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Pluripotent Stem Cells for Regenerative Medicine

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Stem Cells".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 50397

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Special Issue Editor

Prof. Dr. Claudia Spits

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Guest Editor

Research Group Reproduction and Genetics, Vrije Universiteit Brussel, Brussels, Belgium
Interests: human pluripotent stem cells; genome instability; aneuploidy; differentiation capacity; tumorigenesis

Special Issue Information

Dear Colleagues,

Human pluripotent stem cells are slowly but steadily transitioning from bench to bedside, with the first clinical trials showing promising results. Nevertheless, the spectrum of potentially treatable conditions is still limited, and issues such as genome instability and suboptimal differentiation are significant hurdles to the safe transition of these cells to the clinic.

This Special Issue welcomes manuscripts providing insight on aspects relevant to the use of hPSC in regenerative medicine. We are interested in a wide range of work, including differentiation to novel cell types or improvement on existing cell types, and their preclinical testing. Work on biomaterials and scaffolding, with an eye for tissue engineering are also key for advanced hPSC-based therapy. Finally, work on safety, such as addressing the tumorigenic potential of hPSC-derived products, and scalability aspects, such as cell culture, are essential for the successful clinical application of these cells.

Prof. Dr. Claudia Spits
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.

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 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

regenerative medicine
hPSC
differentiation
clinical testing
tissue engineering
genome integrity
tumorigenicity
safety
cell culture

Published Papers (11 papers)

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Research

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23 pages, 10798 KiB

Open AccessArticle

Comparison of Differentiation Pattern and WNT/SHH Signaling in Pluripotent Stem Cells Cultured under Different Conditions

by Barbara Świerczek-Lasek, Damian Dudka, Damian Bauer, Tomasz Czajkowski, Katarzyna Ilach, Władysława Streminska, Agata Kominek, Katarzyna Piwocka, Maria A. Ciemerych and Karolina Archacka

Cells 2021, 10(10), 2743; https://doi.org/10.3390/cells10102743 - 14 Oct 2021

Cited by 2 | Viewed by 2196

Abstract

Pluripotent stem cells (PSCs) are characterized by the ability to self-renew as well as undergo multidirectional differentiation. Culture conditions have a pivotal influence on differentiation pattern. In the current study, we compared the fate of mouse PSCs using two culture media: (1) chemically defined, free of animal reagents, and (2) standard one relying on the serum supplementation. Moreover, we assessed the influence of selected regulators (WNTs, SHH) on PSC differentiation. We showed that the differentiation pattern of PSCs cultured in both systems differed significantly: cells cultured in chemically defined medium preferentially underwent ectodermal conversion while their endo- and mesodermal differentiation was limited, contrary to cells cultured in serum-supplemented medium. More efficient ectodermal differentiation of PSCs cultured in chemically defined medium correlated with higher activity of SHH pathway while endodermal and mesodermal conversion of cells cultured in serum-supplemented medium with higher activity of WNT/JNK pathway. However, inhibition of either canonical or noncanonical WNT pathway resulted in the limitation of endo- and mesodermal conversion of PSCs. In addition, blocking WNT secretion led to the inhibition of PSC mesodermal differentiation, confirming the pivotal role of WNT signaling in this process. In contrast, SHH turned out to be an inducer of PSC ectodermal, not mesodermal differentiation. Full article

(This article belongs to the Special Issue Pluripotent Stem Cells for Regenerative Medicine)

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16 pages, 5633 KiB

Open AccessFeature PaperArticle

Tissue of Origin, but Not XCI State, Influences Germ Cell Differentiation from Human Pluripotent Stem Cells

by Yolanda W. Chang, Arend W. Overeem, Celine M. Roelse, Xueying Fan, Christian Freund and Susana M. Chuva de Sousa Lopes

Cells 2021, 10(9), 2400; https://doi.org/10.3390/cells10092400 - 13 Sep 2021

Cited by 4 | Viewed by 3012

Abstract

Human pluripotent stem cells (hPSCs) are not only a promising tool to investigate differentiation to many cell types, including the germline, but are also a potential source of cells to use for regenerative medicine purposes in the future. However, current in vitro models to generate human primordial germ cell-like cells (hPGCLCs) have revealed high variability regarding differentiation efficiency depending on the hPSC lines used. Here, we investigated whether differences in X chromosome inactivation (XCI) in female hPSCs could contribute to the variability of hPGCLC differentiation efficiency during embryoid body (EB) formation. For this, we first characterized the XCI state in different hPSC lines by investigating the expression of XIST and H3K27me3, followed by differentiation and quantification of hPGCLCs. We observed that the XCI state did not influence the efficiency to differentiate to hPGCLCs; rather, hPSCs derived from cells isolated from urine showed an increased trend towards hPGCLCs differentiation compared to skin-derived hPSCs. In addition, we also characterized the XCI state in the generated hPGCLCs. Interestingly, we observed that independent of the XCI state of the hPSCs used, both hPGCLCs and soma cells in the EBs acquired XIST expression, indicative of an inactive X chromosome. In fact, culture conditions for EB formation seemed to promote XIST expression. Together, our results contribute to understanding how epigenetic properties of hPSCs influence differentiation and to optimize differentiation methods to obtain higher numbers of hPGCLCs, the first step to achieve human in vitro gametogenesis. Full article

(This article belongs to the Special Issue Pluripotent Stem Cells for Regenerative Medicine)

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19 pages, 4756 KiB

Open AccessArticle

PAX7 Balances the Cell Cycle Progression via Regulating Expression of Dnmt3b and Apobec2 in Differentiating PSCs

by Anita Florkowska, Igor Meszka, Joanna Nowacka, Monika Granica, Zuzanna Jablonska, Magdalena Zawada, Lukasz Truszkowski, Maria A. Ciemerych and Iwona Grabowska

Cells 2021, 10(9), 2205; https://doi.org/10.3390/cells10092205 - 26 Aug 2021

Cited by 1 | Viewed by 2938

Abstract

PAX7 transcription factor plays a crucial role in embryonic myogenesis and in adult muscles in which it secures proper function of satellite cells, including regulation of their self renewal. PAX7 downregulation is necessary for the myogenic differentiation of satellite cells induced after muscle damage, what is prerequisite step for regeneration. Using differentiating pluripotent stem cells we documented that the absence of functional PAX7 facilitates proliferation. Such action is executed by the modulation of the expression of two proteins involved in the DNA methylation, i.e., Dnmt3b and Apobec2. Increase in Dnmt3b expression led to the downregulation of the CDK inhibitors and facilitated cell cycle progression. Changes in Apobec2 expression, on the other hand, differently impacted proliferation/differentiation balance, depending on the experimental model used. Full article

(This article belongs to the Special Issue Pluripotent Stem Cells for Regenerative Medicine)

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19 pages, 4144 KiB

Open AccessArticle

Deficiency in MT5-MMP Supports Branching of Human iPSCs-Derived Neurons and Reduces Expression of GLAST/S100 in iPSCs-Derived Astrocytes

by Nikita Arnst, Pedro Belio-Mairal, Laura García-González, Laurie Arnaud, Louise Greetham, Emmanuel Nivet, Santiago Rivera and Alexander Dityatev

Cells 2021, 10(7), 1705; https://doi.org/10.3390/cells10071705 - 06 Jul 2021

Cited by 2 | Viewed by 3135

Abstract

For some time, it has been accepted that the β-site APP cleaving enzyme 1 (BACE1) and the γ-secretase are two main players in the amyloidogenic processing of the β-amyloid precursor protein (APP). Recently, the membrane-type 5 matrix metalloproteinase (MT5-MMP/MMP-24), mainly expressed in the nervous system, has been highlighted as a new key player in APP-processing, able to stimulate amyloidogenesis and also to generate a neurotoxic APP derivative. In addition, the loss of MT5-MMP has been demonstrated to abrogate pathological hallmarks in a mouse model of Alzheimer’s disease (AD), thus shedding light on MT5-MMP as an attractive new therapeutic target. However, a more comprehensive analysis of the role of MT5-MMP is necessary to evaluate how its targeting affects neurons and glia in pathological and physiological situations. In this study, leveraging on CRISPR-Cas9 genome editing strategy, we established cultures of human-induced pluripotent stem cells (hiPSC)-derived neurons and astrocytes to investigate the impact of MT5-MMP deficiency on their phenotypes. We found that MT5-MMP-deficient neurons exhibited an increased number of primary and secondary neurites, as compared to isogenic hiPSC-derived neurons. Moreover, MT5-MMP-deficient astrocytes displayed higher surface area and volume compared to control astrocytes. The MT5-MMP-deficient astrocytes also exhibited decreased GLAST and S100β expression. These findings provide novel insights into the physiological role of MT5-MMP in human neurons and astrocytes, suggesting that therapeutic strategies targeting MT5-MMP should be controlled for potential side effects on astrocytic physiology and neuronal morphology. Full article

(This article belongs to the Special Issue Pluripotent Stem Cells for Regenerative Medicine)

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Graphical abstract

13 pages, 4171 KiB

Open AccessArticle

Generation of Functional Vascular Endothelial Cells and Pericytes from Keratinocyte Derived Human Induced Pluripotent Stem Cells

by Selin Pars, Kevin Achberger, Alexander Kleger, Stefan Liebau and Natalia Pashkovskaia

Cells 2021, 10(1), 74; https://doi.org/10.3390/cells10010074 - 05 Jan 2021

Cited by 6 | Viewed by 4088

Abstract

Human induced pluripotent stem cell (hiPSC)-derived endothelial cells (ECs) and pericytes provide a powerful tool for cardiovascular disease modelling, personalized drug testing, translational medicine, and tissue engineering. Here, we report a novel differentiation protocol that results in the fast and efficient production of ECs and pericytes from keratinocyte-derived hiPSCs. We found that the implementation of a 3D embryoid body (EB) stage significantly improves the differentiation efficiency. Compared with the monolayer-based technique, our protocol yields a distinct EC population with higher levels of EC marker expression such as CD31 and vascular endothelial cadherin (VE-cadherin). Furthermore, the EB-based protocol allows the generation of functional EC and pericyte populations that can promote blood vessel-like structure formation upon co-culturing. Moreover, we demonstrate that the EB-based ECs and pericytes can be successfully used in a microfluidic chip model, forming a stable 3D microvascular network. Overall, the described protocol can be used to efficiently differentiate both ECs and pericytes with distinct and high marker expression from keratinocyte-derived hiPSCs, providing a potent source material for future cardiovascular disease studies. Full article

(This article belongs to the Special Issue Pluripotent Stem Cells for Regenerative Medicine)

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Review

Jump to: Research

27 pages, 3945 KiB

Open AccessReview

The Induced Pluripotent Stem Cells in Articular Cartilage Regeneration and Disease Modelling: Are We Ready for Their Clinical Use?

by Michał S. Lach, Monika A. Rosochowicz, Magdalena Richter, Inga Jagiełło, Wiktoria M. Suchorska and Tomasz Trzeciak

Cells 2022, 11(3), 529; https://doi.org/10.3390/cells11030529 - 03 Feb 2022

Cited by 14 | Viewed by 4245

Abstract

The development of induced pluripotent stem cells has brought unlimited possibilities to the field of regenerative medicine. This could be ideal for treating osteoarthritis and other skeletal diseases, because the current procedures tend to be short-term solutions. The usage of induced pluripotent stem cells in the cell-based regeneration of cartilage damages could replace or improve on the current techniques. The patient’s specific non-invasive collection of tissue for reprogramming purposes could also create a platform for drug screening and disease modelling for an overview of distinct skeletal abnormalities. In this review, we seek to summarise the latest achievements in the chondrogenic differentiation of pluripotent stem cells for regenerative purposes and disease modelling. Full article

(This article belongs to the Special Issue Pluripotent Stem Cells for Regenerative Medicine)

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14 pages, 824 KiB

Open AccessReview

The Impact of Acquired Genetic Abnormalities on the Clinical Translation of Human Pluripotent Stem Cells

by Alexander Keller and Claudia Spits

Cells 2021, 10(11), 3246; https://doi.org/10.3390/cells10113246 - 19 Nov 2021

Cited by 8 | Viewed by 3030

Abstract

Human pluripotent stem cells (hPSC) are known to acquire chromosomal abnormalities, which range from point mutations to large copy number changes, including full chromosome aneuploidy. These aberrations have a wide-ranging influence on the state of cells, in both the undifferentiated and differentiated state. Currently, very little is known on how these abnormalities will impact the clinical translation of hPSC, and particularly their potential to prime cells for oncogenic transformation. A further complication is that many of these abnormalities exist in a mosaic state in culture, which complicates their detection with conventional karyotyping methods. In this review we discuss current knowledge on how these aberrations influence the cell state and how this may impact the future of research and the cells’ clinical potential. Full article

(This article belongs to the Special Issue Pluripotent Stem Cells for Regenerative Medicine)

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14 pages, 934 KiB

Open AccessFeature PaperReview

Erythropoietin (EPO) as a Key Regulator of Erythropoiesis, Bone Remodeling and Endothelial Transdifferentiation of Multipotent Mesenchymal Stem Cells (MSCs): Implications in Regenerative Medicine

by Asterios S. Tsiftsoglou

Cells 2021, 10(8), 2140; https://doi.org/10.3390/cells10082140 - 20 Aug 2021

Cited by 36 | Viewed by 7961

Abstract

Human erythropoietin (EPO) is an N-linked glycoprotein consisting of 166 aa that is produced in the kidney during the adult life and acts both as a peptide hormone and hematopoietic growth factor (HGF), stimulating bone marrow erythropoiesis. EPO production is activated by hypoxia and is regulated via an oxygen-sensitive feedback loop. EPO acts via its homodimeric erythropoietin receptor (EPO-R) that increases cell survival and drives the terminal erythroid maturation of progenitors BFU-Es and CFU-Es to billions of mature RBCs. This pathway involves the activation of multiple erythroid transcription factors, such as GATA1, FOG1, TAL-1, EKLF and BCL11A, and leads to the overexpression of genes encoding enzymes involved in heme biosynthesis and the production of hemoglobin. The detection of a heterodimeric complex of EPO-R (consisting of one EPO-R chain and the CSF2RB β-chain, CD131) in several tissues (brain, heart, skeletal muscle) explains the EPO pleotropic action as a protection factor for several cells, including the multipotent MSCs as well as cells modulating the innate and adaptive immunity arms. EPO induces the osteogenic and endothelial transdifferentiation of the multipotent MSCs via the activation of EPO-R signaling pathways, leading to bone remodeling, induction of angiogenesis and secretion of a large number of trophic factors (secretome). These diversely unique properties of EPO, taken together with its clinical use to treat anemias associated with chronic renal failure and other blood disorders, make it a valuable biologic agent in regenerative medicine for the treatment/cure of tissue de-regeneration disorders. Full article

(This article belongs to the Special Issue Pluripotent Stem Cells for Regenerative Medicine)

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36 pages, 529 KiB

Open AccessReview

Cell Reprogramming to Model Huntington’s Disease: A Comprehensive Review

by Ruth Monk and Bronwen Connor

Cells 2021, 10(7), 1565; https://doi.org/10.3390/cells10071565 - 22 Jun 2021

Cited by 5 | Viewed by 3908

Abstract

Huntington’s disease (HD) is a neurodegenerative disorder characterized by the progressive decline of motor, cognitive, and psychiatric functions. HD results from an autosomal dominant mutation that causes a trinucleotide CAG repeat expansion and the production of mutant Huntingtin protein (mHTT). This results in the initial selective and progressive loss of medium spiny neurons (MSNs) in the striatum before progressing to involve the whole brain. There are currently no effective treatments to prevent or delay the progression of HD as knowledge into the mechanisms driving the selective degeneration of MSNs has been hindered by a lack of access to live neurons from individuals with HD. The invention of cell reprogramming provides a revolutionary technique for the study, and potential treatment, of neurological conditions. Cell reprogramming technologies allow for the generation of live disease-affected neurons from patients with neurological conditions, becoming a primary technique for modelling these conditions in vitro. The ability to generate HD-affected neurons has widespread applications for investigating the pathogenesis of HD, the identification of new therapeutic targets, and for high-throughput drug screening. Cell reprogramming also offers a potential autologous source of cells for HD cell replacement therapy. This review provides a comprehensive analysis of the use of cell reprogramming to model HD and a discussion on recent advancements in cell reprogramming technologies that will benefit the HD field. Full article

(This article belongs to the Special Issue Pluripotent Stem Cells for Regenerative Medicine)

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23 pages, 1561 KiB

Open AccessReview

Stem Cells as a Source of Pancreatic Cells for Production of 3D Bioprinted Bionic Pancreas in the Treatment of Type 1 Diabetes

by Michał Wszoła, Daria Nitarska, Piotr Cywoniuk, Magdalena Gomółka and Marta Klak

Cells 2021, 10(6), 1544; https://doi.org/10.3390/cells10061544 - 18 Jun 2021

Cited by 11 | Viewed by 4986

Abstract

Type 1 diabetes (T1D) is the third most common autoimmune disease which develops due to genetic and environmental risk factors. Often, intensive insulin therapy is insufficient, and patients require a pancreas or pancreatic islets transplant. However, both solutions are associated with many possible complications, including graft rejection. The best approach seems to be a donor-independent T1D treatment strategy based on human stem cells cultured in vitro and differentiated into insulin and glucagon-producing cells (β and α cells, respectively). Both types of cells can then be incorporated into the bio-ink used for 3D printing of the bionic pancreas, which can be transplanted into T1D patients to restore glucose homeostasis. The aim of this review is to summarize current knowledge about stem cells sources and their transformation into key pancreatic cells. Last, but not least, we comment on possible solutions of post-transplant immune response triggered stem cell-derived pancreatic cells and their potential control mechanisms. Full article

(This article belongs to the Special Issue Pluripotent Stem Cells for Regenerative Medicine)

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24 pages, 2206 KiB

Open AccessReview

Towards a Functional Cure for Diabetes Using Stem Cell-Derived Beta Cells: Are We There Yet?

by Stephanie Bourgeois, Toshiaki Sawatani, Annelore Van Mulders, Nico De Leu, Yves Heremans, Harry Heimberg, Miriam Cnop and Willem Staels

Cells 2021, 10(1), 191; https://doi.org/10.3390/cells10010191 - 19 Jan 2021

Cited by 35 | Viewed by 8926

Abstract

Diabetes mellitus is a pandemic metabolic disorder that results from either the autoimmune destruction or the dysfunction of insulin-producing pancreatic beta cells. A promising cure is beta cell replacement through the transplantation of islets of Langerhans. However, donor shortage hinders the widespread implementation of this therapy. Human pluripotent stem cells, including embryonic stem cells and induced pluripotent stem cells, represent an attractive alternative beta cell source for transplantation. Although major advances over the past two decades have led to the generation of stem cell-derived beta-like cells that share many features with genuine beta cells, producing fully mature beta cells remains challenging. Here, we review the current status of beta cell differentiation protocols and highlight specific challenges that are associated with producing mature beta cells. We address the challenges and opportunities that are offered by monogenic forms of diabetes. Finally, we discuss the remaining hurdles for clinical application of stem cell-derived beta cells and the status of ongoing clinical trials. Full article

(This article belongs to the Special Issue Pluripotent Stem Cells for Regenerative Medicine)

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