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Special Issue "iPS Cells for Modelling and Treatment of Human Diseases"

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383).

Deadline for manuscript submissions: closed (31 July 2014)

Special Issue Editor

Guest Editor
Dr. Michael J. Edel

Departament de Ciències Fisiològiques I, Facultat de Medicina, Universitat de Barcelona, Spain
E-Mail
Phone: +34 93 402 4518
Interests: reprogramming to pluripotency; direct reprogramming; embryological development; cell cycle; cancer biology; 3D organ bioengineering; clinical grade cell replacement therapy

Special Issue Information

Dear Colleagues,

The field of reprogramming somatic cells into induced pluripotent stem cells (iPSC) has moved very quickly, from bench to bedside in just eight years since its first discovery. The best example of this is the RIKEN clinical trial this year in Japan, which will use iPSC derived retinal pigmented epithelial (RPE) cells to treat macular degeneration (MD). This is the first human disease to be tested for regeneration and repair by iPSC-derived cells and others will follow in the near future. Currently, there is an intense worldwide research effort to bring stem cell technology to the clinic for application to treat human diseases and pathologies. Human tissue diseases (including those of the lung, heart, brain, spinal cord, and muscles) drive organ bioengineering to the forefront of technology concerning cell replacement therapy. Given the critical mass of research and translational work being performed, iPSCs may very well be the cell type of choice for regenerative medicine in the future. Also, basic science questions, such as efficient differentiation protocols to the correct cell type for regenerating human tissues, the immune response of iPSC replacement therapy and genetic stability of iPSC-derived cells, are currently being investigated for future clinical applications. Please join us in presenting this Special Issue on the state of the art research currently being performed worldwide to bring iPSC to the clinic so as to help understand and treat various human diseases.

Dr. Michael J. Edel
Guest Editor

Submission

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. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as 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 refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed Open Access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 300 CHF (Swiss Francs). English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections.

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Keywords

  • induced pluripotent stem cells
  • differentiation
  • adult stem cell
  • human disease
  • clinical application
  • immune response
  • genetic cell stability

Published Papers (20 papers)

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Research

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Open AccessArticle Scalable Electrophysiological Investigation of iPS Cell-Derived Cardiomyocytes Obtained by a Lentiviral Purification Strategy
J. Clin. Med. 2015, 4(1), 102-123; doi:10.3390/jcm4010102
Received: 20 August 2014 / Accepted: 9 December 2014 / Published: 8 January 2015
Cited by 4 | PDF Full-text (608 KB) | HTML Full-text | XML Full-text
Abstract
Disease-specific induced pluripotent stem (iPS) cells can be generated from patients and differentiated into functional cardiomyocytes for characterization of the disease and for drug screening. In order to obtain pure cardiomyocytes for automated electrophysiological investigation, we here report a novel non-clonal purification strategy
[...] Read more.
Disease-specific induced pluripotent stem (iPS) cells can be generated from patients and differentiated into functional cardiomyocytes for characterization of the disease and for drug screening. In order to obtain pure cardiomyocytes for automated electrophysiological investigation, we here report a novel non-clonal purification strategy by using lentiviral gene transfer of a puromycin resistance gene under the control of a cardiac-specific promoter. We have applied this method to our previous reported wild-type and long QT syndrome 3 (LQTS 3)-specific mouse iPS cells and obtained a pure cardiomyocyte population. These cells were investigated by action potential analysis with manual and automatic planar patch clamp technologies, as well as by recording extracellular field potentials using a microelectrode array system. Action potentials and field potentials showed the characteristic prolongation at low heart rates in LQTS 3-specific, but not in wild-type iPS cell-derived cardiomyocytes. Hence, LQTS 3-specific cardiomyocytes can be purified from iPS cells with a lentiviral strategy, maintain the hallmarks of the LQTS 3 disease and can be used for automated electrophysiological characterization and drug screening. Full article
Figures

Review

Jump to: Research, Other

Open AccessReview The Possible Future Roles for iPSC-Derived Therapy for Autoimmune Diseases
J. Clin. Med. 2015, 4(6), 1193-1206; doi:10.3390/jcm4061193
Received: 31 March 2015 / Revised: 29 April 2015 / Accepted: 11 May 2015 / Published: 28 May 2015
PDF Full-text (121 KB) | HTML Full-text | XML Full-text
Abstract
The ability to generate inducible pluripotent stem cells (iPSCs) and the potential for their use in treatment of human disease is of immense interest. Autoimmune diseases, with their limited treatment choices are a potential target for the clinical application of stem cell and
[...] Read more.
The ability to generate inducible pluripotent stem cells (iPSCs) and the potential for their use in treatment of human disease is of immense interest. Autoimmune diseases, with their limited treatment choices are a potential target for the clinical application of stem cell and iPSC technology. IPSCs provide three potential ways of treating autoimmune disease; (i) providing pure replacement of lost cells (immuno-reconstitution); (ii) through immune-modulation of the disease process in vivo; and (iii) for the purposes of disease modeling in vitro. In this review, we will use examples of systemic, system-specific and organ-specific autoimmunity to explore the potential applications of iPSCs for treatment of autoimmune diseases and review the evidence of iPSC technology in auto-immunity to date. Full article
Open AccessReview Bioengineering and Stem Cell Technology in the Treatment of Congenital Heart Disease
J. Clin. Med. 2015, 4(4), 768-781; doi:10.3390/jcm4040768
Received: 22 December 2014 / Revised: 27 March 2015 / Accepted: 10 April 2015 / Published: 22 April 2015
PDF Full-text (162 KB) | HTML Full-text | XML Full-text
Abstract
Congenital heart disease places a significant burden on the individual, family and community despite significant advances in our understanding of aetiology and treatment. Early research in ischaemic heart disease has paved the way for stem cell technology and bioengineering, which promises to improve
[...] Read more.
Congenital heart disease places a significant burden on the individual, family and community despite significant advances in our understanding of aetiology and treatment. Early research in ischaemic heart disease has paved the way for stem cell technology and bioengineering, which promises to improve both structural and functional aspects of disease. Stem cell therapy has demonstrated significant improvements in cardiac function in adults with ischaemic heart disease. This finding, together with promising case studies in the paediatric setting, demonstrates the potential for this treatment in congenital heart disease. Furthermore, induced pluripotent stems cell technology, provides a unique opportunity to address aetiological, as well as therapeutic, aspects of disease. Full article
Open AccessReview Concise Review: Methods and Cell Types Used to Generate Down Syndrome Induced Pluripotent Stem Cells
J. Clin. Med. 2015, 4(4), 696-714; doi:10.3390/jcm4040696
Received: 9 February 2015 / Revised: 23 March 2015 / Accepted: 31 March 2015 / Published: 15 April 2015
PDF Full-text (316 KB) | HTML Full-text | XML Full-text
Abstract
Down syndrome (DS, trisomy 21), is the most common viable chromosomal disorder, with an incidence of 1 in 800 live births. Its phenotypic characteristics include intellectual impairment and several other developmental abnormalities, for the majority of which the pathogenetic mechanisms remain unknown. Several
[...] Read more.
Down syndrome (DS, trisomy 21), is the most common viable chromosomal disorder, with an incidence of 1 in 800 live births. Its phenotypic characteristics include intellectual impairment and several other developmental abnormalities, for the majority of which the pathogenetic mechanisms remain unknown. Several models have been used to investigate the mechanisms by which the extra copy of chromosome 21 leads to the DS phenotype. In the last five years, several laboratories have been successful in reprogramming patient cells carrying the trisomy 21 anomaly into induced pluripotent stem cells, i.e., T21-iPSCs. In this review, we summarize the different T21-iPSCs that have been generated with a particular interest in the technical procedures and the somatic cell types used for the reprogramming. Full article
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Open AccessReview Patient-Specific iPSC-Derived RPE for Modeling of Retinal Diseases
J. Clin. Med. 2015, 4(4), 567-578; doi:10.3390/jcm4040567
Received: 17 September 2014 / Revised: 26 February 2015 / Accepted: 3 March 2015 / Published: 31 March 2015
Cited by 3 | PDF Full-text (61 KB) | HTML Full-text | XML Full-text
Abstract
Inherited retinal diseases, such as age-related macular degeneration and retinitis pigmentosa, are the leading cause of blindness in the developed world. Currently, treatments for these conditions are limited. Recently, considerable attention has been given to the possibility of using patient-specific induced pluripotent stem
[...] Read more.
Inherited retinal diseases, such as age-related macular degeneration and retinitis pigmentosa, are the leading cause of blindness in the developed world. Currently, treatments for these conditions are limited. Recently, considerable attention has been given to the possibility of using patient-specific induced pluripotent stem cells (iPSCs) as a treatment for these conditions. iPSCs reprogrammed from adult somatic cells offer the possibility of generating patient-specific cell lines in vitro. In this review, we will discuss the current literature pertaining to iPSC modeling of retinal disease, gene therapy of iPSC-derived retinal pigmented epithelium (RPE) cells, and retinal transplantation. We will focus on the use of iPSCs created from patients with inherited eye diseases for testing the efficacy of gene or drug-based therapies, elucidating previously unknown mechanisms and pathways of disease, and as a source of autologous cells for cell replacement. Full article
Open AccessReview Using iPS Cells toward the Understanding of Parkinson’s Disease
J. Clin. Med. 2015, 4(4), 548-566; doi:10.3390/jcm4040548
Received: 23 October 2014 / Revised: 10 February 2015 / Accepted: 10 February 2015 / Published: 30 March 2015
Cited by 4 | PDF Full-text (285 KB) | HTML Full-text | XML Full-text
Abstract
Cellular reprogramming of somatic cells to human pluripotent stem cells (iPSC) represents an efficient tool for in vitro modeling of human brain diseases and provides an innovative opportunity in the identification of new therapeutic drugs. Patient-specific iPSC can be differentiated into disease-relevant cell
[...] Read more.
Cellular reprogramming of somatic cells to human pluripotent stem cells (iPSC) represents an efficient tool for in vitro modeling of human brain diseases and provides an innovative opportunity in the identification of new therapeutic drugs. Patient-specific iPSC can be differentiated into disease-relevant cell types, including neurons, carrying the genetic background of the donor and enabling de novo generation of human models of genetically complex disorders. Parkinson’s disease (PD) is the second most common age-related progressive neurodegenerative disease, which is mainly characterized by nigrostriatal dopaminergic (DA) neuron degeneration and synaptic dysfunction. Recently, the generation of disease-specific iPSC from patients suffering from PD has unveiled a recapitulation of disease-related cell phenotypes, such as abnormal α-synuclein accumulation and alterations in autophagy machinery. The use of patient-specific iPSC has a remarkable potential to uncover novel insights of the disease pathogenesis, which in turn will open new avenues for clinical intervention. This review explores the current Parkinson’s disease iPSC-based models highlighting their role in the discovery of new drugs, as well as discussing the most challenging limitations iPSC-models face today. Full article
Open AccessReview Potential Role of Induced Pluripotent Stem Cells (IPSCs) for Cell-Based Therapy of the Ocular Surface
J. Clin. Med. 2015, 4(2), 318-342; doi:10.3390/jcm4020318
Received: 23 November 2014 / Revised: 24 December 2014 / Accepted: 4 January 2015 / Published: 12 February 2015
Cited by 3 | PDF Full-text (248 KB) | HTML Full-text | XML Full-text
Abstract
The integrity and normal function of the corneal epithelium are crucial for maintaining the cornea’s transparency and vision. The existence of a cell population with progenitor characteristics in the limbus maintains a dynamic of constant epithelial repair and renewal. Currently, cell-based therapies for
[...] Read more.
The integrity and normal function of the corneal epithelium are crucial for maintaining the cornea’s transparency and vision. The existence of a cell population with progenitor characteristics in the limbus maintains a dynamic of constant epithelial repair and renewal. Currently, cell-based therapies for bio replacement—cultured limbal epithelial transplantation (CLET) and cultured oral mucosal epithelial transplantation (COMET)—present very encouraging clinical results for treating limbal stem cell deficiency (LSCD) and restoring vision. Another emerging therapeutic approach consists of obtaining and implementing human progenitor cells of different origins in association with tissue engineering methods. The development of cell-based therapies using stem cells, such as human adult mesenchymal or induced pluripotent stem cells (IPSCs), represent a significant breakthrough in the treatment of certain eye diseases, offering a more rational, less invasive, and better physiological treatment option in regenerative medicine for the ocular surface. This review will focus on the main concepts of cell-based therapies for the ocular surface and the future use of IPSCs to treat LSCD. Full article
Open AccessReview Myogenic Precursors from iPS Cells for Skeletal Muscle Cell Replacement Therapy
J. Clin. Med. 2015, 4(2), 243-259; doi:10.3390/jcm4020243
Received: 1 October 2014 / Accepted: 3 December 2014 / Published: 29 January 2015
Cited by 3 | PDF Full-text (148 KB) | HTML Full-text | XML Full-text
Abstract
The use of adult myogenic stem cells as a cell therapy for skeletal muscle regeneration has been attempted for decades, with only moderate success. Myogenic progenitors (MP) made from induced pluripotent stem cells (iPSCs) are promising candidates for stem cell therapy to regenerate
[...] Read more.
The use of adult myogenic stem cells as a cell therapy for skeletal muscle regeneration has been attempted for decades, with only moderate success. Myogenic progenitors (MP) made from induced pluripotent stem cells (iPSCs) are promising candidates for stem cell therapy to regenerate skeletal muscle since they allow allogenic transplantation, can be produced in large quantities, and, as compared to adult myoblasts, present more embryonic-like features and more proliferative capacity in vitro, which indicates a potential for more self-renewal and regenerative capacity in vivo. Different approaches have been described to make myogenic progenitors either by gene overexpression or by directed differentiation through culture conditions, and several myopathies have already been modeled using iPSC-MP. However, even though results in animal models have shown improvement from previous work with isolated adult myoblasts, major challenges regarding host response have to be addressed and clinically relevant transplantation protocols are lacking. Despite these challenges we are closer than we think to bringing iPSC-MP towards clinical use for treating human muscle disease and sporting injuries. Full article
Open AccessReview Design of a Tumorigenicity Test for Induced Pluripotent Stem Cell (iPSC)-Derived Cell Products
J. Clin. Med. 2015, 4(1), 159-171; doi:10.3390/jcm4010159
Received: 22 October 2014 / Accepted: 22 December 2014 / Published: 14 January 2015
Cited by 4 | PDF Full-text (331 KB) | HTML Full-text | XML Full-text
Abstract
Human Pluripotent Stem Cell (PSC)-derived cell therapy holds enormous promise because of the cells’ “unlimited” proliferative capacity and the potential to differentiate into any type of cell. However, these features of PSC-derived cell products are associated with concerns regarding the generation of iatrogenic
[...] Read more.
Human Pluripotent Stem Cell (PSC)-derived cell therapy holds enormous promise because of the cells’ “unlimited” proliferative capacity and the potential to differentiate into any type of cell. However, these features of PSC-derived cell products are associated with concerns regarding the generation of iatrogenic teratomas or tumors from residual immature or non-terminally differentiated cells in the final cell product. This concern has become a major hurdle to the introduction of this therapy into the clinic. Tumorigenicity testing is therefore a key preclinical safety test in PSC-derived cell therapy. Tumorigenicity testing becomes particularly important when autologous human induced Pluripotent Stem Cell (iPSC)-derived cell products with no immuno-barrier are considered for transplantation. There has been, however, no internationally recognized guideline for tumorigenicity testing of PSC-derived cell products for cell therapy. In this review, we outline the points to be considered in the design and execution of tumorigenicity tests, referring to the tests and laboratory work that we have conducted for an iPSC-derived retinal pigment epithelium (RPE) cell product prior to its clinical use. Full article
Open AccessReview The Potential for iPS-Derived Stem Cells as a Therapeutic Strategy for Spinal Cord Injury: Opportunities and Challenges
J. Clin. Med. 2015, 4(1), 37-65; doi:10.3390/jcm4010037
Received: 1 October 2014 / Accepted: 28 November 2014 / Published: 29 December 2014
Cited by 2 | PDF Full-text (660 KB) | HTML Full-text | XML Full-text
Abstract
Spinal cord injury (SCI) is a devastating trauma causing long-lasting disability. Although advances have occurred in the last decade in the medical, surgical and rehabilitative treatments of SCI, the therapeutic approaches are still not ideal. The use of cell transplantation as a therapeutic
[...] Read more.
Spinal cord injury (SCI) is a devastating trauma causing long-lasting disability. Although advances have occurred in the last decade in the medical, surgical and rehabilitative treatments of SCI, the therapeutic approaches are still not ideal. The use of cell transplantation as a therapeutic strategy for the treatment of SCI is promising, particularly since it can target cell replacement, neuroprotection and regeneration. Cell therapies for treating SCI are limited due to several translational roadblocks, including ethical and practical concerns regarding cell sources. The use of iPSCs has been particularly attractive, since they avoid the ethical and moral concerns that surround other stem cells. Furthermore, various cell types with potential for application in the treatment of SCI can be created from autologous sources using iPSCs. For applications in SCI, the iPSCs can be differentiated into neural precursor cells, neurons, oligodendrocytes, astrocytes, neural crest cells and mesenchymal stromal cells that can act by replacing lost cells or providing environmental support. Some methods, such as direct reprogramming, are being investigated to reduce tumorigenicity and improve reprogramming efficiencies, which have been some of the issues surrounding the use of iPSCs clinically to date. Recently, iPSCs have entered clinical trials for use in age-related macular degeneration, further supporting their promise for translation in other conditions, including SCI. Full article
Open AccessReview iPS Cells for Modelling and Treatment of Retinal Diseases
J. Clin. Med. 2014, 3(4), 1511-1541; doi:10.3390/jcm3041511
Received: 22 September 2014 / Revised: 16 November 2014 / Accepted: 18 November 2014 / Published: 19 December 2014
Cited by 3 | PDF Full-text (2391 KB) | HTML Full-text | XML Full-text
Abstract
For many decades, we have relied on immortalised retinal cell lines, histology of enucleated human eyes, animal models, clinical observation, genetic studies and human clinical trials to learn more about the pathogenesis of retinal diseases and explore treatment options. The recent availability of
[...] Read more.
For many decades, we have relied on immortalised retinal cell lines, histology of enucleated human eyes, animal models, clinical observation, genetic studies and human clinical trials to learn more about the pathogenesis of retinal diseases and explore treatment options. The recent availability of patient-specific induced pluripotent stem cells (iPSC) for deriving retinal lineages has added a powerful alternative tool for discovering new disease-causing mutations, studying genotype-phenotype relationships, performing therapeutics-toxicity screening and developing personalised cell therapy. This review article provides a clinical perspective on the current and potential benefits of iPSC for managing the most common blinding diseases of the eye: inherited retinal diseases and age-related macular degeneration. Full article
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Open AccessReview The Use of Patient-Specific Induced Pluripotent Stem Cells (iPSCs) to Identify Osteoclast Defects in Rare Genetic Bone Disorders
J. Clin. Med. 2014, 3(4), 1490-1510; doi:10.3390/jcm3041490
Received: 2 September 2014 / Revised: 20 November 2014 / Accepted: 20 November 2014 / Published: 17 December 2014
Cited by 2 | PDF Full-text (282 KB) | HTML Full-text | XML Full-text
Abstract
More than 500 rare genetic bone disorders have been described, but for many of them only limited treatment options are available. Challenges for studying these bone diseases come from a lack of suitable animal models and unavailability of skeletal tissues for studies. Effectors
[...] Read more.
More than 500 rare genetic bone disorders have been described, but for many of them only limited treatment options are available. Challenges for studying these bone diseases come from a lack of suitable animal models and unavailability of skeletal tissues for studies. Effectors for skeletal abnormalities of bone disorders may be abnormal bone formation directed by osteoblasts or anomalous bone resorption by osteoclasts, or both. Patient-specific induced pluripotent stem cells (iPSCs) can be generated from somatic cells of various tissue sources and in theory can be differentiated into any desired cell type. However, successful differentiation of hiPSCs into functional bone cells is still a challenge. Our group focuses on the use of human iPSCs (hiPSCs) to identify osteoclast defects in craniometaphyseal dysplasia. In this review, we describe the impact of stem cell technology on research for better treatment of such disorders, the generation of hiPSCs from patients with rare genetic bone disorders and current protocols for differentiating hiPSCs into osteoclasts. Full article
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Open AccessReview Induced Pluripotent Stem Cells Derived from Alzheimer’s Disease Patients: The Promise, the Hope and the Path Ahead
J. Clin. Med. 2014, 3(4), 1402-1436; doi:10.3390/jcm3041402
Received: 14 August 2014 / Revised: 12 November 2014 / Accepted: 14 November 2014 / Published: 12 December 2014
Cited by 1 | PDF Full-text (522 KB) | HTML Full-text | XML Full-text
Abstract
The future hope of generated induced pluripotent stem cells (iPS cells) from Alzheimer’s disease patients is multifold. Firstly, they may help to uncover novel mechanisms of the disease, which could lead to the development of new and unprecedented drugs for patients and secondly,
[...] Read more.
The future hope of generated induced pluripotent stem cells (iPS cells) from Alzheimer’s disease patients is multifold. Firstly, they may help to uncover novel mechanisms of the disease, which could lead to the development of new and unprecedented drugs for patients and secondly, they could also be directly used for screening and testing of potential new compounds for drug discovery. In addition, in the case of familial known mutations, these cells could be targeted by use of advanced gene-editing techniques to correct the mutation and be used for future cell transplantation therapies. This review summarizes the work so far in regards to production and characterization of iPS cell lines from both sporadic and familial Alzheimer’s patients and from other iPS cell lines that may help to model the disease. It provides a detailed comparison between published reports and states the present hurdles we face with this new technology. The promise of new gene-editing techniques and accelerated aging models also aim to move this field further by providing better control cell lines for comparisons and potentially better phenotypes, respectively. Full article
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Open AccessReview Opportunities and Limitations of Modelling Alzheimer’s Disease with Induced Pluripotent Stem Cells
J. Clin. Med. 2014, 3(4), 1357-1372; doi:10.3390/jcm3041357
Received: 27 August 2014 / Revised: 31 October 2014 / Accepted: 12 November 2014 / Published: 5 December 2014
Cited by 2 | PDF Full-text (350 KB) | HTML Full-text | XML Full-text
Abstract
Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) has opened the way for patient-specific disease modelling. Following their differentiation into neuronal cell types, iPSC have enabled the investigation of human neurodegenerative diseases, such as Alzheimer’s disease (AD). While human iPSCs certainly
[...] Read more.
Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) has opened the way for patient-specific disease modelling. Following their differentiation into neuronal cell types, iPSC have enabled the investigation of human neurodegenerative diseases, such as Alzheimer’s disease (AD). While human iPSCs certainly provide great opportunities to repeatedly interrogate specific human brain cell types of individuals with familial and sporadic forms of the disease, the complex aetiology and timescale over which AD develops in humans poses particular challenges to iPSC-based AD models. Here, we discuss the current state-of-play in the context of these and other iPSC model-related challenges and elaborate on likely future developments in this field of research. Full article
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Open AccessReview Comparing ESC and iPSC—Based Models for Human Genetic Disorders
J. Clin. Med. 2014, 3(4), 1146-1162; doi:10.3390/jcm3041146
Received: 10 February 2014 / Revised: 29 September 2014 / Accepted: 30 September 2014 / Published: 24 October 2014
Cited by 5 | PDF Full-text (1255 KB) | HTML Full-text | XML Full-text
Abstract
Traditionally, human disorders were studied using animal models or somatic cells taken from patients. Such studies enabled the analysis of the molecular mechanisms of numerous disorders, and led to the discovery of new treatments. Yet, these systems are limited or even irrelevant in
[...] Read more.
Traditionally, human disorders were studied using animal models or somatic cells taken from patients. Such studies enabled the analysis of the molecular mechanisms of numerous disorders, and led to the discovery of new treatments. Yet, these systems are limited or even irrelevant in modeling multiple genetic diseases. The isolation of human embryonic stem cells (ESCs) from diseased blastocysts, the derivation of induced pluripotent stem cells (iPSCs) from patients’ somatic cells, and the new technologies for genome editing of pluripotent stem cells have opened a new window of opportunities in the field of disease modeling, and enabled studying diseases that couldn’t be modeled in the past. Importantly, despite the high similarity between ESCs and iPSCs, there are several fundamental differences between these cells, which have important implications regarding disease modeling. In this review we compare ESC-based models to iPSC-based models, and highlight the advantages and disadvantages of each system. We further suggest a roadmap for how to choose the optimal strategy to model each specific disorder. Full article
Open AccessReview iPSC-Based Models to Unravel Key Pathogenetic Processes Underlying Motor Neuron Disease Development
J. Clin. Med. 2014, 3(4), 1124-1145; doi:10.3390/jcm3041124
Received: 30 July 2014 / Revised: 19 September 2014 / Accepted: 22 September 2014 / Published: 17 October 2014
Cited by 1 | PDF Full-text (1386 KB) | HTML Full-text | XML Full-text
Abstract
Motor neuron diseases (MNDs) are neuromuscular disorders affecting rather exclusively upper motor neurons (UMNs) and/or lower motor neurons (LMNs). The clinical phenotype is characterized by muscular weakness and atrophy leading to paralysis and almost invariably death due to respiratory failure. Adult MNDs include
[...] Read more.
Motor neuron diseases (MNDs) are neuromuscular disorders affecting rather exclusively upper motor neurons (UMNs) and/or lower motor neurons (LMNs). The clinical phenotype is characterized by muscular weakness and atrophy leading to paralysis and almost invariably death due to respiratory failure. Adult MNDs include sporadic and familial amyotrophic lateral sclerosis (sALS-fALS), while the most common infantile MND is represented by spinal muscular atrophy (SMA). No effective treatment is ccurrently available for MNDs, as for the vast majority of neurodegenerative disorders, and cures are limited to supportive care and symptom relief. The lack of a deep understanding of MND pathogenesis accounts for the difficulties in finding a cure, together with the scarcity of reliable in vitro models. Recent progresses in stem cell field, in particular in the generation of induced Pluripotent Stem Cells (iPSCs) has made possible for the first time obtaining substantial amounts of human cells to recapitulate in vitro some of the key pathogenetic processes underlying MNDs. In the present review, recently published studies involving the use of iPSCs to unravel aspects of ALS and SMA pathogenesis are discussed with an overview of their implications in the process of finding a cure for these still orphan disorders. Full article
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Open AccessReview Clinical Potentials of Cardiomyocytes Derived from Patient-Specific Induced Pluripotent Stem Cells
J. Clin. Med. 2014, 3(4), 1105-1123; doi:10.3390/jcm3041105
Received: 31 July 2014 / Revised: 15 September 2014 / Accepted: 17 September 2014 / Published: 15 October 2014
PDF Full-text (972 KB) | HTML Full-text | XML Full-text
Abstract
The lack of appropriate human cardiomyocyte-based experimental platform has largely hindered the study of cardiac diseases and the development of therapeutic strategies. To date, somatic cells isolated from human subjects can be reprogramed into induced pluripotent stem cells (iPSCs) and subsequently differentiated into
[...] Read more.
The lack of appropriate human cardiomyocyte-based experimental platform has largely hindered the study of cardiac diseases and the development of therapeutic strategies. To date, somatic cells isolated from human subjects can be reprogramed into induced pluripotent stem cells (iPSCs) and subsequently differentiated into functional cardiomyocytes. This powerful reprogramming technology provides a novel in vitro human cell-based platform for the study of human hereditary cardiac disorders. The clinical potential of using iPSCs derived from patients with inherited cardiac disorders for therapeutic studies have been increasingly highlighted. In this review, the standard procedures for generating patient-specific iPSCs and the latest commonly used cardiac differentiation protocols will be outlined. Furthermore, the progress and limitations of current applications of iPSCs and iPSCs-derived cardiomyocytes in cell replacement therapy, disease modeling, drug-testing and toxicology studies will be discussed in detail. Full article
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Open AccessReview Human iPS Cell-Derived Germ Cells: Current Status and Clinical Potential
J. Clin. Med. 2014, 3(4), 1064-1083; doi:10.3390/jcm3041064
Received: 30 July 2014 / Revised: 17 September 2014 / Accepted: 22 September 2014 / Published: 13 October 2014
Cited by 5 | PDF Full-text (1088 KB) | HTML Full-text | XML Full-text
Abstract
Recently, fertile spermatozoa and oocytes were generated from mouse induced pluripotent (iPS) cells using a combined in vitro and in vivo induction system. With regard to germ cell induction from human iPS cells, progress has been made particularly in the male germline, demonstrating
[...] Read more.
Recently, fertile spermatozoa and oocytes were generated from mouse induced pluripotent (iPS) cells using a combined in vitro and in vivo induction system. With regard to germ cell induction from human iPS cells, progress has been made particularly in the male germline, demonstrating in vitro generation of haploid, round spermatids. Although iPS-derived germ cells are expected to be developed to yield a form of assisted reproductive technology (ART) that can address unmet reproductive needs, genetic and/or epigenetic instabilities abound in iPS cell generation and germ cell induction. In addition, there is still room to improve the induction protocol in the female germline. However, rapid advances in stem cell research are likely to make such obstacles surmountable, potentially translating induced germ cells into the clinical setting in the immediate future. This review examines the current status of the induction of germ cells from human iPS cells and discusses the clinical potential, as well as future directions. Full article
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Open AccessReview Potential and Challenges of Induced Pluripotent Stem Cells in Liver Diseases Treatment
J. Clin. Med. 2014, 3(3), 997-1017; doi:10.3390/jcm3030997
Received: 17 July 2014 / Revised: 22 August 2014 / Accepted: 26 August 2014 / Published: 5 September 2014
Cited by 4 | PDF Full-text (752 KB) | HTML Full-text | XML Full-text
Abstract
Tens of millions of patients are affected by liver disease worldwide. Many of these patients can benefit from cell therapy involving living metabolically active cells, either by treatment of their liver disease, or by prevention of their disease phenotype. Cell therapies, including hepatocyte
[...] Read more.
Tens of millions of patients are affected by liver disease worldwide. Many of these patients can benefit from cell therapy involving living metabolically active cells, either by treatment of their liver disease, or by prevention of their disease phenotype. Cell therapies, including hepatocyte transplantation and bioartificial liver (BAL) devices, have been proposed as therapeutic alternatives to the shortage of transplantable livers. Both BAL and hepatocyte transplantation are cellular therapies that avoid use of a whole liver. Hepatocytes are also widely used in drug screening and liver disease modelling. However, the demand for human hepatocytes, heavily outweighs their availability by conventional means. Induced pluripotent stem cells (iPSCs) technology brings together the potential benefits of embryonic stem cells (ESCs) (i.e., self-renewal, pluripotency) and addresses the major ethical and scientific concerns of ESCs: embryo destruction and immune-incompatibility. It has been shown that hepatocyte-like cells (HLCs) can be generated from iPSCs. Furthermore, human iPSCs (hiPSCs) can provide an unlimited source of human hepatocytes and hold great promise for applications in regenerative medicine, drug screening and liver diseases modelling. Despite steady progress, there are still several major obstacles that need to be overcome before iPSCs will reach the bedside. This review will focus on the current state of efforts to derive hiPSCs for potential use in modelling and treatment of liver disease. Full article

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Open AccessCommentary The State of Play with iPSCs and Spinal Cord Injury Models
J. Clin. Med. 2015, 4(1), 193-203; doi:10.3390/jcm4010193
Received: 8 October 2014 / Accepted: 8 December 2014 / Published: 14 January 2015
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Abstract
The application of induced pluripotent stem cell (iPSC) technologies in cell based strategies, for the repair of the central nervous system (with particular focus on the spinal cord), is moving towards the potential use of clinical grade donor cells. The ability of iPSCs
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The application of induced pluripotent stem cell (iPSC) technologies in cell based strategies, for the repair of the central nervous system (with particular focus on the spinal cord), is moving towards the potential use of clinical grade donor cells. The ability of iPSCs to generate donor neuronal, glial and astrocytic phenotypes for transplantation is highlighted here, and we review recent research using iPSCs in attempts to treat spinal cord injury in various animal models. Also discussed are issues relating to the production of clinical grade iPSCs, recent advances in transdifferentiation protocols for iPSC-derived donor cell populations, concerns about tumourogenicity, and whether iPSC technologies offer any advantages over previous donor cell candidates or tissues already in use as therapeutic tools in experimental spinal cord injury studies. Full article

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