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Frontiers on Induced Pluripotent Stem Cells (iPSCs)
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Frontiers on Induced Pluripotent Stem Cells (iPSCs)

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 December 2023) | Viewed by 12274

Special Issue Editor

Dr. Alessandro Romano

E-Mail Website
Guest Editor
Division of Neuroscience, Experimental Neurology Unit, San Raffaele Scientific Institute, 20132 Milano, Italy
Interests: neurodegenerative disesases; amyotropic lateral sclerosis (ALS); human induced pluripotent stem cell models of disease; extracellular vesicles; protein aggregation; RNA metabolism
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Advances in stem cell research offer promising ways of studying embryonic development, cell physiology, disease mechanisms, therapeutic targets, drug toxicity mechanisms, and regeneration. Human iPSC-derived specific cell lineages (such as neurons or cardiomyocytes) are structurally, functionally, and metabolically immature in nature. Due to immature phenotypes, they do not truly recapitulate cell physiology, and they also do not show a eresponse to standard drugs and toxicants. Though immature in nature, many studies have shown its potential application in drug screening, disease modelling, drug discovery, and stem cell therapies. The generation of matured iPSC-derived cell lineages is highly important in animal-test-free drug discovery, disease models, and stem-cell therapies.

This Special Issue is dedicated to highlighting recent and promising developments in the field of stem-cell research. This issue is focusing on the following topics: maturation strategies in iPSC-derived cell lineages, iPSC-based disease models, disease mechanisms in iPSC models, fluorescent screening markers in iPSC models, novel potential pharmacological targets, new drug-screening platforms, tissue regeneration approaches, and the impact of immature cells on drug discovery and stem-cell therapies. We are welcoming original manuscripts and reviews focusing on these topics that will help with understanding  of recent advancements and challenges in these areas.

Dr. Alessandro Romano
Guest Editor

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Keywords

  • in vitro models
  • drug screening
  • disease models
  • regeneration
  • drug screening technologies
  • therapeutic targets
  • fluorescent screening markers
  • disease mechanisms

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Published Papers (6 papers)

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Research

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27 pages, 6019 KiB  
Article
Creation of an Isogenic Human iPSC-Based RGC Model of Dominant Optic Atrophy Harboring the Pathogenic Variant c.1861C>T (p.Gln621Ter) in the OPA1 Gene
by Marta García-López, Lydia Jiménez-Vicente, Raquel González-Jabardo, Helena Dorado, Irene Gómez-Manjón, Miguel Ángel Martín, Carmen Ayuso, Joaquín Arenas and María Esther Gallardo
Int. J. Mol. Sci. 2024, 25(13), 7240; https://doi.org/10.3390/ijms25137240 - 30 Jun 2024
Viewed by 1454
Abstract
Autosomal dominant optic atrophy (ADOA) is a rare progressive disease mainly caused by mutations in OPA1, a nuclear gene encoding for a mitochondrial protein that plays an essential role in mitochondrial dynamics, cell survival, oxidative phosphorylation, and mtDNA maintenance. ADOA is characterized [...] Read more.
Autosomal dominant optic atrophy (ADOA) is a rare progressive disease mainly caused by mutations in OPA1, a nuclear gene encoding for a mitochondrial protein that plays an essential role in mitochondrial dynamics, cell survival, oxidative phosphorylation, and mtDNA maintenance. ADOA is characterized by the degeneration of retinal ganglion cells (RGCs). This causes visual loss, which can lead to legal blindness in many cases. Nowadays, there is no effective treatment for ADOA. In this article, we have established an isogenic human RGC model for ADOA using iPSC technology and the genome editing tool CRISPR/Cas9 from a previously generated iPSC line of an ADOA plus patient harboring the pathogenic variant NM_015560.3: c.1861C>T (p.Gln621Ter) in heterozygosis in OPA1. To this end, a protocol based on supplementing the iPSC culture media with several small molecules and defined factors trying to mimic embryonic development has been employed. Subsequently, the created model was validated, confirming the presence of a defect of intergenomic communication, impaired mitochondrial respiration, and an increase in apoptosis and ROS generation. Finally, we propose the analysis of OPA1 expression by qPCR as an easy read-out method to carry out future drug screening studies using the created RGC model. In summary, this model provides a useful platform for further investigation of the underlying pathophysiological mechanisms of ADOA plus and for testing compounds with potential pharmacological action. Full article
(This article belongs to the Special Issue Frontiers on Induced Pluripotent Stem Cells (iPSCs))
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16 pages, 2316 KiB  
Communication
Murine iPSC-Loaded Scaffold Grafts Improve Bone Regeneration in Critical-Size Bone Defects
by Franziska Kessler, Kevin Arnke, Benjamin Eggerschwiler, Yvonne Neldner, Sonja Märsmann, Olivier Gröninger, Elisa A. Casanova, Fabienne A. Weber, Matthias A. König, Wendelin J. Stark, Hans-Christoph Pape, Paolo Cinelli and Simon Tiziani
Int. J. Mol. Sci. 2024, 25(10), 5555; https://doi.org/10.3390/ijms25105555 - 20 May 2024
Cited by 3 | Viewed by 1292
Abstract
In certain situations, bones do not heal completely after fracturing. One of these situations is a critical-size bone defect where the bone cannot heal spontaneously. In such a case, complex fracture treatment over a long period of time is required, which carries a [...] Read more.
In certain situations, bones do not heal completely after fracturing. One of these situations is a critical-size bone defect where the bone cannot heal spontaneously. In such a case, complex fracture treatment over a long period of time is required, which carries a relevant risk of complications. The common methods used, such as autologous and allogeneic grafts, do not always lead to successful treatment results. Current approaches to increasing bone formation to bridge the gap include the application of stem cells on the fracture side. While most studies investigated the use of mesenchymal stromal cells, less evidence exists about induced pluripotent stem cells (iPSC). In this study, we investigated the potential of mouse iPSC-loaded scaffolds and decellularized scaffolds containing extracellular matrix from iPSCs for treating critical-size bone defects in a mouse model. In vitro differentiation followed by Alizarin Red staining and quantitative reverse transcription polymerase chain reaction confirmed the osteogenic differentiation potential of the iPSCs lines. Subsequently, an in vivo trial using a mouse model (n = 12) for critical-size bone defect was conducted, in which a PLGA/aCaP osteoconductive scaffold was transplanted into the bone defect for 9 weeks. Three groups (each n = 4) were defined as (1) osteoconductive scaffold only (control), (2) iPSC-derived extracellular matrix seeded on a scaffold and (3) iPSC seeded on a scaffold. Micro-CT and histological analysis show that iPSCs grafted onto an osteoconductive scaffold followed by induction of osteogenic differentiation resulted in significantly higher bone volume 9 weeks after implantation than an osteoconductive scaffold alone. Transplantation of iPSC-seeded PLGA/aCaP scaffolds may improve bone regeneration in critical-size bone defects in mice. Full article
(This article belongs to the Special Issue Frontiers on Induced Pluripotent Stem Cells (iPSCs))
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13 pages, 3095 KiB  
Article
Cost-Effective Mechanical Aggregation of Cardiac Progenitors and Encapsulation in Matrigel Support Self-Organization in a Dynamic Culture Environment
by Tiago P. Dias, Sandra N. Pinto, Sandra Carvalho, Tiago G. Fernandes, Fábio Fernandes, Maria Margarida Diogo, Maria C. Peleteiro, Manuel Prieto and Joaquim M. S. Cabral
Int. J. Mol. Sci. 2022, 23(24), 15785; https://doi.org/10.3390/ijms232415785 - 13 Dec 2022
Cited by 1 | Viewed by 2079
Abstract
Human iPSC-derived self-organized cardiac tissues can be valuable for the development of platforms for disease modeling and drug screening, enhancing test accuracy and reducing pharmaceutical industry financial burden. However, current differentiation systems still rely on static culture conditions and specialized commercial microwells for [...] Read more.
Human iPSC-derived self-organized cardiac tissues can be valuable for the development of platforms for disease modeling and drug screening, enhancing test accuracy and reducing pharmaceutical industry financial burden. However, current differentiation systems still rely on static culture conditions and specialized commercial microwells for aggregation, which hinders the full potential of hiPSC-derived cardiac tissues. Herein, we integrate cost-effective and reproducible manual aggregation of hiPSC-derived cardiac progenitors with Matrigel encapsulation and a dynamic culture to support hiPSC cardiac differentiation and self-organization. Manual aggregation at day 7 of cardiac differentiation resulted in 97% of beating aggregates with 78% of cTnT-positive cells. Matrigel encapsulation conjugated with a dynamic culture promoted cell migration and the creation of organized structures, with observed cell polarization and the creation of lumens. In addition, encapsulation increased buoyancy and decreased coalescence of the hiPSC-derived cardiac aggregates. Moreover, VEGF supplementation increased over two-fold the percentage of CD31-positive cells resulting in the emergence of microvessel-like structures. Thus, this study shows that the explored culture parameters support the self-organization of hiPSC-derived cardiac microtissues containing multiple cardiac cell types. Additional stimuli (e.g., BMP) in long-term scalable and fully automatized cultures can further potentiate highly structured and mature hiPSC-derived cardiac models, contributing to the development of reliable platforms for high-throughput drug screening and disease modeling. Full article
(This article belongs to the Special Issue Frontiers on Induced Pluripotent Stem Cells (iPSCs))
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26 pages, 6121 KiB  
Article
Generation of the First Human In Vitro Model for McArdle Disease Based on iPSC Technology
by María del Carmen Ortuño-Costela, Victoria Cerrada, Ana Moreno-Izquierdo, Inés García-Consuegra, Camille Laberthonnière, Mégane Delourme, Rafael Garesse, Joaquín Arenas, Carla Fuster García, Gema García García, José María Millán, Frédérique Magdinier and María Esther Gallardo
Int. J. Mol. Sci. 2022, 23(22), 13964; https://doi.org/10.3390/ijms232213964 - 12 Nov 2022
Cited by 7 | Viewed by 2170
Abstract
McArdle disease is a rare autosomal recessive disorder caused by mutations in the PYGM gene. This gene encodes for the skeletal muscle isoform of glycogen phosphorylase (myophosphorylase), the first enzyme in glycogenolysis. Patients with this disorder are unable to obtain energy from their [...] Read more.
McArdle disease is a rare autosomal recessive disorder caused by mutations in the PYGM gene. This gene encodes for the skeletal muscle isoform of glycogen phosphorylase (myophosphorylase), the first enzyme in glycogenolysis. Patients with this disorder are unable to obtain energy from their glycogen stored in skeletal muscle, prompting an exercise intolerance. Currently, there is no treatment for this disease, and the lack of suitable in vitro human models has prevented the search for therapies against it. In this article, we have established the first human iPSC-based model for McArdle disease. For the generation of this model, induced pluripotent stem cells (iPSCs) from a patient with McArdle disease (harbouring the homozygous mutation c.148C>T; p.R50* in the PYGM gene) were differentiated into myogenic cells able to contract spontaneously in the presence of motor neurons and generate calcium transients, a proof of their maturity and functionality. Additionally, an isogenic skeletal muscle model of McArdle disease was created. As a proof-of-concept, we have tested in this model the rescue of PYGM expression by two different read-through compounds (PTC124 and RTC13). The developed model will be very useful as a platform for testing drugs or compounds with potential pharmacological activity. Full article
(This article belongs to the Special Issue Frontiers on Induced Pluripotent Stem Cells (iPSCs))
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10 pages, 2404 KiB  
Communication
Induced Pluripotent Stem Cell (iPSC) Lines from a Family with Resistant Epileptic Encephalopathy Caused by Compound Heterozygous Mutations in SZT2 Gene
by Cecilia Cattelani, Ingrid Battistella, Francesca Di Leva, Giulia Fioravanti, Francesco Benedicenti, Franco Stanzial, Christine Schwienbacher, Francesca Fanelli, Peter P. Pramstaller, Andrew A. Hicks, Luciano Conti and Corrado Corti
Int. J. Mol. Sci. 2022, 23(21), 13095; https://doi.org/10.3390/ijms232113095 - 28 Oct 2022
Cited by 2 | Viewed by 2040
Abstract
Mutations in the SZT2 gene have been associated with developmental and epileptic encephalopathy-18, a rare severe autosomal recessive neurologic disorder, characterized by psychomotor impairment/intellectual disability, dysmorphic facial features and early onset of refractory seizures. Here we report the generation of the first induced [...] Read more.
Mutations in the SZT2 gene have been associated with developmental and epileptic encephalopathy-18, a rare severe autosomal recessive neurologic disorder, characterized by psychomotor impairment/intellectual disability, dysmorphic facial features and early onset of refractory seizures. Here we report the generation of the first induced pluripotent stem cell (iPSC) lines from a patient with treatment-resistant epilepsy, carrying compound heterozygous mutations in SZT2 (Mut1: c.498G>T and Mut2: c.6553C>T), and his healthy heterozygous parents. Peripheral blood mononuclear cells were reprogrammed by a non-integrating Sendai virus-based reprogramming system. The generated human iPSC lines exhibited expression of the main pluripotency markers, the potential to differentiate into all three germ layers and presented a normal karyotype. These lines represent a valuable resource to study neurodevelopmental alterations, and to obtain mature, pathology-relevant neuronal populations as an in vitro model to perform functional assays and test the patient’s responsiveness to novel antiepileptic treatments. Full article
(This article belongs to the Special Issue Frontiers on Induced Pluripotent Stem Cells (iPSCs))
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Review

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11 pages, 1025 KiB  
Review
Pluripotent Stem Cells of Order Carnivora: Technical Perspective
by Aleksei G. Menzorov
Int. J. Mol. Sci. 2023, 24(4), 3905; https://doi.org/10.3390/ijms24043905 - 15 Feb 2023
Viewed by 1803
Abstract
Human and mouse induced pluripotent stem cells (PSCs) are widely used for studying early embryonic development and for modeling of human diseases. Derivation and studying of PSCs from model organisms beyond commonly used mice and rats may provide new insights into the modeling [...] Read more.
Human and mouse induced pluripotent stem cells (PSCs) are widely used for studying early embryonic development and for modeling of human diseases. Derivation and studying of PSCs from model organisms beyond commonly used mice and rats may provide new insights into the modeling and treating human diseases. The order Carnivora representatives possess unique features and are already used for modeling human-related traits. This review focuses on the technical aspects of derivation of the Carnivora species PSCs as well as their characterization. Current data on dog, feline, ferret, and American mink PSCs are summarized. Full article
(This article belongs to the Special Issue Frontiers on Induced Pluripotent Stem Cells (iPSCs))
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