Special Issue "Pluripotent Stem Cells for Regenerative Medicine"

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

Deadline for manuscript submissions: 31 December 2021.

Special Issue Editor

Prof. Dr. Claudia Spits
E-Mail Website
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 papers will be 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. Cells 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 2000 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 (10 papers)

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Research

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Article
Comparison of Differentiation Pattern and WNT/SHH Signaling in Pluripotent Stem Cells Cultured under Different Conditions
Cells 2021, 10(10), 2743; https://doi.org/10.3390/cells10102743 - 14 Oct 2021
Viewed by 319
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 [...] Read more.
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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Article
Tissue of Origin, but Not XCI State, Influences Germ Cell Differentiation from Human Pluripotent Stem Cells
Cells 2021, 10(9), 2400; https://doi.org/10.3390/cells10092400 - 13 Sep 2021
Viewed by 553
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 [...] Read more.
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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Article
PAX7 Balances the Cell Cycle Progression via Regulating Expression of Dnmt3b and Apobec2 in Differentiating PSCs
Cells 2021, 10(9), 2205; https://doi.org/10.3390/cells10092205 - 26 Aug 2021
Viewed by 739
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 [...] Read more.
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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Article
Deficiency in MT5-MMP Supports Branching of Human iPSCs-Derived Neurons and Reduces Expression of GLAST/S100 in iPSCs-Derived Astrocytes
Cells 2021, 10(7), 1705; https://doi.org/10.3390/cells10071705 - 06 Jul 2021
Viewed by 1016
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 [...] Read more.
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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Article
Generation of Functional Vascular Endothelial Cells and Pericytes from Keratinocyte Derived Human Induced Pluripotent Stem Cells
Cells 2021, 10(1), 74; https://doi.org/10.3390/cells10010074 - 05 Jan 2021
Cited by 1 | Viewed by 1026
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 [...] Read more.
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

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Review
The Impact of Acquired Genetic Abnormalities on the Clinical Translation of Human Pluripotent Stem Cells
Cells 2021, 10(11), 3246; https://doi.org/10.3390/cells10113246 - 19 Nov 2021
Viewed by 291
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. [...] Read more.
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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Review
Erythropoietin (EPO) as a Key Regulator of Erythropoiesis, Bone Remodeling and Endothelial Transdifferentiation of Multipotent Mesenchymal Stem Cells (MSCs): Implications in Regenerative Medicine
Cells 2021, 10(8), 2140; https://doi.org/10.3390/cells10082140 - 20 Aug 2021
Viewed by 797
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 [...] Read more.
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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Review
Cell Reprogramming to Model Huntington’s Disease: A Comprehensive Review
Cells 2021, 10(7), 1565; https://doi.org/10.3390/cells10071565 - 22 Jun 2021
Cited by 1 | Viewed by 721
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 [...] Read more.
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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Review
Stem Cells as a Source of Pancreatic Cells for Production of 3D Bioprinted Bionic Pancreas in the Treatment of Type 1 Diabetes
Cells 2021, 10(6), 1544; https://doi.org/10.3390/cells10061544 - 18 Jun 2021
Cited by 2 | Viewed by 847
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 [...] Read more.
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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Review
Towards a Functional Cure for Diabetes Using Stem Cell-Derived Beta Cells: Are We There Yet?
Cells 2021, 10(1), 191; https://doi.org/10.3390/cells10010191 - 19 Jan 2021
Cited by 5 | Viewed by 2168
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 [...] Read more.
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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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Comparison of differentiation pattern and Wnt/Shh signalling in pluripotent stem cells cultured under different conditions
Authors: Barbara Świerczek-Lasek; Damian Dudka; Damian Bauer; Tomasz Czajkowski; Katarzyna Ilach; Wladyslawa Streminska; Agata Kominek; Katarzyna Piwocka; Maria A. Ciemerych; Karolina Archacka
Affiliation: Faculty of Biology, University of Warsaw; Nencki Insititute of Experimental Biology.

Title: PAX7 impacts at the cell cycle regulation of differentiating mouse pluripotent stem cells.
Authors: Anita Florkowska; Iwona Grabowska; Maria A. Ciemerych; et al.
Affiliation: Faculty of Biology, University of Warsaw

Title: Cell Reprogramming for the Treatment of Huntington’s Disease
Authors: Dr. Ruth Monk and Prof. Bronwen Connor
Affiliation: Department of Pharmacology, Centre for Brain Research, School of Medical Sciences, Faculty of Medical and Health Science, University of Auckland, New Zealand

Title: CRISPR-Cas9 mediated KO of MHCI and MHCII KO in porcine iPSC to generate non-immunogenic stem cells
Authors: Henriette R. Frederiksen; Ditte Pawlowski; Ulrik Døhn; Jan Secher; Pernille Tveden-Nyborg; Kristine Freude
Affiliation: Department for Veterinary and Animal Science, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark

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