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Stem Cells in Health and Disease 2.0

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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: 20 May 2024 | Viewed by 10149

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Dr. Francesca Agriesti

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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
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Dr. Anne Marie Galow

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Research Institute for Livestock Biology (FBN), Institute of Genome Biology, 18196 Dummerstorf, Germany
Interests: stem cell; functional genomic analysis

Special Issue Information

Dear Colleagues,

In recent years, our knowledge about the dual role of stem cells in health and disease has significantly increased. 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 that cannot yet be 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 their 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
Dr. Anne Marie Galow
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

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Stem Cells in Health and Disease in International Journal of Molecular Sciences (12 articles)

Published Papers (10 papers)

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Research

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20 pages, 3155 KiB

Open AccessArticle

In Vitro Modelling of Osteogenesis Imperfecta with Patient-Derived Induced Mesenchymal Stem Cells

by Lauria Claeys, Lidiia Zhytnik, Laura Ventura, Lisanne E. Wisse, Elisabeth M. W. Eekhoff, Gerard Pals, Nathalie Bravenboer, Vivi M. Heine and Dimitra Micha

Int. J. Mol. Sci. 2024, 25(6), 3417; https://doi.org/10.3390/ijms25063417 - 18 Mar 2024

Viewed by 669

Abstract

(1) Mesenchymal stem cells (MSCs) are a valuable cell model to study the bone pathology of Osteogenesis Imperfecta (OI), a rare genetic collagen-related disorder characterized by bone fragility and skeletal dysplasia. We aimed to generate a novel OI induced mesenchymal stem cell (iMSC) model from induced pluripotent stem cells (iPSCs) derived from human dermal fibroblasts. For the first time, OI iMSCs generation was based on an intermediate neural crest cell (iNCC) stage. (2) Skin fibroblasts from healthy individuals and OI patients were reprogrammed into iPSCs and subsequently differentiated into iMSCs via iNCCs. (3) Successful generation of iPSCs from acquired fibroblasts was confirmed with changes in cell morphology, expression of iPSC markers SOX2, NANOG, and OCT4 and three germ-layer tests. Following differentiation into iNCCs, cells presented increased iNCC markers including P75NTR, TFAP2A, and HNK-1 and decreased iPSC markers, shown to reach the iNCC stage. Induction into iMSCs was confirmed by the presence of CD73, CD105, and CD90 markers, low expression of the hematopoietic, and reduced expression of the iNCC markers. iMSCs were trilineage differentiation-competent, confirmed using molecular analyses and staining for cell-type-specific osteoblast, adipocyte, and chondrocyte markers. (4) In the current study, we have developed a multipotent in vitro iMSC model of OI patients and healthy controls able to differentiate into osteoblast-like cells. Full article

(This article belongs to the Special Issue Stem Cells in Health and Disease 2.0)

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19 pages, 1766 KiB

Open AccessArticle

Dachshund Homolog 1: Unveiling Its Potential Role in Megakaryopoiesis and Bacillus anthracis Lethal Toxin-Induced Thrombocytopenia

by Guan-Ling Lin, Hsin-Hou Chang, Wei-Ting Lin, Yu-Shan Liou, Yi-Ling Lai, Min-Hua Hsieh, Po-Kong Chen, Chi-Yuan Liao, Chi-Chih Tsai, Tso-Fu Wang, Sung-Chao Chu, Jyh-Hwa Kau, Hsin-Hsien Huang, Hui-Ling Hsu and Der-Shan Sun

Int. J. Mol. Sci. 2024, 25(6), 3102; https://doi.org/10.3390/ijms25063102 - 07 Mar 2024

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Abstract

Lethal toxin (LT) is the critical virulence factor of Bacillus anthracis, the causative agent of anthrax. One common symptom observed in patients with anthrax is thrombocytopenia, which has also been observed in mice injected with LT. Our previous study demonstrated that LT induces thrombocytopenia by suppressing megakaryopoiesis, but the precise molecular mechanisms behind this phenomenon remain unknown. In this study, we utilized 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced megakaryocytic differentiation in human erythroleukemia (HEL) cells to identify genes involved in LT-induced megakaryocytic suppression. Through cDNA microarray analysis, we identified Dachshund homolog 1 (DACH1) as a gene that was upregulated upon TPA treatment but downregulated in the presence of TPA and LT, purified from the culture supernatants of B. anthracis. To investigate the function of DACH1 in megakaryocytic differentiation, we employed short hairpin RNA technology to knock down DACH1 expression in HEL cells and assessed its effect on differentiation. Our data revealed that the knockdown of DACH1 expression suppressed megakaryocytic differentiation, particularly in polyploidization. We demonstrated that one mechanism by which B. anthracis LT induces suppression of polyploidization in HEL cells is through the cleavage of MEK1/2. This cleavage results in the downregulation of the ERK signaling pathway, thereby suppressing DACH1 gene expression and inhibiting polyploidization. Additionally, we found that known megakaryopoiesis-related genes, such as FOSB, ZFP36L1, RUNX1, FLI1, AHR, and GFI1B genes may be positively regulated by DACH1. Furthermore, we observed an upregulation of DACH1 during in vitro differentiation of CD34–megakaryocytes and downregulation of DACH1 in patients with thrombocytopenia. In summary, our findings shed light on one of the molecular mechanisms behind LT-induced thrombocytopenia and unveil a previously unknown role for DACH1 in megakaryopoiesis. Full article

(This article belongs to the Special Issue Stem Cells in Health and Disease 2.0)

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16 pages, 2940 KiB

Open AccessArticle

Characterisation and Expression of Osteogenic and Periodontal Markers of Bone Marrow Mesenchymal Stem Cells (BM-MSCs) from Diabetic Knee Joints

by Nancy Hussein, Josephine Meade, Hemant Pandit, Elena Jones and Reem El-Gendy

Int. J. Mol. Sci. 2024, 25(5), 2851; https://doi.org/10.3390/ijms25052851 - 01 Mar 2024

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Abstract

Type 2 diabetes mellitus (T2DM) represents a significant health problem globally and is linked to a number of complications such as cardiovascular disease, bone fragility and periodontitis. Autologous bone marrow mesenchymal stem cells (BM-MSCs) are a promising therapeutic approach for bone and periodontal regeneration; however, the effect of T2DM on the expression of osteogenic and periodontal markers in BM-MSCs is not fully established. Furthermore, the effect of the presence of comorbidities such as diabetes and osteoarthritis on BM-MSCs is also yet to be investigated. In the present study, BM-MSCs were isolated from osteoarthritic knee joints of diabetic and nondiabetic donors. Both cell groups were compared for their clonogenicity, proliferation rates, MSC enumeration and expression of surface markers. Formation of calcified deposits and expression of osteogenic and periodontal markers were assessed after 1, 2 and 3 weeks of basal and osteogenic culture. Diabetic and nondiabetic BM-MSCs showed similar clonogenic and growth potentials along with comparable numbers of MSCs. However, diabetic BM-MSCs displayed lower expression of periostin (POSTN) and cementum protein 1 (CEMP-1) at Wk3 osteogenic and Wk1 basal cultures, respectively. BM-MSCs from T2DM patients might be suitable candidates for stem cell-based therapeutics. However, further investigations into these cells’ behaviours in vitro and in vivo under inflammatory environments and hyperglycaemic conditions are still required. Full article

(This article belongs to the Special Issue Stem Cells in Health and Disease 2.0)

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12 pages, 6198 KiB

Open AccessArticle

Combined Use of Tocilizumab and Mesenchymal Stem Cells Attenuate the Development of an Anti-HLA-A2.1 Antibody in a Highly Sensitized Mouse Model

by Xianying Fang, Sheng Cui, Hanbi Lee, Ji Won Min, Sun Woo Lim, Eun-Jee Oh, Chul Woo Yang, Yoo Jin Shin and Byung Ha Chung

Int. J. Mol. Sci. 2024, 25(3), 1378; https://doi.org/10.3390/ijms25031378 - 23 Jan 2024

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Abstract

Sensitization to HLA can result in allograft loss for kidney transplantation (KT) patients. Therefore, it is required to develop an appropriate desensitization (DSZ) technique to remove HLA-donor-specific anti-HLA antibody (DSA) before KT. The aim of this research was to investigate whether combined use of the IL-6 receptor-blocking antibody, tocilizumab (TCZ), and bone-marrow-derived mesenchymal stem cells (BM-MSCs) could attenuate humoral immune responses in an allo-sensitized mouse model developed using HLA.A2 transgenic mice. Wild-type C57BL/6 mice were sensitized with skin allografts from C57BL/6-Tg (HLA-A2.1)1Enge/J mice and treated with TCZ, BM-MSC, or both TCZ and BM-MSC. We compared HLA.A2-specific IgG levels and subsets of T cells and B cells using flow cytometry among groups. HLA.A2-specific IgG level was decreased in all treated groups in comparison with that in the allo-sensitized control (Allo-CONT) group. Its decrease was the most significant in the TCZ + BM-MSC group. Regarding the B cell subset, combined use of TCZ and BM-MSC increased proportions of pre-pro B cells but decreased proportions of mature B cells in BM (p < 0.05 vs. control). In the spleen, an increase in transitional memory was observed with a significant decrease in marginal, follicular, and long-lived plasma B cells (p < 0.05 vs. control) in the TCZ + BM-MSC group. In T cell subsets, Th2 and Th17 cells were significantly decreased, but Treg cells were significantly increased in the TCZ+BM-MSC group compared to those in the Allo-CONT group in the spleen. Regarding RNA levels, IL-10 and Foxp3 showed increased expression, whereas IL-23 and IFN-γ showed decreased expression in the TCZ + BM-MSC group. In conclusion, combined use of TCZ and BM-MSC can inhibit B cell maturation and up-regulate Treg cells, finally resulting in the reduction of HLA.A2-specific IgG in a highly sensitized mouse model. This study suggests that the combined use of TCZ and BM-MSC can be proposed as a novel strategy in a desensitization protocol for highly sensitized patients. Full article

(This article belongs to the Special Issue Stem Cells in Health and Disease 2.0)

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Review

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30 pages, 2470 KiB

Open AccessReview

The Role of Stem Cells in the Treatment of Cardiovascular Diseases

by Estera Bakinowska, Kajetan Kiełbowski, Dominika Boboryko, Aleksandra Wiktoria Bratborska, Joanna Olejnik-Wojciechowska, Marcin Rusiński and Andrzej Pawlik

Int. J. Mol. Sci. 2024, 25(7), 3901; https://doi.org/10.3390/ijms25073901 - 31 Mar 2024

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Abstract

Cardiovascular diseases (CVDs) are the leading cause of death and include several vascular and cardiac disorders, such as atherosclerosis, coronary artery disease, cardiomyopathies, and heart failure. Multiple treatment strategies exist for CVDs, but there is a need for regenerative treatment of damaged heart. Stem cells are a broad variety of cells with a great differentiation potential that have regenerative and immunomodulatory properties. Multiple studies have evaluated the efficacy of stem cells in CVDs, such as mesenchymal stem cells and induced pluripotent stem cell-derived cardiomyocytes. These studies have demonstrated that stem cells can improve the left ventricle ejection fraction, reduce fibrosis, and decrease infarct size. Other studies have investigated potential methods to improve the survival, engraftment, and functionality of stem cells in the treatment of CVDs. The aim of the present review is to summarize the current evidence on the role of stem cells in the treatment of CVDs, and how to improve their efficacy. Full article

(This article belongs to the Special Issue Stem Cells in Health and Disease 2.0)

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38 pages, 2706 KiB

Open AccessReview

Pluripotent Stem Cells as a Preclinical Cellular Model for Studying Hereditary Spastic Paraplegias

by Devid Damiani, Matteo Baggiani, Stefania Della Vecchia, Valentina Naef and Filippo Maria Santorelli

Int. J. Mol. Sci. 2024, 25(5), 2615; https://doi.org/10.3390/ijms25052615 - 23 Feb 2024

Viewed by 763

Abstract

Hereditary spastic paraplegias (HSPs) comprise a family of degenerative diseases mostly hitting descending axons of corticospinal neurons. Depending on the gene and mutation involved, the disease could present as a pure form with limb spasticity, or a complex form associated with cerebellar and/or cortical signs such as ataxia, dysarthria, epilepsy, and intellectual disability. The progressive nature of HSPs invariably leads patients to require walking canes or wheelchairs over time. Despite several attempts to ameliorate the life quality of patients that have been tested, current therapeutical approaches are just symptomatic, as no cure is available. Progress in research in the last two decades has identified a vast number of genes involved in HSP etiology, using cellular and animal models generated on purpose. Although unanimously considered invaluable tools for basic research, those systems are rarely predictive for the establishment of a therapeutic approach. The advent of induced pluripotent stem (iPS) cells allowed instead the direct study of morphological and molecular properties of the patient’s affected neurons generated upon in vitro differentiation. In this review, we revisited all the present literature recently published regarding the use of iPS cells to differentiate HSP patient-specific neurons. Most studies have defined patient-derived neurons as a reliable model to faithfully mimic HSP in vitro, discovering original findings through immunological and –omics approaches, and providing a platform to screen novel or repurposed drugs. Thereby, one of the biggest hopes of current HSP research regards the use of patient-derived iPS cells to expand basic knowledge on the disease, while simultaneously establishing new therapeutic treatments for both generalized and personalized approaches in daily medical practice. Full article

(This article belongs to the Special Issue Stem Cells in Health and Disease 2.0)

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21 pages, 1910 KiB

Open AccessReview

Induced Pluripotent Stem Cells in Drug Discovery and Neurodegenerative Disease Modelling

by Daniela Gois Beghini, Tais Hanae Kasai-Brunswick and Andrea Henriques-Pons

Int. J. Mol. Sci. 2024, 25(4), 2392; https://doi.org/10.3390/ijms25042392 - 18 Feb 2024

Viewed by 1228

Abstract

Induced pluripotent stem cells (iPSCs) are derived from reprogrammed adult somatic cells. These adult cells are manipulated in vitro to express genes and factors essential for acquiring and maintaining embryonic stem cell (ESC) properties. This technology is widely applied in many fields, and much attention has been given to developing iPSC-based disease models to validate drug discovery platforms and study the pathophysiological molecular processes underlying disease onset. Especially in neurological diseases, there is a great need for iPSC-based technological research, as these cells can be obtained from each patient and carry the individual’s bulk of genetic mutations and unique properties. Moreover, iPSCs can differentiate into multiple cell types. These are essential characteristics, since the study of neurological diseases is affected by the limited access to injury sites, the need for in vitro models composed of various cell types, the complexity of reproducing the brain’s anatomy, the challenges of postmortem cell culture, and ethical issues. Neurodegenerative diseases strongly impact global health due to their high incidence, symptom severity, and lack of effective therapies. Recently, analyses using disease specific, iPSC-based models confirmed the efficacy of these models for testing multiple drugs. This review summarizes the advances in iPSC technology used in disease modelling and drug testing, with a primary focus on neurodegenerative diseases, including Parkinson’s and Alzheimer’s diseases. Full article

(This article belongs to the Special Issue Stem Cells in Health and Disease 2.0)

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21 pages, 8354 KiB

Open AccessReview

“Time Is out of Joint” in Pluripotent Stem Cells: How and Why

by Francesca Agriesti, Olga Cela and Nazzareno Capitanio

Int. J. Mol. Sci. 2024, 25(4), 2063; https://doi.org/10.3390/ijms25042063 - 08 Feb 2024

Viewed by 1046

Abstract

The circadian rhythm is necessary for the homeostasis and health of living organisms. Molecular clocks interconnected by transcription/translation feedback loops exist in most cells of the body. A puzzling exemption to this, otherwise, general biological hallmark is given by the cell physiology of pluripotent stem cells (PSCs) that lack circadian oscillations gradually acquired following their in vivo programmed differentiation. This process can be nicely phenocopied following in vitro commitment and reversed during the reprogramming of somatic cells to induce PSCs. The current understanding of how and why pluripotency is “time-uncoupled” is largely incomplete. A complex picture is emerging where the circadian core clockwork is negatively regulated in PSCs at the post-transcriptional/translational, epigenetic, and other-clock-interaction levels. Moreover, non-canonical functions of circadian core-work components in the balance between pluripotency identity and metabolic-driven cell reprogramming are emerging. This review selects and discusses results of relevant recent investigations providing major insights into this context. Full article

(This article belongs to the Special Issue Stem Cells in Health and Disease 2.0)

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13 pages, 1410 KiB

Open AccessReview

The Concept behind the Suitability of Menstrual Blood-Derived Stem Cells for the Management of Vaginal Atrophy among BRCA Mutation Carriers after RRSO

by Mariana Robalo Cordeiro, Bárbara Laranjeiro and Margarida Figueiredo-Dias

Int. J. Mol. Sci. 2024, 25(2), 1025; https://doi.org/10.3390/ijms25021025 - 14 Jan 2024

Viewed by 1085

Abstract

Risk-reducing bilateral salpingo-oophorectomy (RRSO) is recommended for breast cancer gene 1 (BRCA1) and 2 (BRCA2) mutation carriers. A major consequence of RRSO is surgical menopause associated with severe menopausal symptoms, mostly genitourinary complaints. Due to the inherent breast cancer risk, estrogen-based therapies are generally avoided in these patients. So far, the non-hormonal approaches available are not efficient to successfully treat the disabling vaginal atrophy-related symptoms. In regenerative medicine, mesenchymal stem cells (MSC) are the most frequently used cell type due to their remarkable and regenerative characteristics. Therapies based on MSC have revealed positive outcomes regarding symptoms and signs associated with vaginal atrophy by promoting angiogenesis, vaginal restoration, and the proliferation of vaginal mucosa cells. Menstrual blood-derived stem cells (MenSC) are a novel source of MSC, with promising therapeutic potential directly linked to their high proliferative rates; low immunogenicity; non-invasive, easy, and periodic acquisition; and almost no associated ethical issues. In this review, we update the current knowledge and research regarding the potential value of previously preserved MenSC in the therapy of vaginal atrophy among BRCA mutation carriers subjected to RRSO. Full article

(This article belongs to the Special Issue Stem Cells in Health and Disease 2.0)

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43 pages, 1664 KiB

Open AccessReview

Perinatal Tissue-Derived Stem Cells: An Emerging Therapeutic Strategy for Challenging Neurodegenerative Diseases

by Annalisa Bruno, Cristina Milillo, Federico Anaclerio, Carlotta Buccolini, Anastasia Dell’Elice, Ilaria Angilletta, Marco Gatta, Patrizia Ballerini and Ivana Antonucci

Int. J. Mol. Sci. 2024, 25(2), 976; https://doi.org/10.3390/ijms25020976 - 12 Jan 2024

Viewed by 1411

Abstract

Over the past 20 years, stem cell therapy has been considered a promising option for treating numerous disorders, in particular, neurodegenerative disorders. Stem cells exert neuroprotective and neurodegenerative benefits through different mechanisms, such as the secretion of neurotrophic factors, cell replacement, the activation of endogenous stem cells, and decreased neuroinflammation. Several sources of stem cells have been proposed for transplantation and the restoration of damaged tissue. Over recent decades, intensive research has focused on gestational stem cells considered a novel resource for cell transplantation therapy. The present review provides an update on the recent preclinical/clinical applications of gestational stem cells for the treatment of protein-misfolding diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS). However, further studies should be encouraged to translate this promising therapeutic approach into the clinical setting. Full article

(This article belongs to the Special Issue Stem Cells in Health and Disease 2.0)

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