Anti-oncogenic Activities Exhibited By Paracrine Factors Of Mesenchymal Stem Cells Can Be Mediated By Modulation Of KITLG and DKK1 Genes In Glioma Stem Cells, in vitro.

AbstractBoth weak survival ability of stem cells and hostile microenvironment are dual dilemma for cell therapy. Adropin, a bioactive substance, has been demonstrated to be cytoprotective. We therefore hypothesized that adropin may produce dual protective effects on the therapeutic potential of stem cells in myocardial infarction by employing an adropin-based dual treatment of promoting stem cell survival in vitro and modifying microenvironment in vivo. In the current study, adropin (25 ng/ml) in vitro reduced hydrogen peroxide-induced apoptosis in rat bone marrow mesenchymal stem cells (MSCs) and improved MSCs survival with increased phosphorylation of Akt and extracellular regulated protein kinases (ERK) l/2. Adropin-induced cytoprotection was blocked by the inhibitors of Akt and ERK1/2. The left main coronary artery of rats was ligated for 3 or 28 days to induce myocardial infarction. Bromodeoxyuridine (BrdU)-labeled MSCs, which were in vitro pretreated with adropin, were in vivo intramyocardially injected after ischemia, following an intravenous injection of 0.2 mg/kg adropin (dual treatment). Compared with MSCs transplantation alone, the dual treatment with adropin reported a higher level of interleukin-10, a lower level of tumor necrosis factor-α and interleukin-1β in plasma at day 3, and higher left ventricular ejection fraction and expression of paracrine factors at day 28, with less myocardial fibrosis and higher capillary density, and produced more surviving BrdU-positive cells at day 3 and 28. In conclusion, our data evidence that adropin-based dual treatment may enhance the therapeutic potential of MSCs to repair myocardium through paracrine mechanism via the pro-survival pathways.

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Comparison of Immunosuppressive and Angiogenic Properties of Human Amnion-Derived Mesenchymal Stem Cells between 2D and 3D Culture Systems

Stem Cells International ◽

10.1155/2019/7486279 ◽

2019 ◽

Vol 2019 ◽

pp. 1-16 ◽

Cited By ~ 18

Author(s):

Vitale Miceli ◽

Mariangela Pampalone ◽

Serena Vella ◽

Anna Paola Carreca ◽

Giandomenico Amico ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Three Dimensional ◽

3D Culture ◽

Culture Method ◽

Paracrine Factors ◽

Human Amnion ◽

Tissue Repair And Regeneration ◽

3D Culture System

The secretion of potential therapeutic factors by mesenchymal stem cells (MSCs) has aroused much interest given the benefits that it can bring in the field of regenerative medicine. Indeed, the in vitro multipotency of these cells and the secretive capacity of both angiogenic and immunomodulatory factors suggest a role in tissue repair and regeneration. However, during culture, MSCs rapidly lose the expression of key transcription factors associated with multipotency and self-renewal, as well as the ability to produce functional paracrine factors. In our study, we show that a three-dimensional (3D) culture method is effective to induce MSC spheroid formation, to maintain the multipotency and to improve the paracrine activity of a specific population of human amnion-derived MSCs (hAMSCs). The regenerative potential of both 3D culture-derived conditioned medium (3D CM) and their exosomes (EXO) was assessed against 2D culture products. In particular, tubulogenesis assays revealed increased capillary maturation in the presence of 3D CM compared with both 2D CM and 2D EXO. Furthermore, 3D CM had a greater effect on inhibition of PBMC proliferation than both 2D CM and 2D EXO. To support this data, hAMSC spheroids kept in our 3D culture system remained viable and multipotent and secreted considerable amounts of both angiogenic and immunosuppressive factors, which were detected at lower levels in 2D cultures. This work reveals the placenta as an important source of MSCs that can be used for eventual clinical applications as cell-free therapies.

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Paracrine factors of human mesenchymal stem cells increase wound closure and reduce reactive oxygen species production in a traumatic brain injury in vitro model

Human & Experimental Toxicology ◽

10.1177/0960327113509659 ◽

2013 ◽

Vol 33 (7) ◽

pp. 673-684 ◽

Cited By ~ 35

Author(s):

D Torrente ◽

MF Avila ◽

R Cabezas ◽

L Morales ◽

J Gonzalez ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Brain Injury ◽

Wound Closure ◽

Human Mesenchymal Stem Cells ◽

Neuronal Population ◽

Paracrine Factors ◽

Neuroprotective Strategy

Traumatic brain injury (TBI) consists of a primary and a secondary insult characterized by a biochemical cascade that plays a crucial role in cell death in the brain. Despite the major improvements in the acute care of head injury victims, no effective strategies exist for preventing the secondary injury cascade. This lack of success might be due to that most treatments are aimed at targeting neuronal population, even if studies show that astrocytes play a key role after a brain damage. In this work, we propose a new model of in vitro traumatic brain-like injury and use paracrine factors released by human mesenchymal stem cells (hMSCs) as a neuroprotective strategy. Our results demonstrate that hMSC-conditioned medium increased wound closure and proliferation at 12 h and reduced superoxide production to control conditions. This was accompanied by changes in cell morphology and polarity index, as both parameters reflect the ability of cells to migrate toward the wound. These findings indicate that hMSC is an important regulator of oxidative stress production, enhances cells migration, and shall be considered as a useful neuroprotective approach for brain recovery following injury.

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Cartilage Protective and Immunomodulatory Features of Osteoarthritis Synovial Fluid-Treated Adipose-Derived Mesenchymal Stem Cells Secreted Factors and Extracellular Vesicles-Embedded miRNAs

Cells ◽

10.3390/cells10051072 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1072

Author(s):

Enrico Ragni ◽

Alessandra Colombini ◽

Marco Viganò ◽

Francesca Libonati ◽

Carlotta Perucca Orfei ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Synovial Fluid ◽

Extracellular Vesicles ◽

Immune Cell ◽

Macrophage Polarization ◽

M2 Macrophage ◽

Paracrine Factors ◽

Cell Proliferation Inhibition

Intra-articular administration of adipose-derived mesenchymal stem cells (ASCs), either in vitro expanded or within adipose tissue-based products obtained at point-of-care, has gained popularity as innovative regenerative medicine approach for osteoarthritis (OA) treatment. ASCs can stimulate tissue repair and immunomodulation through paracrine factors, both soluble and extracellular vesicles (EV) embedded, collectively defining the secretome. Interaction with the degenerative/inflamed environment is a crucial factor in understanding the finely tuned molecular message but, to date, the majority of reports have described ASC-secretome features in resting conditions or under chemical stimuli far from the in vivo environment of degenerated OA joints. In this report, the secretory profile of ASCs treated with native synovial fluid from OA patients was evaluated, sifting 200 soluble factors and 754 EV-embedded miRNAs. Fifty-eight factors and 223 EV-miRNAs were identified, and discussed in the frame of cartilage and immune cell homeostasis. Bioinformatics gave a molecular basis for M2 macrophage polarization, T cell proliferation inhibition and T reg expansion enhancement, as well as cartilage protection, further confirmed in an in vitro model of OA chondrocytes. Moreover, a strong influence on immune cell chemotaxis emerged. In conclusion, obtained molecular data support the regenerative and immunomodulatory properties of ASCs when interacting with osteoarthritic joint environment.

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Paracrine Factors Secreted by Umbilical Cord-Derived Mesenchymal Stem Cells Induce Angiogenesis In Vitro by a VEGF-Independent Pathway

Stem Cells and Development ◽

10.1089/scd.2014.0184 ◽

2015 ◽

Vol 24 (4) ◽

pp. 437-450 ◽

Cited By ~ 40

Author(s):

Pushpa Kuchroo ◽

Viral Dave ◽

Ajay Vijayan ◽

Chandra Viswanathan ◽

Deepa Ghosh

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Umbilical Cord ◽

Paracrine Factors

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ET-33 * PLACENTA-DERIVED MESENCHYMAL STEM CELLS AND THEIR SECRETED EXOSOMES INHIBIT THE SELF-RENEWAL AND STEMNESS OF GLIOMA STEM CELLS IN VITRO AND IN VIVO

Neuro-Oncology ◽

10.1093/neuonc/nou255.33 ◽

2014 ◽

Vol 16 (suppl 5) ◽

pp. v86-v87

Author(s):

H. K. Lee ◽

E. Buchris ◽

S. Finniss ◽

S. Cazacu ◽

C. Xiang ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

The Self ◽

Glioma Stem Cells ◽

Self Renewal

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Platelet-Derived Growth Factor Stimulated Migration of Bone Marrow Mesenchymal Stem Cells into an Injectable Gelatin-Hydroxyphenyl Propionic Acid Matrix

Biomedicines ◽

10.3390/biomedicines9020203 ◽

2021 ◽

Vol 9 (2) ◽

pp. 203

Author(s):

Wanting Niu ◽

Teck Chuan Lim ◽

Abdulmonem Alshihri ◽

Ravikumar Rajappa ◽

Lishan Wang ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Growth Factor ◽

Propionic Acid ◽

Platelet Derived Growth Factor ◽

Paracrine Factors ◽

Proliferation And Differentiation ◽

Marrow Mesenchymal Stem Cells

Bone marrow mesenchymal stem cells (bMSCs) are responsible in the repair of injured tissue through differentiation into multiple cell types and secretion of paracrine factors, and thus have a broad application profile in tissue engineering/regenerative medicine, especially for the musculoskeletal system. The lesion due to injury or disease may be a closed irregular-shaped cavity deep within tissue necessitating an injectable biomaterial permissive of host (endogenous) cell migration, proliferation and differentiation. Gelatin-hydroxyphenyl propionic acid (Gtn-HPA) is a natural biopolymer hydrogel which is covalently cross-linked by horseradish peroxidase (HRP) and hydrogen peroxide (H2O2) in situ and can be delivered to the lesion by needle injection. Growth factors and cytokines can be directly incorporated into the gel or into nano- and micro-particles, which can be employed for sustained release of biomolecules while maintaining their bioactivity. In this study, we selected polyelectrolyte complex nanoparticles (PCNs) prepared with dextran sulfate and chitosan as the carrier for platelet-derived growth factor (PDGF)-BB and stromal cell-derived factor (SDF)-1α, which have been tested effectively in recruiting stem cells. Our in vitro results showed a high degree of viability of bMSCs through the process of Gtn-HPA covalent cross-linking gelation. The Gtn-HPA matrix was highly permissive of bMSC migration, proliferation, and differentiation. PDGF-BB (20 ng/mL) directly incorporated into the gel and, alternatively, released from PCNs stimulated bMSC migration and proliferation. There were only small differences in the results for the direct incorporation of PDGF into the gel compared with its release from PCNs, and for increased doses of the growth factor (200 ng/mL and 2 µg/mL). In contrast, SDF-1α elicited an increase in migration and proliferation only when released from PCNs; its effect on migration was notably less than PDGF-BB. The in vitro results demonstrate that PDGF-BB substantially increases migration of bMSCs into Gtn-HPA and their proliferation in the gel, and that these benefits can be derived from incorporation of a relatively low dose of the growth factor directly into the gel. These findings commend the use of Gtn-HPA/PDGF-BB as an injectable therapeutic agent to treat defects in musculoskeletal tissues.

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Abstract 2327: Placenta-derived mesenchymal stem cells and their secreted exosomes inhibit the self-renewal and stemness of glioma stem cells in vitro and in vivo

10.1158/1538-7445.am2015-2327 ◽

2015 ◽

Author(s):

Chaya Brodie ◽

Edrat Buchris ◽

Susan Finniss ◽

Simona Cazacu ◽

Cunli Xiang ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

The Self ◽

Glioma Stem Cells ◽

Self Renewal

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Tissue Constructs with Human Adipose-Derived Mesenchymal Stem Cells to Treat Bone Defects in Rats

Materials ◽

10.3390/ma12142268 ◽

2019 ◽

Vol 12 (14) ◽

pp. 2268 ◽

Cited By ~ 8

Author(s):

Guilherme Caetano ◽

Weiguang Wang ◽

Adriana Murashima ◽

José Roberto Passarini ◽

Leonardo Bagne ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Bone Defects ◽

Bone Morphogenetic Protein 2 ◽

Porous Scaffolds ◽

Paracrine Factors ◽

Tissue Constructs ◽

Rat Tissue

The use of porous scaffolds created by additive manufacturing is considered a viable approach for the regeneration of critical-size bone defects. This paper investigates the xenotransplantation of polycaprolactone (PCL) tissue constructs seeded with differentiated and undifferentiated human adipose-derived mesenchymal stem cells (hADSCs) to treat calvarial critical-sized defect in Wistar rats. PCL scaffolds without cells were also considered. In vitro and in vivo biological evaluations were performed to assess the feasibility of these different approaches. In the case of cell seeded scaffolds, it was possible to observe the presence of hADSCs in the rat tissue contributing directly (osteoblasts) and indirectly (stimulation by paracrine factors) to tissue formation, organization and mineralization. The presence of bone morphogenetic protein-2 (BMP-2) in the rat tissue treated with cell-seeded PCL scaffolds suggests that the paracrine factors of undifferentiated hADSC cells could stimulate BMP-2 production by surrounding cells, leading to osteogenesis. Moreover, BMP-2 acts synergistically with growth factors to induce angiogenesis, leading to higher numbers of blood vessels in the groups containing undifferentiated and differentiated hADSCs.

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STEM-19. THE ISOLATION AND IDENTIFICATION OF GLIOMA STEM CELLS AND MESENCHYMAL STEM CELLS FROM HUMAN GLIOMA SPECIMENS

Neuro-Oncology ◽

10.1093/neuonc/noaa215.836 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii200-ii200

Author(s):

Yan-jiao Yu ◽

Wang Jing ◽

Zhong-ping Chen

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Tumor Microenvironment ◽

Cell Suspension ◽

Primary Culture ◽

Glioma Stem Cells ◽

Isolation And Identification ◽

Primary Malignancy ◽

The Relationship

Abstract INTRODUCTION Glioma is the primary malignancy with the highest incidence in central nervous system. Studies have shown that glioma stem cell (GSC) is the important origin for recurrence and closely associated with tumor microenvironment. Glioma-associated human mesenchymal stem cells (GA-hMSCs), as an important part of the tumor microenvironment, might promote proliferation and invasion of GSC. We try to isolate GSCs and GA-hMSCs through glioma primary culture, and investigate the relationship between GSC and GA-hMSCs, as well as their roles in the recurrences of glioma. MATERIALS AND METHODS Five surgical specimens from patients with human high-grade glioma were collected for primary culture. The surgical specimens were cut up and digested with Dispase II (collagenase), terminated by adding plenty of DNase II. Cell suspension was collected and resuspended in conditional medium for MSC or GSC. After being cultured for several passages, GSCs were identified by immunofluorescence, and GA-hMSCs were identified by flow cytometry and in vitro differentiation assays. RESULTS Cell cultures were observed with an inverted phase-contrast microscope after 24 hours. Adherent GA-hMSCs were collected and the supernatant was discarded with non-adherent cells. GSC was cultured as neurospheres. The single-cell suspension was prepared from spheres of GSC to identify their surface expression profile by immunofluorescence assays after several passages. The results confirmed that GSCs positively expressed CD133, Nestin and SOX2, but did not express GFAP and Tublin III. GA-hMSCs positively expressed CD105, CD73, CD90 and negatively expressed CD45 and CD34. GA-hMSCs could differentiate into adipocytes, chondrocytes and osteocytes. CONCLUSION We isolated and identified GSCs and GA-hMSCs from glioma primary culture. Our future work will focus on the relationship between the two types of cells and their roles in the process of tumor recurrence based on the successful isolation of GSC and GA-hMSCs. Keywords: Glioma; Mesenchymal stem cells; Glioma stem cells; Recurrence

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