scholarly journals Mesenchymal Stem Cells Derived from Adipose Accelerate the Progression of Colon Cancer by Inducing a MT-CAFs Phenotype via TRPC3/NF-KB Axis

2021 ◽  
Author(s):  
Chunling Xue ◽  
Yang Gao ◽  
Xuechun Li ◽  
Mingjia Zhang ◽  
Ying Yang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Colon Cancer ◽  
Mesenchymal Stem Cells ◽  
Ion Channel ◽  
Tumor Progression ◽  
Signaling Pathway ◽  
Calcium Influx ◽  
Critical Role ◽  
Migration And Invasion ◽  
Channel Protein

Abstract Background: There is increasing evidence that mesenchymal stem cells (MSCs) help shape the tumor microenvironment and promote tumor progression, and ion channels might play a critical role in this process. Methods: Gene chip was used for a general analysis of gene expression changes in MSC-transformed CAF cells (MT-CAFs). We screened out the ion channel protein TRPC3 with WB detecion and lentivirus knockdown. Calcium influx was detected by two-photon microscope. MTS and Transwell detected growth, migration, and invasion of MT-CAFs and HCT116 cells. Bioinformatic tools and clinical specimens were to assess the relationship between TRPC3 and surrvival.Results: We screened out the ion channel protein TRPC3 with significantly increased expression, which caused calcium influx, and further activated the NF-KB signaling pathway. Knockdown or inhibition of TRPC3 in MSCs significantly reduced the activation of NF-KB, and decreased the growth, migration, and invasion of MT-CAFs. After TRPC3 knockdown, the ability of MT- CAFs to promote tumor migration and invasion was impaired. Conversely, the upregulation of TRPC3 expression in MT-CAFs had the opposite effect. In vivo, TRPC3 expressed on MSCs also contributed to the tumorigenesis and progression of cancer cells. In addition, the Oncomine and GEPIA databases showed that TRPC3 expression is higher in colon cancer tissue compared with normal colon tissues, and is positively correlated with the expression of the CAF genes alpha-smooth muscle (α-SMA/ACTA2) and fibroblast activation protein Alpha (FAP). The disease-free survival of patients with positive TRPC3 expression in mesenchymal cells was significantly shorter than in those with negative expression. Conclusions: These results indicate that TRPC3 expressed on MT-CAFs plays a critical role in tumor progression via the NF-KB signaling pathway, and is correlated with poor prognosis in colon cancer patients. Therefore, TRPC3 may be a novel therapeutic target for the treatment of colon cancer.

scholarly journals Mesenchymal stem cells maintain the stemness of colon cancer stem cells via interleukin-8/mitogen-activated protein kinase signaling pathway

2020 ◽  
Vol 245 (6) ◽  
pp. 562-575
Author(s):  
Xiaoying Ma ◽  
Jiajun Liu ◽  
Xiaotong Yang ◽  
Kai Fang ◽  
Peiyong Zheng ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Colon Cancer ◽  
Mesenchymal Stem Cells ◽  
Signaling Pathway ◽  
Theoretical Basis ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein

Mesenchymal stem cells (MSCs) can act as a carrier in tumor therapy, and tumor suppressor gene-modified MSCs can reach and suppress the tumor. However, in the colon cancer microenvironment, MSCs could promote tumor growth and create the environment that is conducive to the survival of cancer stem cells (CSCs). This study discovered MSCs from three sources (bone marrow, adipose, placenta) could induce the stemness and epithelial–mesenchymal transition (EMT) of HCT116 in vitro, meanwhile adipose- and placenta-derived MSCs increase the proportion of CD133+/CD44+ HCT116. Then, we explored the interaction mechanism between CD133+/CD44+ HCT116 and MSCs by the bioinformatics and in vitro assays. After CD133+/CD44+ HCT116 were co-cultured with MSCs, many cytokines in MSCs were stimulated, including interleukin-8 (IL-8). The binding of IL-8/CXCR2 activates the downstream mitogen-activated protein kinase (MAPK) signaling pathway in colon CSCs, thereby promoting the stemness and EMT. However, inhibition of IL-8/CXCR2/Erk1/2 could reverse the effect of MSCs on CSC stemness. In addition, MSCs co-cultured with CD133+/CD44+ HCT116 produce a carcinoma-associated fibroblast phenotype via intracellular FGF10–PKA–Akt–β-catenin signaling, which can be attenuated by IL-8 peptide inhibitor. To conclude, IL-8 promotes the interaction between colon CSCs and MSCs, and activates the MAPK signaling pathway in colon CSCs, which provides a theoretical basis for the application of MSCs in clinical practice. Impact statement MSCs have the property of chemotaxis and they can migrate to the tumor site by paracrine pathway in the tumor environment, and then interact with tumor cells. Although a mass of studies have been conducted about the impact of MSCs on tumors, it is still controversial whether the exogenous MSCs promote or inhibit tumor growth. In this work, we evaluated the effects of MSCs from three sources (bone marrow, adipose, placenta) on the proliferation, stemness, and metastasis of the colon cancer cells both in vitro and in vivo. Then, we proved the IL-8/CXCR2/MAPK and FGF10–PKA–Akt–β-catenin signaling pathway which mediate the interplay between MSC and CD133+/CD44+ colon cancer cell. This research aims to provide a theoretical basis for the safe application of MSCs in the clinical treatment of colon cancer.

scholarly journals Characterization of Mesenchymal Stem Cells Derived from Bisphosphonate-Related Osteonecrosis of the Jaw Patients’ Gingiva

2021 ◽  
Author(s):  
Mengyu Li ◽  
Jiajia Wang ◽  
Yejia Yu ◽  
Yuqiong Zhou ◽  
Yueqi Shi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Wound Healing ◽  
Mesenchymal Stem Cells ◽  
Signaling Pathway ◽  
Critical Role ◽  
Osteonecrosis Of The Jaw ◽  
Skin Model ◽  
Tgf Β1

AbstractBisphosphonate-related osteonecrosis of the jaw (BRONJ) is a clinical condition that specifically occurs in the oral cavity, characterized by retarded wound healing in oral mucosa accelerating the exposure of bone. Moreover, the pathological mechanism remains poorly understood. Gingival mesenchymal stem cells (GMSCs) play a critical role in gingival healing and soft tissue regeneration. Although previous studies have showed that bisphosphonates (BPs) are highly toxic to healthy GMSC, there is overall lack of direct evidence demonstrating the characterization of GMSCs derived from BRONJ patients. In present study, we isolated GMSCs for the first time from the central area of BRONJ patients’ gingiva (center-BRONJ GMSCs) and the peripheral area (peri-BRONJ GMSCs), and found that they exhibited decreased proliferation, adhesion, migration capacities and underwent early apoptosis in vitro compared control GMSCs. Notably, the central and peripheral BRONJ GMSCs transplantation in a mice excisional skin model also displayed lower cell survival rate and poor healing effects than that of controls. Mechanistically, TGF-β1 signaling pathway was suppressed not only in BRONJ patients’ gingival lesions but also in BRONJ GMSCs transplantation animal model. The results above suggested that under the microenvironment of BRONJ patients, the dysfunction of GMSCs and the suppressed TGF-β1 signaling pathway may be the vital factors in impaired gingival healing, thus contributing to persistent exposure of underlying bone and development of BRONJ. This study provides new insights into the prevention for BRONJ by improving the functions of GMSCs and upregulating TGF-β1 in accelerating gingival wound healing. Graphical Abstract Schematic illustration of the dysfunction of BRONJ GMSCs in vitro and BRONJ GMSCs transplantation in a mice skin model delaying cutaneous wound healing mainly via suppressing TGF-β1 signaling pathway.

scholarly journals An Orchestrated Response To Tumor Signals By Macrophages and Mesenchymal Stem Cells Potentiates Interleukin-6 Secretion In Glioblastoma

2014 ◽  
Vol 1 (1) ◽  
Author(s):  
Kevin Anton ◽  
John Glod
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Cell ◽  
Tumor Progression ◽  
Interleukin 6 ◽  
Critical Role ◽  
Soluble Factors ◽  
Secreted Factors ◽  
Secretion Profile ◽  
Cytokine Secretion Profile

AbstractThe tumor microenvironment plays a critical role in the survival, growth, invasion, and metastasis of solid tumors. However, the mechanisms by which it influences these aspects of tumor progression remain incompletely characterized. In this study, we show that human glioblastoma cells secrete soluble factors that alter the phenotype and cytokine secretion profile of both macrophages and mesenchymal stem cells (MSCs). Macrophages and MSCs respond to tumor-secreted factors by increasing the release of interleukin-6 (IL-6) and this response is potentiated when macrophages and MSCs are combined in co-culture. In glioblastoma, IL-6 has been associated with tumor cell invasion, angiogenesis, tumor cell proliferation, immune suppression, and poor prognosis. Our results suggest that the orchestrated response of macrophages and stromal elements to neoplastic cells enhances tumor progression through the release of soluble factors.

Overexpression of Pygo2 Increases Differentiation of Human Umbilical Cord Mesenchymal Stem Cells into Cardiomyocyte-like Cells

2020 ◽  
Vol 20 (4) ◽  
pp. 318-324 ◽  
Author(s):  
Lei Yang ◽  
Shuoji Zhu ◽  
Yongqing Li ◽  
Jian Zhuang ◽  
Jimei Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Umbilical Cord ◽  
Heart Function ◽  
Critical Role ◽  
Human Umbilical Cord ◽  
Stem Cell Markers ◽  
Quantitative Real Time Pcr ◽  
Qrt Pcr

Background: Our previous studies have shown that Pygo (Pygopus) in Drosophila plays a critical role in adult heart function that is likely conserved in mammals. However, its role in the differentiation of human umbilical cord mesenchymal stem cells (hUC-MSCs) into cardiomyocytes remains unknown. Objective: To investigate the role of pygo2 in the differentiation of hUC-MSCs into cardiomyocytes. Methods: Third passage hUC-MSCs were divided into two groups: a p+ group infected with the GV492-pygo2 virus and a p− group infected with the GV492 virus. After infection and 3 or 21 days of incubation, Quantitative real-time PCR (qRT-PCR) was performed to detect pluripotency markers, including OCT-4 and SOX2. Nkx2.5, Gata-4 and cTnT were detected by immunofluorescence at 7, 14 and 21 days post-infection, respectively. Expression of cardiac-related genes—including Nkx2.5, Gata-4, TNNT2, MEF2c, ISL-1, FOXH1, KDR, αMHC and α-Actin—were analyzed by qRT-PCR following transfection with the virus at one, two and three weeks. Results : After three days of incubation, there were no significant changes in the expression of the pluripotency stem cell markers OCT-4 and SOX2 in the p+ group hUC-MSCs relative to controls (OCT-4: 1.03 ± 0.096 VS 1, P > 0.05, SOX2: 1.071 ± 0.189 VS 1, P > 0.05); however, after 21 days, significant decreases were observed (OCT-4: 0.164 ± 0.098 VS 1, P < 0.01, SOX2: 0.209 ± 0.109 VS 1, P < 0.001). Seven days following incubation, expression of mesoderm specialisation markers, such as Nkx2.5, Gata-4, MEF2c and KDR, were increased; at 14 days following incubation, expression of cardiac genes, such as Nkx2.5, Gata-4, TNNT2, MEF2c, ISL-1, FOXH1, KDR, αMHC and α-Actin, were significantly upregulated in the p+ group relative to the p− group (P < 0.05). Taken together, these findings suggest that overexpression of pygo2 results in more hUCMSCs gradually differentiating into cardiomyocyte-like cells. Conclusion: We are the first to show that overexpression of pygo2 significantly enhances the expression of cardiac-genic genes, including Nkx2.5 and Gata-4, and promotes the differentiation of hUC-MSCs into cardiomyocyte-like cells.

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