scholarly journals A Bifunctional Molecule with Lectin and Protease Inhibitor Activities Isolated from Crataeva tapia Bark Significantly Affects Cocultures of Mesenchymal Stem Cells and Glioblastoma Cells

Molecules ◽  
2019 ◽  
Vol 24 (11) ◽  
pp. 2109 ◽  
Author(s):  
Camila Ramalho Bonturi ◽  
Mariana Cristina Cabral Silva ◽  
Helena Motaln ◽  
Bruno Ramos Salu ◽  
Rodrigo da Silva Ferreira ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Cells ◽  
Tumor Stroma ◽  
Tree Bark ◽  
Cell Contact ◽  
Glioblastoma Cell ◽  
Glioblastoma Cells ◽  
Stromal Microenvironment

Currently available drugs for treatment of glioblastoma, the most aggressive brain tumor, remain inefficient, thus a plethora of natural compounds have already been shown to have antimalignant effects. However, these have not been tested for their impact on tumor cells in their microenvironment-simulated cell models, e.g., mesenchymal stem cells in coculture with glioblastoma cell U87 (GB). Mesenchymal stem cells (MSC) chemotactically infiltrate the glioblastoma microenvironment. Our previous studies have shown that bone-marrow derived MSCs impair U87 growth and invasion via paracrine and cell–cell contact-mediated cross-talk. Here, we report on a plant-derived protein, obtained from Crataeva tapia tree Bark Lectin (CrataBL), having protease inhibitory/lectin activities, and demonstrate its effects on glioblastoma cells U87 alone and their cocultures with MSCs. CrataBL inhibited U87 cell invasion and adhesion. Using a simplified model of the stromal microenvironment, i.e., GB/MSC direct cocultures, we demonstrated that CrataBL, when added in increased concentrations, caused cell cycle arrest and decreased cocultured cells’ viability and proliferation, but not invasion. The cocultured cells’ phenotypes were affected by CrataBL via a variety of secreted immunomodulatory cytokines, i.e., G-CSF, GM-CSF, IL-6, IL-8, and VEGF. We hypothesize that CrataBL plays a role by boosting the modulatory effects of MSCs on these glioblastoma cell lines and thus the effects of this and other natural lectins and/or inhibitors would certainly be different in the tumor microenvironment compared to tumor cells alone. We have provided clear evidence that it makes much more sense testing these potential therapeutic adjuvants in cocultures, mimicking heterogeneous tumor–stroma interactions with cancer cells in vivo. As such, CrataBL is suggested as a new candidate to approach adjuvant treatment of this deadly tumor.

scholarly journals Bone marrow mesenchymal stem cells promote prostate cancer cell stemness via cell–cell contact to activate the Jagged1/Notch1 pathway

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ji-wen Cheng ◽  
Li-xia Duan ◽  
Yang Yu ◽  
Pu Wang ◽  
Jia-le Feng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Western Blot ◽  
Cell Contact ◽  
Activity Levels ◽  
Tumor Resistance ◽  
Cell Cell

Abstract Background Mesenchymal stem cells (MSCs) play a crucial role in cancer development and tumor resistance to therapy in prostate cancer, but the influence of MSCs on the stemness potential of PCa cells by cell–cell contact remains unclear. In this study, we investigated the effect of direct contact of PCa cells with MSCs on the stemness of PCa and its mechanisms. Methods First, the flow cytometry, colony formation, and sphere formation were performed to determine the stemness of PCaMSCs, and the expression of stemness-related molecules (Sox2, Oct4, and Nanog) was investigated by western blot analysis. Then, we used western blot and qPCR to determine the activity levels of two candidate pathways and their downstream stemness-associated pathway. Finally, we verified the role of the significantly changed pathway by assessing the key factors in this pathway via in vitro and in vivo experiments. Results We established that MSCs promoted the stemness of PCa cells by cell–cell contact. We here established that the enhanced stemness of PCaMSCs was independent of the CCL5/CCR5 pathway. We also found that PCaMSCs up-regulated the expression of Notch signaling-related genes, and inhibition of Jagged1-Notch1 signaling in PCaMSCs cells significantly inhibited MSCs-induced stemness and tumorigenesis in vitro and in vivo. Conclusions Our results reveal a novel interaction between MSCs and PCa cells in promoting tumorigenesis through activation of the Jagged1/Notch1 pathway, providing a new therapeutic target for the treatment of PCa.

scholarly journals Research Status of Mesenchymal Stem Cells in Liver Transplantation

2019 ◽  
Vol 28 (12) ◽  
pp. 1490-1506 ◽  
Author(s):  
Yu You ◽  
Di-guang Wen ◽  
Jian-ping Gong ◽  
Zuo-jin Liu
Keyword(s):  
Stem Cells ◽  
Liver Transplantation ◽  
Clinical Trials ◽  
Mesenchymal Stem Cells ◽  
In Vivo Studies ◽  
Cell Contact ◽  
Clinical Effects ◽  
Clinical Safety

Liver transplantation has been deemed the best choice for end-stage liver disease patients but immune rejection after surgery is still a serious problem. Patients have to take immunosuppressive drugs for a long time after liver transplantation, and this often leads to many side effects. Mesenchymal stem cells (MSCs) gradually became of interest to researchers because of their powerful immunomodulatory effects. In the past, a large number of in vitro and in vivo studies have demonstrated the great potential of MSCs for participation in posttransplant immunomodulation. In addition, MSCs also have properties that may potentially benefit patients undergoing liver transplantation. This article aims to provide an overview of the current understanding of the immunomodulation achieved by the application of MSCs in liver transplantation, to discuss the problems that may be encountered when using MSCs in clinical practice, and to describe some of the underlying capabilities of MSCs in liver transplantation. Cell–cell contact, soluble molecules, and exosomes have been suggested to be critical approaches to MSCs’ immunoregulation in vitro; however, the exact mechanism, especially in vivo, is still unclear. In recent years, the clinical safety of MSCs has been proven by a series of clinical trials. The obstacles to the clinical application of MSCs are decreasing, but large sample clinical trials involving MSCs are still needed to further study their clinical effects.

scholarly journals Mesenchymal stem cells inhibit proliferation and apoptosis of tumor cells: impact on in vivo tumor growth

Leukemia ◽  
2006 ◽  
Vol 21 (2) ◽  
pp. 304-310 ◽  
Author(s):  
R Ramasamy ◽  
E W-F Lam ◽  
I Soeiro ◽  
V Tisato ◽  
D Bonnet ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Proliferation And Apoptosis

scholarly journals Mechanisms behind the Immunoregulatory Dialogue between Mesenchymal Stem Cells and Th17 Cells

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1660 ◽  
Author(s):  
Claudia Terraza-Aguirre ◽  
Mauricio Campos-Mora ◽  
Roberto Elizondo-Vega ◽  
Rafael A. Contreras-López ◽  
Patricia Luz-Crawford ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
Lupus Erythematosus ◽  
Th17 Cells ◽  
Cell Contact ◽  
T Helper 17 ◽  
Reduced Frequency

Mesenchymal stem cells (MSCs) exhibit potent immunoregulatory abilities by interacting with cells of the adaptive and innate immune system. In vitro, MSCs inhibit the differentiation of T cells into T helper 17 (Th17) cells and repress their proliferation. In vivo, the administration of MSCs to treat various experimental inflammatory and autoimmune diseases, such as rheumatoid arthritis, type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, and bowel disease showed promising therapeutic results. These therapeutic properties mediated by MSCs are associated with an attenuated immune response characterized by a reduced frequency of Th17 cells and the generation of regulatory T cells. In this manuscript, we review how MSC and Th17 cells interact, communicate, and exchange information through different ways such as cell-to-cell contact, secretion of soluble factors, and organelle transfer. Moreover, we discuss the consequences of this dynamic dialogue between MSC and Th17 well described by their phenotypic and functional plasticity.

scholarly journals The growth inhibitory effect of mesenchymal stem cells on tumor cells in vitro and in vivo

2008 ◽  
Vol 7 (2) ◽  
pp. 245-251 ◽  
Author(s):  
Yan-rong Lu ◽  
Yu Yuan ◽  
Xiu-jie Wang ◽  
Ling-ling Wei ◽  
You-nan Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Cells ◽  
Inhibitory Effect ◽  
Growth Inhibitory Effect ◽  
Growth Inhibitory

scholarly journals Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi's sarcoma

2006 ◽  
Vol 203 (5) ◽  
pp. 1235-1247 ◽  
Author(s):  
Aarif Y. Khakoo ◽  
Shibani Pati ◽  
Stasia A. Anderson ◽  
William Reid ◽  
Mohamed F. Elshal ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stromal Cells ◽  
Kaposi's Sarcoma ◽  
Human Mesenchymal Stem Cells ◽  
Kaposi’S Sarcoma ◽  
Stem Cell Population ◽  
Cell Contact ◽  
Human Mscs

Emerging evidence suggests that both human stem cells and mature stromal cells can play an important role in the development and growth of human malignancies. In contrast to these tumor-promoting properties, we observed that in an in vivo model of Kaposi's sarcoma (KS), intravenously (i.v.) injected human mesenchymal stem cells (MSCs) home to sites of tumorigenesis and potently inhibit tumor growth. We further show that human MSCs can inhibit the in vitro activation of the Akt protein kinase within some but not all tumor and primary cell lines. The inhibition of Akt activity requires the MSCs to make direct cell–cell contact and can be inhibited by a neutralizing antibody against E-cadherin. We further demonstrate that in vivo, Akt activation within KS cells is potently down-regulated in areas adjacent to MSC infiltration. Finally, the in vivo tumor-suppressive effects of MSCs correlates with their ability to inhibit target cell Akt activity, and KS tumors engineered to express a constitutively activated Akt construct are no longer sensitive to i.v. MSC administration. These results suggest that in contrast to other stem cells or normal stromal cells, MSCs possess intrinsic antineoplastic properties and that this stem cell population might be of particular utility for treating those human malignancies characterized by dysregulated Akt.

Dose and Timing Limitations in the Use of Bone Marrow-Derived Mesenchymal Stem Cells for the Treatment of Experimental Arthritis.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2326-2326
Author(s):  
Evangelia Yannaki ◽  
Anastasia Papadopoulou ◽  
Minas Yiangou ◽  
Evangelia Athanasiou ◽  
Argyrw Paraskeva ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
T Cell ◽  
Broad Spectrum ◽  
Synovial Membrane ◽  
Cell Contact ◽  
Dependent Manner

Abstract The recently recognized potential of mesenchymal stem cells (MSCs) to differentiate into a broad spectrum of tissues and to act as immune regulators beyond the barriers of embryonic germ layers and major histocombatibility comlex (MHC) restriction, has emerged intense research interest on their possible use in a broad spectrum of clinical entities. Although the immunoregulatory potential of MSCs has been shown to effectively control GvHD in several preclinical and clinical studies, their role in autoimmune diseases has not been extensively explored in animal models. The goal of this study was to investigate the in vitro effect of rat bone marrow-derived MSCs on cultured fibrobIast-like synoviocytes (FLS) and T-cells from the spleen after induction of adjuvant arthritis (AA) by FCA as well as their in vivo effect in a rat model of AA resembling human rheumatoid arthritis. MSCs were isolated from bone marrow and were characterized by CD45 negativity and CD54, CD29 positivity in FCM analysis. Differentiation assays were performed to confirm their adipogenic, osteogenic and chondrogenic potential. Culture of AA-FLS in the presence of supernatant from syngeneic (syng) or allogeneic (allo) MSCs at passage 2–3, reduced the AA-FLS (p<0.022) and the ConA-stimulated AA-T-cell (p=0.04) proliferation in a dose-dependent manner, as compared to AA-FLS or AA-T-cell proliferation in the absence of supernatant. Cell-to-cell contact by coculture of activated T-cells with syng or allo MSCs produced a stronger inhibition over the supernatant (p<0.0001), in all tested MSCs dilutions and even at the lowest MSCs :T-cell ratio of 0.05:1. The inhibitory effect of allo as compared to syng MSCs in activated AA T-cells, was stronger both by secreted agents (p=0.017) or by cell to cell contact (p=0.0001). In vivo, low doses of syng MSCs (0.5-5x10^5cell/recipient) administered iv, intrasplenic or intrabone marrow, at single or multiple infusions, didn’t significantly reduce the disease score of MSC-treated as compared to control rats. In contrast, repeated, higher dose (6x10^6cell/recipient), iv infusions of syng or allogeneic MSCs from male donors (Y+MSCs) to female recipients, before the onset of AA (d4 and d9 post AA induction) resulted in significantly lower arthritic scores when compared to control animals. MSC-treated animals preserved a rather normal joint architecture with focal synovial hyperplasia, limited pannus formation and without bone destruction or chondroplasia. In contrast, the joints of arthritic control rats, appeared with a thickened synovial membrane, erosive pannus and dense inflammatory cell infiltration, chondroplasia and osteoplasia. Reduced presence of CD3+, CD11b+, NF-kb+ cells and less intense angiogenesis (FVIII+cells) was demonstrated by immunohistochemistry in the synovium of transplanted rats as compared to the control group. No Y+MSCs were detected in the spleen, bone marrow or in cultured FLS from the synovial membrane at day30 post AA induction, by PCR (sry gene), immunohistochemistry (sry protein) or FISH (Y chromosome), suggesting that the observed benefit was mostly a result of immunomodulation not derived by MSCs homing to target tissues, or migration of MSCs to target tissues may have occured earlier. On the other hand, when the same cell dose was injected after the onset of arthritis (d13 and d20 post AA induction) no clinical benefit could be observed. Our data suggest that MSCs may represent a new therapeutic approach for autoimmune arthritis, however, due to dose and timing limitations in their use, further studies are needed to clinically exploit this potential.

scholarly journals Delivery of Anti-miRNA-221 for Colorectal Carcinoma Therapy Using Modified Cord Blood Mesenchymal Stem Cells-Derived Exosomes

2021 ◽  
Vol 8 ◽  
Author(s):  
Siqi Han ◽  
Guangchao Li ◽  
Meng Jia ◽  
Yulu Zhao ◽  
Chenglong He ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cord Blood ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Fusion Gene ◽  
Surface Proteins ◽  
Human Cord Blood

Background: Exosomes, as natural intercellular information carriers, have great potential in the field of drug delivery. Many studies have focused on modifying exosome surface proteins to allow drugs to specifically target cancer cells.Methods: In this study, human cord blood mesenchymal stromal cell-derived exosomes were used in the delivery of anti-miRNA oligonucleotides so as to be specifically ingested by tumor cells to perform anti-tumor functions. Mesenchymal stem cells modified by the fusion gene iRGD-Lamp2b were constructed to separate and purify exosomes, and the anti-miRNA-221 oligonucleotide (AMO) was loaded into the exosomes by electroporation.Results: The AMO-loaded exosomes (AMO-Exos) effectively inhibited the proliferation and clonal formation of colon cancer cells in vitro, and it was further found that AMO-Exos was taken up by tumor cells through interaction with the NRP-1 protein. The results of a xenograft tumor model also showed that iRGD-modified exosomes were obviously enriched in tumor sites, exerting excellent anti-tumor efficacy. In vivo imaging showed that exosomes were mainly distributed in liver, spleen, and lung tissues.Conclusion: Our results suggest that genetically modified exosomes could be an ideal natural nanostructure for anti-miRNA oligonucleotide delivery.

scholarly journals TMIC-37. INTERCELLULAR COMMUNICATION BETWEEN NORMAL AND TUMOR CELLS IN GLIOMA MICROENVIRONMENT

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi255-vi256
Author(s):  
Anwar Hossain ◽  
Irtiza Hasan ◽  
Satoshi Adachi ◽  
Daniel Ledbetter ◽  
Malcolm McDonald ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Microenvironment ◽  
Blood Vessels ◽  
Tumor Cells ◽  
Color Change ◽  
Human Mesenchymal Stem Cells ◽  
Cre Recombinase ◽  
Microvascular Proliferation

Abstract The interactions between tumors cells and their microenvironment are increasingly recognized as contributors to tumor growth and therapeutic resistance in glioblastoma (GBM). Mesenchymal Stem Cells (MSCs) have been implicated as components of the microenvironment of several cancers, but their contribution to GBM remains obscure. Recently we reported that GBMs contain cells resembling human mesenchymal stem cells, called Glioma-associated-MSCs (GA-hMSCs), based on our ability to isolate these cells from patient tumors (Figueroa, et al. Can Res 2017. 77, 5808–5819). In order to characterize the function of these cells in vivo, we used a PDGFRb promoter driven mouse model to track and modulate the behavior of endogenous MSCs (PDGFRb + cells). To generate tumors that mimic gliomas, we injected the RCAS-PDGF avian retrovirus into PDGFRb EGFP/nTVA mice. These mice express EGFP in PDGFRb expressing cells and RCAS receptor TVA under the control of the Nestin promoter and develop tumors. Immunostaining these tumors for GFP and CD31 determined that MSC like cells reside around blood vessels and are likely the major contributor of microvascular proliferation often seen in human gliomas. Additionally, we sought to see if there was communication between MSCs localized around blood vessels and the tumor. To this end, mice with Cre recombinase expression under the PDGFRb promoter were implanted with a GL-261 tumor harboring a dsRed/eGFP Cre recombinase/LoxP site. In these mice, tumor color change from red to green indicates transfer of Cre mRNA or protein from PDGFRb+ cells (MSCs) to tumor cells (GL-261dsRed/eGFP). We observed red to green transition in tumors, indicating that there is transfer of mRNA or protein, and further suggesting that there is direct communication between the tumor microenvironment and the tumor. Taken together, our findings emphasize the crucial role of MSCs in the tumor microenvironment.

scholarly journals Bidirectional and Opposite Effects of Naïve Mesenchymal Stem Cells Ontumor Growth and Progression

2019 ◽  
Vol 9 (4) ◽  
pp. 539-558 ◽  
Author(s):  
Faramarz Rahmatizadeh ◽  
Shiva Gholizadeh-Ghaleh Aziz ◽  
Khodadad Khodadadi ◽  
Maryam Lale Ataei ◽  
Esmaeil Ebrahimie ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Cells ◽  
Molecular Mechanisms ◽  
Tumor Development ◽  
Tumor Stroma ◽  
Cell Types ◽  
Great Promise ◽  
Tumor Tissues ◽  
Essential Components

Cancer has long been considered as a heterogeneous population of uncontrolled proliferation ofdifferent transformed cell types. The recent findings concerning tumorigeneses have highlightedthe fact that tumors can progress through tight relationships among tumor cells, cellular, andnon-cellular components which are present within tumor tissues. In recent years, studies haveshown that mesenchymal stem cells (MSCs) are essential components of non-tumor cells withinthe tumor tissues that can strongly affect tumor development. Several forms of MSCs have beenidentified within tumor stroma. Naïve (innate) mesenchymal stem cells (N-MSCs) derived fromdifferent sources are mostly recruited into the tumor stroma. N-MSCs exert dual and divergenteffects on tumor growth through different conditions and factors such as toll-like receptorpriming (TLR-priming), which is the primary underlying causes of opposite effects. Moreover,MSCs also have the contrary effects by various molecular mechanisms relying on direct cellto-cell connections and indirect communications through the autocrine, paracrine routes, andtumor microenvironment (TME).Overall, cell-based therapies will hold great promise to provide novel anticancer treatments.However, the application of intact MSCs in cancer treatment can theoretically cause adverseclinical outcomes. It is essential that to extensively analysis the effective factors and conditionsin which underlying mechanisms are adopted by MSCs when encounter with cancer.The aim is to review the cellular and molecular mechanisms underlying the dual effects ofMSCs followed by the importance of polarization of MSCs through priming of TLRs.<br />

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