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Stem Cells in Health and Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 25080

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Special Issue Editors

Dr. Francesca Agriesti

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Guest Editor

Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy
Interests: cancer metabolism and cancer stem cell metabolism; metabolic reprogramming and drug sensitivity in several cancer cell models (e.g., osteosarcoma hepatocarcinoma, oral squamous cell carcinoma, leukemia cells); molecular mechanisms responsible for the HCV-related hepatocellular carcinoma; cell differentiation mechanisms and relative interplay with peculiar cancer cells metabolic adaptations; molecular and metabolic pathways of neoplastic malignancies and validation of anti-metabolic drugs as new therapeutic tools
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Claudia Piccoli

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Department of Clinical and Experimental Medicine, Università degli Studi di Foggia, Foggia, Italy
Interests: stem cell; mitochondria; bioenergetics; redox signaling; metabolic profiling; metabolic therapy; mitochondrial metabolism; oxidative stress

Special Issue Information

Dear Colleagues,

In recent years, our knowledge about the dual role of stem cells in health and disease has increased significantly. However, the biological and molecular mechanisms of this double function are yet to be fully understood.

New advancements in stem-cell research open a new door for patients suffering from diseases not yet successfully treated. Stem-cell-based therapy, including embryonic stem cells, human pluripotent stem cells, multipotent mesenchymal stem cells, and neural stem cells, has recently emerged as a key player in regenerative medicine because of the inherent ability of these stem cells to self-renew and the potential to differentiate into other cell types. Moreover, recent advances in cell-reprogramming and genome-editing technologies have provided additional tools for developing more effective and tailored stem-cell-based therapies.

This Special Issue aims to highlight the stem-cell biology in both physiological and pathological conditions, thus expanding the current knowledge and boosting innovative diagnostic and/or therapeutic applications.

Original and review articles, including basic studies, are all welcome for consideration. Research topics may include (but are not limited to) the following:

Molecular and cellular mechanisms governing stem-cell physiology, i.e., self-renewal signalling pathways, differentiation, and metabolic plasticity;
Microenvironmental regulators of stem-cell plasticity and mutual interconversion between healthy and non-healthy stem cells;
Cancer stem cell (CSC) involvement in tumor progression and molecular drivers and mechanisms underlying CSC therapy resistance;
Therapeutic application of stem cells in experimental settings.

Dr. Francesca Agriesti
Prof. Dr. Claudia Piccoli
Guest Editors

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

stem cell regulation
differentiation
pluripotency
reprogramming
stem cell therapy
cancer stem cell/tumor-initiating cell
therapy resistance
regenerative medicine
metabolic plasticity

Related Special Issue

Stem Cells in Health and Disease 2.0 in International Journal of Molecular Sciences (10 articles)

Published Papers (12 papers)

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Research

Jump to: Review

14 pages, 2530 KiB

Open AccessArticle

Comparison of the Therapeutic Effects of Adipose- and Bone Marrow-Derived Mesenchymal Stem Cells on Renal Fibrosis

by Maria Yoshida, Ayumu Nakashima, Naoki Ishiuchi, Kisho Miyasako, Keisuke Morimoto, Yoshiki Tanaka, Kensuke Sasaki, Satoshi Maeda and Takao Masaki

Int. J. Mol. Sci. 2023, 24(23), 16920; https://doi.org/10.3390/ijms242316920 - 29 Nov 2023

Viewed by 970

Abstract

Mesenchymal stem cells (MSCs) have attracted a great deal of interest as a therapeutic tool for renal fibrosis. Although both adipose-derived and bone marrow-derived MSCs (ADSCs and BMSCs, respectively) suppress renal fibrosis, which of these two has a stronger therapeutic effect remains unclear. This study aimed to compare the antifibrotic effects of ADSCs and BMSCs extracted from adipose tissue and bone marrow derived from the same rats. When cultured in serum-containing medium, ADSCs had a more potent inhibitory effect than BMSCs on renal fibrosis induced by ischemia-reperfusion injury in rats. ADSCs and BMSCs cultured in serum-free medium were equally effective in suppressing renal fibrosis. Mice infused with ADSCs (serum-containing or serum-free cultivation) had a higher death rate from pulmonary embolism than those infused with BMSCs. In vitro, mRNA levels of tissue factor, tumor necrosis factor-α-induced protein 6 and prostaglandin E synthase were higher in ADSCs than in BMSCs, while that of vascular endothelial growth factor was higher in BMSCs than in ADSCs. Although ADSCs had a stronger antifibrotic effect, these findings support the consideration of thromboembolism risk in clinical applications. Our results emphasize the importance of deciding between ADSCs and BMSCs based upon the target disease and culture method. Full article

(This article belongs to the Special Issue Stem Cells in Health and Disease)

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13 pages, 10505 KiB

Open AccessArticle

Differentiation Capacity of Porcine Skeletal Muscle-Derived Stem Cells as Intermediate Species between Mice and Humans

by Tetsuro Tamaki, Toshiharu Natsume, Akira Katoh, Nobuyuki Nakajima, Kosuke Saito, Tsuyoshi Fukuzawa, Masayoshi Otake, Satoko Enya, Akihisa Kangawa, Takeshi Imai, Miyu Tamaki and Yoshiyasu Uchiyama

Int. J. Mol. Sci. 2023, 24(12), 9862; https://doi.org/10.3390/ijms24129862 - 7 Jun 2023

Viewed by 1503

Abstract

Large animal experiments are important for preclinical studies of regenerative stem cell transplantation therapy. Therefore, we investigated the differentiation capacity of pig skeletal muscle-derived stem cells (Sk-MSCs) as an intermediate model between mice and humans for nerve muscle regenerative therapy. Enzymatically extracted cells were obtained from green-fluorescence transgenic micro-mini pigs (GFP-Tg MMP) and sorted as CD34+/45− (Sk-34) and CD34−/45−/29+ (Sk-DN) fractions. The ability to differentiate into skeletal muscle, peripheral nerve, and vascular cell lineages was examined via in vitro cell culture and in vivo cell transplantation into the damaged tibialis anterior muscle and sciatic nerves of nude mice and rats. Protein and mRNA levels were analyzed using RT-PCR, immunohistochemistry, and immunoelectron microscopy. The myogenic potential, which was tested by Pax7 and MyoD expression and the formation of muscle fibers, was higher in Sk-DN cells than in Sk-34 cells but remained weak in the latter. In contrast, the capacity to differentiate into peripheral nerve and vascular cell lineages was significantly stronger in Sk-34 cells. In particular, Sk-DN cells did not engraft to the damaged nerve, whereas Sk-34 cells showed active engraftment and differentiation into perineurial/endoneurial cells, endothelial cells, and vascular smooth muscle cells, similar to the human case, as previously reported. Therefore, we concluded that Sk-34 and Sk-DN cells in pigs are closer to those in humans than to those in mice. Full article

(This article belongs to the Special Issue Stem Cells in Health and Disease)

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11 pages, 2011 KiB

Open AccessArticle

Redox-Dependent Modulation of Human Liver Progenitor Cell Line Fate

by Francesco Bellanti, Domenica Mangieri, Giorgia di Bello, Aurelio Lo Buglio, Giuseppe Pannone, Maria Carmela Pedicillo, Alberto Fersini, Michał Dobrakowski, Aleksandra Kasperczyk, Sławomir Kasperczyk and Gianluigi Vendemiale

Int. J. Mol. Sci. 2023, 24(3), 1934; https://doi.org/10.3390/ijms24031934 - 18 Jan 2023

Viewed by 1332

Abstract

Redox homeostasis is determinant in the modulation of quiescence/self-renewal/differentiation of stem cell lines. The aim of this study consisted of defining the impact of redox modifications on cell fate in a human hepatic progenitor line. To achieve this, the HepaRG cell line, which shows oval ductular bipotent characteristics, was used. The impact of redox status on the balance between self-renewal and differentiation of HepaRG cells was investigated using different methodological approaches. A bioinformatic analysis initially proved that the trans-differentiation of HepaRG toward bipotent progenitors is associated with changes in redox metabolism. We then exposed confluent HepaRG (intermediate differentiation phase) to oxidized (H₂O₂) or reduced (N-acetylcysteine) extracellular environments, observing that oxidation promotes the acquisition of a mature HepaRG phenotype, while a reduced culture medium stimulates de-differentiation. These results were finally confirmed through pharmacological modulation of the nuclear factor (erythroid-derived 2)-like 2 (NRF2), a principal modulator of the antioxidant response, in confluent HepaRG. NRF2 inhibition led to intracellular pro-oxidative status and HepaRG differentiation, while its activation was associated with low levels of reactive species and de-differentiation. In conclusion, this study shows that both intra- and extracellular redox balance are crucial in the determination of HepaRG fate. The impact of redox status in the differentiation potential of HepaRG cells is significant on the utilization of this cell line in pre-clinical studies. Full article

(This article belongs to the Special Issue Stem Cells in Health and Disease)

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14 pages, 3429 KiB

Open AccessArticle

Niche-Dependent Regulation of Lkb1 in the Proliferation of Lung Epithelial Progenitor Cells

by Qingwen Ma, Xue Li, Sisi Wang, Qi Wang, Yu Li, Kuan Li, Jianhai Wang, Qiuyang Zhang, Junping Wu and Huaiyong Chen

Int. J. Mol. Sci. 2022, 23(23), 15065; https://doi.org/10.3390/ijms232315065 - 1 Dec 2022

Cited by 3 | Viewed by 1600

Abstract

Lung homeostasis and regeneration depend on lung epithelial progenitor cells. Lkb1 (Liver Kinase B1) has known roles in the differentiation of airway epithelial cells during embryonic development. However, the effects of Lkb1 in adult lung epithelial progenitor cell regeneration and its mechanisms of action have not been determined. In this study, we investigated the mechanism by which Lkb1 regulates lung epithelial progenitor cell regeneration. Organoid culture showed that loss of Lkb1 significantly reduced the proliferation of club cells and alveolar type 2 (AT2) cells in vitro. In the absence of Lkb1, there is a slower recovery rate of the damaged airway epithelium in naphthalene-induced airway epithelial injury and impaired expression of surfactant protein C during bleomycin-induced alveolar epithelial damage. Moreover, the expression of autophagy-related genes was reduced in club cells and increased in AT2 cells, but the expression of Claudin-18 was obviously reduced in AT2 cells after Lkb1 knockdown. On the whole, our findings indicated that Lkb1 may promote the proliferation of lung epithelial progenitor cells via a niche-dependent pathway and is required for the repair of the damaged lung epithelium. Full article

(This article belongs to the Special Issue Stem Cells in Health and Disease)

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Review

Jump to: Research

29 pages, 2474 KiB

Open AccessReview

Modeling Liver Development and Disease in a Dish

by Waqas Iqbal, Yaru Wang, Pingnan Sun and Xiaoling Zhou

Int. J. Mol. Sci. 2023, 24(21), 15921; https://doi.org/10.3390/ijms242115921 - 2 Nov 2023

Viewed by 1296

Abstract

Historically, biological research has relied primarily on animal models. While this led to the understanding of numerous human biological processes, inherent species-specific differences make it difficult to answer certain liver-related developmental and disease-specific questions. The advent of 3D organoid models that are either derived from pluripotent stem cells or generated from healthy or diseased tissue-derived stem cells have made it possible to recapitulate the biological aspects of human organs. Organoid technology has been instrumental in understanding the disease mechanism and complements animal models. This review underscores the advances in organoid technology and specifically how liver organoids are used to better understand human-specific biological processes in development and disease. We also discuss advances made in the application of organoid models in drug screening and personalized medicine. Full article

(This article belongs to the Special Issue Stem Cells in Health and Disease)

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43 pages, 4739 KiB

Open AccessReview

The Crosstalk between Mesenchymal Stromal/Stem Cells and Hepatocytes in Homeostasis and under Stress

by Irina V. Kholodenko, Roman V. Kholodenko and Konstantin N. Yarygin

Int. J. Mol. Sci. 2023, 24(20), 15212; https://doi.org/10.3390/ijms242015212 - 16 Oct 2023

Cited by 1 | Viewed by 1639

Abstract

Liver diseases, characterized by high morbidity and mortality, represent a substantial medical problem globally. The current therapeutic approaches are mainly aimed at reducing symptoms and slowing down the progression of the diseases. Organ transplantation remains the only effective treatment method in cases of severe liver pathology. In this regard, the development of new effective approaches aimed at stimulating liver regeneration, both by activation of the organ’s own resources or by different therapeutic agents that trigger regeneration, does not cease to be relevant. To date, many systematic reviews and meta-analyses have been published confirming the effectiveness of mesenchymal stromal cell (MSC) transplantation in the treatment of liver diseases of various severities and etiologies. However, despite the successful use of MSCs in clinical practice and the promising therapeutic results in animal models of liver diseases, the mechanisms of their protective and regenerative action remain poorly understood. Specifically, data about the molecular agents produced by these cells and mediating their therapeutic action are fragmentary and often contradictory. Since MSCs or MSC-like cells are found in all tissues and organs, it is likely that many key intercellular interactions within the tissue niches are dependent on MSCs. In this context, it is essential to understand the mechanisms underlying communication between MSCs and differentiated parenchymal cells of each particular tissue. This is important both from the perspective of basic science and for the development of therapeutic approaches involving the modulation of the activity of resident MSCs. With regard to the liver, the research is concentrated on the intercommunication between MSCs and hepatocytes under normal conditions and during the development of the pathological process. The goals of this review were to identify the key factors mediating the crosstalk between MSCs and hepatocytes and determine the possible mechanisms of interaction of the two cell types under normal and stressful conditions. The analysis of the hepatocyte–MSC interaction showed that MSCs carry out chaperone-like functions, including the synthesis of the supportive extracellular matrix proteins; prevention of apoptosis, pyroptosis, and ferroptosis; support of regeneration; elimination of lipotoxicity and ER stress; promotion of antioxidant effects; and donation of mitochondria. The underlying mechanisms suggest very close interdependence, including even direct cytoplasm and organelle exchange. Full article

(This article belongs to the Special Issue Stem Cells in Health and Disease)

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16 pages, 1283 KiB

Open AccessReview

Stem Cell Therapy in Children with Traumatic Brain Injury

by Wen-Ya Lin, Kang-Hsi Wu, Chun-Yu Chen, Bei-Cyuan Guo, Yu-Jun Chang, Tai-An Lee, Mao-Jen Lin and Han-Ping Wu

Int. J. Mol. Sci. 2023, 24(19), 14706; https://doi.org/10.3390/ijms241914706 - 28 Sep 2023

Cited by 3 | Viewed by 2098

Abstract

Pediatric traumatic brain injury is a cause of major mortality, and resultant neurological sequelae areassociated with long-term morbidity. Increasing studies have revealed stem cell therapy to be a potential new treatment. However, much work is still required to clarify the mechanism of action of effective stem cell therapy, type of stem cell therapy, optimal timing of therapy initiation, combination of cocurrent medical treatment and patient selection criteria. This paper will focus on stem cell therapy in children with traumatic brain injury. Full article

(This article belongs to the Special Issue Stem Cells in Health and Disease)

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26 pages, 1338 KiB

Open AccessReview

Recent Advances in High-Content Imaging and Analysis in iPSC-Based Modelling of Neurodegenerative Diseases

by Giovanna Menduti and Marina Boido

Int. J. Mol. Sci. 2023, 24(19), 14689; https://doi.org/10.3390/ijms241914689 - 28 Sep 2023

Cited by 1 | Viewed by 1660

Abstract

In the field of neurodegenerative pathologies, the platforms for disease modelling based on patient-derived induced pluripotent stem cells (iPSCs) represent a valuable molecular diagnostic/prognostic tool. Indeed, they paved the way for the in vitro recapitulation of the pathological mechanisms underlying neurodegeneration and for characterizing the molecular heterogeneity of disease manifestations, also enabling drug screening approaches for new therapeutic candidates. A major challenge is related to the choice and optimization of the morpho-functional study designs in human iPSC-derived neurons to deeply detail the cell phenotypes as markers of neurodegeneration. In recent years, the specific combination of high-throughput screening with subcellular resolution microscopy for cell-based high-content imaging (HCI) screening allowed in-depth analyses of cell morphology and neurite trafficking in iPSC-derived neuronal cells by using specific cutting-edge microscopes and automated computational assays. The present work aims to describe the main recent protocols and advances achieved with the HCI analysis in iPSC-based modelling of neurodegenerative diseases, highlighting technical and bioinformatics tips and tricks for further uses and research. To this end, microscopy requirements and the latest computational pipelines to analyze imaging data will be explored, while also providing an overview of the available open-source high-throughput automated platforms. Full article

(This article belongs to the Special Issue Stem Cells in Health and Disease)

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22 pages, 3066 KiB

Open AccessReview

Molecules Inducing Dental Stem Cells Differentiation and Bone Regeneration: State of the Art

by Anastasia Ariano, Francesca Posa, Giuseppina Storlino and Giorgio Mori

Int. J. Mol. Sci. 2023, 24(12), 9897; https://doi.org/10.3390/ijms24129897 - 8 Jun 2023

Cited by 6 | Viewed by 1922

Abstract

Teeth include mesenchymal stem cells (MSCs), which are multipotent cells that promote tooth growth and repair. Dental tissues, specifically the dental pulp and the dental bud, constitute a relevant source of multipotent stem cells, known as dental-derived stem cells (d-DSCs): dental pulp stem cells (DPSCs) and dental bud stem cells (DBSCs). Cell treatment with bone-associated factors and stimulation with small molecule compounds are, among the available methods, the ones who show excellent advantages promoting stem cell differentiation and osteogenesis. Recently, attention has been paid to studies on natural and non-natural compounds. Many fruits, vegetables, and some drugs contain molecules that can enhance MSC osteogenic differentiation and therefore bone formation. The purpose of this review is to examine research work over the past 10 years that has investigated two different types of MSCs from dental tissues that are attractive targets for bone tissue engineering: DPSCs and DBSCs. The reconstruction of bone defects, in fact, is still a challenge and therefore more research is needed; the articles reviewed are meant to identify compounds useful to stimulate d-DSC proliferation and osteogenic differentiation. We only consider the results of the research which is encouraging, assuming that the mentioned compounds are of some importance for bone regeneration. Full article

(This article belongs to the Special Issue Stem Cells in Health and Disease)

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14 pages, 969 KiB

Open AccessReview

The Current State of Osteoarthritis Treatment Options Using Stem Cells for Regenerative Therapy: A Review

by Michael Thoene, Ewa Bejer-Olenska and Joanna Wojtkiewicz

Int. J. Mol. Sci. 2023, 24(10), 8925; https://doi.org/10.3390/ijms24108925 - 18 May 2023

Cited by 4 | Viewed by 2879

Abstract

Articular cartilage has very low metabolic activity. While minor injuries may be spontaneously repaired within the joint by chondrocytes, there is very little chance of a severely impaired joint regenerating itself when damaged. Therefore, any significant joint injury has little chance of spontaneously healing without some type of therapy. This article is a review that will examine the causes of osteoarthritis, both acute and chronic, and how it may be treated using traditional methods as well as with the latest stem cell technology. The latest regenerative therapy is discussed, including the use and potential risks of mesenchymal stem cells for tissue regeneration and implantation. Applications are then discussed for the treatment of OA in humans after using canine animal models. Since the most successful research models of OA were dogs, the first applications for treatment were veterinary. However, the treatment options have now advanced to the point where patients suffering from osteoarthritis may be treated with this technology. A survey of the literature was performed in order to determine the current state of stem cell technology being used in the treatment of osteoarthritis. Then, the stem cell technology was compared with traditional treatment options. Full article

(This article belongs to the Special Issue Stem Cells in Health and Disease)

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17 pages, 1824 KiB

Open AccessReview

Molecular Mechanisms Underlying Pluripotency and Self-Renewal of Embryonic Stem Cells

by Fahimeh Varzideh, Jessica Gambardella, Urna Kansakar, Stanislovas S. Jankauskas and Gaetano Santulli

Int. J. Mol. Sci. 2023, 24(9), 8386; https://doi.org/10.3390/ijms24098386 - 7 May 2023

Cited by 9 | Viewed by 3382

Abstract

Embryonic stem cells (ESCs) are derived from the inner cell mass (ICM) of the blastocyst. ESCs have two distinctive properties: ability to proliferate indefinitely, a feature referred as “self-renewal”, and to differentiate into different cell types, a peculiar characteristic known as “pluripotency”. Self-renewal and pluripotency of ESCs are finely orchestrated by precise external and internal networks including epigenetic modifications, transcription factors, signaling pathways, and histone modifications. In this systematic review, we examine the main molecular mechanisms that sustain self-renewal and pluripotency in both murine and human ESCs. Moreover, we discuss the latest literature on human naïve pluripotency. Full article

(This article belongs to the Special Issue Stem Cells in Health and Disease)

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13 pages, 1049 KiB

Open AccessReview

Stem Cells in Kidney Ischemia: From Inflammation and Fibrosis to Renal Tissue Regeneration

by Rosario Cianci, Mariadelina Simeoni, Eleonora Cianci, Oriana De Marco, Antonio Pisani, Claudio Ferri and Antonietta Gigante

Int. J. Mol. Sci. 2023, 24(5), 4631; https://doi.org/10.3390/ijms24054631 - 27 Feb 2023

Cited by 5 | Viewed by 2387

Abstract

Ischemic nephropathy consists of progressive renal function loss due to renal hypoxia, inflammation, microvascular rarefaction, and fibrosis. We provide a literature review focused on kidney hypoperfusion-dependent inflammation and its influence on renal tissue’s ability to self-regenerate. Moreover, an overview of the advances in regenerative therapy with mesenchymal stem cell (MSC) infusion is provided. Based on our search, we can point out the following conclusions: 1. endovascular reperfusion is the gold-standard therapy for RAS, but its success mostly depends on treatment timeliness and a preserved downstream vascular bed; 2. anti-RAAS drugs, SGLT2 inhibitors, and/or anti-endothelin agents are especially recommended for patients with renal ischemia who are not eligible for endovascular reperfusion for slowing renal damage progression; 3. TGF-β, MCP-1, VEGF, and NGAL assays, along with BOLD MRI, should be extended in clinical practice and applied to a pre- and post-revascularization protocols; 4. MSC infusion appears effective in renal regeneration and could represent a revolutionary treatment for patients with fibrotic evolution of renal ischemia. Full article

(This article belongs to the Special Issue Stem Cells in Health and Disease)

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