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Special Issue "hiPSC-Derived Cells as Models for Drug Discovery 2.0"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 18453

Special Issue Editor

Dr. Rivka Ofir
E-Mail Website
Guest Editor
Regenerative Medicine and Stem Cell (RMSC) Research Center, Ben-Gurion University of the Negev, Beer Sheva, Israel
Interests: reprogramming; differentiation; Brain Blood Barrier (BBB); iPSC; drug discovery; disease in a dish model
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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
  5. 3D models for wound healing, drug discovery, 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

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Keywords

  • iPSC
  • human disease models
  • drug discovery
  • glia cells
  • neurons
  • cardiomyocytes
  • heaptocytes
  • blood-brain-barrier
  • iBMEC
  • astrocytes
  • 3D models

Published Papers (15 papers)

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Research

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Article
Efficient and Easy Conversion of Human iPSCs into Functional Induced Microglia-like Cells
Int. J. Mol. Sci. 2022, 23(9), 4526; https://doi.org/10.3390/ijms23094526 - 20 Apr 2022
Viewed by 721
Abstract
Current protocols converting human induced pluripotent stem cells (iPSCs) into induced microglia-like cells (iMGL) are either dependent on overexpression of transcription factors or require substantial experience in stem-cell technologies. Here, we developed an easy-to-use two-step protocol to convert iPSCs into functional iMGL via: [...] Read more.
Current protocols converting human induced pluripotent stem cells (iPSCs) into induced microglia-like cells (iMGL) are either dependent on overexpression of transcription factors or require substantial experience in stem-cell technologies. Here, we developed an easy-to-use two-step protocol to convert iPSCs into functional iMGL via: (1) highly efficient differentiation of hematopoietic progenitor cells (HPCs) from iPSCs, and (2) optimized maturation of HPCs to iMGL. A sequential harvesting approach led to an increased HPC yield. The protocol implemented a freezing step, thus allowing HPC biobanking and flexible timing of differentiation into iMGL. Our iMGL responded adequately to the inflammatory stimuli LPS, and iMGL RNAseq analysis matched those of other frequently used protocols. Comparing three different coating modalities, we increased the iMGL yield by culturing on uncoated glass surfaces, thereby retaining differentiation efficiency and functional hallmarks of iMGL. In summary, we provide a high-quality, easy-to-use protocol, rendering generation and functional studies on iMGL an accessible lab resource. Full article
(This article belongs to the Special Issue hiPSC-Derived Cells as Models for Drug Discovery 2.0)
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Article
Transcriptome-Wide Analysis Reveals a Role for Extracellular Matrix and Integrin Receptor Genes in Otic Neurosensory Differentiation from Human iPSCs
Int. J. Mol. Sci. 2021, 22(19), 10849; https://doi.org/10.3390/ijms221910849 - 07 Oct 2021
Viewed by 990
Abstract
We analyzed transcriptomic data from otic sensory cells differentiated from human induced pluripotent stem cells (hiPSCs) by a previously described method to gain new insights into the early human otic neurosensory lineage. We identified genes and biological networks not previously described to occur [...] Read more.
We analyzed transcriptomic data from otic sensory cells differentiated from human induced pluripotent stem cells (hiPSCs) by a previously described method to gain new insights into the early human otic neurosensory lineage. We identified genes and biological networks not previously described to occur in the human otic sensory developmental cell lineage. These analyses identified and ranked genes known to be part of the otic sensory lineage program (SIX1, EYA1, GATA3, etc.), in addition to a number of novel genes encoding extracellular matrix (ECM) (COL3A1, COL5A2, DCN, etc.) and integrin (ITG) receptors (ITGAV, ITGA4, ITGA) for ECM molecules. The results were confirmed by quantitative PCR analysis of a comprehensive panel of genes differentially expressed during the time course of hiPSC differentiation in vitro. Immunocytochemistry validated results for select otic and ECM/ITG gene markers in the in vivo human fetal inner ear. Our screen shows ECM and ITG gene expression changes coincident with hiPSC differentiation towards human otic neurosensory cells. Our findings suggest a critical role of ECM-ITG interactions with otic neurosensory lineage genes in early neurosensory development and cell fate determination in the human fetal inner ear. Full article
(This article belongs to the Special Issue hiPSC-Derived Cells as Models for Drug Discovery 2.0)
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Article
Effects of the Selective Serotonin Reuptake Inhibitor Fluoxetine on Developing Neural Circuits in a Model of the Human Fetal Cortex
Int. J. Mol. Sci. 2021, 22(19), 10457; https://doi.org/10.3390/ijms221910457 - 28 Sep 2021
Cited by 1 | Viewed by 1259
Abstract
The developing prenatal brain is particularly susceptible to environmental disturbances. During prenatal brain development, synapses form between neurons, resulting in neural circuits that support complex cognitive functions. In utero exposure to environmental factors such as pharmaceuticals that alter the process of synapse formation [...] Read more.
The developing prenatal brain is particularly susceptible to environmental disturbances. During prenatal brain development, synapses form between neurons, resulting in neural circuits that support complex cognitive functions. In utero exposure to environmental factors such as pharmaceuticals that alter the process of synapse formation increases the risk of neurodevelopmental abnormalities. However, there is a lack of research into how specific environmental factors directly impact the developing neural circuitry of the human brain. For example, selective serotonin reuptake inhibitors are commonly used throughout pregnancy to treat depression, yet their impact on the developing fetal brain remains unclear. Recently, human brain models have provided unprecedented access to the critical window of prenatal brain development. In the present study, we used human neurons and cortical spheroids to determine whether the selective serotonin reuptake inhibitor fluoxetine alters neurite and synapse formation and the development of spontaneous activity within neural circuits. We demonstrate that cortical spheroids express serotonin transporter, thus recapitulating the early developmental expression of serotonin transporter associated with cortical pyramidal neurons. Cortical spheroids also appropriately express serotonin receptors, such as synaptic 5-HT2A and glial 5-HT5A. To determine whether fluoxetine can affect developing neural circuits independent of serotonergic innervation from the dorsal and medial raphe nuclei, we treated cortical neurons and spheroids with fluoxetine. Fluoxetine alters neurite formation in a dose-dependent fashion. Intriguingly, in cortical spheroids, neither acute nor chronic fluoxetine significantly altered excitatory synapse formation. However, only acute, but not chronic fluoxetine exposure altered inhibitory synaptogenesis. Finally, fluoxetine reversibly suppresses neuronal activity in a dose-dependent manner. These results demonstrate that fluoxetine can acutely alter synaptic function in developing neural circuits, but the effects were not long-lasting. This work provides a foundation for future studies to combine serotonergic innervation with cortical spheroids and assess the contributions of fluoxetine-induced alterations in serotonin levels to brain development. Full article
(This article belongs to the Special Issue hiPSC-Derived Cells as Models for Drug Discovery 2.0)
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Article
An Evaluation of Human Induced Pluripotent Stem Cells to Test for Cardiac Developmental Toxicity
Int. J. Mol. Sci. 2021, 22(15), 8114; https://doi.org/10.3390/ijms22158114 - 29 Jul 2021
Cited by 2 | Viewed by 807
Abstract
To prevent congenital defects arising from maternal exposure, safety regulations require pre-market developmental toxicity screens for industrial chemicals and pharmaceuticals. Traditional embryotoxicity approaches depend heavily on the use of low-throughput animal models which may not adequately predict human risk. The validated embryonic stem [...] Read more.
To prevent congenital defects arising from maternal exposure, safety regulations require pre-market developmental toxicity screens for industrial chemicals and pharmaceuticals. Traditional embryotoxicity approaches depend heavily on the use of low-throughput animal models which may not adequately predict human risk. The validated embryonic stem cell test (EST) developed in murine embryonic stem cells addressed the former problem over 15 years ago. Here, we present a proof-of-concept study to address the latter challenge by updating all three endpoints of the classic mouse EST with endpoints derived from human induced pluripotent stem cells (hiPSCs) and human fibroblasts. Exposure of hiPSCs to selected test chemicals inhibited differentiation at lower concentrations than observed in the mouse EST. The hiPSC-EST also discerned adverse developmental outcomes driven by novel environmental toxicants. Evaluation of the early cardiac gene TBX5 yielded similar toxicity patterns as the full-length hiPSC-EST. Together, these findings support the further development of hiPSCs and early molecular endpoints as a biologically relevant embryotoxicity screening approach for individual chemicals and mixtures. Full article
(This article belongs to the Special Issue hiPSC-Derived Cells as Models for Drug Discovery 2.0)
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Article
Electrophysiology of hiPSC-Cardiomyocytes Co-Cultured with HEK Cells Expressing the Inward Rectifier Channel
Int. J. Mol. Sci. 2021, 22(12), 6621; https://doi.org/10.3390/ijms22126621 - 21 Jun 2021
Viewed by 1154
Abstract
The immature electrophysiology of human-induced pluripotent stem cell-derived cardiomyocytes (hiCMs) complicates their use for therapeutic and pharmacological purposes. An insufficient inward rectifying current (IK1) and the presence of a funny current (if) cause spontaneous electrical activity. This study tests the hypothesis [...] Read more.
The immature electrophysiology of human-induced pluripotent stem cell-derived cardiomyocytes (hiCMs) complicates their use for therapeutic and pharmacological purposes. An insufficient inward rectifying current (IK1) and the presence of a funny current (if) cause spontaneous electrical activity. This study tests the hypothesis that the co-culturing of hiCMs with a human embryonic kidney (HEK) cell-line expressing the Kir2.1 channel (HEK-IK1) can generate an electrical syncytium with an adult-like cardiac electrophysiology. The mechanical activity of co-cultures using different HEK-IK1:hiCM ratios was compared with co-cultures using wildtype (HEK–WT:hiCM) or hiCM alone on days 3–8 after plating. Only ratios of 1:3 and 1:1 showed a significant reduction in spontaneous rate at days 4 and 6, suggesting that IK1 was influencing the electrophysiology. Detailed analysis at day 4 revealed an increased incidence of quiescent wells or sub-areas. Electrical activity showed a decreased action potential duration (APD) at 20% and 50%, but not at 90%, alongside a reduced amplitude of the aggregate AP signal. A computational model of the 1:1 co-culture replicates the electrophysiological effects of HEK–WT. The addition of the IK1 conductance reduced the spontaneous rate and APD20, 50 and 90, and minor variation in the intercellular conductance caused quiescence. In conclusion, a 1:1 co-culture HEK-IK1:hiCM caused changes in electrophysiology and spontaneous activity consistent with the integration of IK1 into the electrical syncytium. However, the additional electrical effects of the HEK cell at 1:1 increased the possibility of electrical quiescence before sufficient IK1 was integrated into the syncytium. Full article
(This article belongs to the Special Issue hiPSC-Derived Cells as Models for Drug Discovery 2.0)
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Article
Enhanced Osteogenic Differentiation of Pluripotent Stem Cells via γ-Secretase Inhibition
Int. J. Mol. Sci. 2021, 22(10), 5215; https://doi.org/10.3390/ijms22105215 - 14 May 2021
Cited by 1 | Viewed by 1046
Abstract
Bone healing is a complex, well-organized process. Multiple factors regulate this process, including growth factors, hormones, cytokines, mechanical stimulation, and aging. One of the most important signaling pathways that affect bone healing is the Notch signaling pathway. It has a significant role in [...] Read more.
Bone healing is a complex, well-organized process. Multiple factors regulate this process, including growth factors, hormones, cytokines, mechanical stimulation, and aging. One of the most important signaling pathways that affect bone healing is the Notch signaling pathway. It has a significant role in controlling the differentiation of bone mesenchymal stem cells and forming new bone. Interventions to enhance the healing of critical-sized bone defects are of great importance, and stem cell transplantations are eminent candidates for treating such defects. Understanding how Notch signaling impacts pluripotent stem cell differentiation can significantly enhance osteogenesis and improve the overall healing process upon transplantation. In Rancourt’s lab, mouse embryonic stem cells (ESC) have been successfully differentiated to the osteogenic cell lineage. This study investigates the role of Notch signaling inhibition in the osteogenic differentiation of mouse embryonic and induced pluripotent stem cells (iPS). Our data showed that Notch inhibition greatly enhanced the differentiation of both mouse embryonic and induced pluripotent stem cells. Full article
(This article belongs to the Special Issue hiPSC-Derived Cells as Models for Drug Discovery 2.0)
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Article
Functional and Molecular Properties of DYT-SGCE Myoclonus-Dystonia Patient-Derived Striatal Medium Spiny Neurons
Int. J. Mol. Sci. 2021, 22(7), 3565; https://doi.org/10.3390/ijms22073565 - 30 Mar 2021
Cited by 1 | Viewed by 988
Abstract
Myoclonus-dystonia (DYT-SGCE, formerly DYT11) is characterized by alcohol-sensitive, myoclonic-like appearance of fast dystonic movements. It is caused by mutations in the SGCE gene encoding ε-sarcoglycan leading to a dysfunction of this transmembrane protein, alterations in the cerebello-thalamic pathway and impaired striatal plasticity. To [...] Read more.
Myoclonus-dystonia (DYT-SGCE, formerly DYT11) is characterized by alcohol-sensitive, myoclonic-like appearance of fast dystonic movements. It is caused by mutations in the SGCE gene encoding ε-sarcoglycan leading to a dysfunction of this transmembrane protein, alterations in the cerebello-thalamic pathway and impaired striatal plasticity. To elucidate underlying pathogenic mechanisms, we investigated induced pluripotent stem cell (iPSC)-derived striatal medium spiny neurons (MSNs) from two myoclonus-dystonia patients carrying a heterozygous mutation in the SGCE gene (c.298T>G and c.304C>T with protein changes W100G and R102X) in comparison to two matched healthy control lines. Calcium imaging showed significantly elevated basal intracellular Ca2+ content and lower frequency of spontaneous Ca2+ signals in SGCE MSNs. Blocking of voltage-gated Ca2+ channels by verapamil was less efficient in suppressing KCl-induced Ca2+ peaks of SGCE MSNs. Ca2+ amplitudes upon glycine and acetylcholine applications were increased in SGCE MSNs, but not after GABA or glutamate applications. Expression of voltage-gated Ca2+ channels and most ionotropic receptor subunits was not altered. SGCE MSNs showed significantly reduced GABAergic synaptic density. Whole-cell patch-clamp recordings displayed elevated amplitudes of miniature postsynaptic currents and action potentials in SGCE MSNs. Our data contribute to a better understanding of the pathophysiology and the development of novel therapeutic strategies for myoclonus-dystonia. Full article
(This article belongs to the Special Issue hiPSC-Derived Cells as Models for Drug Discovery 2.0)
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Article
Immunotherapy with 4-1BBL-Expressing iPS Cell‐Derived Myeloid Lines Amplifies Antigen-Specific T Cell Infiltration in Advanced Melanoma
Int. J. Mol. Sci. 2021, 22(4), 1958; https://doi.org/10.3390/ijms22041958 - 16 Feb 2021
Cited by 2 | Viewed by 1511
Abstract
We have established an immune cell therapy with immortalized induced pluripotent stem-cell–derived myeloid lines (iPS-ML). The benefits of using iPS-ML are the infinite proliferative capacity and ease of genetic modification. In this study, we introduced 4-1BBL gene to iPS-ML (iPS-ML-41BBL). The analysis of [...] Read more.
We have established an immune cell therapy with immortalized induced pluripotent stem-cell–derived myeloid lines (iPS-ML). The benefits of using iPS-ML are the infinite proliferative capacity and ease of genetic modification. In this study, we introduced 4-1BBL gene to iPS-ML (iPS-ML-41BBL). The analysis of the cell-surface molecules showed that the expression of CD86 was upregulated in iPS-ML-41BBL more than that in control iPS-ML. Cytokine array analysis was performed using supernatants of the spleen cells that were cocultured with iPS-ML or iPS-ML-41BBL. Multiple cytokines that are beneficial to cancer immunotherapy were upregulated. Peritoneal injections of iPS-ML-41BBL inhibited tumor growth of peritoneally disseminated mouse melanoma and prolonged survival of mice compared to that of iPS-ML. Furthermore, the numbers of antigen-specific CD8+ T cells were significantly increased in the spleen and tumor tissues treated with epitope peptide-pulsed iPS-ML-41BBL compared to those treated with control iPS-ML. The number of CXCR6-positive T cells were increased in the tumor tissues after treatment with iPS-ML-41BBL compared to that with control iPS-ML. These results suggest that iPS-ML-41BBL could activate antigen-specific T cells and promote their infiltration into the tumor tissues. Thus, iPS-ML-41BBL may be a candidate for future immune cell therapy aiming to change immunological “cold tumor” to “hot tumor”. Full article
(This article belongs to the Special Issue hiPSC-Derived Cells as Models for Drug Discovery 2.0)
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Review

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Review
Modeling and Targeting Neuroglial Interactions with Human Pluripotent Stem Cell Models
Int. J. Mol. Sci. 2022, 23(3), 1684; https://doi.org/10.3390/ijms23031684 - 31 Jan 2022
Cited by 1 | Viewed by 1335
Abstract
Generation of relevant and robust models for neurological disorders is of main importance for both target identification and drug discovery. The non-cell autonomous effects of glial cells on neurons have been described in a broad range of neurodegenerative and neurodevelopmental disorders, pointing to [...] Read more.
Generation of relevant and robust models for neurological disorders is of main importance for both target identification and drug discovery. The non-cell autonomous effects of glial cells on neurons have been described in a broad range of neurodegenerative and neurodevelopmental disorders, pointing to neuroglial interactions as novel alternative targets for therapeutics development. Interestingly, the recent breakthrough discovery of human induced pluripotent stem cells (hiPSCs) has opened a new road for studying neurological and neurodevelopmental disorders “in a dish”. Here, we provide an overview of the generation and modeling of both neuronal and glial cells from human iPSCs and a brief synthesis of recent work investigating neuroglial interactions using hiPSCs in a pathophysiological context. Full article
(This article belongs to the Special Issue hiPSC-Derived Cells as Models for Drug Discovery 2.0)
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Review
Human iPSC-Derived Glia as a Tool for Neuropsychiatric Research and Drug Development
Int. J. Mol. Sci. 2021, 22(19), 10254; https://doi.org/10.3390/ijms221910254 - 23 Sep 2021
Viewed by 1279
Abstract
Neuropsychiatric disorders such as schizophrenia or autism spectrum disorder represent a leading and growing burden on worldwide mental health. Fundamental lack in understanding the underlying pathobiology compromises efficient drug development despite the immense medical need. So far, antipsychotic drugs reduce symptom severity and [...] Read more.
Neuropsychiatric disorders such as schizophrenia or autism spectrum disorder represent a leading and growing burden on worldwide mental health. Fundamental lack in understanding the underlying pathobiology compromises efficient drug development despite the immense medical need. So far, antipsychotic drugs reduce symptom severity and enhance quality of life, but there is no cure available. On the molecular level, schizophrenia and autism spectrum disorders correlate with compromised neuronal phenotypes. There is increasing evidence that aberrant neuroinflammatory responses of glial cells account for synaptic pathologies through deregulated communication and reciprocal modulation. Consequently, microglia and astrocytes emerge as central targets for anti-inflammatory treatment to preserve organization and homeostasis of the central nervous system. Studying the impact of neuroinflammation in the context of neuropsychiatric disorders is, however, limited by the lack of relevant human cellular test systems that are able to represent the dynamic cellular processes and molecular changes observed in human tissue. Today, patient-derived induced pluripotent stem cells offer the opportunity to study neuroinflammatory mechanisms in vitro that comprise the genetic background of affected patients. In this review, we summarize the major findings of iPSC-based microglia and astrocyte research in the context of neuropsychiatric diseases and highlight the benefit of 2D and 3D co-culture models for the generation of efficient in vitro models for target screening and drug development. Full article
(This article belongs to the Special Issue hiPSC-Derived Cells as Models for Drug Discovery 2.0)
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Review
Complex Organ Construction from Human Pluripotent Stem Cells for Biological Research and Disease Modeling with New Emerging Techniques
Int. J. Mol. Sci. 2021, 22(19), 10184; https://doi.org/10.3390/ijms221910184 - 22 Sep 2021
Cited by 2 | Viewed by 1206
Abstract
Human pluripotent stem cells (hPSCs) are grouped into two cell types; embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs). hESCs have provided multiple powerful platforms to study human biology, including human development and diseases; however, there were difficulties in the establishment [...] Read more.
Human pluripotent stem cells (hPSCs) are grouped into two cell types; embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs). hESCs have provided multiple powerful platforms to study human biology, including human development and diseases; however, there were difficulties in the establishment of hESCs from human embryo and concerns over its ethical issues. The discovery of hiPSCs has expanded to various applications in no time because hiPSCs had already overcome these problems. Many hPSC-based studies have been performed using two-dimensional monocellular culture methods at the cellular level. However, in many physiological and pathophysiological conditions, intra- and inter-organ interactions play an essential role, which has hampered the establishment of an appropriate study model. Therefore, the application of recently developed technologies, such as three-dimensional organoids, bioengineering, and organ-on-a-chip technology, has great potential for constructing multicellular tissues, generating the functional organs from hPSCs, and recapitulating complex tissue functions for better biological research and disease modeling. Moreover, emerging techniques, such as single-cell transcriptomics, spatial transcriptomics, and artificial intelligence (AI) allowed for a denser and more precise analysis of such heterogeneous and complex tissues. Here, we review the applications of hPSCs to construct complex organs and discuss further prospects of disease modeling and drug discovery based on these PSC-derived organs. Full article
(This article belongs to the Special Issue hiPSC-Derived Cells as Models for Drug Discovery 2.0)
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Review
Perspectives on hiPSC-Derived Muscle Cells as Drug Discovery Models for Muscular Dystrophies
Int. J. Mol. Sci. 2021, 22(17), 9630; https://doi.org/10.3390/ijms22179630 - 06 Sep 2021
Cited by 1 | Viewed by 981
Abstract
Muscular dystrophies are a heterogeneous group of inherited diseases characterized by the progressive degeneration and weakness of skeletal muscles, leading to disability and, often, premature death. To date, no effective therapies are available to halt or reverse the pathogenic process, and meaningful treatments [...] Read more.
Muscular dystrophies are a heterogeneous group of inherited diseases characterized by the progressive degeneration and weakness of skeletal muscles, leading to disability and, often, premature death. To date, no effective therapies are available to halt or reverse the pathogenic process, and meaningful treatments are urgently needed. From this perspective, it is particularly important to establish reliable in vitro models of human muscle that allow the recapitulation of disease features as well as the screening of genetic and pharmacological therapies. We herein review and discuss advances in the development of in vitro muscle models obtained from human induced pluripotent stem cells, which appear to be capable of reproducing the lack of myofiber proteins as well as other specific pathological hallmarks, such as inflammation, fibrosis, and reduced muscle regenerative potential. In addition, these platforms have been used to assess genetic correction strategies such as gene silencing, gene transfer and genome editing with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), as well as to evaluate novel small molecules aimed at ameliorating muscle degeneration. Furthermore, we discuss the challenges related to in vitro drug testing and provide a critical view of potential therapeutic developments to foster the future clinical translation of preclinical muscular dystrophy studies. Full article
(This article belongs to the Special Issue hiPSC-Derived Cells as Models for Drug Discovery 2.0)
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Review
Generation of Hepatobiliary Cell Lineages from Human Induced Pluripotent Stem Cells: Applications in Disease Modeling and Drug Screening
Int. J. Mol. Sci. 2021, 22(15), 8227; https://doi.org/10.3390/ijms22158227 - 30 Jul 2021
Cited by 2 | Viewed by 931
Abstract
The possibility to reproduce key tissue functions in vitro from induced pluripotent stem cells (iPSCs) is offering an incredible opportunity to gain better insight into biological mechanisms underlying development and disease, and a tool for the rapid screening of drug candidates. This review [...] Read more.
The possibility to reproduce key tissue functions in vitro from induced pluripotent stem cells (iPSCs) is offering an incredible opportunity to gain better insight into biological mechanisms underlying development and disease, and a tool for the rapid screening of drug candidates. This review attempts to summarize recent strategies for specification of iPSCs towards hepatobiliary lineages —hepatocytes and cholangiocytes—and their use as platforms for disease modeling and drug testing. The application of different tissue-engineering methods to promote accurate and reliable readouts is discussed. Space is given to open questions, including to what extent these novel systems can be informative. Potential pathways for improvement are finally suggested. Full article
(This article belongs to the Special Issue hiPSC-Derived Cells as Models for Drug Discovery 2.0)
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Review
iPSCs: A Preclinical Drug Research Tool for Neurological Disorders
Int. J. Mol. Sci. 2021, 22(9), 4596; https://doi.org/10.3390/ijms22094596 - 27 Apr 2021
Cited by 7 | Viewed by 1362
Abstract
The development and commercialization of new drugs is an articulated, lengthy, and very expensive process that proceeds through several steps, starting from target identification, screening new leading compounds for testing in preclinical studies, and subsequently in clinical trials to reach the final approval [...] Read more.
The development and commercialization of new drugs is an articulated, lengthy, and very expensive process that proceeds through several steps, starting from target identification, screening new leading compounds for testing in preclinical studies, and subsequently in clinical trials to reach the final approval for therapeutic use. Preclinical studies are usually performed using both cell cultures and animal models, although they do not completely resume the complexity of human diseases, in particular neurodegenerative conditions. To this regard, stem cells represent a powerful tool in all steps of drug discovery. The recent advancement in induced Pluripotent Stem Cells (iPSCs) technology has opened the possibility to obtain patient-specific disease models for drug screening and development. Here, we report the use of iPSCs as a disease model for drug development in the contest of neurological disorders, including Alzheimer’s (AD) and Parkinson’s disease (PD), Amyotrophic lateral Sclerosis (ALS), and Fragile X syndrome (FRAX). Full article
(This article belongs to the Special Issue hiPSC-Derived Cells as Models for Drug Discovery 2.0)
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Review
Current State-of-the-Art and Unresolved Problems in Using Human Induced Pluripotent Stem Cell-Derived Dopamine Neurons for Parkinson’s Disease Drug Development
Int. J. Mol. Sci. 2021, 22(7), 3381; https://doi.org/10.3390/ijms22073381 - 25 Mar 2021
Cited by 4 | Viewed by 1574
Abstract
Human induced pluripotent stem (iPS) cells have the potential to give rise to a new era in Parkinson’s disease (PD) research. As a unique source of midbrain dopaminergic (DA) neurons, iPS cells provide unparalleled capabilities for investigating the pathogenesis of PD, the development [...] Read more.
Human induced pluripotent stem (iPS) cells have the potential to give rise to a new era in Parkinson’s disease (PD) research. As a unique source of midbrain dopaminergic (DA) neurons, iPS cells provide unparalleled capabilities for investigating the pathogenesis of PD, the development of novel anti-parkinsonian drugs, and personalized therapy design. Significant progress in developmental biology of midbrain DA neurons laid the foundation for their efficient derivation from iPS cells. The introduction of 3D culture methods to mimic the brain microenvironment further expanded the vast opportunities of iPS cell-based research of the neurodegenerative diseases. However, while the benefits for basic and applied studies provided by iPS cells receive widespread coverage in the current literature, the drawbacks of this model in its current state, and in particular, the aspects of differentiation protocols requiring further refinement are commonly overlooked. This review summarizes the recent data on general and subtype-specific features of midbrain DA neurons and their development. Here, we review the current protocols for derivation of DA neurons from human iPS cells and outline their general weak spots. The associated gaps in the contemporary knowledge are considered and the possible directions for future research that may assist in improving the differentiation conditions and increase the efficiency of using iPS cell-derived neurons for PD drug development are discussed. Full article
(This article belongs to the Special Issue hiPSC-Derived Cells as Models for Drug Discovery 2.0)
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