/sxab006.
Full textAbstract:
Abstract The degeneration of motor neurons is a pathological hallmark of motor neuron diseases (MNDs), but emerging evidence suggests that neuronal vulnerability extends well beyond this cell subtype. The ability to assess motor function in the clinic is limited to physical examination, electrophysiological measures, and tissue-based or neuroimaging techniques which lack the resolution to accurately assess neuronal dysfunction as the disease progresses. Spinal muscular atrophy (SMA), spinal and bulbar muscular atrophy (SBMA), hereditary spastic paraplegia (HSP), and amyotrophic lateral sclerosis (ALS) are all MNDs with devastating clinical outcomes that contribute significantly to disease burden as patients are no longer able to carry out normal activities of daily living. The critical need to accurately assess the cause and progression of motor neuron dysfunction, especially in the early stages of those diseases, has motivated the use of human iPSC-derived motor neurons (hiPSC-MN) to study the neurobiological mechanisms underlying disease pathogenesis and to generate platforms for therapeutic discovery and testing. As our understanding of MNDs has grown, so too has our need to develop more complex in vitro models which include hiPSC-MN co-cultured with relevant non-neuronal cells in 2D as well as in 3D organoid and spheroid systems. These more complex hiPSC-derived culture systems have led to the implementation of new technologies, including microfluidics, multielectrode array, and machine learning which offer novel insights into the functional correlates of these emerging model systems.
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Akter, Masuma, and Baojin Ding. "Modeling Movement Disorders via Generation of hiPSC-Derived Motor Neurons." Cells 11, no. 23 (November 27, 2022): 3796. http://dx.doi.org/10.3390/cells11233796.
Full textAbstract:
Generation of motor neurons (MNs) from human-induced pluripotent stem cells (hiPSCs) overcomes the limited access to human brain tissues and provides an unprecedent approach for modeling MN-related diseases. In this review, we discuss the recent progression in understanding the regulatory mechanisms of MN differentiation and their applications in the generation of MNs from hiPSCs, with a particular focus on two approaches: induction by small molecules and induction by lentiviral delivery of transcription factors. At each induction stage, different culture media and supplements, typical growth conditions and cellular morphology, and specific markers for validation of cell identity and quality control are specifically discussed. Both approaches can generate functional MNs. Currently, the major challenges in modeling neurological diseases using iPSC-derived neurons are: obtaining neurons with high purity and yield; long-term neuron culture to reach full maturation; and how to culture neurons more physiologically to maximize relevance to in vivo conditions.
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Watts, Michelle E., Chen Wu, and Lee L. Rubin. "Suppression of MAP4K4 Signaling Ameliorates Motor Neuron Degeneration in Amyotrophic Lateral Sclerosis-Molecular Studies Toward New Therapeutics." Journal of Experimental Neuroscience 13 (January 2019): 117906951986279. http://dx.doi.org/10.1177/1179069519862798.
Full textAbstract:
Amyotrophic lateral sclerosis (ALS), the most common motor neuron (MN) disease of adults, is characterized by the degeneration of upper MNs in the motor cortex and lower MNs in the brain stem and spinal cord. Our recent work suggests that a MAP kinase family member, MAP4K4 (mitogen-activated protein kinase kinase kinase kinase 4), regulates MN degeneration in ALS. Activation of MAP4K4 occurs prior to MN death and inhibition of MAP4K4 improves neurite integrity and neuronal viability in a cell autonomous manner. The mechanism through which MAP4K4 reduction specifically modulates MN viability can be attributed to the attenuation of the c-Jun apoptotic pathway, as well as to the activation of FoxO1-mediated autophagy that reduces the accumulation of protein aggregates. We additionally show the feasibility of MAP4K4 as a drug target using a MAP4K4-specific inhibitor, which improves the survival of both primary and induced pluripotent stem cell (iPSC)-derived MNs. Our studies are thus far the first to highlight a MAP4K4-initiated signaling cascade that contributes to MN degeneration in ALS, providing a new mechanism underlying MN death in disease and a druggable target for new therapeutics. We propose exciting future directions and unexplored avenues based upon this work.
8
Bräuer, Stefan, René Günther, Jared Sterneckert, Hannes Glaß, and Andreas Hermann. "Human Spinal Motor Neurons Are Particularly Vulnerable to Cerebrospinal Fluid of Amyotrophic Lateral Sclerosis Patients." International Journal of Molecular Sciences 21, no. 10 (May 18, 2020): 3564. http://dx.doi.org/10.3390/ijms21103564.
Full textAbstract:
Amyotrophic lateral sclerosis (ALS) is the most common and devastating motor neuron (MN) disease. Its pathophysiological cascade is still enigmatic. More than 90% of ALS patients suffer from sporadic ALS, which makes it specifically demanding to generate appropriate model systems. One interesting aspect considering the seeding, spreading and further disease development of ALS is the cerebrospinal fluid (CSF). We therefore asked whether CSF from sporadic ALS patients is capable of causing disease typical changes in human patient-derived spinal MN cultures and thus could represent a novel model system for sporadic ALS. By using induced pluripotent stem cell (iPSC)-derived MNs from healthy controls and monogenetic forms of ALS we could demonstrate a harmful effect of ALS-CSF on healthy donor-derived human MNs. Golgi fragmentation—a typical finding in lower organism models and human postmortem tissue—was induced solely by addition of ALS-CSF, but not control-CSF. No other neurodegenerative hallmarks—including pathological protein aggregation—were found, underpinning Golgi fragmentation as early event in the neurodegenerative cascade. Of note, these changes occurred predominantly in MNs, the cell type primarily affected in ALS. We thus present a novel way to model early features of sporadic ALS.
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Budding, Kevin, Lill Eva Johansen, Inge Van de Walle, Kim Dijkxhoorn, Elisabeth de Zeeuw, Lauri M. Bloemenkamp, Jeroen W. Bos, et al. "Anti-C2 Antibody ARGX-117 Inhibits Complement in a Disease Model for Multifocal Motor Neuropathy." Neurology - Neuroimmunology Neuroinflammation 9, no. 1 (November 10, 2021): e1107. http://dx.doi.org/10.1212/nxi.0000000000001107.
Full textAbstract:
Background and ObjectivesTo determine the role of complement in the disease pathology of multifocal motor neuropathy (MMN), we investigated complement activation, and inhibition, on binding of MMN patient-derived immunoglobulin M (IgM) antibodies in an induced pluripotent stem cell (iPSC)-derived motor neuron (MN) model for MMN.MethodsiPSC-derived MNs were characterized for the expression of complement receptors and membrane-bound regulators, for the binding of circulating IgM anti-GM1 from patients with MMN, and for subsequent fixation of C4 and C3 on incubation with fresh serum. The potency of ARGX-117, a novel inhibitory monoclonal antibody targeting C2, to inhibit fixation of complement was assessed.ResultsiPSC-derived MNs moderately express the complement regulatory proteins CD46 and CD55 and strongly expressed CD59. Furthermore, MNs express C3aR, C5aR, and complement receptor 1. IgM anti-GM1 antibodies in serum from patients with MMN bind to MNs and induce C3 and C4 fixation on incubation with fresh serum. ARGX-117 inhibits complement activation downstream of C4 induced by patient-derived anti-GM1 antibodies bound to MNs.DiscussionBinding of IgM antibodies from patients with MMN to iPSC-derived MNs induces complement activation. By expressing complement regulatory proteins, particularly CD59, MNs are protected against complement-mediated lysis. Yet, because of expressing C3aR, the function of these cells may be affected by complement activation upstream of membrane attack complex formation. ARGX-117 inhibits complement activation upstream of C3 in this disease model for MMN and therefore represents an intervention strategy to prevent harmful effects of complement in MMN.
10
Jin, Mengmeng, Katja Akgün, Tjalf Ziemssen, Markus Kipp, Rene Günther, and Andreas Hermann. "Interleukin-17 and Th17 Lymphocytes Directly Impair Motoneuron Survival of Wildtype and FUS-ALS Mutant Human iPSCs." International Journal of Molecular Sciences 22, no. 15 (July 27, 2021): 8042. http://dx.doi.org/10.3390/ijms22158042.
Full textAbstract:
Amyotrophic lateral sclerosis (ALS) is a progressive disease leading to the degeneration of motor neurons (MNs). Neuroinflammation is involved in the pathogenesis of ALS; however, interactions of specific immune cell types and MNs are not well studied. We recently found a shift toward T helper (Th)1/Th17 cell-mediated, pro-inflammatory immune responses in the peripheral immune system of ALS patients, which positively correlated with disease severity and progression. Whether Th17 cells or their central mediator, Interleukin-17 (IL-17), directly affects human motor neuron survival is currently unknown. Here, we evaluated the contribution of Th17 cells and IL-17 on MN degeneration using the co-culture of iPSC-derived MNs of fused in sarcoma (FUS)-ALS patients and isogenic controls with Th17 lymphocytes derived from ALS patients, healthy controls, and multiple sclerosis (MS) patients (positive control). Only Th17 cells from MS patients induced severe MN degeneration in FUS-ALS as well as in wildtype MNs. Their main effector, IL-17A, yielded in a dose-dependent decline of the viability and neurite length of MNs. Surprisingly, IL-17F did not influence MNs. Importantly, neutralizing IL-17A and anti-IL-17 receptor A treatment reverted all effects of IL-17A. Our results offer compelling evidence that Th17 cells and IL-17A do directly contribute to MN degeneration.
Dissertations / Theses on the topic "IPSC-derived MN"
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BIELLA, FABIO. "INVESTIGATION OF C9ORF72 MOLECULAR HALLMARKS AND DEVELOPMENT OF THERAPEUTIC STRATEGIES." Doctoral thesis, Università degli Studi di Milano, 2021. http://hdl.handle.net/2434/827721.
Full textAbstract:
The majority of genetic Amyotrophic Lateral Sclerosis (ALS) cases are
due to the expansion in the number of an hexanucleotidic repeat in a
non-coding site of the locus C9orf72. Many mechanisms for the
C9orf72-ALS are suggested, both loss of function and gain of function
due to RNA foci and Dipeptide Repeats (DPR) toxicity.
Research on C9orf72-ALS is hindered by the lack of satisfactory
models and by the difficult access to the target cell type. Animal
models fail to recreate all the pathological features and the situation is
further complicated by the presence of many disease modifying genes.
To overcome theseissues, this study takes advantages of the induced
Pluripotent Stem Cells (iPSCs) technology to investigate canonical as
well as more recent C9orf72 molecular hallmarks. The iPSCs carry the
same genetic background of patients and can be further differentiated
in motoneurons (MNs) to study neuronal specific alteration and
comparing C9orf72-expanded cell lines with their isogenic corrected
counterpart, the influence of disease-modifying genes can be
eliminated.
We analysed canonical RNA foci and DPR accumulation finding them
increased in C9orf72 samples in both models. DNA damage
accumulation, a recently discovered C9orf72-ALS feature, was also
increased.
Moreover, in iPSC-derived MNs expression of SEPT7, STMN1 and
STMN2 genes, cytoskeletal regulators with important function in
neuronal cells, has been found altered in C9orf72 background.
Taking advantage of these established models we could also evaluate
the efficacy of a morpholine (MO)-based antisense oligonucleotide
(ASO) therapy as a proof of principle for the feasibility of drug
screening in these models. We foundthat both our MO oligomers were
able to rescue DPR accumulation and DNA damage induction.
Global gene expression analysis has also been performed. From this
investigation a subtle alteration in genes related with neuronal function
in iPSC was detected, while C9orf72 MNs showed deregulation in
pathways related to inflammation and cell-to-cell communication
suggesting a non-cell-autonomous mechanism for the disease.
Interestingly, MOs treatment could rescue these alterations.
Moving forward we started the characterization of a 3D organoidbased model of C9orf72-ALS that can reproduce the complexity of
central nervous system. We found in organoids DPR accumulation
and other disease hallmarks which could not be detected in 2D
models, supporting the promising role of this 3D model.