scholarly journals Secretome of Hypoxic Endothelial Cells Stimulates Bone Marrow-Derived Mesenchymal Stem Cells to Enhance Alternative Activation of Macrophages

2020 ◽  
Vol 21 (12) ◽  
pp. 4409 ◽  
Author(s):  
Kang-Ju Chou ◽  
Chih-Yang Hsu ◽  
Chien-Wei Huang ◽  
Hsin-Yu Chen ◽  
Shih-Hsiang Ou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Mesenchymal Stem Cells ◽  
Macrophage Polarization ◽  
Alternative Activation ◽  
Cellular Interaction ◽  
Cell Contact ◽  
Tnf Α ◽  
Ifn Γ

We intended to explore the cellular interaction between mesenchymal stem cells (MSCs) and injured endothelial cells leading to macrophage alternative polarization in healing kidney ischemic reperfusion injury. In vivo, the amounts of recruited macrophages were significantly mitigated by MSCs in the injured tissues, especially in the group using hematopoietic cell E- and L-selectin ligand (HCELL)-positive MSCs. Compared to controls, MSCs also enhanced expression of CD206 and CD163, which was further enhanced by HCELL expression. In vitro, analysis of cytokines involving macrophage polarization showed IL-13 rather than IL-4 from MSCs agreed with expression of macrophage CD206 in the presence of hypoxic endothelial cells. Among them, HCELL-positive MSCs in contact with hypoxic endothelial cells produced the greatest response, which were reduced without HCELL or using a transwell to prevent cell contact. With blockade of the respective cytokine, downregulated MSCs secretion of IL-13 and CD206 expression were observed using inhibitors of IFN-γ and TNF-α, but not using those of TGF-β and NO. With IFN-γ and TNF-α, MSCs IL-13 secretion and CD206 expression were upregulated. In conclusion, hypoxia induces endothelial cells producing multiple cytokines. Among them, IFN-γ and TNF-α that stimulate MSCs to secrete IL-13 but not IL-4, leading to alternative polarization.

scholarly journals Inflammatory cytokines-stimulated human muscle stem cells ameliorate ulcerative colitis via the IDO-TSG6 axis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shengchao Zhang ◽  
Jiankai Fang ◽  
Zhanhong Liu ◽  
Pengbo Hou ◽  
Lijuan Cao ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Inflammatory Cytokines ◽  
Human Muscle ◽  
Enzyme Linked Immunosorbent Assay ◽  
Muscle Stem Cells ◽  
Tnf Α ◽  
Ifn Γ ◽  
Anti Inflammatory

Abstract Background Muscle stem cells (MuSCs) are absolutely required for the formation, repair, and regeneration of skeletal muscle tissue. Increasing evidence demonstrated that tissue stem cells, especially mesenchymal stem cells (MSCs), can exert therapeutic effects on various degenerative and inflammatory disorders based on their immunoregulatory properties. Human mesenchymal stem cells (hMSCs) treated with interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) were reported to possess anti-inflammatory functions by producing TNF-stimulated gene 6 (TSG-6). However, whether human muscle stem cells (hMuSCs) also possess TSG-6 mediated anti-inflammatory functions has not been explored. Methods The ulcerative colitis mouse model was established by subjecting mice to dextran sulfate sodium (DSS) in drinking water for 7 days. hMuSCs were pretreated with IFN-γ and TNF-α for 48 h and were then transplanted intravenously at day 2 of DSS administration. Body weights were monitored daily. Indoleamine 2,3-dioxygenase (IDO) and TSG-6 in hMuSCs were knocked down with short hairpin RNA (shRNA) and small interfering RNA (siRNA), respectively. Colon tissues were collected for length measurement and histopathological examination. The serum level of IL-6 in mice was measured by enzyme-linked immunosorbent assay (ELISA). Real-time PCR and Western blot analysis were performed to evaluate gene expression. Results hMuSCs treated with inflammatory factors significantly ameliorated inflammatory bowel disease (IBD) symptoms. IDO and TSG-6 were greatly upregulated and required for the beneficial effects of hMuSCs on IBD. Mechanistically, the tryptophan metabolites, kynurenine (KYN) or kynurenic acid (KYNA) produced by IDO, augmented the expression of TSG-6 through activating their common receptor aryl hydrocarbon receptor (AHR). Conclusion Inflammatory cytokines-treated hMuSCs can alleviate DSS-induced colitis through IDO-mediated TSG-6 production.

scholarly journals Tailored Hydrogels as Delivery Platforms for Conditioned Medium from Mesenchymal Stem Cells in a Model of Acute Colitis in Mice

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1127
Author(s):  
Juan Sendon-Lago ◽  
Lorena Garcia-del Rio ◽  
Noemi Eiro ◽  
Patricia Diaz-Rodriguez ◽  
Leandro Avila ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Body Weight ◽  
Conditioned Medium ◽  
Local Treatment ◽  
Histopathological Analysis ◽  
Mrna Levels ◽  
Acute Colitis ◽  
Tnf Α ◽  
Ifn Γ

Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is increasingly prevalent and current therapies are not completely effective. Mesenchymal stem cells are emerging as a promising therapeutic option. Here, the effect of local hydrogel application loaded with conditioned medium (CM) from human uterine cervical stem cells (hUCESC-CM) in an experimental acute colitis mice model has been evaluated. Colitis induction was carried out in C57BL/6 mice by dissolving dextran sulfate sodium (DSS) in drinking water for nine days. Ulcers were treated by rectal administration of either mesalazine (as positive control) or a mucoadhesive and thermosensitive hydrogel loaded with hUCESC-CM (H-hUCESC-CM). Body weight changes, colon length, and histopathological analysis were evaluated. In addition, pro-inflammatory TNF-α, IL-6, and IFN-γ mRNA levels were measured by qPCR. Treatment with H-hUCESC-CM inhibited body weight loss and colon shortening and induced a significant decrease in colon mucosa degeneration, as well as TNF-α, IFN-γ, and IL-6 mRNA levels. Results indicate that H-hUCESC-CM effectively alleviated DSS-induced colitis in mice, suggesting that H-hUCESC-CM may represent an attractive cell-free therapy for local treatment of IBD.

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.

Abstract 558: Microchanneled Polysaccharide Hydrogel Laden With Endothelial Cells and Mesenchymal Stem Cells With VEGF Facilitate Formation of Vascular Structures and Are Effective for Repairing Tissue Ischemia

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Sangho Lee ◽  
Min Kyung Lee ◽  
Hyunjoon Kong ◽  
Young-sup Yoon
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Mesenchymal Stem Cells ◽  
Cell Survival ◽  
Vascular Structure ◽  
Hindlimb Ischemia ◽  
Alginate Hydrogel ◽  
Vessel Formation

Various hydrogels are used to create vascular structure in vitro or to improve cell engraftment to overcome low cell survival in vivo, a main hurdle for bare cell therapy Recently we developed a modified alginate hydrogel within which microchannels are aligned to guide the direction and spatial organization of loaded cells. We investigated whether these cell constructs in which HUVECs and human mesenchymal stem cells (hMSCs) are co-loaded in this novel microchanneled hydrogel facilitate formation of vessels in vitro and in vivo, and enhance recovery of hindlimb ischemia. We crafted a modified alginate hydrogel which has microchannels, incorporates a cell adhesion peptide RGD, and was encapsulated with VEGF. We then compared vascular structure formation between the HUVEC only (2 x 105 cells) group and the HUVEC plus hMSC group. In the HUVEC+hMSC group, we mixed HUVECs and hMSCs at the ratio of 3:1. For cell tracking, we labeled HUVECs with DiO, a green fluorescence dye. After loading cells into the microchannels of the hydrogel, these constructs were cultured for seven days and were examined by confocal microscopy. In the HUVEC only group, HUVECs stands as round shaped cells without forming tubular structures within the hydrogel. However, in the HUVEC+hMSC group, HUVECs were stretched out and connected with each other, and formed vessel-like structure following pre-designed microchannels. These results suggested that hMSCs play a critical role for vessel formation by HUVECs. We next determined their in vivo effects using a mouse hindlimb ischemia model. We found that engineered HUVEC+hMSC group showed significantly higher perfusion over 4 weeks compared to the engineered HUVEC only group or bare cell (HUVEC) group. Confocal microscopic analysis of harvested tissues showed more robust vessel formation within and outside of the cell constructs and longer term cell survival in HUVEC+hMSC group compared to the other groups. In conclusion, this novel microchanneled alginate hydrogel facilitates aligned vessel formation of endothelial cells when combined with MSCs. This vessel-embedded hydrogel constructs consisting of HUVECs and MSCs contribute to perfusable vessel formation, prolong cell survival in vivo, and are effective for recovering limb ischemia.

scholarly journals The Immunomodulatory Effect of Triptolide on Mesenchymal Stem Cells in Vitro

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5011-5011
Author(s):  
Haiping He ◽  
Atsuko Takahashi ◽  
Yuki Yamamoto ◽  
Akiko Hori ◽  
Yuta Miharu ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Cd8 T Cells ◽  
Research Funding ◽  
Complete Medium ◽  
Surface Markers ◽  
Rt Pcr ◽  
Tnf Α ◽  
Ifn Γ

Background: Mesenchymal stromal cells (MSC) are known to have the immunosuppressive ability and have been applied in clinic to treat acute graft-versus-host disease (GVHD), as one of severe complications after hematopoietic stem cells transplantation (HSCT) in Japan. However, MSC are activated to suppress the immune system only upon the stimulation of inflammatory cytokines and the clinical results of MSC therapies for acute GVHD are varied. It is ideal that MSC are primed to be activated and ready to suppress the immunity (=priming) before administration in vivo. Triptolide (TPL) is a diterpene triepoxide purified from a Chinese herb - Tripterygium Wilfordii Hook F (TWHF). It has been shown to possess anti-inflammatory and immunosuppressive properties in vitro. In this study, we aim to use TPL as the activator for umbilical cord-derived MSC (UC-MSC) to entry stronger immunosuppressive status. Methods: The proliferation of UC-MSC with TPL at the indicated concentrations for different time of 24, 48, 72, and 96 hours. Cell counting kit-8(CCK-8) was added in the culture medium to detect cell toxicity and the absorbance was measured using microplate reader. Flow cytometry was used to identify the MSC surface markers expression. TPL-primed UC-MSC were once replaced with fresh medium and co-culture with mixed lymphocyte reaction (MLR) consisted with mononuclear cells (MNCs) stained with CFSE and irradiated allogenic dendritic cell line (PMDC05) in RPMI 1640 medium supplemented with 10 % FBS (complete medium). IDO-1, SOD1, and TGF-β gene expression in TPL-primed UC-MSC and UC-MSC induced by 10 ng/ml IFN-γ and/or 15 ng/ml TNF-α were evaluated by RT-PCR. PDL1 and PDL2 expression in TPL-primed UC-MSC and UC-MSC in response to IFN-γ and/or TNF-α were checked by Flowjo. Results: Exposure of TPL for UC-MSC for 72hour at the concentration above 0.1 μM resulted in the cell damage significantly. Therefore, we added TPL in UC-MSC at 0.01μM of TPL for up to 48 hours, then washed thourouphly for the following culture for experiments. To evaluate the influence of TPL on the surface markers of UC-MSC, we cultured UC-MSC for 4 hours in complete medium following culture with 0.01μM of TPL for 20 hours (TPL-primed UC-MSC). TPL-primed UC-MSC revealed positive for CD105, CD73, and CD90, negative for CD45, CD34, CD14 or CD11b, CD79α or CD19 and HLA-DR surface molecules as same as the non-primed UC-MSC. In MLR suppression by UC-MSC, the TPL-primed UC-MSC activity revealed stronger anti-proliferative effect on the CD4+ and CD8+ T cells activated by allogeneic DC than those of non-primed UC-MSC in MLR. Furthermore, the TPL-primed UC-MSC promoted the expression of IDO-1, SOD1 and TGF-β in response to IFN-γ+/-TNF-α by RT-PCR and enhanced the expression of PD-L1 by FACS analysis. Discussion:In this study, we found the TPL-primed UC-MSC showed stronger antiproliferative potency on CD4+ and CD8+ T cells compared with non-primed UC-MSC. TPL-primed UC-MSC promoted the expression of IDO-1, SOD1 and TGF-β stimulated by IFN-γ+/-TNF-α, although TPL alone did not induce these factors. Furthermore, we found that the PD1 ligand (PD-L1) was induced in TPL-primed UC-MSC, likely IFN-γ enhanced the PD-L1 expression, evaluated by flowcytometry. These results suggested that TPL-primed UC-MSC seemed more sensitive to be activated as the immunosuppressant. Here, we firstly report the new function of TPL to induce the upregulation of immunosuppressive effect, although the mechanisms of TPL inhibition to MSC need to be explore. Conclusively, TPL-primed UC-MSC might be applied for the immunosuppressive inducer of MSC. Figure Disclosures He: SASAGAWA Medical Scholarship: Research Funding; IMSUT Joint Research Project: Research Funding. Nagamura:AMED: Research Funding. Tojo:AMED: Research Funding; Torii Pharmaceutical: Research Funding. Nagamura-Inoue:AMED: Research Funding.

Mesenchymal Stem Cells Support Migration, Extracellular Matrix Invasion, Proliferation, and Survival of Endothelial Cells In Vitro

Stem Cells ◽  
2007 ◽  
Vol 25 (7) ◽  
pp. 1761-1768 ◽  
Author(s):  
Irina A. Potapova ◽  
Glenn R. Gaudette ◽  
Peter R. Brink ◽  
Richard B. Robinson ◽  
Michael R. Rosen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Extracellular Matrix ◽  
Endothelial Cells ◽  
Mesenchymal Stem Cells

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 1,25(OH)2D3 Differently Affects Immunomodulatory Activities of Mesenchymal Stem Cells Depending on the Presence of TNF-α, IL-1β and IFN-γ

2019 ◽  
Vol 8 (12) ◽  
pp. 2211 ◽  
Author(s):  
Christian Behm ◽  
Alice Blufstein ◽  
Johannes Gahn ◽  
Barbara Kubin ◽  
Michael Nemec ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Inflammatory Cytokines ◽  
T Lymphocyte ◽  
T Lymphocyte Proliferation ◽  
Tnf Α ◽  
Ifn Γ ◽  
Anti Inflammatory ◽  
Anti Inflammatory Cytokine ◽  
Necrosis Factor

Periodontal ligament-derived mesenchymal stem cells (hPDLSCs) possess immunomodulatory abilities which are strongly enhanced by various inflammatory cytokines. Vitamin D3 has anti-inflammatory effects on hPDLSCs and immune cells. However, no study to date has directly compared the influence of 1,25(OH)2D3 on the immunomodulatory activities of hPDLSCs in the presence of different cytokines. In the present study, the effects of hPDLSCs treated with tumor necrosis factor (TNF)-α, interleukin (IL)-1β, or interferon (IFN)-γ in the presence of 1,25(OH)2D3 on the proliferation of allogenic CD4+ T lymphocyte or on the functional status of primary CD68+ macrophages were analyzed in coculture models. Additionally, the effects of 1,25(OH)2D3 on TNF-α-, IL-1β-, and IFN-γ-induced gene expression of some immunomodulatory factors in hPDLSCs were compared. Under coculture conditions, 1,25(OH)2D3 increased or decreased CD4+ T lymphocyte proliferation via hPDLSCs, depending on the cytokine. hPDLSCs primed with 1,25(OH)2D3 and different cytokines affected pro- and anti-inflammatory cytokine expression in macrophages variably, depending on the priming cytokine. With one exception, 1,25(OH)2D3 significantly reduced TNF-α-, IL-1β-, and IFN-γ-induced expression of all the investigated immunomediators in hPDLSCs, albeit to different extents. These results suggest that 1,25(OH)2D3 influences the immunomodulatory activities of hPDLSCs depending qualitatively and quantitatively on the presence of certain inflammatory cytokines.

scholarly journals Atherogenic Cytokines Regulate VEGF-A-Induced Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells into Endothelial Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Izuagie Attairu Ikhapoh ◽  
Christopher J. Pelham ◽  
Devendra K. Agrawal
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Endothelial Cells ◽  
Mesenchymal Stem Cells ◽  
Tube Formation ◽  
Ang Ii ◽  
Induced Differentiation ◽  
Endothelial Tube Formation ◽  
Marker Expression

Coronary artery stenting or angioplasty procedures frequently result in long-term endothelial dysfunction or loss and complications including arterial thrombosis and myocardial infarction. Stem cell-based therapies have been proposed to support endothelial regeneration. Mesenchymal stem cells (MSCs) differentiate into endothelial cells (ECs) in the presence of VEGF-Ain vitro. Application of VEGF-A and MSC-derived ECs at the interventional site is a complex clinical challenge. In this study, we examined the effect of atherogenic cytokines (IL-6, TNFα, and Ang II) on EC differentiation and function. MSCs (CD44+, CD73+, CD90+, CD14−, and CD45−) were isolated from the bone marrow of Yucatan microswine. Naïve MSCs cultured in differentiation media containing VEGF-A (50 ng/mL) demonstrated increased expression of EC-specific markers (vWF, PECAM-1, and VE-cadherin), VEGFR-2 and Sox18, and enhanced endothelial tube formation. IL-6 or TNFαcaused a dose-dependent attenuation of EC marker expression in VEGF-A-stimulated MSCs. In contrast, Ang II enhanced EC marker expression in VEGF-A-stimulated MSCs. Addition of Ang II to VEGF-A and IL-6 or TNFαwas sufficient to rescue the EC phenotype. Thus, Ang II promotes but IL-6 and TNFαinhibit VEGF-A-induced differentiation of MSCs into ECs. These findings have important clinical implications for therapies intended to increase cardiac vascularity and reendothelialize coronary arteries following intervention.

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