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The Promise of Induced Pluripotent Stem Cells in the Biomedical Research

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Gene and Cell Therapy".

Deadline for manuscript submissions: closed (15 April 2022) | Viewed by 40822

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Dr. M. Esther Gallardo

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Head of Translational Research with iPS Cells Group, Research Institute Hospital 12 de Octubre, i+12, Madrid, Spain
Interests: induced pluripotent stem cells; McArdle disease; mitochondrial disorders; modeling disorders; CRISPR/Cas9; drug repurposing studies; tissue engineering
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Dear Colleagues,

More than a decade ago, the Japanese scientist Shinya Yamanaka showed that it is possible to convert adult cells into a state similar to that of pluripotent stem cell. These cells, named induced pluripotent stem cells (iPSCs), are similar to embryonic stem cells (ES) and are considered a very promising tool in the field of regenerative medicine. iPSCs, like ES cells, are self-renewing and pluripotent. Furthermore, because iPSCs are obtained from adult cells in vitro, they do not raise the ethical and legal problems associated with the use of ES cells. Because they are generated from the patient, the likelihood of rejection in autologous therapies is believed to be much lower. This Special Issue will address the applications of iPSCs, putting a special emphasis on the investigation of the physiopathogenic mechanisms behind diseases and the search for new therapies against them. Therefore, contributions by experts in the field, in the form of original articles and reviews, are most welcome.

Dr. M. Esther Gallardo
Guest Editor

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Keywords

Induced pluripotent stem cells
drug discovery
cell modelling
cell therapy
personalized medicine
tissue engineering

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The Promise of Induced Pluripotent Stem Cells in the Biomedical Research 2.0 in Biomedicines (1 article)

Published Papers (10 papers)

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Research

Jump to: Review

19 pages, 6167 KiB

Open AccessArticle

A Comparative Study of Cell Culture Conditions during Conversion from Primed to Naive Human Pluripotent Stem Cells

by Irene Romayor, Lara Herrera, Maria Burón, Myriam Martin-Inaraja, Laura Prieto, Jone Etxaniz, Marta Inglés-Ferrándiz, Jose Ramon Pineda and Cristina Eguizabal

Biomedicines 2022, 10(6), 1358; https://doi.org/10.3390/biomedicines10061358 - 9 Jun 2022

Cited by 6 | Viewed by 4455

Abstract

The successful reprogramming of human somatic cells into induced pluripotent stem cells (hiPSCs) represented a turning point in the stem cell research field, owing to their ability to differentiate into any cell type with fewer ethical issues than human embryonic stem cells (hESCs). In mice, PSCs are thought to exist in a naive state, the cell culture equivalent of the immature pre-implantation embryo, whereas in humans, PSCs are in a primed state, which is a more committed pluripotent state than a naive state. Recent studies have focused on capturing a similar cell stage in human cells. Given their earlier developmental stage and therefore lack of cell-of-origin epigenetic memory, these cells would be better candidates for further re-differentiation, use in disease modeling, regenerative medicine and drug discovery. In this study, we used primed hiPSCs and hESCs to evaluate the successful establishment and maintenance of a naive cell stage using three different naive-conversion media, both in the feeder and feeder-free cells conditions. In addition, we compared the directed differentiation capacity of primed and naive cells into the three germ layers and characterized these different cell stages with commonly used pluripotent and lineage-specific markers. Our results show that, in general, naive culture NHSM medium (in both feeder and feeder-free systems) confers greater hiPSCs and hESCs viability and the highest naive pluripotency markers expression. This medium also allows better cell differentiation cells toward endoderm and mesoderm. Full article

(This article belongs to the Special Issue The Promise of Induced Pluripotent Stem Cells in the Biomedical Research)

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18 pages, 4125 KiB

Open AccessArticle

Generation of hiPSC-Derived Skeletal Muscle Cells: Exploiting the Potential of Skeletal Muscle-Derived hiPSCs

by Eric Metzler, Helena Escobar, Daniele Yumi Sunaga-Franze, Sascha Sauer, Sebastian Diecke and Simone Spuler

Biomedicines 2022, 10(5), 1204; https://doi.org/10.3390/biomedicines10051204 - 23 May 2022

Cited by 4 | Viewed by 2817

Abstract

Cell therapies for muscle wasting disorders are on the verge of becoming a realistic clinical perspective. Muscle precursor cells derived from human induced pluripotent stem cells (hiPSCs) represent the key to unrestricted cell numbers indispensable for the treatment of generalized muscle wasting such as cachexia or intensive care unit (ICU)-acquired weakness. We asked how the cell of origin influences efficacy and molecular properties of hiPSC-derived muscle progenitor cells. We generated hiPSCs from primary muscle stem cells and from peripheral blood mononuclear cells (PBMCs) of the same donors (n = 4) and compared their molecular profiles, myogenic differentiation potential, and ability to generate new muscle fibers in vivo. We show that reprogramming into hiPSCs from primary muscle stem cells was faster and 35 times more efficient than from blood cells. Global transcriptome comparison revealed significant differences, but differentiation into induced myogenic cells using a directed transgene-free approach could be achieved with muscle- and PBMC-derived hiPSCs, and both cell types generated new muscle fibers in vivo. Differences in myogenic differentiation efficiency were identified with hiPSCs generated from individual donors. The generation of muscle-stem-cell-derived hiPSCs is a fast and economic method to obtain unrestricted cell numbers for cell-based therapies in muscle wasting disorders, and in this aspect are superior to blood-derived hiPSCs. Full article

(This article belongs to the Special Issue The Promise of Induced Pluripotent Stem Cells in the Biomedical Research)

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19 pages, 5098 KiB

Open AccessArticle

Quantitative Proteomics of Polarised Macrophages Derived from Induced Pluripotent Stem Cells

by Gavuthami Murugesan, Lindsay Davidson, Linda Jannetti, Paul R. Crocker and Bernd Weigle

Biomedicines 2022, 10(2), 239; https://doi.org/10.3390/biomedicines10020239 - 23 Jan 2022

Cited by 3 | Viewed by 3512

Abstract

Macrophages (M_Φ) are highly heterogenous and versatile innate immune cells involved in homeostatic and immune responses. Activated M_Φ can exist in two extreme phenotypes: pro-inflammatory (M1) M_Φ and anti-inflammatory (M2) M_Φ. These phenotypes can be recapitulated in vitro by using ligands of toll-like receptors (TLRs) and cytokines such as IFNγ and IL-4. In recent years, human induced pluripotent stem cells (iPSC)-derived M_Φ have gained major attention, as they are functionally similar to human monocyte-derived M_Φ and are receptive to genome editing. In this study, we polarised iPSC-derived M_Φ to M1 or M2 and analysed their proteome and secretome profiles using quantitative proteomics. These comprehensive proteomic data sets provide new insights into functions of polarised M_Φ. Full article

(This article belongs to the Special Issue The Promise of Induced Pluripotent Stem Cells in the Biomedical Research)

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14 pages, 4733 KiB

Open AccessArticle

Unravelling the Role of PAX2 Mutation in Human Focal Segmental Glomerulosclerosis

by Lorena Longaretti, Piera Trionfini, Valerio Brizi, Christodoulos Xinaris, Caterina Mele, Matteo Breno, Elena Romano, Roberta Giampietro, Giuseppe Remuzzi, Ariela Benigni and Susanna Tomasoni

Biomedicines 2021, 9(12), 1808; https://doi.org/10.3390/biomedicines9121808 - 1 Dec 2021

Cited by 3 | Viewed by 2053

Abstract

No effective treatments are available for familial steroid-resistant Focal Segmental Glomerulosclerosis (FSGS), characterized by proteinuria due to ultrastructural abnormalities in glomerular podocytes. Here, we studied a private PAX2 mutation identified in a patient who developed FSGS in adulthood. By generating adult podocytes using patient-specific induced pluripotent stem cells (iPSC), we developed an in vitro model to dissect the role of this mutation in the onset of FSGS. Despite the PAX2 mutation, patient iPSC properly differentiated into podocytes that exhibited a normal structure and function when compared to control podocytes. However, when exposed to an environmental trigger, patient podocytes were less viable and more susceptible to cell injury. Fixing the mutation improved their phenotype and functionality. Using a branching morphogenesis assay, we documented developmental defects in patient-derived ureteric bud-like tubules that were totally rescued by fixing the mutation. These data strongly support the hypothesis that the PAX2 mutation has a dual effect, first in renal organogenesis, which could account for a suboptimal nephron number at birth, and second in adult podocytes, which are more susceptible to cell death caused by environmental triggers. These abnormalities might translate into the development of proteinuria in vivo, with a progressive decline in renal function, leading to FSGS. Full article

(This article belongs to the Special Issue The Promise of Induced Pluripotent Stem Cells in the Biomedical Research)

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19 pages, 11871 KiB

Open AccessArticle

GDAP1 Involvement in Mitochondrial Function and Oxidative Stress, Investigated in a Charcot-Marie-Tooth Model of hiPSCs-Derived Motor Neurons

by Federica Miressi, Nesrine Benslimane, Frédéric Favreau, Marion Rassat, Laurence Richard, Sylvie Bourthoumieu, Cécile Laroche, Laurent Magy, Corinne Magdelaine, Franck Sturtz, Anne-Sophie Lia and Pierre-Antoine Faye

Biomedicines 2021, 9(8), 945; https://doi.org/10.3390/biomedicines9080945 - 2 Aug 2021

Cited by 10 | Viewed by 3336

Abstract

Mutations in the ganglioside-induced differentiation associated protein 1 (GDAP1) gene have been associated with demyelinating and axonal forms of Charcot-Marie-Tooth (CMT) disease, the most frequent hereditary peripheral neuropathy in humans. Previous studies reported the prevalent GDAP1 expression in neural tissues and cells, from animal models. Here, we described the first GDAP1 functional study on human induced-pluripotent stem cells (hiPSCs)-derived motor neurons, obtained from normal subjects and from a CMT2H patient, carrying the GDAP1 homozygous c.581C>G (p.Ser194*) mutation. At mRNA level, we observed that, in normal subjects, GDAP1 is mainly expressed in motor neurons, while it is drastically reduced in the patient’s cells containing a premature termination codon (PTC), probably degraded by the nonsense-mediated mRNA decay (NMD) system. Morphological and functional investigations revealed in the CMT patient’s motor neurons a decrease of cell viability associated to lipid dysfunction and oxidative stress development. Mitochondrion is a key organelle in oxidative stress generation, but it is also mainly involved in energetic metabolism. Thus, in the CMT patient’s motor neurons, mitochondrial cristae defects were observed, even if no deficit in ATP production emerged. This cellular model of hiPSCs-derived motor neurons underlines the role of mitochondrion and oxidative stress in CMT disease and paves the way for new treatment evaluation. Full article

(This article belongs to the Special Issue The Promise of Induced Pluripotent Stem Cells in the Biomedical Research)

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20 pages, 32420 KiB

Open AccessArticle

AKT Signaling Modifies the Balance between Cell Proliferation and Migration in Neural Crest Cells from Patients Affected with Bosma Arhinia and Microphthalmia Syndrome

by Camille Laberthonnière, Elva Maria Novoa-del-Toro, Raphaël Chevalier, Natacha Broucqsault, Vanitha Venkoba Rao, Jean Philippe Trani, Karine Nguyen, Shifeng Xue, Bruno Reversade, Jérôme D. Robin, Anais Baudot and Frédérique Magdinier

Biomedicines 2021, 9(7), 751; https://doi.org/10.3390/biomedicines9070751 - 29 Jun 2021

Cited by 5 | Viewed by 3234

Abstract

Over the recent years, the SMCHD1 (Structural Maintenance of Chromosome flexible Hinge Domain Containing 1) chromatin-associated factor has triggered increasing interest after the identification of variants in three rare and unrelated diseases, type 2 Facio Scapulo Humeral Dystrophy (FSHD2), Bosma Arhinia and Microphthalmia Syndrome (BAMS), and the more recently isolated hypogonadotrophic hypogonadism (IHH) combined pituitary hormone deficiency (CPHD) and septo-optic dysplasia (SOD). However, it remains unclear why certain mutations lead to a specific muscle defect in FSHD while other are associated with severe congenital anomalies. To gain further insights into the specificity of SMCHD1 variants and identify pathways associated with the BAMS phenotype and related neural crest defects, we derived induced pluripotent stem cells from patients carrying a mutation in this gene. We differentiated these cells in neural crest stem cells and analyzed their transcriptome by RNA-Seq. Besides classical differential expression analyses, we analyzed our data using MOGAMUN, an algorithm allowing the extraction of active modules by integrating differential expression data with biological networks. We found that in BAMS neural crest cells, all subnetworks that are associated with differentially expressed genes converge toward a predominant role for AKT signaling in the control of the cell proliferation–migration balance. Our findings provide further insights into the distinct mechanism by which defects in neural crest migration might contribute to the craniofacial anomalies in BAMS. Full article

(This article belongs to the Special Issue The Promise of Induced Pluripotent Stem Cells in the Biomedical Research)

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Review

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16 pages, 744 KiB

Open AccessReview

Induced Pluripotent Stem Cells for Treatment of Alzheimer’s and Parkinson’s Diseases

by David A Yefroyev and Sha Jin

Biomedicines 2022, 10(2), 208; https://doi.org/10.3390/biomedicines10020208 - 19 Jan 2022

Cited by 19 | Viewed by 7930

Abstract

Neurodegenerative diseases are a group of debilitating pathologies in which neuronal tissue dies due to the buildup of neurotoxic plaques, resulting in detrimental effects on cognitive ability, motor control, and everyday function. Stem cell technology offers promise in addressing this problem on multiple fronts, but the conventional sourcing of pluripotent stem cells involves harvesting from aborted embryonic tissue, which comes with strong ethical and practical concerns. The keystone discovery of induced pluripotent stem cell (iPSC) technology provides an alternative and endless source, circumventing the unfavorable issues with embryonic stem cells, and yielding fundamental advantages. This review highlights iPSC technology, the pathophysiology of two major neurodegenerative diseases, Alzheimer’s and Parkinson’s, and then illustrates current state-of-the-art approaches towards the treatment of the diseases using iPSCs. The technologies discussed in the review emphasize in vitro therapeutic neural cell and organoid development for disease treatment, pathological modeling of neurodegenerative diseases, and 3D bioprinting as it applies to both. Full article

(This article belongs to the Special Issue The Promise of Induced Pluripotent Stem Cells in the Biomedical Research)

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25 pages, 1007 KiB

Open AccessReview

iPSC Therapy for Myocardial Infarction in Large Animal Models: Land of Hope and Dreams

by Daina Martínez-Falguera, Oriol Iborra-Egea and Carolina Gálvez-Montón

Biomedicines 2021, 9(12), 1836; https://doi.org/10.3390/biomedicines9121836 - 5 Dec 2021

Cited by 11 | Viewed by 4276

Abstract

Myocardial infarction is the main driver of heart failure due to ischemia and subsequent cell death, and cell-based strategies have emerged as promising therapeutic methods to replace dead tissue in cardiovascular diseases. Research in this field has been dramatically advanced by the development of laboratory-induced pluripotent stem cells (iPSCs) that harbor the capability to become any cell type. Like other experimental strategies, stem cell therapy must meet multiple requirements before reaching the clinical trial phase, and in vivo models are indispensable for ensuring the safety of such novel therapies. Specifically, translational studies in large animal models are necessary to fully evaluate the therapeutic potential of this approach; to empirically determine the optimal combination of cell types, supplementary factors, and delivery methods to maximize efficacy; and to stringently assess safety. In the present review, we summarize the main strategies employed to generate iPSCs and differentiate them into cardiomyocytes in large animal species; the most critical differences between using small versus large animal models for cardiovascular studies; and the strategies that have been pursued regarding implanted cells’ stage of differentiation, origin, and technical application. Full article

(This article belongs to the Special Issue The Promise of Induced Pluripotent Stem Cells in the Biomedical Research)

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33 pages, 4043 KiB

Open AccessReview

Human iPSC-Derived Neurons as A Platform for Deciphering the Mechanisms behind Brain Aging

by Chuan-Chuan Chao, Po-Wen Shen, Tsai-Yu Tzeng, Hsing-Jien Kung, Ting-Fen Tsai and Yu-Hui Wong

Biomedicines 2021, 9(11), 1635; https://doi.org/10.3390/biomedicines9111635 - 7 Nov 2021

Cited by 6 | Viewed by 4725

Abstract

With an increased life expectancy among humans, aging has recently emerged as a major focus in biomedical research. The lack of in vitro aging models—especially for neurological disorders, where access to human brain tissues is limited—has hampered the progress in studies on human brain aging and various age-associated neurodegenerative diseases at the cellular and molecular level. In this review, we provide an overview of age-related changes in the transcriptome, in signaling pathways, and in relation to epigenetic factors that occur in senescent neurons. Moreover, we explore the current cell models used to study neuronal aging in vitro, including immortalized cell lines, primary neuronal culture, neurons directly converted from fibroblasts (Fib-iNs), and iPSC-derived neurons (iPSC-iNs); we also discuss the advantages and limitations of these models. In addition, the key phenotypes associated with cellular senescence that have been observed by these models are compared. Finally, we focus on the potential of combining human iPSC-iNs with genome editing technology in order to further our understanding of brain aging and neurodegenerative diseases, and discuss the future directions and challenges in the field. Full article

(This article belongs to the Special Issue The Promise of Induced Pluripotent Stem Cells in the Biomedical Research)

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17 pages, 2985 KiB

Open AccessReview

The Cutting Edge of Disease Modeling: Synergy of Induced Pluripotent Stem Cell Technology and Genetically Encoded Biosensors

by Kamila R. Valetdinova, Tuyana B. Malankhanova, Suren M. Zakian and Sergey P. Medvedev

Biomedicines 2021, 9(8), 960; https://doi.org/10.3390/biomedicines9080960 - 5 Aug 2021

Cited by 2 | Viewed by 2802

Abstract

The development of cell models of human diseases based on induced pluripotent stem cells (iPSCs) and a cell therapy approach based on differentiated iPSC derivatives has provided a powerful stimulus in modern biomedical research development. Moreover, it led to the creation of personalized regenerative medicine. Due to this, in the last decade, the pathological mechanisms of many monogenic diseases at the cell level have been revealed, and clinical trials of various cell products derived from iPSCs have begun. However, it is necessary to reach a qualitatively new level of research with cell models of diseases based on iPSCs for more efficient searching and testing of drugs. Biosensor technology has a great application prospect together with iPSCs. Biosensors enable researchers to monitor ions, molecules, enzyme activities, and channel conformation in live cells and use them in live imaging and drug screening. These probes facilitate the measurement of steady-state concentrations or activity levels and the observation and quantification of in vivo flux and kinetics. Real-time monitoring of drug action in a specific cellular compartment, organ, or tissue type; the ability to screen at the single-cell resolution; and the elimination of the false-positive results caused by low drug bioavailability that is not detected by in vitro testing methods are a few of the benefits of using biosensors in drug screening. Here, we discuss the possibilities of using biosensor technology in combination with cell models based on human iPSCs and gene editing systems. Furthermore, we focus on the current achievements and problems of using these methods. Full article

(This article belongs to the Special Issue The Promise of Induced Pluripotent Stem Cells in the Biomedical Research)

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