iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases 2022

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

Deadline for manuscript submissions: closed (15 June 2023) | Viewed by 45256

Special Issue Editors


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Guest Editor
Institute of Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University, 40225 Dusseldorf, Germany
Interests: iPSC-based disease modelling; Alzheimer's disease; Nijmegen breakage syndrome; steatosis patients; acute and chronic kidney injury
Special Issues, Collections and Topics in MDPI journals

E-Mail Website
Guest Editor
Institute of Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University, 40225 Dusseldorf, Germany
Interests: pluripotent stem cells; in vitro differentiation; hepatocytes; non alcoholic fatty liver disease; epigenetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Since the generation of human-induced pluripotent stem cells (iPSCs) in 2007, numerous protocols have been developed to differentiate iPSCs into cells of all three germ layers. iPSC-derived cellular products have already been applied in regenerative medicine-based therapies. 

In addition to therapy, in vitro differentiated cells are currently used for drug testing, development, and disease modeling to give valuable insights into underlying mechanisms. iPSC-derived 3D organoids are composed of distinct cell types characteristic within the organ under investigation and adopt specific organ-related structure, thus further increasing their maturity and utility compared to 2D cultured cells. Furthermore, culturing of organoids employing organ-on-a-chip systems has added an additional level of sophistication and enhancement, thus enabling investigations at near-physiological levels. 

In this Special Issue, we call for original research, review articles, and meta-analyses related to iPSC-based 2D and 3D disease modeling, encompassing organs derived from all three germ layers. In addition, we are interested in studies demonstrating the therapeutic usefulness and safety of iPSC-derived cells. 

Prof. Dr. James Adjaye
Dr. Nina Graffmann
Guest Editors

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Keywords

  • Induced pluripotent stem cells (iPSCs)
  • genome editing
  • disease modeling
  • organoids
  • organ-on-a-chip
  • cellular therapeutics
  • bioinformatics

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Published Papers (17 papers)

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Research

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20 pages, 5373 KiB  
Article
Genetic and Pharmacological YAP Activation Induces Proliferation and Improves Survival in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes
by Thuy Anh Bui, Nicholas Stafford and Delvac Oceandy
Cells 2023, 12(17), 2121; https://doi.org/10.3390/cells12172121 - 22 Aug 2023
Viewed by 1838
Abstract
Cardiomyocyte loss following myocardial infarction cannot be addressed with current clinical therapies. Cell therapy with induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) is a potential approach to replace cardiomyocyte loss. However, engraftment rates in pre-clinical studies have been low, highlighting a need to refine [...] Read more.
Cardiomyocyte loss following myocardial infarction cannot be addressed with current clinical therapies. Cell therapy with induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) is a potential approach to replace cardiomyocyte loss. However, engraftment rates in pre-clinical studies have been low, highlighting a need to refine current iPSC-CM technology. In this study, we demonstrated that inducing Yes-associated protein (YAP) by genetic and pharmacological approaches resulted in increased iPSC-CM proliferation and reduced apoptosis in response to oxidative stress. Interestingly, iPSC-CM maturation was differently affected by each strategy, with genetic activation of YAP resulting in a more immature cardiomyocyte-like phenotype not witnessed upon pharmacological YAP activation. Overall, we conclude that YAP activation in iPSC-CMs enhances cell survival and proliferative capacity. Therefore, strategies targeting YAP, or its upstream regulator the Hippo signalling pathway, could potentially be used to improve the efficacy of iPSC-CM technology for use as a future regenerative therapy in myocardial infarction. Full article
(This article belongs to the Special Issue iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases 2022)
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19 pages, 3012 KiB  
Article
An Improved Protocol for Targeted Differentiation of Primed Human Induced Pluripotent Stem Cells into HLA-G-Expressing Trophoblasts to Enable the Modeling of Placenta-Related Disorders
by Ian O. Shum, Sylvia Merkert, Svitlana Malysheva, Kirsten Jahn, Nico Lachmann, Murielle Verboom, Helge Frieling, Michael Hallensleben and Ulrich Martin
Cells 2023, 12(16), 2070; https://doi.org/10.3390/cells12162070 - 15 Aug 2023
Viewed by 1411
Abstract
Abnormalities at any stage of trophoblast development may result in pregnancy-related complications. Many of these adverse outcomes are discovered later in pregnancy, but the underlying pathomechanisms are constituted during the first trimester. Acquiring developmentally relevant material to elucidate the disease mechanisms is difficult. [...] Read more.
Abnormalities at any stage of trophoblast development may result in pregnancy-related complications. Many of these adverse outcomes are discovered later in pregnancy, but the underlying pathomechanisms are constituted during the first trimester. Acquiring developmentally relevant material to elucidate the disease mechanisms is difficult. Human pluripotent stem cell (hPSC) technology can provide a renewable source of relevant cells. BMP4, A83-01, and PD173074 (BAP) treatment drives trophoblast commitment of hPSCs toward syncytiotrophoblast (STB), but lacks extravillous trophoblast (EVT) cells. EVTs mediate key functions during placentation, remodeling of uterine spiral arteries, and maintenance of immunological tolerance. We optimized the protocol for a more efficient generation of HLA-Gpos EVT-like trophoblasts from primed hiPSCs. Increasing the concentrations of A83-01 and PD173074, while decreasing bulk cell density resulted in an increase in HLA-G of up to 71%. Gene expression profiling supports the advancements of our treatment regarding the generation of trophoblast cells. The reported differentiation protocol will allow for an on-demand access to human trophoblast cells enriched for HLA-Gpos EVT-like cells, allowing for the elucidation of placenta-related disorders and investigating the immunological tolerance toward the fetus, overcoming the difficulties in obtaining primary EVTs without the need for a complex differentiation pathway via naïve pluripotent or trophoblast stem cells. Full article
(This article belongs to the Special Issue iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases 2022)
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14 pages, 2074 KiB  
Article
Excitatory Neurons Derived from Human-Induced Pluripotent Stem Cells Show Transcriptomic Differences in Alzheimer’s Patients from Controls
by Ram Sagar, Ioannis Azoidis, Cristina Zivko, Ariadni Xydia, Esther S. Oh, Paul B. Rosenberg, Constantine G. Lyketsos, Vasiliki Mahairaki and Dimitrios Avramopoulos
Cells 2023, 12(15), 1990; https://doi.org/10.3390/cells12151990 - 2 Aug 2023
Cited by 3 | Viewed by 1652
Abstract
The recent advances in creating pluripotent stem cells from somatic cells and differentiating them into a variety of cell types is allowing us to study them without the caveats associated with disease-related changes. We generated induced Pluripotent Stem Cells (iPSCs) from eight Alzheimer’s [...] Read more.
The recent advances in creating pluripotent stem cells from somatic cells and differentiating them into a variety of cell types is allowing us to study them without the caveats associated with disease-related changes. We generated induced Pluripotent Stem Cells (iPSCs) from eight Alzheimer’s disease (AD) patients and six controls and used lentiviral delivery to differentiate them into excitatory glutamatergic neurons. We then performed RNA sequencing on these neurons and compared the Alzheimer’s and control transcriptomes. We found that 621 genes show differences in expression levels at adjusted p < 0.05 between the case and control derived neurons. These genes show significant overlap and directional concordance with genes reported from a single-cell transcriptome study of AD patients; they include five genes implicated in AD from genome-wide association studies and they appear to be part of a larger functional network as indicated by an excess of interactions between them observed in the protein–protein interaction database STRING. Exploratory analysis with Uniform Manifold Approximation and Projection (UMAP) suggests distinct clusters of patients, based on gene expression, who may be clinically different. Our research outcomes will enable the precise identification of distinct biological subtypes among individuals with Alzheimer’s disease, facilitating the implementation of tailored precision medicine strategies. Full article
(This article belongs to the Special Issue iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases 2022)
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19 pages, 4207 KiB  
Article
Application-Oriented Bulk Cryopreservation of Human iPSCs in Cryo Bags Followed by Direct Inoculation in Scalable Suspension Bioreactors for Expansion and Neural Differentiation
by Ina Meiser, Monica Alstrup, Elham Khalesi, Bianca Stephan, Anna M. Speicher, Julia Majer, Chee Keong Kwok, Julia C. Neubauer, Mattias Hansson and Heiko Zimmermann
Cells 2023, 12(14), 1914; https://doi.org/10.3390/cells12141914 - 22 Jul 2023
Cited by 1 | Viewed by 1491
Abstract
Stem cell-based therapies are promising tools for regenerative medicine and require bulk numbers of high-quality cells. Currently, cells are produced on demand and have a limited shelf-life as conventional cryopreservation is primarily designed for stock keeping. We present a study on bulk cryopreservation [...] Read more.
Stem cell-based therapies are promising tools for regenerative medicine and require bulk numbers of high-quality cells. Currently, cells are produced on demand and have a limited shelf-life as conventional cryopreservation is primarily designed for stock keeping. We present a study on bulk cryopreservation of the human iPSC lines UKKi011-A and BIONi010-C-41. By increasing cell concentration and volume, compared to conventional cryopreservation routines in cryo vials, one billion cells were frozen in 50 mL cryo bags. Upon thawing, the cells were immediately seeded in scalable suspension-based bioreactors for expansion to assess the stemness maintenance and for neural differentiation to assess their differentiation potential on the gene and protein levels. Both the conventional and bulk cryo approach show comparative results regarding viability and aggregation upon thawing and bioreactor inoculation. Reduced performance compared to the non-frozen control was compensated within 3 days regarding biomass yield. Stemness was maintained upon thawing in expansion. In neural differentiation, a delay of the neural marker expression on day 4 was compensated at day 9. We conclude that cryopreservation in cryo bags, using high cell concentrations and volumes, does not alter the cells’ fate and is a suitable technology to avoid pre-cultivation and enable time- and cost-efficient therapeutic approaches with bulk cell numbers. Full article
(This article belongs to the Special Issue iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases 2022)
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38 pages, 12473 KiB  
Article
Molecular and Functional Characterization of Different BrainSphere Models for Use in Neurotoxicity Testing on Microelectrode Arrays
by Julia Hartmann, Noah Henschel, Kristina Bartmann, Arif Dönmez, Gabriele Brockerhoff, Katharina Koch and Ellen Fritsche
Cells 2023, 12(9), 1270; https://doi.org/10.3390/cells12091270 - 27 Apr 2023
Cited by 4 | Viewed by 2790
Abstract
The currently accepted methods for neurotoxicity (NT) testing rely on animal studies. However, high costs and low testing throughput hinder their application for large numbers of chemicals. To overcome these limitations, in vitro methods are currently being developed based on human-induced pluripotent stem [...] Read more.
The currently accepted methods for neurotoxicity (NT) testing rely on animal studies. However, high costs and low testing throughput hinder their application for large numbers of chemicals. To overcome these limitations, in vitro methods are currently being developed based on human-induced pluripotent stem cells (hiPSC) that allow higher testing throughput at lower costs. We applied six different protocols to generate 3D BrainSphere models for acute NT evaluation. These include three different media for 2D neural induction and two media for subsequent 3D differentiation resulting in self-organized, organotypic neuron/astrocyte microtissues. All induction protocols yielded nearly 100% NESTIN-positive hiPSC-derived neural progenitor cells (hiNPCs), though with different gene expression profiles concerning regional patterning. Moreover, gene expression and immunocytochemistry analyses revealed that the choice of media determines neural differentiation patterns. On the functional level, BrainSpheres exhibited different levels of electrical activity on microelectrode arrays (MEA). Spike sorting allowed BrainSphere functional characterization with the mixed cultures consisting of GABAergic, glutamatergic, dopaminergic, serotonergic, and cholinergic neurons. A test method for acute NT testing, the human multi-neurotransmitter receptor (hMNR) assay, was proposed to apply such MEA-based spike sorting. These models are promising tools not only in toxicology but also for drug development and disease modeling. Full article
(This article belongs to the Special Issue iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases 2022)
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16 pages, 2521 KiB  
Article
Inducible MLL-AF9 Expression Drives an AML Program during Human Pluripotent Stem Cell-Derived Hematopoietic Differentiation
by Branco M. H. Heuts, Saioa Arza-Apalategi, Sinne G. Alkema, Esther Tijchon, Laura Jussen, Saskia M. Bergevoet, Bert A. van der Reijden and Joost H. A. Martens
Cells 2023, 12(8), 1195; https://doi.org/10.3390/cells12081195 - 20 Apr 2023
Cited by 2 | Viewed by 2568
Abstract
A t(9;11)(p22;q23) translocation produces the MLL-AF9 fusion protein, which is found in up to 25% of de novo AML cases in children. Despite major advances, obtaining a comprehensive understanding of context-dependent MLL-AF9-mediated gene programs during early hematopoiesis is challenging. Here, we generated a [...] Read more.
A t(9;11)(p22;q23) translocation produces the MLL-AF9 fusion protein, which is found in up to 25% of de novo AML cases in children. Despite major advances, obtaining a comprehensive understanding of context-dependent MLL-AF9-mediated gene programs during early hematopoiesis is challenging. Here, we generated a human inducible pluripotent stem cell (hiPSC) model with a doxycycline dose-dependent MLL-AF9 expression. We exploited MLL-AF9 expression as an oncogenic hit to uncover epigenetic and transcriptomic effects on iPSC-derived hematopoietic development and the transformation into (pre-)leukemic states. In doing so, we observed a disruption in early myelomonocytic development. Accordingly, we identified gene profiles that were consistent with primary MLL-AF9 AML and uncovered high-confidence MLL-AF9-associated core genes that are faithfully represented in primary MLL-AF9 AML, including known and presently unknown factors. Using single-cell RNA-sequencing, we identified an increase of CD34 expressing early hematopoietic progenitor-like cell states as well as granulocyte-monocyte progenitor-like cells upon MLL-AF9 activation. Our system allows for careful chemically controlled and stepwise in vitro hiPSC-derived differentiation under serum-free and feeder-free conditions. For a disease that currently lacks effective precision medicine, our system provides a novel entry-point into exploring potential novel targets for personalized therapeutic strategies. Full article
(This article belongs to the Special Issue iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases 2022)
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19 pages, 4777 KiB  
Article
Developmental Changes of Human Neural Progenitor Cells Grafted into the Ventricular System and Prefrontal Cortex of Mouse Brain in Utero
by Maria Llach Pou, Camille Thiberge, Michiel Van der Zwan, Annousha Devi Govindan, Stéphanie Pons, Uwe Maskos and Isabelle Cloëz-Tayarani
Cells 2023, 12(7), 1067; https://doi.org/10.3390/cells12071067 - 31 Mar 2023
Cited by 1 | Viewed by 2280
Abstract
The transplantation of neural progenitors into a host brain represents a useful tool to evaluate the involvement of cell-autonomous processes and host local cues in the regulation of neuronal differentiation during the development of the mammalian brain. Human brain development starts at the [...] Read more.
The transplantation of neural progenitors into a host brain represents a useful tool to evaluate the involvement of cell-autonomous processes and host local cues in the regulation of neuronal differentiation during the development of the mammalian brain. Human brain development starts at the embryonic stages, in utero, with unique properties at its neotenic stages. We analyzed the engraftment and differentiation of human neuronal progenitor cells (hNPCs) transplanted in utero into the mouse brain. The influence of the environment was studied by transplanting human NPCs within the lateral ventricles (LV), compared with the prefrontal cortex (PFC) of immunocompetent mice. We developed a semi-automated method to accurately quantify the number of cell bodies and the distribution of neuronal projections among the different mouse brain structures, at 1 and 3 months post-transplantation (MPT). Our data show that human NPCs can differentiate between immature “juvenile” neurons and more mature pyramidal cells in a reproducible manner. Depending on the injection site, LV vs. PFC, specific fetal local environments could modify the synaptogenesis processes while maintaining human neoteny. The use of immunocompetent mice as host species allows us to investigate further neuropathological conditions making use of all of the engineered mouse models already available. Full article
(This article belongs to the Special Issue iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases 2022)
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22 pages, 4244 KiB  
Article
iPSC-Derived Striatal Medium Spiny Neurons from Patients with Multiple System Atrophy Show Hypoexcitability and Elevated α-Synuclein Release
by Lisa M. Henkel, Svenja Kankowski, Thiemo M. Moellenkamp, Nadine J. Smandzich, Sigrid Schwarz, Alessio Di Fonzo, Gudrun Göhring, Günter Höglinger and Florian Wegner
Cells 2023, 12(2), 223; https://doi.org/10.3390/cells12020223 - 4 Jan 2023
Viewed by 2564
Abstract
Multiple system atrophy of the parkinsonian type (MSA-P) is a rare, fatal neurodegenerative disease with sporadic onset. It is still unknown if MSA-P is a primary oligodendropathy or caused by neuronal pathophysiology leading to severe, α-synuclein-associated neurodegeneration, mainly in the striatum. In this [...] Read more.
Multiple system atrophy of the parkinsonian type (MSA-P) is a rare, fatal neurodegenerative disease with sporadic onset. It is still unknown if MSA-P is a primary oligodendropathy or caused by neuronal pathophysiology leading to severe, α-synuclein-associated neurodegeneration, mainly in the striatum. In this study, we generated and differentiated induced pluripotent stem cells (iPSCs) from patients with the clinical diagnosis of probable MSA-P (n = 3) and from three matched healthy controls into GABAergic striatal medium spiny neurons (MSNs). We found a significantly elevated release and neuronal distribution for α-synuclein, as well as hypoexcitability in the MSNs derived from the MSA-P patients compared to the healthy controls. These data suggest that the striatal hypoexcitable neurons of MSA-P patients contribute to a pathological α-synuclein burden which is likely to spread to neighboring cells and projection targets, facilitating disease progression. Full article
(This article belongs to the Special Issue iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases 2022)
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18 pages, 2443 KiB  
Article
Generation of CD34+CD43+ Hematopoietic Progenitors to Induce Thymocytes from Human Pluripotent Stem Cells
by Léa Flippe, Anne Gaignerie, Céline Sérazin, Olivier Baron, Xavier Saulquin, Ignacio Anegon, Laurent David and Carole Guillonneau
Cells 2022, 11(24), 4046; https://doi.org/10.3390/cells11244046 - 14 Dec 2022
Cited by 2 | Viewed by 3558
Abstract
Immunotherapy using primary T cells has revolutionized medical care in some pathologies in recent years, but limitations associated to challenging cell genome edition, insufficient cell number production, the use of only autologous cells, and the lack of product standardization have limited its clinical [...] Read more.
Immunotherapy using primary T cells has revolutionized medical care in some pathologies in recent years, but limitations associated to challenging cell genome edition, insufficient cell number production, the use of only autologous cells, and the lack of product standardization have limited its clinical use. The alternative use of T cells generated in vitro from human pluripotent stem cells (hPSCs) offers great advantages by providing a self-renewing source of T cells that can be readily genetically modified and facilitate the use of standardized universal off-the-shelf allogeneic cell products and rapid clinical access. However, despite their potential, a better understanding of the feasibility and functionality of T cells differentiated from hPSCs is necessary before moving into clinical settings. In this study, we generated human-induced pluripotent stem cells from T cells (T-iPSCs), allowing for the preservation of already recombined TCR, with the same properties as human embryonic stem cells (hESCs). Based on these cells, we differentiated, with high efficiency, hematopoietic progenitor stem cells (HPSCs) capable of self-renewal and differentiation into any cell blood type, in addition to DN3a thymic progenitors from several T-iPSC lines. In order to better comprehend the differentiation, we analyzed the transcriptomic profiles of the different cell types and demonstrated that HPSCs differentiated from hiPSCs had very similar profiles to cord blood hematopoietic stem cells (HSCs). Furthermore, differentiated T-cell progenitors had a similar profile to thymocytes at the DN3a stage of thymic lymphopoiesis. Therefore, utilizing this approach, we were able to regenerate precursors of therapeutic human T cells in order to potentially treat a wide range of diseases. Full article
(This article belongs to the Special Issue iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases 2022)
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20 pages, 5158 KiB  
Article
Deciphering Transcriptional Networks during Human Cardiac Development
by Robin Canac, Bastien Cimarosti, Aurore Girardeau, Virginie Forest, Pierre Olchesqui, Jeremie Poschmann, Richard Redon, Patricia Lemarchand, Nathalie Gaborit and Guillaume Lamirault
Cells 2022, 11(23), 3915; https://doi.org/10.3390/cells11233915 - 3 Dec 2022
Cited by 2 | Viewed by 1607
Abstract
Human heart development is governed by transcription factor (TF) networks controlling dynamic and temporal gene expression alterations. Therefore, to comprehensively characterize these transcriptional regulations, day-to-day transcriptomic profiles were generated throughout the directed cardiac differentiation, starting from three distinct human- induced pluripotent stem cell [...] Read more.
Human heart development is governed by transcription factor (TF) networks controlling dynamic and temporal gene expression alterations. Therefore, to comprehensively characterize these transcriptional regulations, day-to-day transcriptomic profiles were generated throughout the directed cardiac differentiation, starting from three distinct human- induced pluripotent stem cell lines from healthy donors (32 days). We applied an expression-based correlation score to the chronological expression profiles of the TF genes, and clustered them into 12 sequential gene expression waves. We then identified a regulatory network of more than 23,000 activation and inhibition links between 216 TFs. Within this network, we observed previously unknown inferred transcriptional activations linking IRX3 and IRX5 TFs to three master cardiac TFs: GATA4, NKX2-5 and TBX5. Luciferase and co-immunoprecipitation assays demonstrated that these five TFs could (1) activate each other’s expression; (2) interact physically as multiprotein complexes; and (3) together, finely regulate the expression of SCN5A, encoding the major cardiac sodium channel. Altogether, these results unveiled thousands of interactions between TFs, generating multiple robust hypotheses governing human cardiac development. Full article
(This article belongs to the Special Issue iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases 2022)
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24 pages, 3885 KiB  
Article
Autologous iPSC-Derived Human Neuromuscular Junction to Model the Pathophysiology of Hereditary Spastic Paraplegia
by Domiziana Costamagna, Valérie Casters, Marc Beltrà, Maurilio Sampaolesi, Anja Van Campenhout, Els Ortibus, Kaat Desloovere and Robin Duelen
Cells 2022, 11(21), 3351; https://doi.org/10.3390/cells11213351 - 24 Oct 2022
Cited by 4 | Viewed by 2420
Abstract
Hereditary spastic paraplegia (HSP) is a heterogeneous group of genetic neurodegenerative disorders, characterized by progressive lower limb spasticity and weakness resulting from retrograde axonal degeneration of motor neurons (MNs). Here, we generated in vitro human neuromuscular junctions (NMJs) from five HSP patient-specific induced [...] Read more.
Hereditary spastic paraplegia (HSP) is a heterogeneous group of genetic neurodegenerative disorders, characterized by progressive lower limb spasticity and weakness resulting from retrograde axonal degeneration of motor neurons (MNs). Here, we generated in vitro human neuromuscular junctions (NMJs) from five HSP patient-specific induced pluripotent stem cell (hiPSC) lines, by means of microfluidic strategy, to model disease-relevant neuropathologic processes. The strength of our NMJ model lies in the generation of lower MNs and myotubes from autologous hiPSC origin, maintaining the genetic background of the HSP patient donors in both cell types and in the cellular organization due to the microfluidic devices. Three patients characterized by a mutation in the SPG3a gene, encoding the ATLASTIN GTPase 1 protein, and two patients with a mutation in the SPG4 gene, encoding the SPASTIN protein, were included in this study. Differentiation of the HSP-derived lines gave rise to lower MNs that could recapitulate pathological hallmarks, such as axonal swellings with accumulation of Acetyl-α-TUBULIN and reduction of SPASTIN levels. Furthermore, NMJs from HSP-derived lines were lower in number and in contact point complexity, denoting an impaired NMJ profile, also confirmed by some alterations in genes encoding for proteins associated with microtubules and responsible for axonal transport. Considering the complexity of HSP, these patient-derived neuronal and skeletal muscle cell co-cultures offer unique tools to study the pathologic mechanisms and explore novel treatment options for rescuing axonal defects and diverse cellular processes, including membrane trafficking, intracellular motility and protein degradation in HSP. Full article
(This article belongs to the Special Issue iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases 2022)
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Review

Jump to: Research

35 pages, 5714 KiB  
Review
Human iPSCs as Model Systems for BMP-Related Rare Diseases
by Gonzalo Sánchez-Duffhues and Christian Hiepen
Cells 2023, 12(17), 2200; https://doi.org/10.3390/cells12172200 - 2 Sep 2023
Viewed by 2401
Abstract
Disturbances in bone morphogenetic protein (BMP) signalling contribute to onset and development of a number of rare genetic diseases, including Fibrodysplasia ossificans progressiva (FOP), Pulmonary arterial hypertension (PAH), and Hereditary haemorrhagic telangiectasia (HHT). After decades of animal research to build a solid foundation [...] Read more.
Disturbances in bone morphogenetic protein (BMP) signalling contribute to onset and development of a number of rare genetic diseases, including Fibrodysplasia ossificans progressiva (FOP), Pulmonary arterial hypertension (PAH), and Hereditary haemorrhagic telangiectasia (HHT). After decades of animal research to build a solid foundation in understanding the underlying molecular mechanisms, the progressive implementation of iPSC-based patient-derived models will improve drug development by addressing drug efficacy, specificity, and toxicity in a complex humanized environment. We will review the current state of literature on iPSC-derived model systems in this field, with special emphasis on the access to patient source material and the complications that may come with it. Given the essential role of BMPs during embryonic development and stem cell differentiation, gain- or loss-of-function mutations in the BMP signalling pathway may compromise iPSC generation, maintenance, and differentiation procedures. This review highlights the need for careful optimization of the protocols used. Finally, we will discuss recent developments towards complex in vitro culture models aiming to resemble specific tissue microenvironments with multi-faceted cellular inputs, such as cell mechanics and ECM together with organoids, organ-on-chip, and microfluidic technologies. Full article
(This article belongs to the Special Issue iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases 2022)
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15 pages, 1459 KiB  
Review
Human and Pig Pluripotent Stem Cells: From Cellular Products to Organogenesis and Beyond
by Yiyi Xuan, Björn Petersen and Pentao Liu
Cells 2023, 12(16), 2075; https://doi.org/10.3390/cells12162075 - 16 Aug 2023
Cited by 1 | Viewed by 2621
Abstract
Pluripotent stem cells (PSCs) are important for studying development and hold great promise in regenerative medicine due to their ability to differentiate into various cell types. In this review, we comprehensively discuss the potential applications of both human and pig PSCs and provide [...] Read more.
Pluripotent stem cells (PSCs) are important for studying development and hold great promise in regenerative medicine due to their ability to differentiate into various cell types. In this review, we comprehensively discuss the potential applications of both human and pig PSCs and provide an overview of the current progress and challenges in this field. In addition to exploring the therapeutic uses of PSC-derived cellular products, we also shed light on their significance in the study of interspecies chimeras, which has led to the creation of transplantable human or humanized pig organs. Moreover, we emphasize the importance of pig PSCs as an ideal cell source for genetic engineering, facilitating the development of genetically modified pigs for pig-to-human xenotransplantation. Despite the achievements that have been made, further investigations and refinement of PSC technologies are necessary to unlock their full potential in regenerative medicine and effectively address critical healthcare challenges. Full article
(This article belongs to the Special Issue iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases 2022)
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21 pages, 1620 KiB  
Review
Induced Pluripotent Stem Cells and Their Applications in Amyotrophic Lateral Sclerosis
by Hongmei Du, Zijun Huo, Yanchun Chen, Zhenhan Zhao, Fandi Meng, Xuemei Wang, Shiyue Liu, Haoyun Zhang, Fenghua Zhou, Jinmeng Liu, Lingyun Zhang, Shuanhu Zhou, Yingjun Guan and Xin Wang
Cells 2023, 12(6), 971; https://doi.org/10.3390/cells12060971 - 22 Mar 2023
Cited by 10 | Viewed by 3603
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that results in the loss of motor function in the central nervous system (CNS) and ultimately death. The mechanisms underlying ALS pathogenesis have not yet been fully elucidated, and ALS cannot be treated effectively. [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that results in the loss of motor function in the central nervous system (CNS) and ultimately death. The mechanisms underlying ALS pathogenesis have not yet been fully elucidated, and ALS cannot be treated effectively. Most studies have applied animal or single-gene intervention cell lines as ALS disease models, but they cannot accurately reflect the pathological characteristics of ALS. Induced pluripotent stem cells (iPSCs) can be reprogrammed from somatic cells, possessing the ability to self-renew and differentiate into a variety of cells. iPSCs can be obtained from ALS patients with different genotypes and phenotypes, and the genetic background of the donor cells remains unchanged during reprogramming. iPSCs can differentiate into neurons and glial cells related to ALS. Therefore, iPSCs provide an excellent method to evaluate the impact of diseases on ALS patients. Moreover, patient-derived iPSCs are obtained from their own somatic cells, avoiding ethical concerns and posing only a low risk of immune rejection. The iPSC technology creates new hope for ALS treatment. Here, we review recent studies on iPSCs and their applications in disease modeling, drug screening and cell therapy in ALS, with a particular focus on the potential for ALS treatment. Full article
(This article belongs to the Special Issue iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases 2022)
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18 pages, 1065 KiB  
Review
Pluripotent Stem Cells in Disease Modeling and Drug Discovery for Myotonic Dystrophy Type 1
by Noémie Bérenger-Currias, Cécile Martinat and Sandrine Baghdoyan
Cells 2023, 12(4), 571; https://doi.org/10.3390/cells12040571 - 10 Feb 2023
Cited by 1 | Viewed by 1849
Abstract
Myotonic dystrophy type 1 (DM1) is a progressive multisystemic disease caused by the expansion of a CTG repeat tract within the 3′ untranslated region (3′ UTR) of the dystrophia myotonica protein kinase gene (DMPK). Although DM1 is considered to be the [...] Read more.
Myotonic dystrophy type 1 (DM1) is a progressive multisystemic disease caused by the expansion of a CTG repeat tract within the 3′ untranslated region (3′ UTR) of the dystrophia myotonica protein kinase gene (DMPK). Although DM1 is considered to be the most frequent myopathy of genetic origin in adults, DM1 patients exhibit a vast diversity of symptoms, affecting many different organs. Up until now, different in vitro models from patients’ derived cells have largely contributed to the current understanding of DM1. Most of those studies have focused on muscle physiopathology. However, regarding the multisystemic aspect of DM1, there is still a crucial need for relevant cellular models to cover the whole complexity of the disease and open up options for new therapeutic approaches. This review discusses how human pluripotent stem cell–based models significantly contributed to DM1 mechanism decoding, and how they provided new therapeutic strategies that led to actual phase III clinical trials. Full article
(This article belongs to the Special Issue iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases 2022)
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30 pages, 2643 KiB  
Review
Bioengineering Human Pluripotent Stem Cell-Derived Retinal Organoids and Optic Vesicle-Containing Brain Organoids for Ocular Diseases
by Peggy Arthur, Laureana Muok, Aakash Nathani, Eric Z. Zeng, Li Sun, Yan Li and Mandip Singh
Cells 2022, 11(21), 3429; https://doi.org/10.3390/cells11213429 - 30 Oct 2022
Cited by 5 | Viewed by 4108
Abstract
Retinal organoids are three-dimensional (3D) structures derived from human pluripotent stem cells (hPSCs) that mimic the retina’s spatial and temporal differentiation, making them useful as in vitro retinal development models. Retinal organoids can be assembled with brain organoids, the 3D self-assembled aggregates derived [...] Read more.
Retinal organoids are three-dimensional (3D) structures derived from human pluripotent stem cells (hPSCs) that mimic the retina’s spatial and temporal differentiation, making them useful as in vitro retinal development models. Retinal organoids can be assembled with brain organoids, the 3D self-assembled aggregates derived from hPSCs containing different cell types and cytoarchitectures that resemble the human embryonic brain. Recent studies have shown the development of optic cups in brain organoids. The cellular components of a developing optic vesicle-containing organoids include primitive corneal epithelial and lens-like cells, retinal pigment epithelia, retinal progenitor cells, axon-like projections, and electrically active neuronal networks. The importance of retinal organoids in ocular diseases such as age-related macular degeneration, Stargardt disease, retinitis pigmentosa, and diabetic retinopathy are described in this review. This review highlights current developments in retinal organoid techniques, and their applications in ocular conditions such as disease modeling, gene therapy, drug screening and development. In addition, recent advancements in utilizing extracellular vesicles secreted by retinal organoids for ocular disease treatments are summarized. Full article
(This article belongs to the Special Issue iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases 2022)
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24 pages, 25303 KiB  
Review
Bilirubin-Induced Neurological Damage: Current and Emerging iPSC-Derived Brain Organoid Models
by Abida Islam Pranty, Sara Shumka and James Adjaye
Cells 2022, 11(17), 2647; https://doi.org/10.3390/cells11172647 - 25 Aug 2022
Cited by 10 | Viewed by 4275
Abstract
Bilirubin-induced neurological damage (BIND) has been a subject of studies for decades, yet the molecular mechanisms at the core of this damage remain largely unknown. Throughout the years, many in vivo chronic bilirubin encephalopathy models, such as the Gunn rat and transgenic mice, [...] Read more.
Bilirubin-induced neurological damage (BIND) has been a subject of studies for decades, yet the molecular mechanisms at the core of this damage remain largely unknown. Throughout the years, many in vivo chronic bilirubin encephalopathy models, such as the Gunn rat and transgenic mice, have further elucidated the molecular basis of bilirubin neurotoxicity as well as the correlations between high levels of unconjugated bilirubin (UCB) and brain damage. Regardless of being invaluable, these models cannot accurately recapitulate the human brain and liver system; therefore, establishing a physiologically recapitulating in vitro model has become a prerequisite to unveil the breadth of complexities that accompany the detrimental effects of UCB on the liver and developing human brain. Stem-cell-derived 3D brain organoid models offer a promising platform as they bear more resemblance to the human brain system compared to existing models. This review provides an explicit picture of the current state of the art, advancements, and challenges faced by the various models as well as the possibilities of using stem-cell-derived 3D organoids as an efficient tool to be included in research, drug screening, and therapeutic strategies for future clinical applications. Full article
(This article belongs to the Special Issue iPS Cells (iPSCs) for Modelling and Treatment of Human Diseases 2022)
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