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Special Issue "hiPSC-Derived Cells as Models for Drug Discovery"

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: 31 December 2020.

Special Issue Editor

Dr. Rivka Ofir
Website
Guest Editor
Regenerative Medicine and Stem Cell (RMSC) Research Center, Ben-Gurion University of the Negev, Israel
Interests: reprogramming; differentiation; Brain Blood Barrier (BBB); iPSC; drug discovery; disease in a dish model

Special Issue Information

Dear Colleagues,

More than 85% of pre-clinically tested drugs, fail during clinical trials, which results in a long and inefficient and costly process, suggesting that animal models are often poor predictors of human biology. The ability to perform research on human is limited by the lack of physiologically relevant cells (especially the development and assessment of human brain cells and human heart cells). Currently, there are technologies to reprogram adult, somatic cells (e.g. skin biopsy, blood cells, etc) back into a pluripotent stage, termed induced pluripotent stem cells (iPSCs), and to differentiate pluripotent cells in vitro into many cell types of the body like heart, muscle, brain cells, etc. These capabilities opened a new era in human disease modeling.

For this Special Issue, we would like to invite papers that follow this concept: To use iPSC-derived cells (cardiomyocytes, fibroblasts, glial cells, neurons, astrocytes, brain microvascular endothelial cells and more) as disease models to screen leads for drugs.

Suggest models like, but not limited to:

  1. A blood-brain-barrier (BBB) model composed of iPSC-derived neurons, astrocytes and brain microvascular endothelial cells (iBMECs) to predict if drugs penetrate or damage the BBB.
  2. Neuro-regeneration vs neurodegeneration: hiPSC-derived neurological disease models, models for Traumatic Brain Injury (TBI), to suggest compounds that will follow the concept of inducing Neuro-regeneration instead of inhibiting neuro-degeneration.
  3. hiPSC-derived sensory cells for identifying pain relievers
  4. hiPSC-derived microglia cells for treating neurological diseases, and more

Suggest methodologies for monitoring drug effects in iPSC-derived disease models:

e.g. Following screening compounds, iPSC-derived neural cells will be tested for differentiation potential, proliferation and viability by quantification of protein expression, such as βIII-tubulin for neurons and GFAP for astrocytes. To assess functionality of the cells following drug exposure, Microelectrode arrays (MEA) recording for measuring excitability of neuronal cells and cellular permeability and resistance of iBMECs will be monitored. 

Dr. Rivka Ofir
Guest Editor

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 papers will be 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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • iPSC
  • human disease models
  • drug discovery
  • glia cells
  • neurons
  • cardiomyocytes
  • heaptocytes
  • blood-brain-barrier
  • iBMEC
  • astrocytes

Published Papers (7 papers)

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Research

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Open AccessArticle
Robust and Scalable Angiogenesis Assay of Perfused 3D Human iPSC-Derived Endothelium for Anti-Angiogenic Drug Screening
Int. J. Mol. Sci. 2020, 21(13), 4804; https://doi.org/10.3390/ijms21134804 - 07 Jul 2020
Abstract
To advance pre-clinical vascular drug research, in vitro assays are needed that closely mimic the process of angiogenesis in vivo. Such assays should combine physiological relevant culture conditions with robustness and scalability to enable drug screening. We developed a perfused 3D angiogenesis [...] Read more.
To advance pre-clinical vascular drug research, in vitro assays are needed that closely mimic the process of angiogenesis in vivo. Such assays should combine physiological relevant culture conditions with robustness and scalability to enable drug screening. We developed a perfused 3D angiogenesis assay that includes endothelial cells (ECs) from induced pluripotent stem cells (iPSC) and assessed its performance and suitability for anti-angiogenic drug screening. Angiogenic sprouting was compared with primary ECs and showed that the microvessels from iPSC-EC exhibit similar sprouting behavior, including tip cell formation, directional sprouting and lumen formation. Inhibition with sunitinib, a clinically used vascular endothelial growth factor (VEGF) receptor type 2 inhibitor, and 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), a transient glycolysis inhibitor, both significantly reduced the sprouting of both iPSC-ECs and primary ECs, supporting that both cell types show VEGF gradient-driven angiogenic sprouting. The assay performance was quantified for sunitinib, yielding a minimal signal window of 11 and Z-factor of at least 0.75, both meeting the criteria to be used as screening assay. In conclusion, we have developed a robust and scalable assay that includes physiological relevant culture conditions and is amenable to screening of anti-angiogenic compounds. Full article
(This article belongs to the Special Issue hiPSC-Derived Cells as Models for Drug Discovery)
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Open AccessArticle
Human Spinal Motor Neurons Are Particularly Vulnerable to Cerebrospinal Fluid of Amyotrophic Lateral Sclerosis Patients
Int. J. Mol. Sci. 2020, 21(10), 3564; https://doi.org/10.3390/ijms21103564 - 18 May 2020
Cited by 1
Abstract
Amyotrophic lateral sclerosis (ALS) is the most common and devastating motor neuron (MN) disease. Its pathophysiological cascade is still enigmatic. More than 90% of ALS patients suffer from sporadic ALS, which makes it specifically demanding to generate appropriate model systems. One interesting aspect [...] Read more.
Amyotrophic lateral sclerosis (ALS) is the most common and devastating motor neuron (MN) disease. Its pathophysiological cascade is still enigmatic. More than 90% of ALS patients suffer from sporadic ALS, which makes it specifically demanding to generate appropriate model systems. One interesting aspect considering the seeding, spreading and further disease development of ALS is the cerebrospinal fluid (CSF). We therefore asked whether CSF from sporadic ALS patients is capable of causing disease typical changes in human patient-derived spinal MN cultures and thus could represent a novel model system for sporadic ALS. By using induced pluripotent stem cell (iPSC)-derived MNs from healthy controls and monogenetic forms of ALS we could demonstrate a harmful effect of ALS-CSF on healthy donor-derived human MNs. Golgi fragmentation—a typical finding in lower organism models and human postmortem tissue—was induced solely by addition of ALS-CSF, but not control-CSF. No other neurodegenerative hallmarks—including pathological protein aggregation—were found, underpinning Golgi fragmentation as early event in the neurodegenerative cascade. Of note, these changes occurred predominantly in MNs, the cell type primarily affected in ALS. We thus present a novel way to model early features of sporadic ALS. Full article
(This article belongs to the Special Issue hiPSC-Derived Cells as Models for Drug Discovery)
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Open AccessArticle
Inhibition of RNA Helicase Activity Prevents Coxsackievirus B3-Induced Myocarditis in Human iPS Cardiomyocytes
Int. J. Mol. Sci. 2020, 21(9), 3041; https://doi.org/10.3390/ijms21093041 - 25 Apr 2020
Abstract
Aims: Coxsackievirus B3 (CVB3) is known to be an important cause of myocarditis and dilated cardiomyopathy. Enterovirus-2C (E2C) is a viral RNA helicase. It inhibits host protein synthesis. Based on these facts, we hypothesize that the inhibition of 2C may suppress virus replication [...] Read more.
Aims: Coxsackievirus B3 (CVB3) is known to be an important cause of myocarditis and dilated cardiomyopathy. Enterovirus-2C (E2C) is a viral RNA helicase. It inhibits host protein synthesis. Based on these facts, we hypothesize that the inhibition of 2C may suppress virus replication and prevent enterovirus-mediated cardiomyopathy. Methods and Results: We generated a chemically modified enterovirus-2C inhibitor (E2CI). From the in vitro assay, E2CI was showed strong antiviral effects. For in vivo testing, mice were treated with E2CI intraperitoneally injected daily for three consecutive days at a dose of 8 mg/kg per day, after CVB3 post-infection (p.i) (CVB3 + E2CI, n = 33). For the infected controls (CVB3 only, n = 35), mice were injected with PBS (phosphate buffered saline) in a DBA/2 strain to establish chronic myocarditis. The four-week survival rate of E2CI-treated mice was significantly higher than that of controls (92% vs. 71%; p < 0.05). Virus titers and myocardial damage were significantly reduced in the E2CI treated group. In addition, echocardiography indicated that E2CI administration dramatically maintained mouse heart function compared to control at day 28 p.i chronic stage (LVIDD, 3.1 ± 0.08 vs. 3.9 ± 0.09, p < 0.01; LVDS, 2.0 ± 0.07 vs. 2.5 ± 0.07, p < 0.001; FS, 34.8 ± 1.6% vs. 28.5 ± 1.5%; EF, 67. 9 ± 2.9% vs. 54.7 ± 4.7%, p < 0.05; CVB3 + E2CI, n = 6 vs. CVB3, n = 4). Moreover, E2CI is effectively worked in human iPS (induced pluripotent stem cell) derived cardiomyocytes. Conclusion: Enterovirus-2C inhibitor (E2CI) was significantly reduced viral replication, chronic myocardium damage, and CVB3-induced mortality in DBA/2 mice. These results suggested that E2CI is a novel therapeutic agent for the treatment of enterovirus-mediated diseases. Full article
(This article belongs to the Special Issue hiPSC-Derived Cells as Models for Drug Discovery)
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Open AccessArticle
Electrophysiological Abnormalities in VLCAD Deficient hiPSC-Cardiomyocytes Can Be Improved by Lowering Accumulation of Fatty Acid Oxidation Intermediates
Int. J. Mol. Sci. 2020, 21(7), 2589; https://doi.org/10.3390/ijms21072589 - 08 Apr 2020
Cited by 2
Abstract
Patients with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) can present with life-threatening cardiac arrhythmias. The pathophysiological mechanism is unknown. We reprogrammed fibroblasts from one mildly and one severely affected VLCADD patient, into human induced pluripotent stem cells (hiPSCs) and differentiated these into cardiomyocytes [...] Read more.
Patients with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) can present with life-threatening cardiac arrhythmias. The pathophysiological mechanism is unknown. We reprogrammed fibroblasts from one mildly and one severely affected VLCADD patient, into human induced pluripotent stem cells (hiPSCs) and differentiated these into cardiomyocytes (VLCADD-CMs). VLCADD-CMs displayed shorter action potentials (APs), more delayed afterdepolarizations (DADs) and higher systolic and diastolic intracellular Ca2+ concentration ([Ca2+]i) than control CMs. The mitochondrial booster resveratrol mitigated the biochemical, electrophysiological and [Ca2+]i changes in the mild but not in the severe VLCADD-CMs. Accumulation of potentially toxic intermediates of fatty acid oxidation was blocked by substrate reduction with etomoxir. Incubation with etomoxir led to marked prolongation of AP duration and reduced DADs and [Ca2+]i in both VLCADD-CMs. These results provide compelling evidence that reduced accumulation of fatty acid oxidation intermediates, either by enhanced fatty acid oxidation flux through increased mitochondria biogenesis (resveratrol) or by inhibition of fatty acid transport into the mitochondria (etomoxir), rescues pro-arrhythmia defects in VLCADD-CMs and open doors for new treatments. Full article
(This article belongs to the Special Issue hiPSC-Derived Cells as Models for Drug Discovery)
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Review

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Open AccessReview
Patient-Derived Induced Pluripotent Stem Cell-Based Models in Parkinson’s Disease for Drug Identification
Int. J. Mol. Sci. 2020, 21(19), 7113; https://doi.org/10.3390/ijms21197113 - 26 Sep 2020
Abstract
Parkinson’s disease (PD) is a common progressive neurodegenerative disorder characterized by loss of striatal-projecting dopaminergic neurons of the ventral forebrain, resulting in motor and cognitive deficits. Despite extensive efforts in understanding PD pathogenesis, no disease-modifying drugs exist. Recent advances in cell reprogramming technologies [...] Read more.
Parkinson’s disease (PD) is a common progressive neurodegenerative disorder characterized by loss of striatal-projecting dopaminergic neurons of the ventral forebrain, resulting in motor and cognitive deficits. Despite extensive efforts in understanding PD pathogenesis, no disease-modifying drugs exist. Recent advances in cell reprogramming technologies have facilitated the generation of patient-derived models for sporadic or familial PD and the identification of early, potentially triggering, pathological phenotypes while they provide amenable systems for drug discovery. Emerging developments highlight the enhanced potential of using more sophisticated cellular systems, including neuronal and glial co-cultures as well as three-dimensional systems that better simulate the human pathophysiology. In combination with high-throughput high-content screening technologies, these approaches open new perspectives for the identification of disease-modifying compounds. In this review, we discuss current advances and the challenges ahead in the use of patient-derived induced pluripotent stem cells for drug discovery in PD. We address new concepts implicating non-neuronal cells in disease pathogenesis and highlight the necessity for functional assays, such as calcium imaging and multi-electrode array recordings, to predict drug efficacy. Finally, we argue that artificial intelligence technologies will be pivotal for analysis of the large and complex data sets obtained, becoming game-changers in the process of drug discovery. Full article
(This article belongs to the Special Issue hiPSC-Derived Cells as Models for Drug Discovery)
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Open AccessReview
Human Pluripotent Stem Cell-Derived Neural Cells as a Relevant Platform for Drug Screening in Alzheimer’s Disease
Int. J. Mol. Sci. 2020, 21(18), 6867; https://doi.org/10.3390/ijms21186867 - 18 Sep 2020
Abstract
Extracellular amyloid-beta deposition and intraneuronal Tau-laden neurofibrillary tangles are prime features of Alzheimer’s disease (AD). The pathology of AD is very complex and still not fully understood, since different neural cell types are involved in the disease. Although neuronal function is clearly deteriorated [...] Read more.
Extracellular amyloid-beta deposition and intraneuronal Tau-laden neurofibrillary tangles are prime features of Alzheimer’s disease (AD). The pathology of AD is very complex and still not fully understood, since different neural cell types are involved in the disease. Although neuronal function is clearly deteriorated in AD patients, recently, an increasing number of evidences have pointed towards glial cell dysfunction as one of the main causative phenomena implicated in AD pathogenesis. The complex disease pathology together with the lack of reliable disease models have precluded the development of effective therapies able to counteract disease progression. The discovery and implementation of human pluripotent stem cell technology represents an important opportunity in this field, as this system allows the generation of patient-derived cells to be used for disease modeling and therapeutic target identification and as a platform to be employed in drug discovery programs. In this review, we discuss the current studies using human pluripotent stem cells focused on AD, providing convincing evidences that this system is an excellent opportunity to advance in the comprehension of AD pathology, which will be translated to the development of the still missing effective therapies. Full article
(This article belongs to the Special Issue hiPSC-Derived Cells as Models for Drug Discovery)
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Open AccessReview
iPSC-Derived Liver Organoids: A Journey from Drug Screening, to Disease Modeling, Arriving to Regenerative Medicine
Int. J. Mol. Sci. 2020, 21(17), 6215; https://doi.org/10.3390/ijms21176215 - 27 Aug 2020
Abstract
Liver transplantation is the most common treatment for patients suffering from liver failure that is caused by congenital diseases, infectious agents, and environmental factors. Despite a high rate of patient survival following transplantation, organ availability remains the key limiting factor. As such, research [...] Read more.
Liver transplantation is the most common treatment for patients suffering from liver failure that is caused by congenital diseases, infectious agents, and environmental factors. Despite a high rate of patient survival following transplantation, organ availability remains the key limiting factor. As such, research has focused on the transplantation of different cell types that are capable of repopulating and restoring liver function. The best cellular mix capable of engrafting and proliferating over the long-term, as well as the optimal immunosuppression regimens, remain to be clearly well-defined. Hence, alternative strategies in the field of regenerative medicine have been explored. Since the discovery of induced pluripotent stem cells (iPSC) that have the potential of differentiating into a broad spectrum of cell types, many studies have reported the achievement of iPSCs differentiation into liver cells, such as hepatocytes, cholangiocytes, endothelial cells, and Kupffer cells. In parallel, an increasing interest in the study of self-assemble or matrix-guided three-dimensional (3D) organoids have paved the way for functional bioartificial livers. In this review, we will focus on the recent breakthroughs in the development of iPSCs-based liver organoids and the major drawbacks and challenges that need to be overcome for the development of future applications. Full article
(This article belongs to the Special Issue hiPSC-Derived Cells as Models for Drug Discovery)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Author: Rebecca Matsas 

Title: Patient-derived induced pluripotent stem cell-based models in Parkinson's disease for drug identification

Author: Andreas Hermann

Title: hiPSC-derived motor neurons 

Author: Vincent van Duinen

Title: A microfluidic 3D drug screening platform for anti-angiogenic compounds on iPSC derived endothelial cells

 

 

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