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New Insights into Human Mesenchymal Stem Cells

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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 (20 January 2025) | Viewed by 12184

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Special Issue Editor

Dr. Daiva Bironaite

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Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, LT-08410 Vilnius, Lithuania
Interests: cell death; survival mechanisms; intracellular signaling pathways; oxidative stress; adult human mesenchymal stem/stromal cells; tissue regeneration
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Special Issue Information

Dear Colleagues,

MSCs, multipotent and non-hematopoietic mesenchymal stem/stromal cells, were first described by hematologist A. Friedenstein more than 50 years ago. Since then, their roles in various tissue-related processes, such as homeostasis, differentiation, signaling, and many others, have been investigated. Since MSCs are present in all organs and tissues, they play important roles in tissue regeneration processes as well as in the development of many chronic autoimmune or degenerative diseases that have been shown to be related to the dysfunction or depletion of MSCs.

Recently, multiple studies in vitro, as well as in vivo, have demonstrated MSCs regulating basic cellular processes, such as inflammation, oxidative stress, angiogenesis, etc., having broad therapeutic applications due to their low immune rejection. However, despite the direct use of MSCs in cell-based therapy, MSCs also act as paracrine regulators, i.e., MSCs secrete cytokines, hormones, extracellular vesicles, and other compounds, preventing the inconveniences associated with cell-based therapy, such as cell survival, heterogeneity, and functioning.

In addition, the multiple cell–cell-based and paracrine effects of MSCs and/or subpopulations also allow them to be investigated in combination with various tissue engineering scaffolds, hydrogels, or other cell–matrix biomodel systems in vitro and in vivo, adjusting various types of intracellular and extracellular stimuli in order to improve therapeutic applicability. The prevalence and multifunctionality of MSCs still do not lose scientific interest, forcing the search for new methods of investigation.

Dr. Daiva Bironaité
Guest Editor

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Keywords

mesenchymal stem/stromal cells (MSCs)
proliferation
differentiation
death/survival
internal and external stimuli
therapeutic drugs
subpopulations
cell–cell and cell–matrix interactions

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Published Papers (5 papers)

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Research

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26 pages, 9307 KiB

Open AccessArticle

Cellular In Vitro Responses Induced by Human Mesenchymal Stem/Stromal Cell-Derived Extracellular Vesicles Obtained from Suspension Culture

by Ingrid L. M. Souza, Andreia A. Suzukawa, Raphaella Josino, Bruna H. Marcon, Anny W. Robert, Patrícia Shigunov, Alejandro Correa and Marco A. Stimamiglio

Int. J. Mol. Sci. 2024, 25(14), 7605; https://doi.org/10.3390/ijms25147605 - 11 Jul 2024

Cited by 2 | Viewed by 1930

Abstract

Mesenchymal stem/stromal cells (MSCs) and their extracellular vesicles (MSC-EVs) have been described to have important roles in tissue regeneration, including tissue repair, control of inflammation, enhancing angiogenesis, and regulating extracellular matrix remodeling. MSC-EVs have many advantages for use in regeneration therapies such as facility for dosage, histocompatibility, and low immunogenicity, thus possessing a lower possibility of rejection. In this work, we address the potential activity of MSC-EVs isolated from adipose-derived MSCs (ADMSC-EVs) cultured on cross-linked dextran microcarriers, applied to test the scalability and reproducibility of EV production. Isolated ADMSC-EVs were added into cultured human dermal fibroblasts (NHDF-1), keratinocytes (HaCat), endothelial cells (HUVEC), and THP-1 cell-derived macrophages to evaluate cellular responses (i.e., cell proliferation, cell migration, angiogenesis induction, and macrophage phenotype-switching). ADMSC viability and phenotype were assessed during cell culture and isolated ADMSC-EVs were monitored by nanotracking particle analysis, electron microscopy, and immunophenotyping. We observed an enhancement of HaCat proliferation; NHDF-1 and HaCat migration; endothelial tube formation on HUVEC; and the expression of inflammatory cytokines in THP-1-derived macrophages. The increased expression of TGF-β and IL-1β was observed in M1 macrophages treated with higher doses of ADMSC-EVs. Hence, EVs from microcarrier-cultivated ADMSCs are shown to modulate cell behavior, being able to induce skin tissue related cells to migrate and proliferate as well as stimulate angiogenesis and cause balance between pro- and anti-inflammatory responses in macrophages. Based on these findings, we suggest that the isolation of EVs from ADMSC suspension cultures makes it possible to induce in vitro cellular responses of interest and obtain sufficient particle numbers for the development of in vivo concept tests for tissue regeneration studies. Full article

(This article belongs to the Special Issue New Insights into Human Mesenchymal Stem Cells)

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14 pages, 7077 KiB

Open AccessArticle

Mesenchymal Stem Cells Increase Drug Tolerance of A431 Cells Only in 3D Spheroids, Not in 2D Co-Cultures

by Flóra Vajda, Áron Szepesi, Zsuzsa Erdei, Edit Szabó, György Várady, Dániel Kiss, László Héja, Katalin Német, Gergely Szakács and András Füredi

Int. J. Mol. Sci. 2024, 25(8), 4515; https://doi.org/10.3390/ijms25084515 - 20 Apr 2024

Cited by 1 | Viewed by 2148

Abstract

Mesenchymal stem cells (MSCs) are an integral part of the tumor microenvironment (TME); however, their role is somewhat controversial: conflicting reports suggest that, depending on the stage of tumor development, MSCs can either support or suppress tumor growth and spread. Additionally, the influence of MSCs on drug resistance is also ambiguous. Previously, we showed that, despite MSCs proliferating significantly more slowly than cancer cells, there are chemotherapeutic drugs which proved to be similarly toxic to both cell types. Here we established 2D co-cultures and 3D co-culture spheroids from different ratios of GFP-expressing, adipose tissue-derived MSCs and A431 epidermoid carcinoma cells tagged with mCherry to investigate the effect of MSCs on cancer cell growth, survival, and drug sensitivity. We examined the cytokine secretion profile of mono- and co-cultures, explored the inner structure of the spheroids, applied MSC-(nutlin-3) and cancer cell-targeting (cisplatin) treatments separately, monitored the response with live-cell imaging and identified a new, double-fluorescent cell type emerging from these cultures. In 2D co-cultures, no effect on proliferation or drug sensitivity was observed, regardless of the changes in cytokine secretion induced by the co-culture. Conversely, 3D spheroids developed a unique internal structure consisting of MSCs, which significantly improved cancer cell survival and resilience to treatment, suggesting that physical proximity and cell–cell connections are required for MSCs to considerably affect nearby cancer cells. Our results shed light on MSC–cancer cell interactions and could help design new, better treatment options for tumors. Full article

(This article belongs to the Special Issue New Insights into Human Mesenchymal Stem Cells)

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20 pages, 2146 KiB

Open AccessArticle

Mesenchymal Stromal Cells from Perinatal Tissues as an Alternative for Ex Vivo Expansion of Hematopoietic Progenitor and Stem Cells from Umbilical Cord Blood

by Ximena Bonilla, Ana Milena Lara, Manuela Llano-León, David A. López-González, David G. Hernández-Mejía, Rosa Helena Bustos, Bernardo Camacho-Rodríguez and Ana-María Perdomo-Arciniegas

Int. J. Mol. Sci. 2023, 24(21), 15544; https://doi.org/10.3390/ijms242115544 - 24 Oct 2023

Cited by 2 | Viewed by 1983

Abstract

Umbilical cord blood (UCB) serves as a source of hematopoietic stem and progenitor cells (HSPCs) utilized in the regeneration of hematopoietic and immune systems, forming a crucial part of the treatment for various benign and malignant hematological diseases. UCB has been utilized as an alternative HSPC source to bone marrow (BM). Although the use of UCB has extended transplantation access to many individuals, it still encounters significant challenges in selecting a histocompatible UCB unit with an adequate cell dose for a substantial proportion of adults with malignant hematological diseases. Consequently, recent research has focused on developing ex vivo expansion strategies for UCB HSPCs. Our results demonstrate that co-cultures with the investigated mesenchymal stromal cells (MSCs) enable a 10- to 15-fold increase in the cellular dose of UCB HSPCs while partially regulating the proliferation capacity when compared to HSPCs expanded with early acting cytokines. Furthermore, the secretory profile of UCB-derived MSCs closely resembles that of BM-derived MSCs. Moreover, both co-cultures exhibit alterations in cytokine secretion, which could potentially impact HSPC proliferation during the expansion process. This study underscores the fact that UCB-derived MSCs possess a remarkably similar supportive capacity to BM-derived MSCs, implying their potential use as feeder layers in the ex vivo expansion process of HSPCs. Full article

(This article belongs to the Special Issue New Insights into Human Mesenchymal Stem Cells)

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Review

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16 pages, 592 KiB

Open AccessReview

Dual-Double Stem Cell Ovarian Therapy: A Comprehensive Approach in Regenerative Medicine

by Aleksandar Ljubić, Marija Dinić, Dajana Švraka and Svetlana Vujović

Int. J. Mol. Sci. 2025, 26(1), 69; https://doi.org/10.3390/ijms26010069 - 25 Dec 2024

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Abstract

Dual-double stem cell therapy, which integrates mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs), represents a cutting-edge approach in regenerative medicine, particularly for conditions such as ovarian decline, premature ovarian insufficiency (POI), and induced ovarian failure. This therapy leverages the unique properties of MSCs and HSCs, enhancing tissue repair, immune modulation, and overall regenerative outcomes. MSCs, known for their ability to differentiate into various cell types, provide a supportive microenvironment and secrete bioactive molecules that promote angiogenesis and reduce inflammation. HSCs, crucial for hematopoiesis and immune function, further enhance this environment by supporting hematopoietic processes and immune regulation. Clinical evidence increasingly supports the effectiveness of stem cell therapy in ovarian regeneration. Studies have demonstrated improved folliculogenesis, normalization of hormone profiles, and successful pregnancies in patients with POI. Furthermore, recent clinical trials in various medical fields underline the superior potential of dual-double therapy compared to monotherapies involving MSCs or HSCs alone, enhancing tissue repair and functional outcomes. However, despite these benefits, the therapy presents risks that require careful consideration. For autologous MSC therapy involving expanded cell populations, risks include tumorigenic potential, with evidence of sarcoma formation in certain cases of cultured MSCs. In contrast, autologous non-expanded MSC and HSC therapies may be limited by low cell yields, potentially compromising therapeutic efficacy. Additionally, non-expanded HSC therapy poses risks of insufficient cell numbers for successful engraftment and delayed immune reconstitution. These considerations underscore the importance of quality control and rigorous screening to optimize safety and efficacy. This article explores the mechanisms of action, clinical applications, and potential complications of dual-double stem cell therapy, underscoring the need for continued research and optimized protocols to enhance safety and outcomes in ovarian insufficiency and related conditions, offering new hope for affected women. Full article

(This article belongs to the Special Issue New Insights into Human Mesenchymal Stem Cells)

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26 pages, 972 KiB

Open AccessReview

Mesenchymal Stromal Cells for Aging Cartilage Regeneration: A Review

by Kun-Chi Wu, Yu-Hsun Chang, Dah-Ching Ding and Shinn-Zong Lin

Int. J. Mol. Sci. 2024, 25(23), 12911; https://doi.org/10.3390/ijms252312911 - 30 Nov 2024

Cited by 4 | Viewed by 3012

Abstract

Cartilage degeneration is a key feature of aging and osteoarthritis, characterized by the progressive deterioration of joint function, pain, and limited mobility. Current treatments focus on symptom relief, not cartilage regeneration. Mesenchymal stromal cells (MSCs) offer a promising therapeutic option due to their capability to differentiate into chondrocytes, modulate inflammation, and promote tissue regeneration. This review explores the potential of MSCs for cartilage regeneration, examining their biological properties, action mechanisms, and applications in preclinical and clinical settings. MSCs derived from bone marrow, adipose tissue, and other sources can self-renew and differentiate into multiple cell types. In aging cartilage, they aid in tissue regeneration by secreting growth factors and cytokines that enhance repair and modulate immune responses. Recent preclinical studies show that MSCs can restore cartilage integrity, reduce inflammation, and improve joint function, although clinical translation remains challenging due to limitations such as cell viability, scalability, and regulatory concerns. Advancements in MSC delivery, including scaffold-based approaches and engineered exosomes, may improve therapeutic effectiveness. Potential risks, such as tumorigenicity and immune rejection, are also discussed, emphasizing the need for optimized treatment protocols and large-scale clinical trials to develop effective, minimally invasive therapies for cartilage regeneration. Full article

(This article belongs to the Special Issue New Insights into Human Mesenchymal Stem Cells)

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