Mesenchymal Stem Cells: Intrinsic/Extrinsic Factors Regulating Stemness, Growth, and Differentiation

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Stem Cells".

Deadline for manuscript submissions: closed (15 September 2022) | Viewed by 17625

Special Issue Editors


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Guest Editor
Department of Molecular Medicine, College of Medicine, Ewha Womans University, 25 Magokdong-ro-2-gil, Gangseo-gu, Seoul 07804, Republic of Korea
Interests: regenerative medicine; mesenchymal stem cells; differentiation factors; signaling pathway; nitric oxide; far-infrared radiation
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Guest Editor
Institute of Convergence Medicine, Ewha Womans University Mokdong Hospital, Ewha Womans University, 1071 Anyanycheon-ro, Yangcheon-gu, Seoul 07985, Republic of Korea
Interests: mesenchymal stem cells; regenerative medicine; epigenetics; immunotoxicology; immunomodulation; inflammation
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Guest Editor
Unit of Histology, Embryology and Applied Biology, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Via Belmeloro 8, 40126 Bologna, BO, Italy
Interests: human mesenchymal stem cells; cell senescence; cell biology; cell differentiation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mesenchymal stem/stromal cells (MSCs) are adult stem cells with the capability of self-renewal and multilineage differentiation into skeletal and/or mesodermal tissues, including bone, fat, cartilage, and muscle tissues. Bone marrow has been the primary site for obtaining MSCs, but recent studies have indicated that MSCs are also present at other tissue sites, including adipose, muscle, skin, liver, umbilical cord, tonsil, and blood tissue, and even in urine samples, all of which play a role in regenerating damaged tissues or regulating inflammation or other undiscovered functions. Approximately 50 years have passed since MSC-like cells were first discovered, and many studies have been carried out to outline the characteristics of MSCs and to investigate their potential therapeutic implications in regenerative medicine and immunomodulation. However, only a few have successfully managed to reach clinical availability, implying that we probably do not yet have a full understanding of the biology of MSCs.

For this Special Issue, we invite authors/experts to submit high-quality original research articles that further expand our knowledge of and provide us with insights into MSCs. We are particularly interested in studies illustrating intrinsic/extrinsic cellular and molecular factors regulating stemness, growth, and differentiation of tissue-specific MSCs as well as their potential implications for tissue engineering and regenerative medicine.

Prof. Inho Jo
Dr. Steve (Se-Young) Oh
Dr. Federica Facchin
Guest Editor

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Keywords

  • tissue-specific mesenchymal stem cells
  • factors
  • stemness
  • growth
  • differentiation
  • tissue engineering
  • regenerative medicine.

Published Papers (6 papers)

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Research

20 pages, 6947 KiB  
Article
Stem Cells from Healthy and Tendinopathic Human Tendons: Morphology, Collagen and Cytokines Expression and Their Response to T3 Thyroid Hormone
by Maria Camilla Ciardulli, Pasqualina Scala, Valentina Giudice, Antonietta Santoro, Carmine Selleri, Francesco Oliva, Nicola Maffulli and Giovanna Della Porta
Cells 2022, 11(16), 2545; https://doi.org/10.3390/cells11162545 - 16 Aug 2022
Cited by 7 | Viewed by 2539
Abstract
The aim of this study was to investigate the effect of triiodothyronine (T3) on tendon specific markers and cytokines expression of stem cells extracted from human tendons. Indeed, thyroid hormones have been reported to be protective factors, maintaining tendons’ homeostasis, whereas tendinopathy is [...] Read more.
The aim of this study was to investigate the effect of triiodothyronine (T3) on tendon specific markers and cytokines expression of stem cells extracted from human tendons. Indeed, thyroid hormones have been reported to be protective factors, maintaining tendons’ homeostasis, whereas tendinopathy is believed to be related to a failed healing response. Healthy and tendinopathic human tendons were harvested to isolate tendon stem/progenitor cells (TSPCs). TSPCs obtained from pathological samples showed gene expression and morphological modifications at baseline in comparison with cells harvested from healthy tissues. When cells were maintained in a medium supplemented with T3 (10−6 M), only pathological populations showed a significant upregulation of tenogenic markers (DCN, TNC, COL1A1, COL3A1). Immunostaining revealed that healthy cells constantly released type I collagen, typical of tendon matrix, whereas pathological ones overexpressed and secreted type III collagen, typical of scarred and impaired tissue. Pathological cells also overexpressed pro- and anti-inflammatory cytokines, suggesting an impaired balance in the presence of T3, without STAT3 activation. Moreover, DKK-1 was significantly high in the culture medium of pathological cell cultures and was reversed by T3. This study opens perspectives on the complex biochemical alteration of cells from pathological tendons, which may lead to the chronic disease context with an impaired extracellular matrix. Full article
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13 pages, 4628 KiB  
Article
Tensin Regulates Fundamental Biological Processes by Interacting with Integrins of Tonsil-Derived Mesenchymal Stem Cells
by Gi Cheol Park, Ji Min Kim, Sung-Chan Shin, Yong-il Cheon, Eui-Suk Sung, Minhyung Lee, Jin-Choon Lee and Byung-Joo Lee
Cells 2022, 11(15), 2333; https://doi.org/10.3390/cells11152333 - 29 Jul 2022
Cited by 2 | Viewed by 1784
Abstract
Human tonsil-derived mesenchymal stem cells (TMSCs) have a superior proliferation rate and differentiation potential compared to adipose-tissue-derived MSCs (AMSCs) or bone-marrow-derived MSCs (BMSCs). TMSCs exhibit a significantly higher expression of the tensin3 gene (TNS3) than AMSCs or BMSCs. TNS is involved [...] Read more.
Human tonsil-derived mesenchymal stem cells (TMSCs) have a superior proliferation rate and differentiation potential compared to adipose-tissue-derived MSCs (AMSCs) or bone-marrow-derived MSCs (BMSCs). TMSCs exhibit a significantly higher expression of the tensin3 gene (TNS3) than AMSCs or BMSCs. TNS is involved in cell adhesion and migration by binding to integrin beta-1 (ITG β1) in focal adhesion. Here, we investigated the roles of four TNS isoforms, including TNS3 and their relationship with integrin in various biological processes of TMSCs. Suppressing TNS1 and TNS3 significantly decreased the cell count. The knockdown of TNS1 and TNS3 increased the gene and protein expression levels of p16, p19, and p21. TNS1 and TNS3 also have a significant effect on cell migration. Transfecting with siRNA TNS3 significantly reduced Oct4, Nanog, and Sox-2 levels. Conversely, when TNS4 was silenced, Oct4 and Sox-2 levels significantly increase. TNS1 and TNS3 promote osteogenic and adipogenic differentiation, whereas TNS4 inhibits adipogenic differentiation of TMSCs. TNS3 is involved in the control of focal adhesions by regulating integrin. Thus, TNS enables TMSCs to possess a higher proliferative capacity and differentiation potential than other MSCs. Notably, TNS3 plays a vital role in TMSC biology by regulating ITGβ1 activity. Full article
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30 pages, 11363 KiB  
Article
Cytochalasin B Modulates Nanomechanical Patterning and Fate in Human Adipose-Derived Stem Cells
by Eva Bianconi, Riccardo Tassinari, Andrea Alessandrini, Gregorio Ragazzini, Claudia Cavallini, Provvidenza Maria Abruzzo, Giovannamaria Petrocelli, Luca Pampanella, Raffaella Casadei, Margherita Maioli, Silvia Canaider, Federica Facchin and Carlo Ventura
Cells 2022, 11(10), 1629; https://doi.org/10.3390/cells11101629 - 12 May 2022
Cited by 8 | Viewed by 3236
Abstract
Cytoskeletal proteins provide architectural and signaling cues within cells. They are able to reorganize themselves in response to mechanical forces, converting the stimuli received into specific cellular responses. Thus, the cytoskeleton influences cell shape, proliferation, and even differentiation. In particular, the cytoskeleton affects [...] Read more.
Cytoskeletal proteins provide architectural and signaling cues within cells. They are able to reorganize themselves in response to mechanical forces, converting the stimuli received into specific cellular responses. Thus, the cytoskeleton influences cell shape, proliferation, and even differentiation. In particular, the cytoskeleton affects the fate of mesenchymal stem cells (MSCs), which are highly attractive candidates for cell therapy approaches due to their capacity for self-renewal and multi-lineage differentiation. Cytochalasin B (CB), a cyto-permeable mycotoxin, is able to inhibit the formation of actin microfilaments, resulting in direct effects on cell biological properties. Here, we investigated for the first time the effects of different concentrations of CB (0.1–10 μM) on human adipose-derived stem cells (hASCs) both after 24 h (h) of CB treatment and 24 h after CB wash-out. CB influenced the metabolism, proliferation, and morphology of hASCs in a dose-dependent manner, in association with progressive disorganization of actin microfilaments. Furthermore, the removal of CB highlighted the ability of cells to restore their cytoskeletal organization. Finally, atomic force microscopy (AFM) revealed that cytoskeletal changes induced by CB modulated the viscoelastic properties of hASCs, influencing their stiffness and viscosity, thereby affecting adipogenic fate. Full article
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21 pages, 4986 KiB  
Article
Endo- and Exometabolome Crosstalk in Mesenchymal Stem Cells Undergoing Osteogenic Differentiation
by Daniela S. C. Bispo, Lenka Michálková, Marlene Correia, Catarina S. H. Jesus, Iola F. Duarte, Brian J. Goodfellow, Mariana B. Oliveira, João F. Mano and Ana M. Gil
Cells 2022, 11(8), 1257; https://doi.org/10.3390/cells11081257 - 7 Apr 2022
Cited by 8 | Viewed by 3091
Abstract
This paper describes, for the first time to our knowledge, a lipidome and exometabolome characterization of osteogenic differentiation for human adipose tissue stem cells (hAMSCs) using nuclear magnetic resonance (NMR) spectroscopy. The holistic nature of NMR enabled the time-course evolution of cholesterol, mono- [...] Read more.
This paper describes, for the first time to our knowledge, a lipidome and exometabolome characterization of osteogenic differentiation for human adipose tissue stem cells (hAMSCs) using nuclear magnetic resonance (NMR) spectroscopy. The holistic nature of NMR enabled the time-course evolution of cholesterol, mono- and polyunsaturated fatty acids (including ω-6 and ω-3 fatty acids), several phospholipids (phosphatidylcholine, phosphatidylethanolamine, sphingomyelins, and plasmalogens), and mono- and triglycerides to be followed. Lipid changes occurred almost exclusively between days 1 and 7, followed by a tendency for lipidome stabilization after day 7. On average, phospholipids and longer and more unsaturated fatty acids increased up to day 7, probably related to plasma membrane fluidity. Articulation of lipidome changes with previously reported polar endometabolome profiling and with exometabolome changes reported here in the same cells, enabled important correlations to be established during hAMSC osteogenic differentiation. Our results supported hypotheses related to the dynamics of membrane remodelling, anti-oxidative mechanisms, protein synthesis, and energy metabolism. Importantly, the observation of specific up-taken or excreted metabolites paves the way for the identification of potential osteoinductive metabolites useful for optimized osteogenic protocols. Full article
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16 pages, 11665 KiB  
Article
Valproic Acid-Induced CCN1 Promotes Osteogenic Differentiation by Increasing CCN1 Protein Stability through HDAC1 Inhibition in Tonsil-Derived Mesenchymal Stem Cells
by Yeonsil Yu, Se-Young Oh, Ha Yeong Kim, Ji-Young Choi, Sangmee Ahn Jo and Inho Jo
Cells 2022, 11(3), 534; https://doi.org/10.3390/cells11030534 - 3 Feb 2022
Cited by 12 | Viewed by 2512
Abstract
Our previous study found that the level of CCN1 increases as osteogenic differentiation progresses in tonsil-derived mesenchymal stem cells (TMSCs). This study investigated how CCN1 is regulated through HDAC inhibition in TMSCs and their relationship with osteogenesis. Valproic acid (VPA) (1–5 mM), a [...] Read more.
Our previous study found that the level of CCN1 increases as osteogenic differentiation progresses in tonsil-derived mesenchymal stem cells (TMSCs). This study investigated how CCN1 is regulated through HDAC inhibition in TMSCs and their relationship with osteogenesis. Valproic acid (VPA) (1–5 mM), a well-known histone deacetylase (HDAC) inhibitor, strongly inhibited TMSC proliferation without altering MSC-specific surface markers, CD14, 34, 45, 73, 90 and 105. However, CD146 expression increased at 5 mM VPA. VPA increased osteogenic differentiation of TMSCs but decreased adipogenesis and chondrogenesis, as evidenced by the cell-specific staining of differentiation. The former was validated by the increased osteocalcin (OCN). The changes in CCN1 by VPA was biphasic; it increased until 48 h and decreased thereafter. Knockdown of CCN1 by using siRNA inhibited the osteogenic effect of VPA. VPA had no effect on CCN1 mRNA expression, but inhibition of protein synthesis by cycloheximide showed that VPA slowed down the CCN1 protein degradation. Moreover, overexpression of HDAC1 completely inhibited VPA-induced CCN1. Our results indicate that VPA inhibits the HDAC1, inducing CCN1 protein stability rather than gene expression, thereby promoting osteogenic differentiation of TMSCs. These findings present the noble implication of VPA as an inhibitor of HDAC1 to facilitate CCN1-induced osteogenic differentiation of MSCs. Full article
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16 pages, 3047 KiB  
Article
A Comparative Study of the Effect of Anatomical Site on Multiple Differentiation of Adipose-Derived Stem Cells in Rats
by Hanan Hendawy, Masahiro Kaneda, Elsayed Metwally, Kazumi Shimada, Takashi Tanaka and Ryou Tanaka
Cells 2021, 10(9), 2469; https://doi.org/10.3390/cells10092469 - 18 Sep 2021
Cited by 7 | Viewed by 2764
Abstract
Mesenchymal stem cells (MSCs) derived from adipose tissue are evolved into various cell-based regenerative approaches. Adipose-derived stem cells (ASCs) isolated from rats are commonly used in tissue engineering studies. Still, there is a gap in knowledge about how the harvest locations influence and [...] Read more.
Mesenchymal stem cells (MSCs) derived from adipose tissue are evolved into various cell-based regenerative approaches. Adipose-derived stem cells (ASCs) isolated from rats are commonly used in tissue engineering studies. Still, there is a gap in knowledge about how the harvest locations influence and guide cell differentiation. This study aims to investigate how the harvesting site affects stem-cell-specific surface markers expression, pluripotency, and differentiation potential of ASCs in female Sprague Dawley rats. ASCs were extracted from the adipose tissue of the peri-ovarian, peri-renal, and mesenteric depots and were compared in terms of cell morphology. MSCs phenotype was validated by cell surfaces markers using flow cytometry. Moreover, pluripotent gene expression of Oct4, Nanog, Sox2, Rex-1, and Tert was evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR). ASCs multipotency was evaluated by specific histological stains, and the results were confirmed by quantitative polymerase chain reaction (RT-qPCR) expression analysis of specific genes. There was a non-significant difference detected in the cell morphology and immunophenotype between different harvesting sites. ASCs from multiple locations were significantly varied in their capacity to differentiate into adipocytes, osteoblastic cells, and chondrocytes. To conclude, depot selection is a critical element that should be considered when using ASCs in tissue-specific cell-based regenerative therapies research. Full article
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