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Stem Cells — from Bench to Bedside

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 47617

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Prof. Dr. Marcin Majka

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Department of Transplantation, Jagiellonian University, Krakow, Poland
Interests: cervical cancer; metabolic reprogramming; metformin; caffeic acid; 5′-adenosine monophosphate-activated protein kinase (AMPK)
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Dear Colleagues,

Despite enormous progress in cardiovascular medicine, many fundamental treatments remain palliative rather than curative, leading to suboptimal clinical outcomes. One such example is heart failure, resulting from loss of contractile myocardial tissue.

The emergence of a new field, regenerative medicine with cell replacement therapy enabling recovery of injured tissues and activation of endogenous processes of tissue repair, opens novel paths and new perspectives for development of curative therapies. In this Special Issue devoted to stem cell-based therapies we will discuss recent breakthroughs both in the areas of basic and translational research and clinical medicine. We aim to depict cutting-edge data on recent progress in understanding stem cells biology in relation to their therapeutic potential, new approaches in tracking and imaging of both stem cells and tissues/organs undergoing regeneration, and data from clinical trials of cell-based therapies. Moreover, the mechanisms of stem cells activity including extracellular vesicle production and potential use will be presented.

Prof. Dr. Marcin Majka
Guest Editor

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Keywords

stem cells
cell tracking
tissue imaging
replacement therapy
extracellular vesicles

Published Papers (11 papers)

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Research

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14 pages, 3639 KiB

Open AccessArticle

Effects of Survival Motor Neuron Protein on Germ Cell Development in Mouse and Human

by Wei-Fang Chang, Min Peng, Jing Hsu, Jie Xu, Huan-Chieh Cho, Hsiu-Mei Hsieh-Li, Ji-Long Liu, Chung-Hao Lu and Li-Ying Sung

Int. J. Mol. Sci. 2021, 22(2), 661; https://doi.org/10.3390/ijms22020661 - 11 Jan 2021

Cited by 1 | Viewed by 2818

Abstract

Survival motor neuron (SMN) is ubiquitously expressed in many cell types and its encoding gene, survival motor neuron 1 gene (SMN1), is highly conserved in various species. SMN is involved in the assembly of RNA spliceosomes, which are important for pre-mRNA splicing. A severe neurogenic disease, spinal muscular atrophy (SMA), is caused by the loss or mutation of SMN1 that specifically occurred in humans. We previously reported that SMN plays roles in stem cell biology in addition to its roles in neuron development. In this study, we investigated whether SMN can improve the propagation of spermatogonia stem cells (SSCs) and facilitate the spermatogenesis process. In in vitro culture, SSCs obtained from SMA model mice showed decreased growth rate accompanied by significantly reduced expression of spermatogonia marker promyelocytic leukemia zinc finger (PLZF) compared to those from heterozygous and wild-type littermates; whereas SMN overexpressed SSCs showed enhanced cell proliferation and improved potency. In vivo, the superior ability of homing and complete performance in differentiating progeny was shown in SMN overexpressed SSCs in host seminiferous tubule of transplant experiments compared to control groups. To gain insights into the roles of SMN in clinical infertility, we derived human induced pluripotent stem cells (hiPSCs) from azoospermia patients (AZ-hiPSCs) and from healthy control (ct-hiPSCs). Despite the otherwise comparable levels of hallmark iPCS markers, lower expression level of SMN1 was found in AZ-hiPSCs compared with control hiPSCs during in vitro primordial germ cell like cells (PGCLCs) differentiation. On the other hand, overexpressing hSMN1 in AZ-hiPSCs led to increased level of pluripotent markers such as OCT4 and KLF4 during PGCLC differentiation. Our work reveal novel roles of SMN in mammalian spermatogenesis and suggest new therapeutic targets for azoospermia treatment. Full article

(This article belongs to the Special Issue Stem Cells — from Bench to Bedside)

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14 pages, 3524 KiB

Open AccessArticle

The Chick Chorioallantoic Membrane Model: A New In Vivo Tool to Evaluate Breast Cancer Stem Cell Activity

by Marta Teixeira Pinto, Ana Sofia Ribeiro, Inês Conde, Rita Carvalho and Joana Paredes

Int. J. Mol. Sci. 2021, 22(1), 334; https://doi.org/10.3390/ijms22010334 - 30 Dec 2020

Cited by 18 | Viewed by 3859

Abstract

The high plasticity of cancer stem-like cells (CSCs) allows them to differentiate and proliferate, specifically when xenotransplanted subcutaneously into immunocompromised mice. CSCs are highly tumorigenic, even when inoculated in small numbers. Thus, in vivo limiting dilution assays (LDA) in mice are the current gold standard method to evaluate CSC enrichment and activity. The chick embryo chorioallantoic membrane (CAM) is a low cost, naturally immune-incompetent and reproducible model widely used to evaluate the spontaneous growth of human tumor cells. Here, we established a CAM-LDA assay able to rapidly reproduce tumor specificities—in particular, the ability of the small population of CSCs to form tumors. We used a panel of organotropic metastatic breast cancer cells, which show an enrichment in a stem cell gene signature, enhanced CD44⁺/CD24^−/low cell surface expression and increased mammosphere-forming efficiency (MFE). The size of CAM-xenografted tumors correlate with the number of inoculated cancer cells, following mice xenograft growth pattern. CAM and mice tumors are histologically comparable, displaying both breast CSC markers CD44 and CD49f. Therefore, we propose a new tool for studying CSC prevalence and function—the chick CAM-LDA—a model with easy handling, accessibility, rapid growth and the absence of ethical and regulatory constraints. Full article

(This article belongs to the Special Issue Stem Cells — from Bench to Bedside)

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16 pages, 4827 KiB

Open AccessArticle

Promoting Effect of Basic Fibroblast Growth Factor in Synovial Mesenchymal Stem Cell-Based Cartilage Regeneration

by Gensuke Okamura, Kosuke Ebina, Makoto Hirao, Ryota Chijimatsu, Yasukazu Yonetani, Yuki Etani, Akira Miyama, Kenji Takami, Atsushi Goshima, Hideki Yoshikawa, Takuya Ishimoto, Takayoshi Nakano, Masayuki Hamada, Takashi Kanamoto and Ken Nakata

Int. J. Mol. Sci. 2021, 22(1), 300; https://doi.org/10.3390/ijms22010300 - 30 Dec 2020

Cited by 12 | Viewed by 3047

Abstract

Synovial mesenchymal stem cell (SMSC) is the promising cell source of cartilage regeneration but has several issues to overcome such as limited cell proliferation and heterogeneity of cartilage regeneration ability. Previous reports demonstrated that basic fibroblast growth factor (bFGF) can promote proliferation and cartilage differentiation potential of MSCs in vitro, although no reports show its beneficial effect in vivo. The purpose of this study is to investigate the promoting effect of bFGF on cartilage regeneration using human SMSC in vivo. SMSCs were cultured with or without bFGF in a growth medium, and 2 × 10⁵ cells were aggregated to form a synovial pellet. Synovial pellets were implanted into osteochondral defects induced in the femoral trochlea of severe combined immunodeficient mice, and histological evaluation was performed after eight weeks. The presence of implanted SMSCs was confirmed by the observation of human vimentin immunostaining-positive cells. Interestingly, broad lacunae structures and cartilage substrate stained by Safranin-O were observed only in the bFGF (+) group. The bFGF (+) group had significantly higher O’Driscoll scores in the cartilage repair than the bFGF (−) group. The addition of bFGF to SMSC growth culture may be a useful treatment option to promote cartilage regeneration in vivo. Full article

(This article belongs to the Special Issue Stem Cells — from Bench to Bedside)

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20 pages, 4282 KiB

Open AccessArticle

Quantitative Proteomic Profiling of Small Molecule Treated Mesenchymal Stem Cells Using Chemical Probes

by Jerran Santos, Sibasish Dolai, Matthew B. O’Rourke, Fei Liu, Matthew P. Padula, Mark P. Molloy and Bruce K. Milthorpe

Int. J. Mol. Sci. 2021, 22(1), 160; https://doi.org/10.3390/ijms22010160 - 26 Dec 2020

Cited by 2 | Viewed by 2435

Abstract

The differentiation of human adipose derived stem cells toward a neural phenotype by small molecules has been a vogue topic in the last decade. The characterization of the produced cells has been explored on a broad scale, examining morphological and specific surface protein markers; however, the lack of insight into the expression of functional proteins and their interactive partners is required to further understand the extent of the process. The phenotypic characterization by proteomic profiling allows for a substantial in-depth analysis of the molecular machinery induced and directing the cellular changes through the process. Herein we describe the temporal analysis and quantitative profiling of neural differentiating human adipose-derived stem cells after sub-proteome enrichment using a bisindolylmaleimide chemical probe. The results show that proteins enriched by the Bis-probe were identified reproducibly with 133, 118, 126 and 89 proteins identified at timepoints 0, 1, 6 and 12, respectively. Each temporal timepoint presented several shared and unique proteins relative to neural differentiation and their interactivity. The major protein classes enriched and quantified were enzymes, structural and ribosomal proteins that are integral to differentiation pathways. There were 42 uniquely identified enzymes identified in the cells, many acting as hubs in the networks with several interactions across the network modulating key biological pathways. From the cohort, it was found by gene ontology analysis that 18 enzymes had direct involvement with neurogenic differentiation. Full article

(This article belongs to the Special Issue Stem Cells — from Bench to Bedside)

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12 pages, 6325 KiB

Open AccessArticle

Simulated Microgravity Suppresses Osteogenic Differentiation of Mesenchymal Stem Cells by Inhibiting Oxidative Phosphorylation

by Lin Liu, Yansiwei Cheng, Jie Wang, Zhongjie Ding, Alexander Halim, Qing Luo and Guanbin Song

Int. J. Mol. Sci. 2020, 21(24), 9747; https://doi.org/10.3390/ijms21249747 - 21 Dec 2020

Cited by 12 | Viewed by 2094

Abstract

Studies showed that energy metabolism plays a pivotal role in the differentiation of stem cells. Previous studies revealed that simulated microgravity (SMG) inhibits osteogenic differentiation of mesenchymal stem cells (MSCs). However, the underlying relationship between osteogenesis and energy metabolism under SMG conditions is not fully understood. In the present study, we investigated mitochondrial oxidative phosphorylation (OXPHOS) by assessing the level of peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α), mitochondrial DNA (mtDNA) copy number, mitochondrial mass and oxygen consumption rate (OCR) during osteogenesis of MSCs under SMG conditions. We found that SMG inhibited osteogenic differentiation and OXPHOS of MSCs. Moreover, the expression of sirtuin 1 (Sirt1), an important energy sensor, significantly decreased. After upregulating the expression of Sirt1 using resveratrol, an activator of Sirt1, SMG-inhibited OXPHOS and osteogenic differentiation of MSCs were recovered. Taken together, our results suggest that SMG suppresses osteogenic differentiation of MSCs by inhibiting OXPHOS, indicating that OXPHOS might serve as a potential therapeutic target for repairing bone loss under microgravity conditions. Full article

(This article belongs to the Special Issue Stem Cells — from Bench to Bedside)

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25 pages, 2121 KiB

Open AccessArticle

Insights into Species Preservation: Cryobanking of Rabbit Somatic and Pluripotent Stem Cells

by Lucie Gavin-Plagne, Florence Perold, Pierre Osteil, Sophie Voisin, Synara Cristina Moreira, Quitterie Combourieu, Véronique Saïdou, Magali Mure, Gérard Louis, Anne Baudot, Samuel Buff, Thierry Joly and Marielle Afanassieff

Int. J. Mol. Sci. 2020, 21(19), 7285; https://doi.org/10.3390/ijms21197285 - 02 Oct 2020

Cited by 6 | Viewed by 2938

Abstract

Induced pluripotent stem cells (iPSCs) are obtained by genetically reprogramming adult somatic cells via the overexpression of specific pluripotent genes. The resulting cells possess the same differentiation properties as blastocyst-stage embryonic stem cells (ESCs) and can be used to produce new individuals by embryonic complementation, nuclear transfer cloning, or in vitro fertilization after differentiation into male or female gametes. Therefore, iPSCs are highly valuable for preserving biodiversity and, together with somatic cells, can enlarge the pool of reproductive samples for cryobanking. In this study, we subjected rabbit iPSCs (rbiPSCs) and rabbit ear tissues to several cryopreservation conditions with the aim of defining safe and non-toxic slow-freezing protocols. We compared a commercial synthetic medium (STEM ALPHA.CRYO3) with a biological medium based on fetal bovine serum (FBS) together with low (0–5%) and high (10%) concentrations of dimethyl sulfoxide (DMSO). Our data demonstrated the efficacy of a CRYO3-based medium containing 4% DMSO for the cryopreservation of skin tissues and rbiPSCs. Specifically, this medium provided similar or even better biological results than the commonly used freezing medium composed of FBS and 10% DMSO. The results of this study therefore represent an encouraging first step towards the use of iPSCs for species preservation. Full article

(This article belongs to the Special Issue Stem Cells — from Bench to Bedside)

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23 pages, 4428 KiB

Open AccessArticle

Origin of the Induced Pluripotent Stem Cells Affects Their Differentiation into Dopaminergic Neurons

by Paula Chlebanowska, Maciej Sułkowski, Klaudia Skrzypek, Anna Tejchman, Agata Muszyńska, Rezvan Noroozi and Marcin Majka

Int. J. Mol. Sci. 2020, 21(16), 5705; https://doi.org/10.3390/ijms21165705 - 09 Aug 2020

Cited by 11 | Viewed by 4814

Abstract

Neuronal differentiation of human induced pluripotent stem (iPS) cells, both in 2D models and 3D systems in vitro, allows for the study of disease pathomechanisms and the development of novel therapies. To verify if the origin of donor cells used for reprogramming to iPS cells can influence the differentiation abilities of iPS cells, peripheral blood mononuclear cells (PBMC) and keratinocytes were reprogrammed to iPS cells using the Sendai viral vector and were subsequently checked for pluripotency markers and the ability to form teratomas in vivo. Then, iPS cells were differentiated into dopaminergic neurons in 2D and 3D cultures. Both PBMC and keratinocyte-derived iPS cells were similarly reprogrammed to iPS cells, but they displayed differences in gene expression profiles and in teratoma compositions in vivo. During 3D organoid formation, the origin of iPS cells affected the levels of FOXA2 and LMX1A only in the first stages of neural differentiation, whereas in the 2D model, differences were detected at the levels of both early and late neural markers FOXA2, LMX1A, NURR1, TUBB and TH. To conclude, the origin of iPS cells may significantly affect iPS differentiation abilities in teratomas, as well as exerting effects on 2D differentiation into dopaminergic neurons and the early stages of 3D midbrain organoid formation. Full article

(This article belongs to the Special Issue Stem Cells — from Bench to Bedside)

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Review

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13 pages, 623 KiB

Open AccessReview

Plasticity of Intestinal Epithelium: Stem Cell Niches and Regulatory Signals

by Ken Kurokawa, Yoku Hayakawa and Kazuhiko Koike

Int. J. Mol. Sci. 2021, 22(1), 357; https://doi.org/10.3390/ijms22010357 - 31 Dec 2020

Cited by 39 | Viewed by 10311

Abstract

The discovery of Lgr5+ intestinal stem cells (ISCs) triggered a breakthrough in the field of ISC research. Lgr5+ ISCs maintain the homeostasis of the intestinal epithelium in the steady state, while these cells are susceptible to epithelial damage induced by chemicals, pathogens, or irradiation. During the regeneration process of the intestinal epithelium, more quiescent +4 stem cells and short-lived transit-amplifying (TA) progenitor cells residing above Lgr5+ ISCs undergo dedifferentiation and act as stem-like cells. In addition, several recent reports have shown that a subset of terminally differentiated cells, including Paneth cells, tuft cells, or enteroendocrine cells, may also have some degree of plasticity in specific situations. The function of ISCs is maintained by the neighboring stem cell niches, which strictly regulate the key signal pathways in ISCs. In addition, various inflammatory cytokines play critical roles in intestinal regeneration and stem cell functions following epithelial injury. Here, we summarize the current understanding of ISCs and their niches, review recent findings regarding cellular plasticity and its regulatory mechanism, and discuss how inflammatory cytokines contribute to epithelial regeneration. Full article

(This article belongs to the Special Issue Stem Cells — from Bench to Bedside)

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25 pages, 1739 KiB

Open AccessReview

Challenges in Bone Tissue Regeneration: Stem Cell Therapy, Biofunctionality and Antimicrobial Properties of Novel Materials and Its Evolution

by Oliver Riester, Max Borgolte, René Csuk and Hans-Peter Deigner

Int. J. Mol. Sci. 2021, 22(1), 192; https://doi.org/10.3390/ijms22010192 - 27 Dec 2020

Cited by 27 | Viewed by 5551

Abstract

An aging population leads to increasing demand for sustained quality of life with the aid of novel implants. Patients expect fast healing and few complications after surgery. Increased biofunctionality and antimicrobial behavior of implants, in combination with supportive stem cell therapy, can meet these expectations. Recent research in the field of bone implants and the implementation of autologous mesenchymal stem cells in the treatment of bone defects is outlined and evaluated in this review. The article highlights several advantages, limitations and advances for metal-, ceramic- and polymer-based implants and discusses the future need for high-throughput screening systems used in the evaluation of novel developed materials and stem cell therapies. Automated cell culture systems, microarray assays or microfluidic devices are required to efficiently analyze the increasing number of new materials and stem cell-assisted therapies. Approaches described in the literature to improve biocompatibility, biofunctionality and stem cell differentiation efficiencies of implants range from the design of drug-laden nanoparticles to chemical modification and the selection of materials that mimic the natural tissue. Combining suitable implants with mesenchymal stem cell treatment promises to shorten healing time and increase treatment success. Most research studies focus on creating antibacterial materials or modifying implants with antibacterial coatings in order to address the increasing number of complications after surgeries that are mostly caused by bacterial infections. Moreover, treatment of multiresistant pathogens will pose even bigger challenges in hospitals in the future, according to the World Health Organization (WHO). These antibacterial materials will help to reduce infections after surgery and the number of antibiotic treatments that contribute to the emergence of new multiresistant pathogens, whilst the antibacterial implants will help reduce the amount of antibiotics used in clinical treatment. Full article

(This article belongs to the Special Issue Stem Cells — from Bench to Bedside)

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15 pages, 1272 KiB

Open AccessReview

Current Status of Cell-Based Therapy in Patients with Critical Limb Ischemia

by Frantisek Jaluvka, Peter Ihnat, Juraj Madaric, Adela Vrtkova, Jaroslav Janosek and Vaclav Prochazka

Int. J. Mol. Sci. 2020, 21(23), 8999; https://doi.org/10.3390/ijms21238999 - 26 Nov 2020

Cited by 19 | Viewed by 2918

Abstract

(1) Background: The treatment of peripheral arterial disease (PAD) is focused on improving perfusion and oxygenation in the affected limb. Standard revascularization methods include bypass surgery, endovascular interventional procedures, or hybrid revascularization. Cell-based therapy can be an alternative strategy for patients with no-option critical limb ischemia who are not eligible for endovascular or surgical procedures. (2) Aims: The aim of this narrative review was to provide an up-to-date critical overview of the knowledge and evidence-based medicine data on the position of cell therapy in the treatment of PAD. The current evidence on the cell-based therapy is summarized and future perspectives outlined, emphasizing the potential of exosomal cell-free approaches in patients with critical limb ischemia. (3) Methods: Cochrane and PubMed databases were searched for keywords “critical limb ischemia and cell therapy”. In total, 589 papers were identified, 11 of which were reviews and 11 were meta-analyses. These were used as the primary source of information, using cross-referencing for identification of additional papers. (4) Results: Meta-analyses focusing on cell therapy in PAD treatment confirm significantly greater odds of limb salvage in the first year after the cell therapy administration. Reported odds ratio estimates of preventing amputation being mostly in the region 1.6–3, although with a prolonged observation period, it seems that the odds ratio can grow even further. The odds of wound healing were at least two times higher when compared with the standard conservative therapy. Secondary endpoints of the available meta-analyses are also included in this review. Improvement of perfusion and oxygenation parameters in the affected limb, pain regression, and claudication interval prolongation are discussed. (5) Conclusions: The available evidence-based medicine data show that this technique is safe, associated with minimum complications or adverse events, and effective. Full article

(This article belongs to the Special Issue Stem Cells — from Bench to Bedside)

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18 pages, 875 KiB

Open AccessReview

Induced Pluripotent Stem Cells: Hope in the Treatment of Diseases, including Muscular Dystrophies

by Daniela Gois Beghini, Samuel Iwao Horita, Cynthia Machado Cascabulho, Luiz Anastácio Alves and Andrea Henriques-Pons

Int. J. Mol. Sci. 2020, 21(15), 5467; https://doi.org/10.3390/ijms21155467 - 30 Jul 2020

Cited by 10 | Viewed by 6074

Abstract

Induced pluripotent stem (iPS) cells are laboratory-produced cells that combine the biological advantages of somatic adult and stem cells for cell-based therapy. The reprogramming of cells, such as fibroblasts, to an embryonic stem cell-like state is done by the ectopic expression of transcription factors responsible for generating embryonic stem cell properties. These primary factors are octamer-binding transcription factor 4 (Oct3/4), sex-determining region Y-box 2 (Sox2), Krüppel-like factor 4 (Klf4), and the proto-oncogene protein homolog of avian myelocytomatosis (c-Myc). The somatic cells can be easily obtained from the patient who will be subjected to cellular therapy and be reprogrammed to acquire the necessary high plasticity of embryonic stem cells. These cells have no ethical limitations involved, as in the case of embryonic stem cells, and display minimal immunological rejection risks after transplant. Currently, several clinical trials are in progress, most of them in phase I or II. Still, some inherent risks, such as chromosomal instability, insertional tumors, and teratoma formation, must be overcome to reach full clinical translation. However, with the clinical trials and extensive basic research studying the biology of these cells, a promising future for human cell-based therapies using iPS cells seems to be increasingly clear and close. Full article

(This article belongs to the Special Issue Stem Cells — from Bench to Bedside)

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