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Human Stem Cells in Disease Modelling, Drug Discovery and Regenerative...
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Human Stem Cells in Disease Modelling, Drug Discovery and Regenerative Medicine

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

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 40123

Special Issue Editors

Dr. Nuno Jorge Lamas

E-Mail Website
Guest Editor
1. Life and Health Sciences Research Institute (ICVS), School of Medicine, Campus of Gualtar, University of Minho, 4710-057 Braga, Portugal
2. ICVS/3B's, PT Government Associate Laboratory, Braga, Guimarães, Portugal
3. Anatomic Pathology Service, Pathology Department, Centro Hospitalar e Universitário do Porto, Largo Professor Abel Salazar, 4099-001 Porto, Portugal
Interests: human pluripotent stem cells (hPSCs); drug screening; disease modelling; amyotrophic lateral sclerosis (ALS); pathology
Dr. Laurent Roybon

E-Mail Website
Guest Editor
Van Andel Institute, 333 Bostwick Ave N.E., Grand Rapids, MI 49503, USA
Interests: induced pluripotent stem cells; human disease modelling in vitro and in vivo; interaction neurons-glia in health and disease; neurodevelopment

Special Issue Information

Dear Colleagues,

In recent decades, the ability to isolate, differentiate and efficiently grow in vitro different types of human stem cells including induced pluripotent stem cells, has allowed unprecedented discoveries on the mechanisms of human developmental biology, new opportunities for the development of disease models in vitro and in vivo, new platforms for drug discovery and drug repurposing, as well as the development of innovative strategies directed at the long-aimed cell and organ replacement therapies.

In this Special Issue on human stem cells, we will highlight the most recent developments in the field, covering aspects not only at the fundamental research level but also at the pre-clinical and clinical levels, aiming to discuss the hurdles and challenges precluding their translation into effective clinical applicable strategies.

We welcome original research articles, perspectives, mini-reviews and more comprehensive review papers.

Dr. Nuno Jorge Lamas
Dr. Laurent Roybon
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • human stem cells
  • human pluripotent stem cells
  • drug screening
  • regenerative medicine
  • disease modelling in vitro and in vivo
  • interaction neurons-glia in disease and models of diseases

Published Papers (15 papers)

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Research

Jump to: Review

16 pages, 6586 KiB  
Article
Filamin C Deficiency Impairs Sarcomere Stability and Activates Focal Adhesion Kinase through PDGFRA Signaling in Induced Pluripotent Stem Cell-Derived Cardiomyocytes
by Shanshan Gao, Lingaonan He, Chi Keung Lam, Matthew R. G. Taylor, Luisa Mestroni, Raffaella Lombardi and Suet Nee Chen
Cells 2024, 13(3), 278; https://doi.org/10.3390/cells13030278 - 02 Feb 2024
Cited by 1 | Viewed by 1048
Abstract
Truncating mutations in filamin C (FLNC) are associated with dilated cardiomyopathy and arrhythmogenic cardiomyopathy. FLNC is an actin-binding protein and is known to interact with transmembrane and structural proteins; hence, the ablation of FLNC in cardiomyocytes is expected to dysregulate cell [...] Read more.
Truncating mutations in filamin C (FLNC) are associated with dilated cardiomyopathy and arrhythmogenic cardiomyopathy. FLNC is an actin-binding protein and is known to interact with transmembrane and structural proteins; hence, the ablation of FLNC in cardiomyocytes is expected to dysregulate cell adhesion, cytoskeletal organization, sarcomere structural integrity, and likely nuclear function. Our previous study showed that the transcriptional profiles of FLNC homozygous deletions in human pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are highly comparable to the transcriptome profiles of hiPSC-CMs from patients with FLNC truncating mutations. Therefore, in this study, we used CRISPR-Cas-engineered hiPSC-derived FLNC knockout cardiac myocytes as a model of FLNC cardiomyopathy to determine pathogenic mechanisms and to examine structural changes caused by FLNC deficiency. RNA sequencing data indicated the significant upregulation of focal adhesion signaling and the dysregulation of thin filament genes in FLNC-knockout (FLNCKO) hiPSC-CMs compared to isogenic hiPSC-CMs. Furthermore, our findings suggest that the complete loss of FLNC in cardiomyocytes led to cytoskeletal defects and the activation of focal adhesion kinase. Pharmacological inhibition of PDGFRA signaling using crenolanib (an FDA-approved drug) reduced focal adhesion kinase activation and partially normalized the focal adhesion signaling pathway. The findings from this study suggest the opportunity in repurposing FDA-approved drug as a therapeutic strategy to treat FLNC cardiomyopathy. Full article
(This article belongs to the Special Issue Human Stem Cells in Disease Modelling, Drug Discovery and Regenerative Medicine)
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22 pages, 6147 KiB  
Article
Treating Parkinson’s Disease with Human Bone Marrow Mesenchymal Stem Cell Secretome: A Translational Investigation Using Human Brain Organoids and Different Routes of In Vivo Administration
by Bárbara Mendes-Pinheiro, Jonas Campos, Ana Marote, Carina Soares-Cunha, Sarah L. Nickels, Anna S. Monzel, Jorge R. Cibrão, Eduardo Loureiro-Campos, Sofia C. Serra, Sandra Barata-Antunes, Sara Duarte-Silva, Luísa Pinto, Jens C. Schwamborn and António J. Salgado
Cells 2023, 12(21), 2565; https://doi.org/10.3390/cells12212565 - 02 Nov 2023
Viewed by 1636
Abstract
Parkinson’s disease (PD) is the most common movement disorder, characterized by the progressive loss of dopaminergic neurons from the nigrostriatal system. Currently, there is no treatment that retards disease progression or reverses damage prior to the time of clinical diagnosis. Mesenchymal stem cells [...] Read more.
Parkinson’s disease (PD) is the most common movement disorder, characterized by the progressive loss of dopaminergic neurons from the nigrostriatal system. Currently, there is no treatment that retards disease progression or reverses damage prior to the time of clinical diagnosis. Mesenchymal stem cells (MSCs) are one of the most extensively studied cell sources for regenerative medicine applications, particularly due to the release of soluble factors and vesicles, known as secretome. The main goal of this work was to address the therapeutic potential of the secretome collected from bone-marrow-derived MSCs (BM-MSCs) using different models of the disease. Firstly, we took advantage of an optimized human midbrain-specific organoid system to model PD in vitro using a neurotoxin-induced model through 6-hydroxydopamine (6-OHDA) exposure. In vivo, we evaluated the effects of BM-MSC secretome comparing two different routes of secretome administration: intracerebral injections (a two-site single administration) against multiple systemic administration. The secretome of BM-MSCs was able to protect from dopaminergic neuronal loss, these effects being more evident in vivo. The BM-MSC secretome led to motor function recovery and dopaminergic loss protection; however, multiple systemic administrations resulted in larger therapeutic effects, making this result extremely relevant for potential future clinical applications. Full article
(This article belongs to the Special Issue Human Stem Cells in Disease Modelling, Drug Discovery and Regenerative Medicine)
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15 pages, 8424 KiB  
Article
Influence of Extracellular Matrix Components on the Differentiation of Periodontal Ligament Stem Cells in Collagen I Hydrogel
by Alexey A. Ivanov, Alla V. Kuznetsova, Olga P. Popova, Tamara I. Danilova, Andrey V. Latyshev and Oleg O. Yanushevich
Cells 2023, 12(19), 2335; https://doi.org/10.3390/cells12192335 - 22 Sep 2023
Cited by 1 | Viewed by 1024
Abstract
Regeneration of periodontal tissues requires an integrated approach to the restoration of the periodontal ligament, cementum, and alveolar bone surrounding the teeth. Current strategies in endogenous regenerative dentistry widely use biomaterials, in particular the decellularized extracellular matrix (dECM), to facilitate the recruitment of [...] Read more.
Regeneration of periodontal tissues requires an integrated approach to the restoration of the periodontal ligament, cementum, and alveolar bone surrounding the teeth. Current strategies in endogenous regenerative dentistry widely use biomaterials, in particular the decellularized extracellular matrix (dECM), to facilitate the recruitment of populations of resident cells into damaged tissues and stimulate their proliferation and differentiation. The purpose of our study was to evaluate the effect of the exogenous components of the extracellular matrix (hyaluronic acid, laminin, fibronectin) on the differentiation of periodontal ligament stem cells (PDLSCs) cultured with dECM (combinations of decellularized tooth matrices and periodontal ligament) in a 3D collagen I hydrogel. The immunohistochemical expression of various markers in PDLSCs was assessed quantitatively and semi-quantitatively on paraffin sections. The results showed that PDLSCs cultured under these conditions for 14 days exhibited phenotypic characteristics consistent with osteoblast-like and odontoblast-like cells. This potential has been demonstrated by the expression of osteogenic differentiation markers (OC, OPN, ALP) and odontogenic markers (DSPP). This phenomenon corresponds to the in vivo state of the periodontal ligament, in which cells at the interface between bone and cementum tend to differentiate into osteoblasts or cementoblasts. The addition of fibronectin to the dECM most effectively induces the differentiation of PDLSCs into osteoblast-like and odontoblast-like cells under 3D culture conditions. Therefore, this bioengineered construct has a high potential for future use in periodontal tissue regeneration. Full article
(This article belongs to the Special Issue Human Stem Cells in Disease Modelling, Drug Discovery and Regenerative Medicine)
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19 pages, 2323 KiB  
Article
Primary Ciliary Dyskinesia Patient-Specific hiPSC-Derived Airway Epithelium in Air-Liquid Interface Culture Recapitulates Disease Specific Phenotypes In Vitro
by Laura von Schledorn, David Puertollano Martín, Nicole Cleve, Janina Zöllner, Doris Roth, Ben Ole Staar, Jan Hegermann, Felix C. Ringshausen, Janna Nawroth, Ulrich Martin and Ruth Olmer
Cells 2023, 12(11), 1467; https://doi.org/10.3390/cells12111467 - 24 May 2023
Cited by 3 | Viewed by 2029
Abstract
Primary ciliary dyskinesia (PCD) is a rare heterogenic genetic disorder associated with perturbed biogenesis or function of motile cilia. Motile cilia dysfunction results in diminished mucociliary clearance (MCC) of pathogens in the respiratory tract and chronic airway inflammation and infections successively causing progressive [...] Read more.
Primary ciliary dyskinesia (PCD) is a rare heterogenic genetic disorder associated with perturbed biogenesis or function of motile cilia. Motile cilia dysfunction results in diminished mucociliary clearance (MCC) of pathogens in the respiratory tract and chronic airway inflammation and infections successively causing progressive lung damage. Current approaches to treat PCD are symptomatic, only, indicating an urgent need for curative therapeutic options. Here, we developed an in vitro model for PCD based on human induced pluripotent stem cell (hiPSC)-derived airway epithelium in Air-Liquid-Interface cultures. Applying transmission electron microscopy, immunofluorescence staining, ciliary beat frequency, and mucociliary transport measurements, we could demonstrate that ciliated respiratory epithelia cells derived from two PCD patient-specific hiPSC lines carrying mutations in DNAH5 and NME5, respectively, recapitulate the respective diseased phenotype on a molecular, structural and functional level. Full article
(This article belongs to the Special Issue Human Stem Cells in Disease Modelling, Drug Discovery and Regenerative Medicine)
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19 pages, 3719 KiB  
Article
ZnT8 Loss of Function Mutation Increases Resistance of Human Embryonic Stem Cell-Derived Beta Cells to Apoptosis in Low Zinc Condition
by Lina Sui, Qian Du, Anthony Romer, Qi Su, Pauline L. Chabosseau, Yurong Xin, Jinrang Kim, Sandra Kleiner, Guy A. Rutter and Dieter Egli
Cells 2023, 12(6), 903; https://doi.org/10.3390/cells12060903 - 15 Mar 2023
Cited by 2 | Viewed by 1845
Abstract
The rare SLC30A8 mutation encoding a truncating p.Arg138* variant (R138X) in zinc transporter 8 (ZnT8) is associated with a 65% reduced risk for type 2 diabetes. To determine whether ZnT8 is required for beta cell development and function, we derived human pluripotent stem [...] Read more.
The rare SLC30A8 mutation encoding a truncating p.Arg138* variant (R138X) in zinc transporter 8 (ZnT8) is associated with a 65% reduced risk for type 2 diabetes. To determine whether ZnT8 is required for beta cell development and function, we derived human pluripotent stem cells carrying the R138X mutation and differentiated them into insulin-producing cells. We found that human pluripotent stem cells with homozygous or heterozygous R138X mutation and the null (KO) mutation have normal efficiency of differentiation towards insulin-producing cells, but these cells show diffuse granules that lack crystalline zinc-containing insulin granules. Insulin secretion is not compromised in vitro by KO or R138X mutations in human embryonic stem cell-derived beta cells (sc-beta cells). Likewise, the ability of sc-beta cells to secrete insulin and maintain glucose homeostasis after transplantation into mice was comparable across different genotypes. Interestingly, sc-beta cells with the SLC30A8 KO mutation showed increased cytoplasmic zinc, and cells with either KO or R138X mutation were resistant to apoptosis when extracellular zinc was limiting. These findings are consistent with a protective role of zinc in cell death and with the protective role of zinc in T2D. Full article
(This article belongs to the Special Issue Human Stem Cells in Disease Modelling, Drug Discovery and Regenerative Medicine)
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25 pages, 3598 KiB  
Article
High Accuracy Classification of Developmental Toxicants by In Vitro Tests of Human Neuroepithelial and Cardiomyoblast Differentiation
by Florian Seidel, Anna Cherianidou, Franziska Kappenberg, Miriam Marta, Nadine Dreser, Jonathan Blum, Tanja Waldmann, Nils Blüthgen, Johannes Meisig, Katrin Madjar, Margit Henry, Tamara Rotshteyn, Andreas Scholtz-Illigens, Rosemarie Marchan, Karolina Edlund, Marcel Leist, Jörg Rahnenführer, Agapios Sachinidis and Jan Georg Hengstler
Cells 2022, 11(21), 3404; https://doi.org/10.3390/cells11213404 - 27 Oct 2022
Cited by 3 | Viewed by 1830
Abstract
Human-relevant tests to predict developmental toxicity are urgently needed. A currently intensively studied approach makes use of differentiating human stem cells to measure chemically-induced deviations of the normal developmental program, as in a recent study based on cardiac differentiation (UKK2). Here, we (i) [...] Read more.
Human-relevant tests to predict developmental toxicity are urgently needed. A currently intensively studied approach makes use of differentiating human stem cells to measure chemically-induced deviations of the normal developmental program, as in a recent study based on cardiac differentiation (UKK2). Here, we (i) tested the performance of an assay modeling neuroepithelial differentiation (UKN1), and (ii) explored the benefit of combining assays (UKN1 and UKK2) that model different germ layers. Substance-induced cytotoxicity and genome-wide expression profiles of 23 teratogens and 16 non-teratogens at human-relevant concentrations were generated and used for statistical classification, resulting in accuracies of the UKN1 assay of 87–90%. A comparison to the UKK2 assay (accuracies of 90–92%) showed, in general, a high congruence in compound classification that may be explained by the fact that there was a high overlap of signaling pathways. Finally, the combination of both assays improved the prediction compared to each test alone, and reached accuracies of 92–95%. Although some compounds were misclassified by the individual tests, we conclude that UKN1 and UKK2 can be used for a reliable detection of teratogens in vitro, and that a combined analysis of tests that differentiate hiPSCs into different germ layers and cell types can even further improve the prediction of developmental toxicants. Full article
(This article belongs to the Special Issue Human Stem Cells in Disease Modelling, Drug Discovery and Regenerative Medicine)
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17 pages, 2558 KiB  
Article
Cartilaginous Metabolomics Reveals the Biochemical-Niche Fate Control of Bone Marrow-Derived Stem Cells
by Haining Peng, Yi Zhang, Zhongkai Ren, Ziran Wei, Renjie Chen, Yingze Zhang, Xiaohong Huang and Tengbo Yu
Cells 2022, 11(19), 2951; https://doi.org/10.3390/cells11192951 - 21 Sep 2022
Cited by 2 | Viewed by 2024
Abstract
Joint disorders have become a global health issue with the growth of the aging population. Screening small active molecules targeting chondrogenic differentiation of bone marrow-derived stem cells (BMSCs) is of urgency. In this study, microfracture was employed to create a regenerative niche in [...] Read more.
Joint disorders have become a global health issue with the growth of the aging population. Screening small active molecules targeting chondrogenic differentiation of bone marrow-derived stem cells (BMSCs) is of urgency. In this study, microfracture was employed to create a regenerative niche in rabbits (n = 9). Cartilage samples were collected four weeks post-surgery. Microfracture-caused morphological (n = 3) and metabolic (n = 6) changes were detected. Non-targeted metabolomic analysis revealed that there were 96 differentially expressed metabolites (DEMs) enriched in 70 pathways involved in anti-inflammation, lipid metabolism, signaling transduction, etc. Among the metabolites, docosapentaenoic acid 22n-3 (DPA) and ursodeoxycholic acid (UDCA) functionally facilitated cartilage defect healing, i.e., increasing the vitality and adaptation of the BMSCs, chondrogenic differentiation, and chondrocyte functionality. Our findings firstly reveal the differences in metabolomic activities between the normal and regenerated cartilages and provide a list of endogenous biomolecules potentially involved in the biochemical-niche fate control for chondrogenic differentiation of BMSCs. Ultimately, the biomolecules may serve as anti-aging supplements for chondrocyte renewal or as drug candidates for cartilage regenerative medicine. Full article
(This article belongs to the Special Issue Human Stem Cells in Disease Modelling, Drug Discovery and Regenerative Medicine)
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Graphical abstract

24 pages, 5585 KiB  
Article
Distinct and Dynamic Transcriptome Adaptations of iPSC-Generated Astrocytes after Cytokine Stimulation
by Anna-Sophie Spreng, Markus Brüll, Heidrun Leisner, Ilinca Suciu and Marcel Leist
Cells 2022, 11(17), 2644; https://doi.org/10.3390/cells11172644 - 25 Aug 2022
Cited by 4 | Viewed by 2655
Abstract
Astrocytes (ACs) do not only play a role in normal neurogenesis and brain homeostasis, but also in inflammatory and neurodevelopmental disorders. We studied here the different patterns of inflammatory activation triggered by cytokines in human induced pluripotent stem cell (iPSC)-derived ACs. An optimized [...] Read more.
Astrocytes (ACs) do not only play a role in normal neurogenesis and brain homeostasis, but also in inflammatory and neurodevelopmental disorders. We studied here the different patterns of inflammatory activation triggered by cytokines in human induced pluripotent stem cell (iPSC)-derived ACs. An optimized differentiation protocol provided non-inflamed ACs. These cells reacted to TNFα with a rapid translocation of NFκB, while AC precursors showed little response. Transcriptome changes were quantified at seven time points (2–72 h) after stimulation with TNFα, IFNγ or TNFα plus IFNγ. TNFα triggered a strong response within 2 h. It peaked from 12–24 h and reverted towards the ground state after 72 h. Activation by IFNγ was also rapid, but the response pattern differed from that of TNFα. For instance, several chemokines up-regulated by TNFα were not affected by IFNγ. Instead, MHC-II-related antigen presentation was drastically enhanced. The combination of the two cytokines led to a stronger and more persistent response. For instance, TRIB3 up-regulation by the combination of TNFα plus IFNγ may have slowed NFκB inactivation. Additionally, highly synergistic regulation was observed for inflammation modifiers, such as CASP4, and for STAT1-controlled genes. The combination of the cytokines also increased oxidative stress markers (e.g., CHAC1), led to phenotypic changes in ACs and triggered markers related to cell death. In summary, these data demonstrate that there is a large bandwidth of pro-inflammatory AC states, and that single markers are not suitable to describe AC activation or their modulation in disease, development and therapy. Full article
(This article belongs to the Special Issue Human Stem Cells in Disease Modelling, Drug Discovery and Regenerative Medicine)
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17 pages, 5520 KiB  
Article
In Vitro Drug Screening Using iPSC-Derived Cardiomyocytes of a Long QT-Syndrome Patient Carrying KCNQ1 & TRPM4 Dual Mutation: An Experimental Personalized Treatment
by Feifei Wang, Yafan Han, Wanyue Sang, Lu Wang, Xiaoyan Liang, Liang Wang, Qiang Xing, Yankai Guo, Jianghua Zhang, Ling Zhang, Tuerhong Zukela, Jiasuoer Xiaokereti, Yanmei Lu, Xianhui Zhou, Baopeng Tang and Yaodong Li
Cells 2022, 11(16), 2495; https://doi.org/10.3390/cells11162495 - 11 Aug 2022
Cited by 3 | Viewed by 2127
Abstract
Congenital long QT syndrome is a type of inherited cardiovascular disorder characterized by prolonged QT interval. Patient often suffer from syncopal episodes, electrocardiographic abnormalities and life-threatening arrhythmia. Given the complexity of the root cause of the disease, a combination of clinical diagnosis and [...] Read more.
Congenital long QT syndrome is a type of inherited cardiovascular disorder characterized by prolonged QT interval. Patient often suffer from syncopal episodes, electrocardiographic abnormalities and life-threatening arrhythmia. Given the complexity of the root cause of the disease, a combination of clinical diagnosis and drug screening using patient-derived cardiomyocytes represents a more effective way to identify potential cures. We identified a long QT syndrome patient carrying a heterozygous KCNQ1 c.656G>A mutation and a heterozygous TRPM4 c.479C>T mutation. Implantation of implantable cardioverter defibrillator in combination with conventional medication demonstrated limited success in ameliorating long-QT-syndrome-related symptoms. Frequent defibrillator discharge also caused deterioration of patient quality of life. Aiming to identify better therapeutic agents and treatment strategy, we established a patient-specific iPSC line carrying the dual mutations and differentiated these patient-specific iPSCs into cardiomyocytes. We discovered that both verapamil and lidocaine substantially shortened the QT interval of the long QT syndrome patient-specific cardiomyocytes. Verapamil treatment was successful in reducing defibrillator discharge frequency of the KCNQ1/TRPM4 dual mutation patient. These results suggested that verapamil and lidocaine could be alternative therapeutic agents for long QT syndrome patients that do not respond well to conventional treatments. In conclusion, our approach indicated the usefulness of the in vitro disease model based on patient-specific iPSCs in identifying pharmacological mechanisms and drug screening. The long QT patient-specific iPSC line carrying KCNQ1/TRPM4 dual mutations also represents a tool for further understanding long QT syndrome pathogenesis. Full article
(This article belongs to the Special Issue Human Stem Cells in Disease Modelling, Drug Discovery and Regenerative Medicine)
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Review

Jump to: Research

26 pages, 2210 KiB  
Review
Management of Rheumatoid Arthritis: Possibilities and Challenges of Mesenchymal Stromal/Stem Cell-Based Therapies
by Yusuke Shimizu, Edward Hosea Ntege, Chinatsu Azuma, Fuminari Uehara, Takashi Toma, Kotaro Higa, Hiroki Yabiku, Naoki Matsuura, Yoshikazu Inoue and Hiroshi Sunami
Cells 2023, 12(14), 1905; https://doi.org/10.3390/cells12141905 - 21 Jul 2023
Viewed by 2113
Abstract
Rheumatoid arthritis (RA) is a highly prevalent, chronic, and progressive autoimmune disorder primarily affecting joints and muscles. The associated inflammation, pain, and motor restriction negatively impact patient quality of life (QOL) and can even contribute to premature mortality. Further, conventional treatments such as [...] Read more.
Rheumatoid arthritis (RA) is a highly prevalent, chronic, and progressive autoimmune disorder primarily affecting joints and muscles. The associated inflammation, pain, and motor restriction negatively impact patient quality of life (QOL) and can even contribute to premature mortality. Further, conventional treatments such as antiinflammatory drugs are only symptomatic. Substantial progress has been made on elucidating the etiopathology of overt RA, in particular the contributions of innate and adaptive immune system dysfunction to chronic inflammation. Although the precise mechanisms underlying onset and progression remain elusive, the discovery of new drug targets, early diagnosis, and new targeted treatments have greatly improved the prognosis and QOL of patients with RA. However, a sizable proportion of patients develop severe adverse effects, exhibit poor responses, or cannot tolerate long-term use of these drugs, necessitating more effective and safer therapeutic alternatives. Mounting preclinical and clinical evidence suggests that the transplantation of multipotent adult stem cells such as mesenchymal stromal/stem cells is a safe and effective treatment strategy for controlling chronic inflammation and promoting tissue regeneration in patients with intractable diseases, including RA. This review describes the current status of MSC-based therapies for RA as well as the opportunities and challenges to broader clinical application. Full article
(This article belongs to the Special Issue Human Stem Cells in Disease Modelling, Drug Discovery and Regenerative Medicine)
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37 pages, 1260 KiB  
Review
Human Stem Cells for Cardiac Disease Modeling and Preclinical and Clinical Applications—Are We on the Road to Success?
by Cátia D. Correia, Anita Ferreira, Mónica T. Fernandes, Bárbara M. Silva, Filipa Esteves, Helena S. Leitão, José Bragança and Sofia M. Calado
Cells 2023, 12(13), 1727; https://doi.org/10.3390/cells12131727 - 27 Jun 2023
Cited by 6 | Viewed by 3308
Abstract
Cardiovascular diseases (CVDs) are pointed out by the World Health Organization (WHO) as the leading cause of death, contributing to a significant and growing global health and economic burden. Despite advancements in clinical approaches, there is a critical need for innovative cardiovascular treatments [...] Read more.
Cardiovascular diseases (CVDs) are pointed out by the World Health Organization (WHO) as the leading cause of death, contributing to a significant and growing global health and economic burden. Despite advancements in clinical approaches, there is a critical need for innovative cardiovascular treatments to improve patient outcomes. Therapies based on adult stem cells (ASCs) and embryonic stem cells (ESCs) have emerged as promising strategies to regenerate damaged cardiac tissue and restore cardiac function. Moreover, the generation of human induced pluripotent stem cells (iPSCs) from somatic cells has opened new avenues for disease modeling, drug discovery, and regenerative medicine applications, with fewer ethical concerns than those associated with ESCs. Herein, we provide a state-of-the-art review on the application of human pluripotent stem cells in CVD research and clinics. We describe the types and sources of stem cells that have been tested in preclinical and clinical trials for the treatment of CVDs as well as the applications of pluripotent stem-cell-derived in vitro systems to mimic disease phenotypes. How human stem-cell-based in vitro systems can overcome the limitations of current toxicological studies is also discussed. Finally, the current state of clinical trials involving stem-cell-based approaches to treat CVDs are presented, and the strengths and weaknesses are critically discussed to assess whether researchers and clinicians are getting closer to success. Full article
(This article belongs to the Special Issue Human Stem Cells in Disease Modelling, Drug Discovery and Regenerative Medicine)
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52 pages, 4550 KiB  
Review
Transition from Animal-Based to Human Induced Pluripotent Stem Cells (iPSCs)-Based Models of Neurodevelopmental Disorders: Opportunities and Challenges
by Sara Guerreiro and Patrícia Maciel
Cells 2023, 12(4), 538; https://doi.org/10.3390/cells12040538 - 07 Feb 2023
Cited by 1 | Viewed by 3300
Abstract
Neurodevelopmental disorders (NDDs) arise from the disruption of highly coordinated mechanisms underlying brain development, which results in impaired sensory, motor and/or cognitive functions. Although rodent models have offered very relevant insights to the field, the translation of findings to clinics, particularly regarding therapeutic [...] Read more.
Neurodevelopmental disorders (NDDs) arise from the disruption of highly coordinated mechanisms underlying brain development, which results in impaired sensory, motor and/or cognitive functions. Although rodent models have offered very relevant insights to the field, the translation of findings to clinics, particularly regarding therapeutic approaches for these diseases, remains challenging. Part of the explanation for this failure may be the genetic differences—some targets not being conserved between species—and, most importantly, the differences in regulation of gene expression. This prompts the use of human-derived models to study NDDS. The generation of human induced pluripotent stem cells (hIPSCs) added a new suitable alternative to overcome species limitations, allowing for the study of human neuronal development while maintaining the genetic background of the donor patient. Several hIPSC models of NDDs already proved their worth by mimicking several pathological phenotypes found in humans. In this review, we highlight the utility of hIPSCs to pave new paths for NDD research and development of new therapeutic tools, summarize the challenges and advances of hIPSC-culture and neuronal differentiation protocols and discuss the best way to take advantage of these models, illustrating this with examples of success for some NDDs. Full article
(This article belongs to the Special Issue Human Stem Cells in Disease Modelling, Drug Discovery and Regenerative Medicine)
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25 pages, 1513 KiB  
Review
The Breakthroughs and Caveats of Using Human Pluripotent Stem Cells in Modeling Alzheimer’s Disease
by Katja Maria Sahlgren Bendtsen and Vanessa Jane Hall
Cells 2023, 12(3), 420; https://doi.org/10.3390/cells12030420 - 27 Jan 2023
Cited by 9 | Viewed by 5525
Abstract
Modeling Alzheimer’s disease (AD) using human-induced pluripotent stem cells (iPSCs) is a field now spanning 15 years. Developments in the field have shown a shift in using simple 2D cortical neuron models to more advanced tri-cultures and 3D cerebral organoids that recapitulate more [...] Read more.
Modeling Alzheimer’s disease (AD) using human-induced pluripotent stem cells (iPSCs) is a field now spanning 15 years. Developments in the field have shown a shift in using simple 2D cortical neuron models to more advanced tri-cultures and 3D cerebral organoids that recapitulate more features of the disease. This is largely due to development and optimization of new cell protocols. In this review, we highlight recent major breakthroughs in the AD field and the implications this has in modeling AD using iPSCs (AD-iPSCs). To date, AD-iPSCs have been largely used to recapitulate and study impaired amyloid precursor protein (APP) processing and tau phosphorylation in both familial and sporadic AD. AD-iPSCs have also been studied for varying neuronal and glial dysfunctions. Moreover, they have been useful for discovering new molecular mechanisms, such as identifying proteins that bridge APP processing with tau phosphorylation and for identifying molecular pathways that bridge APP processing dysfunction with impaired cholesterol biosynthesis. Perhaps the greatest use of AD-iPSCs has been in discovering compounds via drug screening, that reduce amyloid beta (Aβ) in neurons, such as the anti-inflammatory compound, cromolyn, and antiparasitic drugs, avermectins. In addition, high content screening using AD-iPSCs has led to the identification of statins that can reduce levels of phosphorylated tau (p-Tau) in neurons. Some of these compounds have made it through to testing in human clinical trials. Improvements in omic technologies including single cell RNA sequencing and proteomics as well as advances in production of iPSC-cerebral organoids and tri-cultures is likely to result in the further discovery of new drugs and treatments for AD. Some caveats remain in the field, including, long experimental conditions to create mature neurons, high costs of media that limit research capabilities, and a lack of reproducibility using current iPSC-cerebral organoid protocols. Despite these current limitations, AD-iPSCs remain an excellent cellular model for studying AD mechanisms and for drug discovery. Full article
(This article belongs to the Special Issue Human Stem Cells in Disease Modelling, Drug Discovery and Regenerative Medicine)
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16 pages, 1746 KiB  
Review
Human In Vitro Models of Epilepsy Using Embryonic and Induced Pluripotent Stem Cells
by Muhammad Shahid Javaid, Tracie Tan, Naomi Dvir, Alison Anderson, Terence J. O’Brien, Patrick Kwan and Ana Antonic-Baker
Cells 2022, 11(24), 3957; https://doi.org/10.3390/cells11243957 - 07 Dec 2022
Cited by 8 | Viewed by 2783
Abstract
The challenges in making animal models of complex human epilepsy phenotypes with varied aetiology highlights the need to develop alternative disease models that can address the limitations of animal models by effectively recapitulating human pathophysiology. The advances in stem cell technology provide an [...] Read more.
The challenges in making animal models of complex human epilepsy phenotypes with varied aetiology highlights the need to develop alternative disease models that can address the limitations of animal models by effectively recapitulating human pathophysiology. The advances in stem cell technology provide an opportunity to use human iPSCs to make disease-in-a-dish models. The focus of this review is to report the current information and progress in the generation of epileptic patient-specific iPSCs lines, isogenic control cell lines, and neuronal models. These in vitro models can be used to study the underlying pathological mechanisms of epilepsies, anti-seizure medication resistance, and can also be used for drug testing and drug screening with their isogenic control cell lines. Full article
(This article belongs to the Special Issue Human Stem Cells in Disease Modelling, Drug Discovery and Regenerative Medicine)
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33 pages, 2365 KiB  
Review
Stem Cell-Based Therapeutic Strategies for Premature Ovarian Insufficiency and Infertility: A Focus on Aging
by Ilyas Ali, Arshad Ahmed Padhiar, Ting Wang, Liangge He, Mingzhuang Chen, Shengda Wu, Yan Zhou and Guangqian Zhou
Cells 2022, 11(23), 3713; https://doi.org/10.3390/cells11233713 - 22 Nov 2022
Cited by 8 | Viewed by 5218
Abstract
Reproductive aging is on the rise globally and inseparable from the entire aging process. An extreme form of reproductive aging is premature ovarian insufficiency (POI), which to date has mostly been of idiopathic etiology, thus hampering further clinical applications and associated with enormous [...] Read more.
Reproductive aging is on the rise globally and inseparable from the entire aging process. An extreme form of reproductive aging is premature ovarian insufficiency (POI), which to date has mostly been of idiopathic etiology, thus hampering further clinical applications and associated with enormous socioeconomic and personal costs. In the field of reproduction, the important functional role of inflammation-induced ovarian deterioration and therapeutic strategies to prevent ovarian aging and increase its function are current research hotspots. This review discusses the general pathophysiology and relative causes of POI and comprehensively describes the association between the aging features of POI and infertility. Next, various preclinical studies of stem cell therapies with potential for POI treatment and their molecular mechanisms are described, with particular emphasis on the use of human induced pluripotent stem cell (hiPSC) technology in the current scenario. Finally, the progress made in the development of hiPSC technology as a POI research tool for engineering more mature and functional organoids suitable as an alternative therapy to restore infertility provides new insights into therapeutic vulnerability, and perspectives on this exciting research on stem cells and the derived exosomes towards more effective POI diagnosis and treatment are also discussed. Full article
(This article belongs to the Special Issue Human Stem Cells in Disease Modelling, Drug Discovery and Regenerative Medicine)
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