Dear Colleagues,

Over the last decade, pluripotent cells such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have provided us with unprecedented opportunities to elucidate disease mechanisms and interrogate molecular mechanisms controlling cell fate changes in vitro. However, despite the progress made worldwide regarding our knowledge of how pluripotency is regained through cell reprogramming, how it is preserved under proper culture conditions, and how it is lost during differentiation, the complete picture of the molecular underpinnings involved in these cell specification processes has yet to be drawn, therefore limiting their promising therapeutic potential. It was not until recently that exciting studies using improved methodologies, including high-throughput sequencing and mass spectrometry approaches, have allowed for the identification of potential modulators that might be fundamental to nuclear gene regulation of cell reprogramming and pluripotent behavior. Moreover, new evidence has established novel regulatory layers, including chemical RNA modifications and metabolic and signaling pathways, that participate in the transcriptional and epigenetic control of pluripotency and that can be affected in human diseases. From this perspective, the main purpose of this Special Issue is to present a collection of original research articles and reviews on recent fundamental molecular mechanisms governing the acquisition, maintenance, and exit of pluripotency together with novel applications of pluripotent cells including in disease modeling, drug discovery, and toxicity screening.

Dr. Miguel Fidalgo
Dr. Ana Sevilla
Dr. Francesca Aguilo
Guest Editors

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Editorial

Jump to: Research, Review

4 pages, 225 KiB  

Open AccessEditorial

Understanding the Molecular Basis of iPSC Reprogrammed Cells to Fulfil Their Expectations in Future Clinical Applications

by Verónica González-Fernández and Ana Sevilla

Cells 2022, 11(17), 2714; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11172714 - 31 Aug 2022

Viewed by 1399

Abstract

IPSC-based disease modelling and pluripotency studies have sparked widespread enthusiasm for more than 16 years of research [...] Full article

(This article belongs to the Special Issue Molecular Basis and Applications of Cell Reprogramming and Pluripotency)

Research

Jump to: Editorial, Review

25 pages, 2531 KiB  

Open AccessArticle

Standardization of Cell Culture Conditions and Routine Genomic Screening under a Quality Management System Leads to Reduced Genomic Instability in hPSCs

by Francisco J. Molina-Ruiz, Clelia Introna, Georgina Bombau, Mireia Galofre and Josep M. Canals

Cells 2022, 11(13), 1984; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11131984 - 21 Jun 2022

Cited by 4 | Viewed by 2049

Abstract

Human pluripotent stem cells (hPSCs) have generated unprecedented interest in the scientific community, given their potential applications in regenerative medicine, disease modeling, toxicology and drug screening. However, hPSCs are prone to acquire genomic alterations in vitro, mainly due to suboptimal culture conditions and [...] Read more.

Human pluripotent stem cells (hPSCs) have generated unprecedented interest in the scientific community, given their potential applications in regenerative medicine, disease modeling, toxicology and drug screening. However, hPSCs are prone to acquire genomic alterations in vitro, mainly due to suboptimal culture conditions and inappropriate routines to monitor genome integrity. This poses a challenge to both the safety of clinical applications and the reliability of basic and translational hPSC research. In this study, we aim to investigate if the implementation of a Quality Management System (QMS) such as ISO9001:2015 to ensure reproducible and standardized cell culture conditions and genomic screening strategies can decrease the prevalence of genomic alterations affecting hPSCs used for research applications. To this aim, we performed a retrospective analysis of G-banding karyotype and Comparative Genomic Hybridization array (aCGH) data generated by our group over a 5-year span of different hESC and hiPSC cultures. This work demonstrates that application of a QMS to standardize cell culture conditions and genomic monitoring routines leads to a striking improvement of genomic stability in hPSCs cultured in vitro, as evidenced by a reduced probability of potentially pathogenic chromosomal aberrations and subchromosomal genomic alterations. These results support the need to implement QMS in academic laboratories performing hPSC research. Full article

(This article belongs to the Special Issue Molecular Basis and Applications of Cell Reprogramming and Pluripotency)

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18 pages, 6560 KiB  

Open AccessArticle

Umbilical Cord Tissue as a Source of Young Cells for the Derivation of Induced Pluripotent Stem Cells Using Non-Integrating Episomal Vectors and Feeder-Free Conditions

by Aisha Mohamed, Theresa Chow, Jennifer Whiteley, Amanda Fantin, Kersti Sorra, Ryan Hicks and Ian M. Rogers

Cells 2021, 10(1), 49; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10010049 - 31 Dec 2020

Cited by 6 | Viewed by 4007

Abstract

The clinical application of induced pluripotent stem cells (iPSC) needs to balance the use of an autologous source that would be a perfect match for the patient against any safety or efficacy issues that might arise with using cells from an older patient [...] Read more.

The clinical application of induced pluripotent stem cells (iPSC) needs to balance the use of an autologous source that would be a perfect match for the patient against any safety or efficacy issues that might arise with using cells from an older patient or donor. Drs. Takahashi and Yamanaka and the Office of Cellular and Tissue-based Products (PMDA), Japan, have had concerns over the existence of accumulated DNA mutations in the cells of older donors and the possibility of long-term negative effects. To mitigate the risk, they have chosen to partner with the Umbilical Cord (UC) banks in Japan to source allogeneic-matched donor cells. Production of iPSCs from UC blood cells (UCB) has been successful; however, reprogramming blood cells requires cell enrichment with columns or flow cytometry and specialized growth media. These requirements add to the cost of production and increase the manipulation of the cells, which complicates the regulatory approval process. Alternatively, umbilical cord tissue mesenchymal stromal cells (CT-MSCs) have the same advantage as UCB cells of being a source of young donor cells. Crucially, CT-MSCs are easier and less expensive to harvest and grow compared to UCB cells. Here, we demonstrate that CT-MSCs can be easily isolated without expensive enzymatic treatment or columns and reprogramed well using episomal vectors, which allow for the removal of the reprogramming factors after a few passages. Together the data indicates that CT-MSCs are a viable source of donor cells for the production of clinical-grade, patient matched iPSCs. Full article

(This article belongs to the Special Issue Molecular Basis and Applications of Cell Reprogramming and Pluripotency)

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18 pages, 21229 KiB  

Open AccessArticle

Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Show Comparable Functionality to Their Autologous Origin

by Mark Jakob, Mario Hambrecht, Jennifer L. Spiegel, Julia Kitz, Martin Canis, Ralf Dressel and Katrin Streckfuss-Bömeke

Cells 2021, 10(1), 33; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10010033 - 28 Dec 2020

Cited by 8 | Viewed by 3693

Abstract

A multimodal therapeutic approach involving radiotherapy is required when treating head and neck squamous cell carcinoma. However, radiotherapy is restricted due to its high risk for damages to the surrounding healthy tissue of the treated area. Tissue regeneration and wound healing is promoted [...] Read more.

A multimodal therapeutic approach involving radiotherapy is required when treating head and neck squamous cell carcinoma. However, radiotherapy is restricted due to its high risk for damages to the surrounding healthy tissue of the treated area. Tissue regeneration and wound healing is promoted by the survival and regenerative capacities of tissue-resident or invading stem cells. Mesenchymal stem cells (MSCs) exhibit a promising therapeutic potential in the field of cell-based tissue engineering and regenerative medicine due to their immunomodulatory properties and differentiation capacity. However, the generation of MSCs for therapeutic applications is still a major challenge. We aimed to produce highly homogeneous induced pluripotent stem cell-derived mesenchymal stem cells (iP-MSCs) in an autologous manner from initially isolated human mucosa mesenchymal stem cells (mMSCs) of the upper respiratory tract. Therefore, mMSCs were reprogrammed into induced pluripotent stem cells (iPSCs) by non-integrative chromosomal technologies and differentiated into corresponding iP-MSCs. We demonstrated that mMSCs and iP-MSCs show similar cell characteristics in terms of morphology, clonogenic potential, differentiation, and surface phenotype. Moreover, iP-MSCs demonstrated related immunosuppressive capacity as mMSCs including the secretion of cytokines, and T cell inhibition. Therefore, generating iP-MSCs in an autologous manner may be a novel personalized treatment option in regenerative medicine. Full article

(This article belongs to the Special Issue Molecular Basis and Applications of Cell Reprogramming and Pluripotency)

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Review

Jump to: Editorial, Research

18 pages, 854 KiB  

Open AccessReview

Epigenetics, Enhancer Function and 3D Chromatin Organization in Reprogramming to Pluripotency

by Andreas Hörnblad and Silvia Remeseiro

Cells 2022, 11(9), 1404; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11091404 - 21 Apr 2022

Cited by 4 | Viewed by 3201

Abstract

Genome architecture, epigenetics and enhancer function control the fate and identity of cells. Reprogramming to induced pluripotent stem cells (iPSCs) changes the transcriptional profile and chromatin landscape of the starting somatic cell to that of the pluripotent cell in a stepwise manner. Changes [...] Read more.

Genome architecture, epigenetics and enhancer function control the fate and identity of cells. Reprogramming to induced pluripotent stem cells (iPSCs) changes the transcriptional profile and chromatin landscape of the starting somatic cell to that of the pluripotent cell in a stepwise manner. Changes in the regulatory networks are tightly regulated during normal embryonic development to determine cell fate, and similarly need to function in cell fate control during reprogramming. Switching off the somatic program and turning on the pluripotent program involves a dynamic reorganization of the epigenetic landscape, enhancer function, chromatin accessibility and 3D chromatin topology. Within this context, we will review here the current knowledge on the processes that control the establishment and maintenance of pluripotency during somatic cell reprogramming. Full article

(This article belongs to the Special Issue Molecular Basis and Applications of Cell Reprogramming and Pluripotency)

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18 pages, 2230 KiB  

Open AccessReview

LSD1: Expanding Functions in Stem Cells and Differentiation

by Carlos Martinez-Gamero, Sandhya Malla and Francesca Aguilo

Cells 2021, 10(11), 3252; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10113252 - 20 Nov 2021

Cited by 22 | Viewed by 4566

Abstract

Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSC) provide a powerful model system to uncover fundamental mechanisms that control cellular identity during mammalian development. Histone methylation governs gene expression programs that play a key role in the regulation of the balance [...] Read more.

Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSC) provide a powerful model system to uncover fundamental mechanisms that control cellular identity during mammalian development. Histone methylation governs gene expression programs that play a key role in the regulation of the balance between self-renewal and differentiation of ESCs. Lysine-specific demethylase 1 (LSD1, also known as KDM1A), the first identified histone lysine demethylase, demethylates H3K4me1/2 and H3K9me1/2 at target loci in a context-dependent manner. Moreover, it has also been shown to demethylate non-histone substrates playing a central role in the regulation of numerous cellular processes. In this review, we summarize current knowledge about LSD1 and the molecular mechanism by which LSD1 influences the stem cells state, including the regulatory circuitry underlying self-renewal and pluripotency. Full article

(This article belongs to the Special Issue Molecular Basis and Applications of Cell Reprogramming and Pluripotency)

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18 pages, 1458 KiB  

Open AccessFeature PaperReview

Cardiotoxicity of Antineoplastic Therapies and Applications of Induced Pluripotent Stem Cell-Derived Cardiomyocytes

by Mo-Fan Huang, Lon Kai Pang, Yi-Hung Chen, Ruiying Zhao and Dung-Fang Lee

Cells 2021, 10(11), 2823; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10112823 - 21 Oct 2021

Cited by 7 | Viewed by 3267

Abstract

The therapeutic landscape for the treatment of cancer has evolved significantly in recent decades, aided by the development of effective oncology drugs. However, many cancer drugs are often poorly tolerated by the body and in particular the cardiovascular system, causing adverse and sometimes [...] Read more.

The therapeutic landscape for the treatment of cancer has evolved significantly in recent decades, aided by the development of effective oncology drugs. However, many cancer drugs are often poorly tolerated by the body and in particular the cardiovascular system, causing adverse and sometimes fatal side effects that negate the chemotherapeutic benefits. The prevalence and severity of chemotherapy-induced cardiotoxicity warrants a deeper investigation of the mechanisms and implicating factors in this phenomenon, and a consolidation of scientific efforts to develop mitigating strategies. Aiding these efforts is the emergence of induced pluripotent stem cells (iPSCs) in recent years, which has allowed for the generation of iPSC-derived cardiomyocytes (iPSC-CMs): a human-based, patient-derived, and genetically variable platform that can be applied to the study of chemotherapy-induced cardiotoxicity and beyond. After surveying chemotherapy-induced cardiotoxicity and the associated chemotherapeutic agents, we discuss the use of iPSC-CMs in cardiotoxicity modeling, drug screening, and other potential applications. Improvements to the iPSC-CM platform, such as the development of more adult-like cardiomyocytes and ongoing advances in biotechnology, will only enhance the utility of iPSC-CMs in both basic science and clinical applications. Full article

(This article belongs to the Special Issue Molecular Basis and Applications of Cell Reprogramming and Pluripotency)

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19 pages, 1633 KiB  

Open AccessReview

iPSC Preparation and Epigenetic Memory: Does the Tissue Origin Matter?

by Giuseppe Scesa, Raffaella Adami and Daniele Bottai

Cells 2021, 10(6), 1470; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10061470 - 11 Jun 2021

Cited by 35 | Viewed by 8206

Abstract

The production of induced pluripotent stem cells (iPSCs) represent a breakthrough in regenerative medicine, providing new opportunities for understanding basic molecular mechanisms of human development and molecular aspects of degenerative diseases. In contrast to human embryonic stem cells (ESCs), iPSCs do not raise [...] Read more.

The production of induced pluripotent stem cells (iPSCs) represent a breakthrough in regenerative medicine, providing new opportunities for understanding basic molecular mechanisms of human development and molecular aspects of degenerative diseases. In contrast to human embryonic stem cells (ESCs), iPSCs do not raise any ethical concerns regarding the onset of human personhood. Still, they present some technical issues related to immune rejection after transplantation and potential tumorigenicity, indicating that more steps forward must be completed to use iPSCs as a viable tool for in vivo tissue regeneration. On the other hand, cell source origin may be pivotal to iPSC generation since residual epigenetic memory could influence the iPSC phenotype and transplantation outcome. In this paper, we first review the impact of reprogramming methods and the choice of the tissue of origin on the epigenetic memory of the iPSCs or their differentiated cells. Next, we describe the importance of induction methods to determine the reprogramming efficiency and avoid integration in the host genome that could alter gene expression. Finally, we compare the significance of the tissue of origin and the inter-individual genetic variation modification that has been lightly evaluated so far, but which significantly impacts reprogramming. Full article

(This article belongs to the Special Issue Molecular Basis and Applications of Cell Reprogramming and Pluripotency)

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