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Application of Induced Pluripotent Stem Cells in Personalized Medicine

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A special issue of Journal of Personalized Medicine (ISSN 2075-4426). This special issue belongs to the section "Clinical Medicine, Cell, and Organism Physiology".

Deadline for manuscript submissions: closed (25 October 2021) | Viewed by 17982

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Special Issue Editor

Dr. Sylwia Bobis-Wozowicz

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Guest Editor

Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland

Special Issue Information

Dear colleagues,

The generation of induced pluripotent stem cells (iPSCs) by somatic cell reprogramming constitutes one of the greatest discoveries in the field of regenerative medicine to date. Owing to their unlimited potential to self-renew and the ability to differentiate into any cell type, iPSCs hold great promise to develop cell-based personalized therapies for a variety of diseases.

The aim of this Special Issue is to present the latest advances in the applications of the iPSCs-based technologies in regenerative medicine, with respect to the updates in differentiation protocols, organoids formation, drug screening, disease modelling, and gene therapy approaches.

Since the breakthrough experiments from the Yamanaka group in 2006 for a mouse system and a year later for human cells, the number of potential applications of iPSCs has rapidly expanded. Remarkably, the use of iPSCs is devoid of ethical concerns associated with embryonic stem cells, which may accelerate the clinical translation of the iPSC technology from bench to bedside.

iPSC-based studies have fostered the discovery of novel pathological mechanisms of human diseases, stimulated the development of new drugs, and paved the way for the development of precision medicine. In particular, the combination of human iPSC technology with recent advances in gene editing and 3D organoids makes iPSC-based platforms very powerful tools in preclinical studies.

We invite the submission of original manuscripts and review articles covering various aspects of the utility of iPSC-based technologies in personalized medicine, from the latest improvements in differentiation protocols, organoids formation, drug screening and disease modelling systems, genome editing and gene therapy platforms, to the application of iPSC-derived cells in clinical trials.

Dr. Sylwia Bobis-Wozowicz
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Personalized 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 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

induced pluripotent stem cells
personalized medicine
organoids
disease modeling
cell therapy
gene therapy
genome editing
drugs screening
regenerative medicine
clinical trials

Published Papers (4 papers)

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Research

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21 pages, 3646 KiB

Open AccessArticle

Efficient Genetic Safety Switches for Future Application of iPSC-Derived Cell Transplants

by Julia Dahlke, Juliane W. Schott, Philippe Vollmer Barbosa, Denise Klatt, Anton Selich, Nico Lachmann, Michael Morgan, Thomas Moritz and Axel Schambach

J. Pers. Med. 2021, 11(6), 565; https://doi.org/10.3390/jpm11060565 - 17 Jun 2021

Cited by 11 | Viewed by 3098

Abstract

Induced pluripotent stem cell (iPSC)-derived cell products hold great promise as a potential cell source in personalized medicine. As concerns about the potential risk of graft-related severe adverse events, such as tumor formation from residual pluripotent cells, currently restrict their applicability, we established an optimized tool for therapeutic intervention that allows drug-controlled, specific and selective ablation of either iPSCs or the whole graft through genetic safety switches. To identify the best working system, different tools for genetic iPSC modification, promoters to express safety switches and different safety switches were combined. Suicide effects were slightly stronger when the suicide gene was delivered through lentiviral (LV) vectors compared to integration into the AAVS1 locus through TALEN technology. An optimized HSV-thymidine kinase and the inducible Caspase 9 both mediated drug-induced, efficient in vitro elimination of transgene-positive iPSCs. Choice of promoter allowed selective elimination of distinct populations within the graft: the hOct4 short response element restricted transgene expression to iPSCs, while the CAGs promoter ubiquitously drove expression in iPSCs and their progeny. Remarkably, both safety switches were able to prevent in vivo teratoma development and even effectively eliminated established teratomas formed by LV CAGs-transgenic iPSCs. These optimized tools to increase safety provide an important step towards clinical application of iPSC-derived transplants. Full article

(This article belongs to the Special Issue Application of Induced Pluripotent Stem Cells in Personalized Medicine)

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18 pages, 2589 KiB

Open AccessArticle

Genetic Correction of IL-10RB Deficiency Reconstitutes Anti-Inflammatory Regulation in iPSC-Derived Macrophages

by Dirk Hoffmann, Johanna Sens, Sebastian Brennig, Daniel Brand, Friederike Philipp, Philippe Vollmer Barbosa, Johannes Kuehle, Doris Steinemann, Daniela Lenz, Theresa Buchegger, Michael Morgan, Christine S. Falk, Christoph Klein, Nico Lachmann and Axel Schambach

J. Pers. Med. 2021, 11(3), 221; https://doi.org/10.3390/jpm11030221 - 20 Mar 2021

Cited by 5 | Viewed by 2698

Abstract

Patient material from rare diseases such as very early-onset inflammatory bowel disease (VEO-IBD) is often limited. The use of patient-derived induced pluripotent stem cells (iPSCs) for disease modeling is a promising approach to investigate disease pathomechanisms and therapeutic strategies. We successfully developed VEO-IBD patient-derived iPSC lines harboring a mutation in the IL-10 receptor β-chain (IL-10RB) associated with defective IL-10 signaling. To characterize the disease phenotype, healthy control and VEO-IBD iPSCs were differentiated into macrophages. IL-10 stimulation induced characteristic signal transducer and activator of transcription 3 (STAT3) and suppressor of cytokine signaling 3 (SOCS3) downstream signaling and anti-inflammatory regulation of lipopolysaccharide (LPS)-mediated cytokine secretion in healthy control iPSC-derived macrophages. In contrast, IL-10 stimulation of macrophages derived from patient iPSCs did not result in STAT3 phosphorylation and subsequent SOCS3 expression, recapitulating the phenotype of cells from patients with IL-10RB deficiency. In line with this, LPS-induced cytokine secretion (e.g., IL-6 and tumor necrosis factor-α (TNF-α)) could not be downregulated by exogenous IL-10 stimulation in VEO-IBD iPSC-derived macrophages. Correction of the IL-10RB defect via lentiviral gene therapy or genome editing in the adeno-associated virus integration site 1 (AAVS1) safe harbor locus led to reconstitution of the anti-inflammatory response. Corrected cells showed IL-10RB expression, IL-10-inducible phosphorylation of STAT3, and subsequent SOCS3 expression. Furthermore, LPS-mediated TNF-α secretion could be modulated by IL-10 stimulation in gene-edited VEO-IBD iPSC-derived macrophages. Our established disease models provide the opportunity to identify and validate new curative molecular therapies and to investigate phenotypes and consequences of additional individual IL-10 signaling pathway-dependent VEO-IBD mutations. Full article

(This article belongs to the Special Issue Application of Induced Pluripotent Stem Cells in Personalized Medicine)

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26 pages, 11242 KiB

Open AccessArticle

A Human Induced Pluripotent Stem Cell-Derived Isogenic Model of Huntington’s Disease Based on Neuronal Cells Has Several Relevant Phenotypic Abnormalities

by Tuyana Malankhanova, Lyubov Suldina, Elena Grigor’eva, Sergey Medvedev, Julia Minina, Ksenia Morozova, Elena Kiseleva, Suren Zakian and Anastasia Malakhova

J. Pers. Med. 2020, 10(4), 215; https://doi.org/10.3390/jpm10040215 - 9 Nov 2020

Cited by 13 | Viewed by 5927

Abstract

Huntington’s disease (HD) is a severe neurodegenerative disorder caused by a CAG triplet expansion in the first exon of the HTT gene. Here we report the introduction of an HD mutation into the genome of healthy human embryonic fibroblasts through CRISPR/Cas9-mediated homologous recombination. We verified the specificity of the created HTT-editing system and confirmed the absence of undesirable genomic modifications at off-target sites. We showed that both mutant and control isogenic induced pluripotent stem cells (iPSCs) derived by reprogramming of the fibroblast clones can be differentiated into striatal medium spiny neurons. We next demonstrated phenotypic abnormalities in the mutant iPSC-derived neural cells, including impaired neural rosette formation and increased sensitivity to growth factor withdrawal. Moreover, using electron microscopic analysis, we detected a series of ultrastructural defects in the mutant neurons, which did not contain huntingtin aggregates, suggesting that these defects appear early in HD development. Thus, our study describes creation of a new isogenic iPSC-based cell system that models HD and recapitulates HD-specific disturbances in the mutant cells, including some ultrastructural features implemented for the first time. Full article

(This article belongs to the Special Issue Application of Induced Pluripotent Stem Cells in Personalized Medicine)

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Review

Jump to: Research

25 pages, 3157 KiB

Open AccessFeature PaperReview

Oxygen as a Master Regulator of Human Pluripotent Stem Cell Function and Metabolism

by Kinga Nit, Malgorzata Tyszka-Czochara and Sylwia Bobis-Wozowicz

J. Pers. Med. 2021, 11(9), 905; https://doi.org/10.3390/jpm11090905 - 10 Sep 2021

Cited by 12 | Viewed by 5230

Abstract

Human-induced pluripotent stem cells (hiPSCs) offer numerous possibilities in science and medicine, particularly when combined with precise genome editing methods. hiPSCs are artificially generated equivalents of human embryonic stem cells (hESCs), which possess an unlimited ability to self-renew and the potential to differentiate into any cell type of the human body. Importantly, generating patient-specific hiPSCs enables personalized drug testing or autologous cell therapy upon differentiation into a desired cell line. However, to ensure the highest standard of hiPSC-based biomedical products, their safety and reliability need to be proved. One of the key factors influencing human pluripotent stem cell (hPSC) characteristics and function is oxygen concentration in their microenvironment. In recent years, emerging data have pointed toward the beneficial effect of low oxygen pressure (hypoxia) on both hiPSCs and hESCs. In this review, we examine the state-of-the-art research on the oxygen impact on hiPSC functions and activity with an emphasis on their niche, metabolic state, reprogramming efficiency, and differentiation potential. We also discuss the similarities and differences between PSCs and cancer stem cells (CSCs) with respect to the role of oxygen in both cell types. Full article

(This article belongs to the Special Issue Application of Induced Pluripotent Stem Cells in Personalized Medicine)

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