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Mesenchymal 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 January 2022) | Viewed by 52625

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Prof. Dr. Vladislav Volarevic

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Faculty of Medical Sciences, Department for Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research, University of Kragujevac, Kragujevac, Serbia
Interests: Mesenchymal stem cells; T lymphocytes; flow cytometry; immunity; immunology of infectious diseases; immunomodulation; molecular immunology; inflammation
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Dear Colleagues,

Mesenchymal stem cells (MSCs) are self-renewable, adult stem cells that reside in almost all postnatal tissue and organs, where they regulate homeostasis and promote the repair and regeneration of injured tissues. Damage-associated molecular patterns and alarmins, released from injured cells, induce the activation of MSCs, which, in turn, prevent the apoptosis of uninjured parenchymal cells and stimulate their survival and proliferation. MSCs suppress the effector functions of inflammatory neutrophils, monocytes, T lymphocytes, and natural killer (NK) and natural killer T (NKT) cells and promote the generation and expansion of immunosuppressive T regulatory cells (Tregs), leading to the alleviation of ongoing inflammation. Additionally, MSCs induce neoangiogenesis and promote the homing of alternatively activated macrophages and tolerogenic dendritic cells (DCs) to the inflamed tissues, where these immunoregulatory cells enhance the endogenous healing process.

MSC-derived extracellular vesicles (MSC-EVs) have shown beneficial therapeutic effects similar to those observed after the transplantation of their parental cells. MSC-EVs, distributed via biological fluids, can easily penetrate through the tissues and reach the target cells (even distant ones), enabling both paracrine and endocrine effects. MSC-EVs rapidly diffuse throughout the tissue, successfully delivering trophic and immunomodulatory factors that results in the attenuation of tissue injury and inflammation.

Therefore, due to their immunosuppressive and regenerative properties, MSCs and their EVs have been considered as potentially new therapeutic agents in the treatment of inflammatory and degenerative diseases.

This Special Issue calls for original research and review articles that may provide novel insights regarding the molecular and cellular mechanisms that are responsible for MSC-based effects and also current knowledge and future perspectives regarding the therapeutic application of MSCs and MSC-EVs in experimental and clinical settings.

Prof. Dr. Vladislav Volarevic
Guest Editor

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Related Special Issue

Mesenchymal Stem Cells in Health and Disease 3.0 in International Journal of Molecular Sciences

Published Papers (11 papers)

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Research

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15 pages, 2974 KiB

Open AccessArticle

Store-Operated Ca²⁺ Entry Contributes to Piezo1-Induced Ca²⁺ Increase in Human Endometrial Stem Cells

by Vladislav Chubinskiy-Nadezhdin, Svetlana Semenova, Valeria Vasileva, Alla Shatrova, Natalia Pugovkina and Yuri Negulyaev

Int. J. Mol. Sci. 2022, 23(7), 3763; https://doi.org/10.3390/ijms23073763 - 29 Mar 2022

Cited by 11 | Viewed by 2761

Abstract

Endometrial mesenchymal stem cells (eMSCs) are a specific class of stromal cells which have the capability to migrate, develop and differentiate into different types of cells such as adipocytes, osteocytes or chondrocytes. It is this unique plasticity that makes the eMSCs significant for cellular therapy and regenerative medicine. Stem cells choose their way of development by analyzing the extracellular and intracellular signals generated by a mechanical force from the microenvironment. Mechanosensitive channels are part of the cellular toolkit that feels the mechanical environment and can transduce mechanical stimuli to intracellular signaling pathways. Here, we identify previously recorded, mechanosensitive (MS), stretch-activated channels as Piezo1 proteins in the plasma membrane of eMSCs. Piezo1 activity triggered by the channel agonist Yoda1 elicits influx of Ca²⁺, a known modulator of cytoskeleton reorganization and cell motility. We found that store-operated Ca²⁺ entry (SOCE) formed by Ca²⁺-selective channel ORAI1 and Ca²⁺ sensors STIM1/STIM2 contributes to Piezo1-induced Ca²⁺ influx in eMSCs. Particularly, the Yoda1-induced increase in intracellular Ca²⁺ ([Ca²⁺]_i) is partially abolished by 2-APB, a well-known inhibitor of SOCE. Flow cytometry analysis and wound healing assay showed that long-term activation of Piezo1 or SOCE does not have a cytotoxic effect on eMSCs but suppresses their migratory capacity and the rate of cell proliferation. We propose that the Piezo1 and SOCE are both important determinants in [Ca²⁺]_i regulation, which critically affects the migratory activity of eMSCs and, therefore, could influence the regenerative potential of these cells. Full article

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

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17 pages, 3508 KiB

Open AccessArticle

Generation of Mesenchymal Cell Lines Derived from Aged Donors

by María Piñeiro-Ramil, Clara Sanjurjo-Rodríguez, Silvia Rodríguez-Fernández, Rocío Castro-Viñuelas, Tamara Hermida-Gómez, Francisco J. Blanco-García, Isaac Fuentes-Boquete and Silvia Díaz-Prado

Int. J. Mol. Sci. 2021, 22(19), 10667; https://doi.org/10.3390/ijms221910667 - 01 Oct 2021

Cited by 6 | Viewed by 2414

Abstract

Background: Mesenchymal stromal cells (MSCs) have the capacity for self-renewal and multi-differentiation, and for this reason they are considered a potential cellular source in regenerative medicine of cartilage and bone. However, research on this field is impaired by the predisposition of primary MSCs to senescence during culture expansion. Therefore, the aim of this study was to generate and characterize immortalized MSC (iMSC) lines from aged donors. Methods: Primary MSCs were immortalized by transduction of simian virus 40 large T antigen (SV40LT) and human telomerase reverse transcriptase (hTERT). Proliferation, senescence, phenotype and multi-differentiation potential of the resulting iMSC lines were analyzed. Results: MSCs proliferate faster than primary MSCs, overcome senescence and are phenotypically similar to primary MSCs. Nevertheless, their multi-differentiation potential is unbalanced towards the osteogenic lineage. There are no clear differences between osteoarthritis (OA) and non-OA iMSCs in terms of proliferation, senescence, phenotype or differentiation potential. Conclusions: Primary MSCs obtained from elderly patients can be immortalized by transduction of SV40LT and hTERT. The high osteogenic potential of iMSCs converts them into an excellent cellular source to take part in in vitro models to study bone tissue engineering. Full article

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

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11 pages, 2211 KiB

Open AccessArticle

Alteration of 3D Matrix Stiffness Regulates Viscoelasticity of Human Mesenchymal Stem Cells

by Ting-Wei Kao, Arthur Chiou, Keng-Hui Lin, Yi-Shiuan Liu and Oscar Kuang-Sheng Lee

Int. J. Mol. Sci. 2021, 22(5), 2441; https://doi.org/10.3390/ijms22052441 - 28 Feb 2021

Cited by 5 | Viewed by 2310

Abstract

Human mesenchymal stem cells (hMSCs) possess potential of bone formation and were proposed as ideal material against osteoporosis. Although interrogation of directing effect on lineage specification by physical cues has been proposed, how mechanical stimulation impacts intracellular viscoelasticity during osteogenesis remained enigmatic. Cyto-friendly 3D matrix was prepared with polyacrylamide and conjugated fibronectin. The hMSCs were injected with fluorescent beads and chemically-induced toward osteogenesis. The mechanical properties were assessed using video particle tracking microrheology. Inverted epifluorescence microscope was exploited to capture the Brownian trajectory of hMSCs. Mean square displacement was calculated and transformed into intracellular viscoelasticity. Two different stiffness of microspheres (12 kPa, 1 kPa) were established. A total of 45 cells were assessed. hMSCs possessed equivalent mechanical traits initially in the first week, while cells cultured in rigid matrix displayed significant elevation over elastic (G′) and viscous moduli (G″) on day 7 (p < 0.01) and 14 (p < 0.01). However, after two weeks, soft niches no longer stiffened hMSCs, whereas the effect by rigid substrates was consistently during the entire differentiation course. Stiffness of matrix impacted the viscoelasticity of hMSCs. Detailed recognition of how microenvironment impacts mechanical properties and differentiation of hMSCs will facilitate the advancement of tissue engineering and regenerative medicine. Full article

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

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11 pages, 5688 KiB

Open AccessCommunication

Deficit in Adipose Differentiation in Mesenchymal Stem Cells Derived from Chronic Rhinosinusitis Nasal Polyps Compared to Nasal Mucosal Tissue

by Emanuela Chiarella, Nicola Lombardo, Nadia Lobello, Giovanna Lucia Piazzetta, Helen Linda Morrone, Maria Mesuraca and Heather Mandy Bond

Int. J. Mol. Sci. 2020, 21(23), 9214; https://doi.org/10.3390/ijms21239214 - 03 Dec 2020

Cited by 15 | Viewed by 2297

Abstract

Chronic rhinosinusitis of the nasal mucosa is an inflammatory disease of paranasal sinuses, which causes rhinorrhea, nasal congestion, and hyposmia, and in some cases, it can result in the development of nasal polyposis. Nasal polyps are benign lobular-shaped growths that project in the nasal cavities; they originate from inflammation in the paranasal mucous membrane and are associated with a high expression of interleukins (IL)-4, IL-5, IL-13, and IgE. Polyps derive from the epithelial–mesenchymal transition of the nasal epithelium resulting in a nasal tissue remodeling. Nasal polyps from three patients with chronic rhinosinusitis as well as control non-polyp nasal mucosa were used to isolate and cultivate mesenchymal stem cells characterized as CD73⁺, CD90⁺, CD105⁺/CD14⁻, CD34⁻, and CD45⁻. Mesenchymal stem cells (MSCs) cultures were induced to differentiate toward adipocytes, where lipid droplets and adipocyte genes PPARγ2, ADIPO-Q, and FABP4 were observed in control non-polyp nasal mucosa-derived mesenchymal cells but were scarcely present in the cultures derived from the nasal polyps, where apoptosis was evident. The modulation of the response to adipogenic stimulus in polyps represents a change in the molecular response that controls the cascade required for differentiation as well as possible means to specifically target these cells, sparing the normal mucosa of the nasal sinuses. Full article

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

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Review

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21 pages, 3044 KiB

Open AccessReview

Stem Cell Therapy: From Idea to Clinical Practice

by Mohammad Mousaei Ghasroldasht, Jin Seok, Hang-Soo Park, Farzana Begum Liakath Ali and Ayman Al-Hendy

Int. J. Mol. Sci. 2022, 23(5), 2850; https://doi.org/10.3390/ijms23052850 - 05 Mar 2022

Cited by 47 | Viewed by 13273

Abstract

Regenerative medicine is a new and promising mode of therapy for patients who have limited or no other options for the treatment of their illness. Due to their pleotropic therapeutic potential through the inhibition of inflammation or apoptosis, cell recruitment, stimulation of angiogenesis, and differentiation, stem cells present a novel and effective approach to several challenging human diseases. In recent years, encouraging findings in preclinical studies have paved the way for many clinical trials using stem cells for the treatment of various diseases. The translation of these new therapeutic products from the laboratory to the market is conducted under highly defined regulations and directives provided by competent regulatory authorities. This review seeks to familiarize the reader with the process of translation from an idea to clinical practice, in the context of stem cell products. We address some required guidelines for clinical trial approval, including regulations and directives presented by the Food and Drug Administration (FDA) of the United States, as well as those of the European Medicine Agency (EMA). Moreover, we review, summarize, and discuss regenerative medicine clinical trial studies registered on the Clinicaltrials.gov website. Full article

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

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18 pages, 2041 KiB

Open AccessReview

MSCs as Tumor-Specific Vectors for the Delivery of Anticancer Agents—A Potential Therapeutic Strategy in Cancer Diseases: Perspectives for Quinazoline Derivatives

by Monika Szewc, Elżbieta Radzikowska-Bűchner, Paulina Wdowiak, Joanna Kozak, Piotr Kuszta, Ewa Niezabitowska, Joanna Matysiak, Konrad Kubiński and Maciej Masłyk

Int. J. Mol. Sci. 2022, 23(5), 2745; https://doi.org/10.3390/ijms23052745 - 02 Mar 2022

Cited by 5 | Viewed by 2645

Abstract

Mesenchymal stem cells (MSCs) are considered to be a powerful tool in the treatment of various diseases. Scientists are particularly interested in the possibility of using MSCs in cancer therapy. The research carried out so far has shown that MSCs possess both potential pro-oncogenic and anti-oncogenic properties. It has been confirmed that MSCs can regulate tumor cell growth through a paracrine mechanism, and molecules secreted by MSCs can promote or block a variety of signaling pathways. These findings may be crucial in the development of new MSC-based cell therapeutic strategies. The abilities of MSCs such as tumor tropism, deep migration and immune evasion have evoked considerable interest in their use as tumor-specific vectors for small-molecule anticancer agents. Studies have shown that MSCs can be successfully loaded with chemotherapeutic drugs such as gemcitabine and paclitaxel, and can release them at the site of primary and metastatic neoplasms. The inhibitory effect of MSCs loaded with anti-cancer agents on the proliferation of cancer cells has also been observed. However, not all known chemotherapeutic agents can be used in this approach, mainly due to their cytotoxicity towards MSCs and insufficient loading and release capacity. Quinazoline derivatives appear to be an attractive choice for this therapeutic solution due to their biological and pharmacological properties. There are several quinazolines that have been approved for clinical use as anticancer drugs by the US Food and Drug Administration (FDA). It gives hope that the synthesis of new quinazoline derivatives and the development of methods of their application may contribute to the establishment of highly effective therapies for oncological patients. However, a deeper understanding of interactions between MSCs and tumor cells, and the exploration of the possibilities of using quinazoline derivatives in MSC-based therapy is necessary to achieve this goal. The aim of this review is to discuss the prospects for using MSC-based cell therapy in cancer treatment and the potential use of quinazolines in this procedure. Full article

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

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12 pages, 1154 KiB

Open AccessReview

Mesenchymal Stem Cells: Therapeutic Mechanisms for Stroke

by Yuchen Zhang, Naijun Dong, Huanle Hong, Jingxuan Qi, Shibo Zhang and Jiao Wang

Int. J. Mol. Sci. 2022, 23(5), 2550; https://doi.org/10.3390/ijms23052550 - 25 Feb 2022

Cited by 16 | Viewed by 3664

Abstract

Due to aging of the world’s population, stroke has become increasingly prevalent, leading to a rise in socioeconomic burden. In the recent past, stroke research and treatment have become key scientific issues that need urgent solutions, with a sharp focus on stem cell transplantation, which is known to treat neurodegenerative diseases related to traumatic brain injuries, such as stroke. Indeed, stem cell therapy has brought hope to many stroke patients, both in animal and clinical trials. Mesenchymal stem cells (MSCs) are most commonly utilized in biological medical research, due to their pluripotency and universality. MSCs are often obtained from adipose tissue and bone marrow, and transplanted via intravenous injection. Therefore, this review will discuss the therapeutic mechanisms of MSCs and extracellular vehicles (EVs) secreted by MSCs for stroke, such as in attenuating inflammation through immunomodulation, releasing trophic factors to promote therapeutic effects, inducing angiogenesis, promoting neurogenesis, reducing the infarct volume, and replacing damaged cells. Full article

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

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12 pages, 1140 KiB

Open AccessReview

Mesenchymal Stem Cell: A Friend or Foe in Anti-Tumor Immunity

by Carl Randall Harrell, Ana Volarevic, Valentin G. Djonov, Nemanja Jovicic and Vladislav Volarevic

Int. J. Mol. Sci. 2021, 22(22), 12429; https://doi.org/10.3390/ijms222212429 - 18 Nov 2021

Cited by 26 | Viewed by 4199

Abstract

Mesenchymal stem cells (MSCs) are self-renewable, multipotent stem cells that regulate the phenotype and function of all immune cells that participate in anti-tumor immunity. MSCs modulate the antigen-presenting properties of dendritic cells, affect chemokine and cytokine production in macrophages and CD4+ T helper cells, alter the cytotoxicity of CD8+ T lymphocytes and natural killer cells and regulate the generation and expansion of myeloid-derived suppressor cells and T regulatory cells. As plastic cells, MSCs adopt their phenotype and function according to the cytokine profile of neighboring tumor-infiltrated immune cells. Depending on the tumor microenvironment to which they are exposed, MSCs may obtain pro- and anti-tumorigenic phenotypes and may enhance or suppress tumor growth. Due to their tumor-homing properties, MSCs and their exosomes may be used as vehicles for delivering anti-tumorigenic agents in tumor cells, attenuating their viability and invasive characteristics. Since many factors affect the phenotype and function of MSCs in the tumor microenvironment, a better understanding of signaling pathways that regulate the cross-talk between MSCs, immune cells and tumor cells will pave the way for the clinical use of MSCs in cancer immunotherapy. In this review article, we summarize current knowledge on the molecular and cellular mechanisms that are responsible for the MSC-dependent modulation of the anti-tumor immune response and we discuss different insights regarding therapeutic potential of MSCs in the therapy of malignant diseases. Full article

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

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27 pages, 8210 KiB

Open AccessReview

Mesenchymal Stem Cell-Based Therapy for Rheumatoid Arthritis

by Madina Sarsenova, Assel Issabekova, Saule Abisheva, Kristina Rutskaya-Moroshan, Vyacheslav Ogay and Arman Saparov

Int. J. Mol. Sci. 2021, 22(21), 11592; https://doi.org/10.3390/ijms222111592 - 27 Oct 2021

Cited by 36 | Viewed by 9206

Abstract

Mesenchymal stem cells (MSCs) have great potential to differentiate into various types of cells, including but not limited to, adipocytes, chondrocytes and osteoblasts. In addition to their progenitor characteristics, MSCs hold unique immunomodulatory properties that provide new opportunities in the treatment of autoimmune diseases, and can serve as a promising tool in stem cell-based therapy. Rheumatoid arthritis (RA) is a chronic systemic autoimmune disorder that deteriorates quality and function of the synovium membrane, resulting in chronic inflammation, pain and progressive cartilage and bone destruction. The mechanism of RA pathogenesis is associated with dysregulation of innate and adaptive immunity. Current conventional treatments by steroid drugs, antirheumatic drugs and biological agents are being applied in clinical practice. However, long-term use of these drugs causes side effects, and some RA patients may acquire resistance to these drugs. In this regard, recently investigated MSC-based therapy is considered as a promising approach in RA treatment. In this study, we review conventional and modern treatment approaches, such as MSC-based therapy through the understanding of the link between MSCs and the innate and adaptive immune systems. Moreover, we discuss recent achievements in preclinical and clinical studies as well as various strategies for the enhancement of MSC immunoregulatory properties. Full article

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

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16 pages, 630 KiB

Open AccessReview

Nasal Polyposis: Insights in Epithelial-Mesenchymal Transition and Differentiation of Polyp Mesenchymal Stem Cells

by Emanuela Chiarella, Nicola Lombardo, Nadia Lobello, Annamaria Aloisio, Teodoro Aragona, Corrado Pelaia, Stefania Scicchitano, Heather Mandy Bond and Maria Mesuraca

Int. J. Mol. Sci. 2020, 21(18), 6878; https://doi.org/10.3390/ijms21186878 - 19 Sep 2020

Cited by 25 | Viewed by 4666

Abstract

Chronic rhinosinusitis is a common inflammatory disease of paranasal sinuses, which causes rhinorrhea, nasal congestion, and hyposmia. The genetic predisposition or the exposure to irritants can sustain the inflammatory response and the development of nasal polyposis. Nasal polyps are benign and teardrop-shaped growths that project in the nasal cavities, and originate from the ethmoid sinuses. This inflammatory process is associated with high expression of IL-4, IL-5 and IL-13 and IgE. Antibodies targeting these cytokines or receptors represent a therapeutic strategy in the treatment of nasal polyposis in combination with corticosteroids. The molecular pathogenesis of nasal polyps in chronic rhinosinusitis (CRS) patients is associated with remodeling transition, a process in which epithelial cells lose their typical phenotype, acquiring a mesenchymal-like aspect. TGFβ/SMAD, ERK, and Wnt/β-catenin pathways are altered during the nasal tissue remodeling. miRNA and inhibitor molecules targeting these signaling pathways are able to interfere with the process; which could lead to alternative therapies. Nasal polyps are an alternative source of mesenchymal stem cells, which can be isolated from surgical biopsies. A molecular understanding of the biology of PO-MSCs will contribute to the delineating inflammatory process underlying the development of nasal polyps. Full article

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

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10 pages, 1203 KiB

Open AccessReview

Tunneling Nanotubes-Mediated Protection of Mesenchymal Stem Cells: An Update from Preclinical Studies

by Thangavelu Soundara Rajan, Agnese Gugliandolo, Placido Bramanti and Emanuela Mazzon

Int. J. Mol. Sci. 2020, 21(10), 3481; https://doi.org/10.3390/ijms21103481 - 14 May 2020

Cited by 19 | Viewed by 3825

Abstract

Tunneling nanotubes (TNTs) are thin membrane elongations among the cells that mediate the trafficking of subcellular organelles, biomolecules, and cues. Mesenchymal stem cells (MSCs) receive substantial attention in tissue engineering and regenerative medicine. Many MSCs-based clinical trials are ongoing for dreadful diseases including cancer and neurodegenerative diseases. Mitochondrial trafficking through TNTs is one of the mechanisms used by MSCs to repair tissue damage and to promote tissue regeneration. Preclinical studies linked with ischemia, oxidative stress, mitochondrial damage, inflammation, and respiratory illness have demonstrated the therapeutic efficacy of MSCs via TNTs-mediated transfer of mitochondria and other molecules into the injured cells. On the other hand, MSCs-based cancer studies showed that TNTs may modulate chemoresistance in tumor cells as a result of mitochondrial trafficking. In the present review, we discuss the role of TNTs from preclinical studies associated with MSCs treatment. We discuss the impact of TNTs formation between MSCs and cancer cells and emphasize to study the importance of TNTs-mediated MSCs protection in disease models. Full article

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

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