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Disease Modeling Using Human Induced Pluripotent Stem Cells
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Disease Modeling Using Human Induced Pluripotent Stem Cells

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

Deadline for manuscript submissions: closed (30 September 2018) | Viewed by 62747

Special Issue Editors

Prof. Dr. Luisa Barzon

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Guest Editor
Department of Molecular Medicine, University of Padova, 35121 Padova, Italy
Interests: surveillance, diagnosis, and pathogenesis of emerging vector-borne viral infections; pathogenesis, diagnosis, and prevention of human papillomavirus-related diseases; investigation of virus–host interactions; development of patient-specific models of human susceptibility to viral infections; application of innovative molecular methods in infectious disease diagnosis
Special Issues, Collections and Topics in MDPI journals
Prof. Marta Trevisan

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Guest Editor
Department of Molecular Medicine, University of Padova, 35121 Padova, Italy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Recent advances in cell reprogramming and genome editing technologies that allow the generation of patient-specific induced pluripotent stem cells (iPSCs) from differentiated somatic cells and their genetic modification has provided unprecedented sources of human cells for regenerative medicine applications and models to study human diseases. Human iPSCs have been generated from a variety of somatic cells and have been differentiated into almost any cell type of the body, including disease-relevant cell types, like cardiomyocytes, hepatocytes, and neurons. These cells have been also successfully used to recreate mini-organs in a petri dish that recapitulate the cytoarchitecture of the diseased tissue from a pathophysiological and a molecular point of view. If derived from patients with a disease phenotype, these cells will express the entire genetic background of the patient and the genetic modifiers that have a role in disease pathogenesis. Moreover, patient-specific iPSC-derived cells enable personalized therapies and can be employed to either discover new therapeutics or perform toxicity assays in high-throughput screenings. Applications include monogenic diseases, but even complex and multi-factorial disorders, such as cancer, degenerative, psychiatric, and infectious diseases.

We invite you to contribute original articles that describe iPSC-derived disease-in-a-dish models, their use in the recapitulation and the deepening of the molecular mechanisms underlying the disease, and in drug discovery studies. Review articles are also welcome.

Prof. Luisa Barzon
Prof. Marta Trevisan
Guest Editors

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Keywords

  • Induced pluripotent stem cells
  • Organoids
  • Organ-on-chip technologies
  • Patient-specific disease model
  • Genome editing
  • Disease modeling
  • Regenerative medicine
  • Drug discovery
  • Drug testing and toxicity
  • Clinical trials in the dish
  • Personalized medicine

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Published Papers (8 papers)

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Research

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24 pages, 8557 KiB  
Article
Large-Scale Simulation of the Phenotypical Variability Induced by Loss-of-Function Long QT Mutations in Human Induced Pluripotent Stem Cell Cardiomyocytes
by Michelangelo Paci, Simona Casini, Milena Bellin, Jari Hyttinen and Stefano Severi
Int. J. Mol. Sci. 2018, 19(11), 3583; https://doi.org/10.3390/ijms19113583 - 13 Nov 2018
Cited by 17 | Viewed by 4028
Abstract
Loss-of-function long QT (LQT) mutations inducing LQT1 and LQT2 syndromes have been successfully translated to human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) used as disease-specific models. However, their in vitro investigation mainly relies on experiments using small numbers of cells. This is especially [...] Read more.
Loss-of-function long QT (LQT) mutations inducing LQT1 and LQT2 syndromes have been successfully translated to human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) used as disease-specific models. However, their in vitro investigation mainly relies on experiments using small numbers of cells. This is especially critical when working with cells as heterogeneous as hiPSC-CMs. We aim (i) to investigate in silico the ionic mechanisms underlying LQT1 and LQT2 hiPSC-CM phenotypic variability, and (ii) to enable massive in silico drug tests on mutant hiPSC-CMs. We combined (i) data of control and mutant slow and rapid delayed rectifying K+ currents, IKr and IKs respectively, (ii) a recent in silico hiPSC-CM model, and (iii) the population of models paradigm to generate control and mutant populations for LQT1 and LQT2 cardiomyocytes. Our four populations contain from 1008 to 3584 models. In line with the experimental in vitro data, mutant in silico hiPSC-CMs showed prolonged action potential (AP) duration (LQT1: +14%, LQT2: +39%) and large electrophysiological variability. Finally, the mutant populations were split into normal-like hiPSC-CMs (with action potential duration similar to control) and at risk hiPSC-CMs (with clearly prolonged action potential duration). At risk mutant hiPSC-CMs carried higher expression of L-type Ca2+, lower expression of IKr and increased sensitivity to quinidine as compared to mutant normal-like hiPSC-CMs, resulting in AP abnormalities. In conclusion, we were able to reproduce the two most common LQT syndromes with large-scale simulations, which enable investigating biophysical mechanisms difficult to assess in vitro, e.g., how variations of ion current expressions in a physiological range can impact on AP properties of mutant hiPSC-CMs. Full article
(This article belongs to the Special Issue Disease Modeling Using Human Induced Pluripotent Stem Cells)
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18 pages, 6578 KiB  
Article
Inhibition of Arachidonate 12/15-Lipoxygenase Improves α-Galactosidase Efficacy in iPSC-Derived Cardiomyocytes from Fabry Patients
by Yueh Chien, Shih-Jie Chou, Yuh-Lih Chang, Hsin-Bang Leu, Yi-Ping Yang, Ping-Hsing Tsai, Ying-Hsiu Lai, Kuan-Hsuan Chen, Wei-Chao Chang, Shih-Hsien Sung and Wen-Chung Yu
Int. J. Mol. Sci. 2018, 19(5), 1480; https://doi.org/10.3390/ijms19051480 - 16 May 2018
Cited by 10 | Viewed by 4935
Abstract
(1) Background: A high incidence of intervening sequence (IVS)4+919 G>A mutation with later-onset cardiac phenotype have been reported in a majority of Taiwan Fabry cohorts. Some evidence indicated that conventional biomarkers failed to predict the long-term progression and therapeutic outcome; (2) Methods: In [...] Read more.
(1) Background: A high incidence of intervening sequence (IVS)4+919 G>A mutation with later-onset cardiac phenotype have been reported in a majority of Taiwan Fabry cohorts. Some evidence indicated that conventional biomarkers failed to predict the long-term progression and therapeutic outcome; (2) Methods: In this study, we constructed an induced pluripotent stem cell (iPSC)-based platform from Fabry cardiomyopathy (FC) patients carrying IVS4+919 G>A mutation to screen for potential targets that may help the conventional treatment; (3) Results: The FC-patient-derived iPSC-differentiated cardiomyocytes (FC-iPSC-CMs) carried an expected IVS4+919 G>A genetic mutation and recapitulated several FC characteristics, including low α-galactosidase A enzyme activity and cellular hypertrophy. The proteomic analysis revealed that arachidonate 12/15-lipoxygenase (Alox12/15) was the most highly upregulated marker in FC-iPSC-CMs, and the metabolites of Alox12/15, 12(S)- and 15(S)-hydroxyeicosatetraenoic acid (HETE), were also elevated in the culture media. Late administration of Alox12/15 pharmacological inhibitor LOXBlock-1 combined with α-galactosidase, but not α-galactosidase alone, effectively reduced cardiomyocyte hypertrophy, the secretion of 12(S)- and 15(S)-HETE and the upregulation of fibrotic markers at the late phase of FC; (4) Conclusions: Our study demonstrates that cardiac Alox12/15 and circulating 12(S)-HETE/15(S)-HETE are involved in the pathogenesis of FC with IVS4+919 G>A mutation. Full article
(This article belongs to the Special Issue Disease Modeling Using Human Induced Pluripotent Stem Cells)
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7171 KiB  
Article
Elongation of Axon Extension for Human iPSC-Derived Retinal Ganglion Cells by a Nano-Imprinted Scaffold
by Tien-Chun Yang, Jen-Hua Chuang, Waradee Buddhakosai, Wen-Ju Wu, Chen-Ju Lee, Wun-Syuan Chen, Yi-Ping Yang, Ming-Chia Li, Chi-Hsien Peng and Shih-Jen Chen
Int. J. Mol. Sci. 2017, 18(9), 2013; https://doi.org/10.3390/ijms18092013 - 20 Sep 2017
Cited by 30 | Viewed by 8596
Abstract
Optic neuropathies, such as glaucoma and Leber’s hereditary optic neuropathy (LHON) lead to retinal ganglion cell (RGC) loss and therefore motivate the application of transplantation technique into disease therapy. However, it is a challenge to direct the transplanted optic nerve axons to the [...] Read more.
Optic neuropathies, such as glaucoma and Leber’s hereditary optic neuropathy (LHON) lead to retinal ganglion cell (RGC) loss and therefore motivate the application of transplantation technique into disease therapy. However, it is a challenge to direct the transplanted optic nerve axons to the correct location of the retina. The use of appropriate scaffold can promote the proper axon growth. Recently, biocompatible materials have been integrated into the medical field, such as tissue engineering and reconstruction of damaged tissues or organs. We, herein, utilized nano-imprinting to create a scaffold mimicking the in vitro tissue microarchitecture, and guiding the axonal growth and orientation of the RGCs. We observed that the robust, long, and organized axons of human induced pluripotent stem cell (iPSC)-derived RGCs projected axially along the scaffold grooves. The RGCs grown on the scaffold expressed the specific neuronal biomarkers indicating their proper functionality. Thus, based on our in vitro culture system, this device can be useful for the neurophysiological analysis and transplantation for ophthalmic neuropathy treatment. Full article
(This article belongs to the Special Issue Disease Modeling Using Human Induced Pluripotent Stem Cells)
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Review

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18 pages, 471 KiB  
Review
Modeling Parkinson’s Disease and Atypical Parkinsonian Syndromes Using Induced Pluripotent Stem Cells
by Takayasu Mishima, Shinsuke Fujioka, Jiro Fukae, Junichi Yuasa-Kawada and Yoshio Tsuboi
Int. J. Mol. Sci. 2018, 19(12), 3870; https://doi.org/10.3390/ijms19123870 - 4 Dec 2018
Cited by 10 | Viewed by 6184
Abstract
Parkinson’s disease (PD) and atypical parkinsonian syndromes are age-dependent multifactorial neurodegenerative diseases, which are clinically characterized by bradykinesia, tremor, muscle rigidity and postural instability. Although these diseases share several common clinical phenotypes, their pathophysiological aspects vary among the disease categories. Extensive animal-based approaches, [...] Read more.
Parkinson’s disease (PD) and atypical parkinsonian syndromes are age-dependent multifactorial neurodegenerative diseases, which are clinically characterized by bradykinesia, tremor, muscle rigidity and postural instability. Although these diseases share several common clinical phenotypes, their pathophysiological aspects vary among the disease categories. Extensive animal-based approaches, as well as postmortem studies, have provided important insights into the disease mechanisms and potential therapeutic targets. However, the exact pathological mechanisms triggering such diseases still remain elusive. Furthermore, the effects of drugs observed in animal models are not always reproduced in human clinical trials. By using induced pluripotent stem cell (iPSC) technology, it has become possible to establish patient-specific iPSCs from their somatic cells and to effectively differentiate these iPSCs into different types of neurons, reproducing some key aspects of the disease phenotypes in vitro. In this review, we summarize recent findings from iPSC-based modeling of PD and several atypical parkinsonian syndromes including multiple system atrophy, frontotemporal dementia and parkinsonism linked to chromosome 17 and Perry syndrome. Furthermore, we discuss future challenges and prospects for modeling and understanding PD and atypical parkinsonian syndromes. Full article
(This article belongs to the Special Issue Disease Modeling Using Human Induced Pluripotent Stem Cells)
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19 pages, 289 KiB  
Review
Many Cells Make Life Work—Multicellularity in Stem Cell-Based Cardiac Disease Modelling
by Brian X. Wang, Worrapong Kit-Anan and Cesare M. N. Terracciano
Int. J. Mol. Sci. 2018, 19(11), 3361; https://doi.org/10.3390/ijms19113361 - 27 Oct 2018
Cited by 11 | Viewed by 7792
Abstract
Cardiac disease causes 33% of deaths worldwide but our knowledge of disease progression is still very limited. In vitro models utilising and combining multiple, differentiated cell types have been used to recapitulate the range of myocardial microenvironments in an effort to delineate the [...] Read more.
Cardiac disease causes 33% of deaths worldwide but our knowledge of disease progression is still very limited. In vitro models utilising and combining multiple, differentiated cell types have been used to recapitulate the range of myocardial microenvironments in an effort to delineate the mechanical, humoral, and electrical interactions that modulate the cardiac contractile function in health and the pathogenesis of human disease. However, due to limitations in isolating these cell types and changes in their structure and function in vitro, the field is now focused on the development and use of stem cell-derived cell types, most notably, human-induced pluripotent stem cell-derived CMs (hiPSC-CMs), in modelling the CM function in health and patient-specific diseases, allowing us to build on the findings from studies using animal and adult human CMs. It is becoming increasingly appreciated that communications between cardiomyocytes (CMs), the contractile cell of the heart, and the non-myocyte components of the heart not only regulate cardiac development and maintenance of health and adult CM functions, including the contractile state, but they also regulate remodelling in diseases, which may cause the chronic impairment of the contractile function of the myocardium, ultimately leading to heart failure. Within the myocardium, each CM is surrounded by an intricate network of cell types including endothelial cells, fibroblasts, vascular smooth muscle cells, sympathetic neurons, and resident macrophages, and the extracellular matrix (ECM), forming complex interactions, and models utilizing hiPSC-derived cell types offer a great opportunity to investigate these interactions further. In this review, we outline the historical and current state of disease modelling, focusing on the major milestones in the development of stem cell-derived cell types, and how this technology has contributed to our knowledge about the interactions between CMs and key non-myocyte components of the heart in health and disease, in particular, heart failure. Understanding where we stand in the field will be critical for stem cell-based applications, including the modelling of diseases that have complex multicellular dysfunctions. Full article
(This article belongs to the Special Issue Disease Modeling Using Human Induced Pluripotent Stem Cells)
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17 pages, 799 KiB  
Review
Disease Modeling Using 3D Organoids Derived from Human Induced Pluripotent Stem Cells
by Beatrice Xuan Ho, Nicole Min Qian Pek and Boon-Seng Soh
Int. J. Mol. Sci. 2018, 19(4), 936; https://doi.org/10.3390/ijms19040936 - 21 Mar 2018
Cited by 120 | Viewed by 18558
Abstract
The rising interest in human induced pluripotent stem cell (hiPSC)-derived organoid culture has stemmed from the manipulation of various combinations of directed multi-lineage differentiation and morphogenetic processes that mimic organogenesis. Organoids are three-dimensional (3D) structures that are comprised of multiple cell types, self-organized [...] Read more.
The rising interest in human induced pluripotent stem cell (hiPSC)-derived organoid culture has stemmed from the manipulation of various combinations of directed multi-lineage differentiation and morphogenetic processes that mimic organogenesis. Organoids are three-dimensional (3D) structures that are comprised of multiple cell types, self-organized to recapitulate embryonic and tissue development in vitro. This model has been shown to be superior to conventional two-dimensional (2D) cell culture methods in mirroring functionality, architecture, and geometric features of tissues seen in vivo. This review serves to highlight recent advances in the 3D organoid technology for use in modeling complex hereditary diseases, cancer, host–microbe interactions, and possible use in translational and personalized medicine where organoid cultures were used to uncover diagnostic biomarkers for early disease detection via high throughput pharmaceutical screening. In addition, this review also aims to discuss the advantages and shortcomings of utilizing organoids in disease modeling. In summary, studying human diseases using hiPSC-derived organoids may better illustrate the processes involved due to similarities in the architecture and microenvironment present in an organoid, which also allows drug responses to be properly recapitulated in vitro. Full article
(This article belongs to the Special Issue Disease Modeling Using Human Induced Pluripotent Stem Cells)
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23 pages, 1012 KiB  
Review
From the Psychiatrist’s Couch to Induced Pluripotent Stem Cells: Bipolar Disease in a Dish
by Anke Hoffmann, Vincenza Sportelli, Michael Ziller and Dietmar Spengler
Int. J. Mol. Sci. 2018, 19(3), 770; https://doi.org/10.3390/ijms19030770 - 8 Mar 2018
Cited by 15 | Viewed by 6187
Abstract
Bipolar disease (BD) is one of the major public health burdens worldwide and more people are affected every year. Comprehensive genetic studies have associated thousands of single nucleotide polymorphisms (SNPs) with BD risk; yet, very little is known about their functional roles. Induced [...] Read more.
Bipolar disease (BD) is one of the major public health burdens worldwide and more people are affected every year. Comprehensive genetic studies have associated thousands of single nucleotide polymorphisms (SNPs) with BD risk; yet, very little is known about their functional roles. Induced pluripotent stem cells (iPSCs) are powerful tools for investigating the relationship between genotype and phenotype in disease-relevant tissues and cell types. Neural cells generated from BD-specific iPSCs are thought to capture associated genetic risk factors, known and unknown, and to allow the analysis of their effects on cellular and molecular phenotypes. Interestingly, an increasing number of studies on BD-derived iPSCs report distinct alterations in neural patterning, postmitotic calcium signaling, and neuronal excitability. Importantly, these alterations are partly normalized by lithium, a first line treatment in BD. In light of these exciting findings, we discuss current challenges to the field of iPSC-based disease modelling and future steps to be taken in order to fully exploit the potential of this approach for the investigation of BD and the development of new therapies. Full article
(This article belongs to the Special Issue Disease Modeling Using Human Induced Pluripotent Stem Cells)
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621 KiB  
Review
The Potential of iPSCs for the Treatment of Premature Aging Disorders
by Claudia Compagnucci and Enrico Bertini
Int. J. Mol. Sci. 2017, 18(11), 2350; https://doi.org/10.3390/ijms18112350 - 7 Nov 2017
Cited by 9 | Viewed by 5642
Abstract
Premature aging disorders including Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome, are a group of rare monogenic diseases leading to reduced lifespan of the patients. Importantly, these disorders mimic several features of physiological aging. Despite the interest on the study of these diseases, [...] Read more.
Premature aging disorders including Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome, are a group of rare monogenic diseases leading to reduced lifespan of the patients. Importantly, these disorders mimic several features of physiological aging. Despite the interest on the study of these diseases, the underlying biological mechanisms remain unknown and no treatment is available. Recent studies on HGPS (due to mutations of the LMNA gene encoding for the nucleoskeletal proteins lamin A/C) have reported disruptions in cellular and molecular mechanisms modulating genomic stability and stem cell populations, thus giving the nuclear lamina a relevant function in nuclear organization, epigenetic regulation and in the maintenance of the stem cell pool. In this context, modeling premature aging with induced pluripotent stem cells (iPSCs) offers the possibility to study these disorders during self-renewal and differentiation into relevant cell types. iPSCs generated by cellular reprogramming from adult somatic cells allows researchers to understand pathophysiological mechanisms and enables the performance of drug screenings. Moreover, the recent development of precision genome editing offers the possibility to study the complex mechanisms underlying senescence and the possibility to correct disease phenotypes, paving the way for future therapeutic interventions. Full article
(This article belongs to the Special Issue Disease Modeling Using Human Induced Pluripotent Stem Cells)
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