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Mesenchymal Stem Cells: Cross-Talk with the Microenvironment
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Mesenchymal Stem Cells: Cross-Talk with the Microenvironment

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

Deadline for manuscript submissions: 20 March 2025 | Viewed by 7632

Special Issue Editors

Dr. Natella Enukashvily

E-Mail Website
Guest Editor
Laboratory of the Non-Coding DNA Study, Institute of Cytology RAS, Saint Petersburg 194064, Russia
Interests: physiology of multipotent mesenchymal stromal cells and neural crest stem cells; non-coding RNA; genome architecture; endothelial-mesenchymal transition
Dr. Anna Malashicheva

E-Mail Website
Guest Editor
Laboratory of Regenerative Biomedicine, Institute of Cytology, Saint Petersburg 194064, Russia
Interests: Notch signaling; osteogenic differentiation; mesenchymal stem cells; endothelial-mesenchymal interactions
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Multipotent mesenchymal stromal cells (mMSC) are involved in building up the stroma of most organs. These cells are involved in bone marrow hematopoietic niche in health and disease. They are also one of the keys stromal components of solid tumor. Though mesenchymal stem cells are capable to multilineage differentiation, their main role is to fine-tune the functioning of adjacent cells. mMSC mediate the fine balance between differentiation, proliferation, self-renewal and quiescence via intracellular regulatory networks and cell-to-cell interaction. Only in concert with their specialized microenvironment they retain their unique properties. This local microenvironment is termed ‘the stem cell niche’. The interaction between mesenchymal stem cells and the surrounding cells works both ways: adjacent cells influence and are influenced by mMSC. In this Special Issue devoted to mMSC interaction with their neighborhood we will discuss recent breakthroughs in this topic and their impact on basic research and the concept of mMSC clinical application. We aim to depict recent data on our progress in understanding the mechanisms of mMSC bidirectional interaction with their microenvironment. The data will broaden our understanding of mMSC therapeutic potential and bring new ideas on possible clinical applications.

Dr. Natella Enukashvily
Dr. Anna Malashicheva
Guest Editors

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Keywords

  • mesenchymal stem cell niche
  • microenvironment
  • cell-to-cell interaction
  • tumor microenvironment
  • inflammation
  • stem cells transcriptome
  • extracellular vesicles

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Published Papers (5 papers)

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Research

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20 pages, 1174 KiB  
Article
Selected microRNA Expression and Protein Regulator Secretion by Adipose Tissue-Derived Mesenchymal Stem Cells and Metabolic Syndrome
by Grzegorz Wystrychowski, Klaudia Simka-Lampa, Agnieszka Witkowska, Ewelina Sobecko, Aleksandra Skubis-Sikora, Bartosz Sikora, Ewa Wojtyna, Agnieszka Golda, Katarzyna Gwizdek, Marta Wróbel, Łukasz Sędek, Sylwia Górczyńska-Kosiorz, Nikola Szweda-Gandor, Wanda Trautsolt, Tomasz Francuz, Celina Kruszniewska-Rajs and Joanna Gola
Int. J. Mol. Sci. 2024, 25(12), 6644; https://doi.org/10.3390/ijms25126644 - 17 Jun 2024
Viewed by 1034
Abstract
The role of adipose mesenchymal stem cells (Ad-MSCs) in metabolic syndrome remains unclear. We aimed to assess the expression of selected microRNAs in Ad-MSCs of non-diabetic adults in relation to Ad-MSC secretion of protein regulators and basic metabolic parameters. Ten obese, eight overweight, [...] Read more.
The role of adipose mesenchymal stem cells (Ad-MSCs) in metabolic syndrome remains unclear. We aimed to assess the expression of selected microRNAs in Ad-MSCs of non-diabetic adults in relation to Ad-MSC secretion of protein regulators and basic metabolic parameters. Ten obese, eight overweight, and five normal weight subjects were enrolled: 19 females and 4 males; aged 43.0 ± 8.9 years. Ad-MSCs were harvested from abdominal subcutaneous fat. Ad-MSC cellular expressions of four microRNAs (2−ΔCt values) and concentrations of IL-6, IL-10, VEGF, and IGF-1 in the Ad-MSC-conditioned medium were assessed. The expressions of miR-21, miR-122, or miR-192 did not correlate with clinical parameters (age, sex, BMI, visceral fat, HOMA-IR, fasting glycemia, HbA1c, serum lipids, CRP, and eGFR). Conversely, the expression of miR-155 was lowest in obese subjects (3.69 ± 2.67 × 10−3 vs. 7.07 ± 4.42 × 10−3 in overweight and 10.25 ± 7.05 × 10−3 in normal weight ones, p = 0.04). The expression of miR-155 correlated inversely with BMI (sex-adjusted r = −0.64; p < 0.01), visceral adiposity (r = −0.49; p = 0.03), and serum CRP (r = −0.63; p < 0.01), whereas it correlated positively with serum HDL cholesterol (r = 0.51; p = 0.02). Moreover, miR-155 synthesis was associated marginally negatively with Ad-MSC secretion of IGF-1 (r = −0.42; p = 0.05), and positively with that of IL-10 (r = 0.40; p = 0.06). Ad-MSC expression of miR-155 appears blunted in visceral obesity, which correlates with Ad-MSC IGF-1 hypersecretion and IL-10 hyposecretion, systemic microinflammation, and HDL dyslipidemia. Ad-MSC studies in metabolic syndrome should focus on miR-155. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells: Cross-Talk with the Microenvironment)
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18 pages, 6257 KiB  
Article
Laminin Alpha 2 Enhances the Protective Effect of Exosomes on Human iPSC-Derived Cardiomyocytes in an In Vitro Ischemia-Reoxygenation Model
by Fernanda C. P. Mesquita, Madelyn King, Patricia Luciana da Costa Lopez, Shiyanth Thevasagayampillai, Preethi H. Gunaratne and Camila Hochman-Mendez
Int. J. Mol. Sci. 2024, 25(7), 3773; https://doi.org/10.3390/ijms25073773 - 28 Mar 2024
Cited by 1 | Viewed by 1729
Abstract
Ischemic heart disease, a leading cause of death worldwide, manifests clinically as myocardial infarction. Contemporary therapies using mesenchymal stromal cells (MSCs) and their derivative (exosomes, EXOs) were developed to decrease the progression of cell damage during ischemic injury. Laminin alpha 2 (LAMA2) is [...] Read more.
Ischemic heart disease, a leading cause of death worldwide, manifests clinically as myocardial infarction. Contemporary therapies using mesenchymal stromal cells (MSCs) and their derivative (exosomes, EXOs) were developed to decrease the progression of cell damage during ischemic injury. Laminin alpha 2 (LAMA2) is an important extracellular matrix protein of the heart. Here, we generated MSC-derived exosomes cultivated under LAMA2 coating to enhance human-induced pluripotent stem cell (hiPSC)-cardiomyocyte recognition of LAMA2-EXOs, thus, increasing cell protection during ischemia reoxygenation. We mapped the mRNA content of LAMA2 and gelatin-EXOs and identified 798 genes that were differentially expressed, including genes associated with cardiac muscle development and extracellular matrix organization. Cells were treated with LAMA2-EXOs 2 h before a 4 h ischemia period (1% O2, 5% CO2, glucose-free media). LAMA2-EXOs had a two-fold protective effect compared to non-treatment on plasma membrane integrity and the apoptosis activation pathway; after a 1.5 h recovery period (20% O2, 5% CO2, cardiomyocyte-enriched media), cardiomyocytes treated with LAMA2-EXOs showed faster recovery than did the control group. Although EXOs had a protective effect on endothelial cells, there was no LAMA2-enhanced protection on these cells. This is the first report of LAMA2-EXOs used to treat cardiomyocytes that underwent ischemia-reoxygenation injury. Overall, we showed that membrane-specific EXOs may help improve cardiomyocyte survival in treating ischemic cardiovascular disease. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells: Cross-Talk with the Microenvironment)
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14 pages, 5488 KiB  
Article
Synergistic Therapeutic Potential of Dual 3D Mesenchymal Stem Cell Therapy in an Ischemic Hind Limb Mouse Model
by Dong-Sik Chae, Sang Joon An, Seongho Han and Sung-Whan Kim
Int. J. Mol. Sci. 2023, 24(19), 14620; https://doi.org/10.3390/ijms241914620 - 27 Sep 2023
Cited by 1 | Viewed by 1480
Abstract
Three-dimensional (3D) culture systems have been widely used to promote the viability and metabolic activity of mesenchymal stem cells (MSCs). The aim of this study was to explore the synergistic benefits of using dual 3D MSC culture systems to promote vascular regeneration and [...] Read more.
Three-dimensional (3D) culture systems have been widely used to promote the viability and metabolic activity of mesenchymal stem cells (MSCs). The aim of this study was to explore the synergistic benefits of using dual 3D MSC culture systems to promote vascular regeneration and enhance therapeutic potential. We used various experimental assays, including dual 3D cultures of human adipose MSCs (hASCs), quantitative reverse transcription polymerase chain reaction (qRT-PCR), in vitro cell migration, Matrigel tube network formation, Matrigel plug assay, therapeutic assays using an ischemic hind limb mouse model, and immunohistochemical analysis. Our qRT-PCR results revealed that fibroblast growth factor 2 (FGF-2), granulocyte chemotactic protein-2 (GCP-2), and vascular endothelial growth factor-A (VEGF-A) were highly upregulated in conventional 3D-cultured hASCs (ASC-3D) than in two-dimensional (2D)-cultured hASCs. Hepatocyte growth factor (HGF), insulin-like growth factor-1 (IGF-1), and stromal-cell-derived factor-1 (SDF-1) showed higher expression levels in cytokine-cocktail-based, 3D-cultured hASCs (ASC-3Dc). A conditioned medium (CM) mixture of dual 3D ASCs (D-3D; ASC-3D + ASC-3Dc) resulted in higher migration and Matrigel tube formation than the CM of single 3D ASCs (S-3D; ASC-3D). Matrigel plugs containing D-3D contained more red blood cells than those containing S-3D. D-3D transplantation into ischemic mouse hind limbs prevented limb loss and augmented blood perfusion when compared to S-3D transplantation. Transplanted D-3D also revealed a high capillary density and angiogenic cytokine levels and transdifferentiated into endothelial-like cells in the hind limb muscle. These findings highlight the benefits of using the dual 3D culture system to optimize stem-cell-based therapeutic strategies, thereby advancing the therapeutic strategy for ischemic vascular disease and tissue regeneration. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells: Cross-Talk with the Microenvironment)
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22 pages, 26689 KiB  
Article
EGF, TGF-α and Amphiregulin Differently Regulate Endometrium-Derived Mesenchymal Stromal/Stem Cells
by Rimma Sergeevna Kamentseva, Marianna Viktorovna Kharchenko, Gulnara Vladikovna Gabdrahmanova, Michael Alexandrovich Kotov, Vera Vladislavovna Kosheverova and Elena Sergeevna Kornilova
Int. J. Mol. Sci. 2023, 24(17), 13408; https://doi.org/10.3390/ijms241713408 - 29 Aug 2023
Cited by 2 | Viewed by 1545
Abstract
The prototypical receptor tyrosine kinase epidermal growth factor receptor (EGFR) is regulated by a set of its ligands, which determines the specificity of signaling and intracellular fate of the receptor. The EGFR signaling system is well characterized in immortalized cell lines such as [...] Read more.
The prototypical receptor tyrosine kinase epidermal growth factor receptor (EGFR) is regulated by a set of its ligands, which determines the specificity of signaling and intracellular fate of the receptor. The EGFR signaling system is well characterized in immortalized cell lines such as HeLa derived from tumor tissues, but much less is known about EGFR function in untransformed multipotent stromal/stem cells (MSCs). We compared the effect of epidermal growth factor (EGF), transforming growth factor-α (TGF-α) and amphiregulin (AREG) on physiological responses in endometrial MSCs (enMSC) and HeLa cells. In addition, using Western blotting and confocal microscopy, we studied the internalization and degradation of EGFR stimulated by the three ligands in these cell lines. We demonstrated that unlike HeLa, EGF and TGF-α, but not AREG, stimulated enMSC proliferation and prevented decidual differentiation in an EGFR-dependent manner. In HeLa cells, EGF targeted EGFR for degradation, while TGF-α stimulated its recycling. Surprisingly, in enMSC, both ligands caused EGFR degradation. In both cell lines, AREG-EGFR internalization was not registered. In HeLa cells, EGFR was degraded within 2 h, restoring its level in 24 h, while in enMSC, degradation took more than 4–8 h, and the low EGFR level persisted for several days. This indicates that EGFR homeostasis in MSCs may differ significantly from that in immortalized cell lines. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells: Cross-Talk with the Microenvironment)
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Review

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12 pages, 2685 KiB  
Review
The Complex Interplay of TGF-β and Notch Signaling in the Pathogenesis of Fibrosis
by Nadezhda Bakalenko, Evdokiya Kuznetsova and Anna Malashicheva
Int. J. Mol. Sci. 2024, 25(19), 10803; https://doi.org/10.3390/ijms251910803 - 8 Oct 2024
Viewed by 991
Abstract
Fibrosis is a major medical challenge, as it leads to irreversible tissue remodeling and organ dysfunction. Its progression contributes significantly to morbidity and mortality worldwide, with limited therapeutic options available. Extensive research on the molecular mechanisms of fibrosis has revealed numerous factors and [...] Read more.
Fibrosis is a major medical challenge, as it leads to irreversible tissue remodeling and organ dysfunction. Its progression contributes significantly to morbidity and mortality worldwide, with limited therapeutic options available. Extensive research on the molecular mechanisms of fibrosis has revealed numerous factors and signaling pathways involved. However, the interactions between these pathways remain unclear. A comprehensive understanding of the entire signaling network that drives fibrosis is still missing. The TGF-β and Notch signaling pathways play a key role in fibrogenesis, and this review focuses on their functional interplay and molecular mechanisms. Studies have shown synergy between TGF-β and Notch cascades in fibrosis, but antagonistic interactions can also occur, especially in cardiac fibrosis. The molecular mechanisms of these interactions vary depending on the cell context. Understanding these complex and context-dependent interactions is crucial for developing effective strategies for treating fibrosis. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells: Cross-Talk with the Microenvironment)
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