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Cells
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Cell-Based Models of Diseases for Drug Discovery
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Cell-Based Models of Diseases for Drug Discovery

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

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 33965

Special Issue Editor

Dr. Jason Ear

E-Mail Website
Guest Editor
Assistant Professor, Biological Sciences Department, Cal State Polytechnic University Pomona, Pomona, CA, USA
Interests: cell Signaling; cell biology; signal transduction; disease modeling; genome engineering; small molecule testing; biotherapeutics

Special Issue Information

Dear Colleagues,

Cell-based assays that model aspects of diseases are crucial for preclinical drug discovery. From neurodegenerative disorders to cancers, advance culturing techniques such as induced pluripotent stem cells (iPSCs) and three-dimensional (3D) co-culture have enabled scientists to better model human diseases in the laboratory in order to gain a better understanding of the underlying mechanisms. Complementing these culture methods with gene editing technologies can further add to the translational relevance of the cells as a preclinical drug discovery platform. Continual improvements in culturing methodologies and developments in functional/phenotypic cell-based assays will ensure that we continue to make advancements to treat human diseases.

Dr. Jason Ear
Guest Editor

Manuscript Submission Information

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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

  • disease model
  • cell-based assays
  • drug discovery/screening

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Published Papers (7 papers)

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Research

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15 pages, 2618 KiB  
Article
An Ex Vivo 3D Tumor Microenvironment-Mimicry Culture to Study TAM Modulation of Cancer Immunotherapy
by Yan-Ruide Li, Yanqi Yu, Adam Kramer, Ryan Hon, Matthew Wilson, James Brown and Lili Yang
Cells 2022, 11(9), 1583; https://doi.org/10.3390/cells11091583 - 8 May 2022
Cited by 14 | Viewed by 5178
Abstract
Tumor-associated macrophages (TAMs) accumulate in the solid tumor microenvironment (TME) and have been shown to promote tumor growth and dampen antitumor immune responses. TAM-mediated suppression of T-cell antitumor reactivity is considered to be a major obstacle for many immunotherapies, including immune checkpoint blockade [...] Read more.
Tumor-associated macrophages (TAMs) accumulate in the solid tumor microenvironment (TME) and have been shown to promote tumor growth and dampen antitumor immune responses. TAM-mediated suppression of T-cell antitumor reactivity is considered to be a major obstacle for many immunotherapies, including immune checkpoint blockade and adoptive T/CAR-T-cell therapies. An ex vivo culture system closely mimicking the TME can greatly facilitate the study of cancer immunotherapies. Here, we report the development of a 3D TME-mimicry culture that is comprised of the three major components of a human TME, including human tumor cells, TAMs, and tumor antigen-specific T cells. This TME-mimicry culture can readout the TAM-mediated suppression of T-cell antitumor reactivity, and therefore can be used to study TAM modulation of T-cell-based cancer immunotherapy. As a proof-of-principle, the studies of a PD-1/PD-L1 blockade therapy and a MAO-A blockade therapy were performed and validated. Full article
(This article belongs to the Special Issue Cell-Based Models of Diseases for Drug Discovery)
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21 pages, 9764 KiB  
Article
Cardiac Ischemia On-a-Chip: Antiarrhythmic Effect of Levosimendan on Ischemic Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes
by Mahmoud Gaballah, Kirsi Penttinen, Joose Kreutzer, Antti-Juhana Mäki, Pasi Kallio and Katriina Aalto-Setälä
Cells 2022, 11(6), 1045; https://doi.org/10.3390/cells11061045 - 19 Mar 2022
Cited by 13 | Viewed by 5129
Abstract
Ischemic heart disease (IHD) is one of the leading causes of mortality worldwide. Preserving functionality and preventing arrhythmias of the heart are key principles in the management of patients with IHD. Levosimendan, a unique calcium (Ca2+) enhancer with inotropic activity, has [...] Read more.
Ischemic heart disease (IHD) is one of the leading causes of mortality worldwide. Preserving functionality and preventing arrhythmias of the heart are key principles in the management of patients with IHD. Levosimendan, a unique calcium (Ca2+) enhancer with inotropic activity, has been introduced into clinical usage for heart failure treatment. Human-induced pluripotent cell-derived cardiomyocytes (hiPSC-CMs) offer an opportunity to better understand the pathophysiological mechanisms of the disease as well as to serve as a platform for drug screening. Here, we developed an in vitro IHD model using hiPSC-CMs in hypoxic conditions and defined the effects of the subsequent hypoxic stress on CMs functionality. Furthermore, the effect of levosimendan on hiPSC-CMs functionality was evaluated during and after hypoxic stress. The morphology, contractile, Ca2+-handling, and gene expression properties of hiPSC-CMs were investigated in response to hypoxia. Hypoxia resulted in significant cardiac arrhythmia and decreased Ca2+ transient amplitude. In addition, disorganization of sarcomere structure was observed after hypoxia induction. Interestingly, levosimendan presented significant antiarrhythmic properties, as the arrhythmia was abolished or markedly reduced with levosimendan treatment either during or after the hypoxic stress. Moreover, levosimendan presented significant protection from the sarcomere alterations induced by hypoxia. In conclusion, this chip model appears to be a suitable preclinical representation of IHD. With this hypoxia platform, detailed knowledge of the disease pathophysiology can be obtained. The antiarrhythmic effect of levosimendan was clearly observed, suggesting a possible new clinical use for the drug. Full article
(This article belongs to the Special Issue Cell-Based Models of Diseases for Drug Discovery)
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17 pages, 2471 KiB  
Article
Rapid Generation of Ventral Spinal Cord-like Astrocytes from Human iPSCs for Modeling Non-Cell Autonomous Mechanisms of Lower Motor Neuron Disease
by Vincent Soubannier, Mathilde Chaineau, Lale Gursu, Ghazal Haghi, Anna Kristyna Franco Flores, Guy Rouleau, Thomas M. Durcan and Stefano Stifani
Cells 2022, 11(3), 399; https://doi.org/10.3390/cells11030399 - 24 Jan 2022
Cited by 6 | Viewed by 4079
Abstract
Astrocytes play important roles in the function and survival of neuronal cells. Dysfunctions of astrocytes are associated with numerous disorders and diseases of the nervous system, including motor neuron diseases such as amyotrophic lateral sclerosis (ALS). Human-induced pluripotent stem cell (iPSC)-based approaches are [...] Read more.
Astrocytes play important roles in the function and survival of neuronal cells. Dysfunctions of astrocytes are associated with numerous disorders and diseases of the nervous system, including motor neuron diseases such as amyotrophic lateral sclerosis (ALS). Human-induced pluripotent stem cell (iPSC)-based approaches are becoming increasingly important for the study of the mechanisms underlying the involvement of astrocytes in non-cell autonomous processes of motor neuron degeneration in ALS. These studies must account for the molecular and functional diversity among astrocytes in different regions of the brain and spinal cord. It is essential that the most pathologically relevant astrocyte preparations are used when investigating non-cell autonomous mechanisms of either upper or lower motor neuron degeneration in ALS. Here, we describe the efficient and streamlined generation of human iPSC-derived astrocytes with molecular and biological properties similar to physiological astrocytes in the ventral spinal cord. These induced astrocytes exhibit spontaneous and ATP-induced calcium transients, and lack signs of overt activation. Human iPSC-derived astrocytes with ventral spinal cord features offer advantages over more generic astrocyte preparations for the study of both ventral spinal cord astrocyte biology and the involvement of astrocytes in mechanisms of lower motor neuron degeneration in ALS. Full article
(This article belongs to the Special Issue Cell-Based Models of Diseases for Drug Discovery)
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19 pages, 2357 KiB  
Article
Use of Cytokine Mix-, Imiquimod-, and Serum-Induced Monoculture and Lipopolysaccharide- and Interferon Gamma-Treated Co-Culture to Establish In Vitro Psoriasis-like Inflammation Models
by Katarzyna Bocheńska, Marta Moskot and Magdalena Gabig-Cimińska
Cells 2021, 10(11), 2985; https://doi.org/10.3390/cells10112985 - 2 Nov 2021
Cited by 9 | Viewed by 3911
Abstract
Psoriasis (Ps), commonly perceived as a skin and joint disorder, has a complex basis and results from disturbances in the sophisticated network between skin and the immune system. This makes it difficult to properly depict the complete pathomechanism on an in vitro scale. [...] Read more.
Psoriasis (Ps), commonly perceived as a skin and joint disorder, has a complex basis and results from disturbances in the sophisticated network between skin and the immune system. This makes it difficult to properly depict the complete pathomechanism on an in vitro scale. Deciphering the complicated or even subtle modulation of intra- and intercellular factors, assisted by the implementation of in vitro human skin models, may provide the opportunity to dissect the disease background step by step. In addition to reconstructed artificial skin substitutes, which mimic the native physiological context, in vitro models are conducive to the broad “3 Rs” philosophy (reduce, refine, and replace) and represent important tools for basic and applied skin research. To meet the need for a more comprehensive in vitro Ps model, a set of various experimental conditions was applied in this study. The selection of in vitro treatment that mimicked the Ps phenotype was illustrated by analyses of discriminating biomarker genes involved in the pathogenesis of the disease, i.e., keratinocyte differentiation markers, antimicrobial peptides, chemokines, and proliferation markers. This resulted in a reproducible protocol for the use of the primary skin keratinocyte (pKC) monoculture treated with a cytokine cocktail (5MIX, i.e., interleukin (IL) 1 alpha (IL-1α), IL-17A, IL-22, oncostatin M (OSM), and tumour necrosis factor alpha (TNF-α)) at a calcium (Ca2+) concentration (i.e., 2 mM) in an applied medium, which best mirrored the in vitro Ps-like inflammatory model. In addition, based on waste skin material, the method has the potential for extensive experimentation, both in detailed molecular studies and preclinical tests. Full article
(This article belongs to the Special Issue Cell-Based Models of Diseases for Drug Discovery)
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20 pages, 2949 KiB  
Article
Penile Cancer-Derived Cells Molecularly Characterized as Models to Guide Targeted Therapies
by Hellen Kuasne, Luisa Matos do Canto, Mads Malik Aagaard, Juan Jose Moyano Muñoz, Camille De Jamblinne, Fabio Albuquerque Marchi, Cristovam Scapulatempo-Neto, Eliney Ferreira Faria, Ademar Lopes, Sébastien Carréno and Silvia Regina Rogatto
Cells 2021, 10(4), 814; https://doi.org/10.3390/cells10040814 - 6 Apr 2021
Cited by 10 | Viewed by 3759
Abstract
Penile cancer (PeCa) is a common disease in poor and developing countries, showing high morbidity rates. Despite the recent progress in understanding the molecular events involved in PeCa, the lack of well-characterized in vitro models precludes new advances in anticancer drug development. Here [...] Read more.
Penile cancer (PeCa) is a common disease in poor and developing countries, showing high morbidity rates. Despite the recent progress in understanding the molecular events involved in PeCa, the lack of well-characterized in vitro models precludes new advances in anticancer drug development. Here we describe the establishment of five human primary penile cancer-derived cell cultures, including two epithelial and three cancer-associated fibroblast (CAF) cells. Using high-throughput genomic approaches, we found that the epithelial PeCa derived- cells recapitulate the molecular alterations of their primary tumors and present the same deregulated signaling pathways. The differentially expressed genes and proteins identified are components of key oncogenic pathways, including EGFR and PI3K/AKT/mTOR. We showed that epithelial PeCa derived cells presented a good response to cisplatin, a common therapeutic approach used in PeCa patients. The growth of a PeCa-derived cell overexpressing EGFR was inhibited by EGFR inhibitors (cetuximab, gefitinib, and erlotinib). We also identified CAF signature markers in three PeCa-derived cells with fibroblast-like morphology, indicating that those cells are suitable models for PeCa microenvironment studies. We thus demonstrate the utility of PeCa cell models to dissect mechanisms that promote penile carcinogenesis, which are useful models to evaluate therapeutic approaches for the disease. Full article
(This article belongs to the Special Issue Cell-Based Models of Diseases for Drug Discovery)
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Review

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25 pages, 4195 KiB  
Review
Contribution of Human Pluripotent Stem Cell-Based Models to Drug Discovery for Neurological Disorders
by Alexandra Benchoua, Marie Lasbareilles and Johana Tournois
Cells 2021, 10(12), 3290; https://doi.org/10.3390/cells10123290 - 24 Nov 2021
Cited by 8 | Viewed by 4169
Abstract
One of the major obstacles to the identification of therapeutic interventions for central nervous system disorders has been the difficulty in studying the step-by-step progression of diseases in neuronal networks that are amenable to drug screening. Recent advances in the field of human [...] Read more.
One of the major obstacles to the identification of therapeutic interventions for central nervous system disorders has been the difficulty in studying the step-by-step progression of diseases in neuronal networks that are amenable to drug screening. Recent advances in the field of human pluripotent stem cell (PSC) biology offers the capability to create patient-specific human neurons with defined clinical profiles using reprogramming technology, which provides unprecedented opportunities for both the investigation of pathogenic mechanisms of brain disorders and the discovery of novel therapeutic strategies via drug screening. Many examples not only of the creation of human pluripotent stem cells as models of monogenic neurological disorders, but also of more challenging cases of complex multifactorial disorders now exist. Here, we review the state-of-the art brain cell types obtainable from PSCs and amenable to compound-screening formats. We then provide examples illustrating how these models contribute to the definition of new molecular or functional targets for drug discovery and to the design of novel pharmacological approaches for rare genetic disorders, as well as frequent neurodegenerative diseases and psychiatric disorders. Full article
(This article belongs to the Special Issue Cell-Based Models of Diseases for Drug Discovery)
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40 pages, 3072 KiB  
Review
The Challenging Melanoma Landscape: From Early Drug Discovery to Clinical Approval
by Mariana Matias, Jacinta O. Pinho, Maria João Penetra, Gonçalo Campos, Catarina Pinto Reis and Maria Manuela Gaspar
Cells 2021, 10(11), 3088; https://doi.org/10.3390/cells10113088 - 9 Nov 2021
Cited by 28 | Viewed by 6337
Abstract
Melanoma is recognized as the most dangerous type of skin cancer, with high mortality and resistance to currently used treatments. To overcome the limitations of the available therapeutic options, the discovery and development of new, more effective, and safer therapies is required. In [...] Read more.
Melanoma is recognized as the most dangerous type of skin cancer, with high mortality and resistance to currently used treatments. To overcome the limitations of the available therapeutic options, the discovery and development of new, more effective, and safer therapies is required. In this review, the different research steps involved in the process of antimelanoma drug evaluation and selection are explored, including information regarding in silico, in vitro, and in vivo experiments, as well as clinical trial phases. Details are given about the most used cell lines and assays to perform both two- and three-dimensional in vitro screening of drug candidates towards melanoma. For in vivo studies, murine models are, undoubtedly, the most widely used for assessing the therapeutic potential of new compounds and to study the underlying mechanisms of action. Here, the main melanoma murine models are described as well as other animal species. A section is dedicated to ongoing clinical studies, demonstrating the wide interest and successful efforts devoted to melanoma therapy, in particular at advanced stages of the disease, and a final section includes some considerations regarding approval for marketing by regulatory agencies. Overall, considerable commitment is being directed to the continuous development of optimized experimental models, important for the understanding of melanoma biology and for the evaluation and validation of novel therapeutic strategies. Full article
(This article belongs to the Special Issue Cell-Based Models of Diseases for Drug Discovery)
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