Mesenchymal stem cells and a vitamin D receptor agonist additively suppress T helper 17 cells and the related inflammatory response in the kidney

2014 ◽  
Vol 307 (12) ◽  
pp. F1412-F1426 ◽  
Author(s):  
Michelle M. Duffy ◽  
Bairbre A. McNicholas ◽  
David A. Monaghan ◽  
Shirley A. Hanley ◽  
Jill M. McMahon ◽  
...  
Keyword(s):  
Stem Cells ◽  
Vitamin D ◽  
Mesenchymal Stem Cells ◽  
Vitamin D Receptor ◽  
Inflammatory Responses ◽  
Interstitial Fibrosis ◽  
T Helper ◽  
Lymphocyte Antigen ◽  
Inflammatory Monocytes

Mesenchymal stem cells (MSCs) suppress T helper (Th)17 cell differentiation and are being clinically pursued for conditions associated with aberrant Th17 responses. Whether such immunomodulatory effects are enhanced by coadministration of MSCs with other agents is not well known. In the present study, individual and combined effects of MSCs and the vitamin D receptor (VDR) agonist paricalcitol on Th17 induction were investigated in vitro and in a mouse model of sterile kidney inflammation (unilateral ureteral obstruction). In vitro, MSCs and paricalcitol additively suppressed Th17 differentiation, although only MSCs suppressed expression of Th17-associated transcriptions factors. Combined administration of MSCs and paricalcitol resulted in an early ( day 3) reduction of intrarenal CD4+ and CD8+ T cells, CD11b+/lymphocyte antigen 6G+ neutrophils, and inflammatory (lymphocyte antigen 6Chi) monocytes as well as reduced transcript for IL-17 compared with untreated animals. Later ( day 8), obstructed kidneys of MSC/paricalcitol double-treated mice, but not mice treated with either intervention alone, had reduced tubular injury and interstitial fibrosis as well as lower numbers of neutrophils and inflammatory monocytes and an increase in the ratio between M2 (CD206+) and M1 (CD206−) macrophages compared with control mice. Adjunctive therapy with VDR agonists may enhance the immunosuppressive properties of MSCs in the setting of pathogenic Th17-type immune responses and related inflammatory responses.

scholarly journals Targeting Vitamin-D receptor (VDR) by a small molecule antagonist MeTC7 inhibits PD-L1 but controls THMYCN neuroblastoma growth PD-L1 independently

2020 ◽  
Author(s):  
Rakesh K. Singh ◽  
KyuKwang Kim ◽  
Rachael B. Rowswell-Turner ◽  
Jeanne N. Hansen ◽  
Negar Khazan ◽  
...  
Keyword(s):  
Vitamin D ◽  
Cancer Cells ◽  
Small Molecule ◽  
Vitamin D Receptor ◽  
Surface Expression ◽  
Small Molecule Antagonist ◽  
Inflammatory Monocytes ◽  
Pancreatic Cancer Cells ◽  
Stat3 Phosphorylation

AbstractVitamin-D receptor (VDR) mRNA is enriched in malignant lung, ovarian and pancreatic tissues and showed poor prognoses. Calcitriol and stable or CRISPR-directed VDR upregulation increased PD-L1mRNA and protein expression in cancer cells in-vitro. A ChIP assay showed the binding of VDR with VDREPD-L1. Stattic, a STAT3 phosphorylation inhibitor blocked calcitriol or VDR overexpression induced PD-L1 upregulation. MeTC7, a VDR antagonist developed by us, reduced PD-L1 expression on macrophages, ovarian, lung, breast, and pancreatic cancer cells in-vitro. In radiotherapy inducible PD-L1 model of orthotopic MC38 murine colon cancer, MeTC7 decreased PD-L1 surface expression, suppressed inflammatory monocytes (IMs) population and increased intra-tumoral CD69+PD1+CD8+T-cells. Intriguingly, MeTC7 reduced TH-MYCN transgenic neuroblastoma tumor growth without affecting PD-L1 and tumor immune milieu. In summary, Vitamin-D/VDR drives PD-L1 expression on cancer cells via STAT-3. Inhibiting VDR exhibited anti-checkpoint effects in orthotopic colon tumors, whereas PDL1-independent and anti-VDR/MYCN effects controlled growth of transgenic neuroblastoma and xenografted tumors.SummaryVitamin-D/VDR induces PD-L1 expression on cancer cells via STAT-3; and targeting VDR by a novel small molecule antagonist MeTC7 exhibits both anti-PD-L1 and anti-VDR/MYCN effects in tumor models.

The role of micro-vibration parameters in inflammatory responses of macrophages cultured on biphasic calcium phosphate ceramics and the resultant influence on osteogenic differentiation of mesenchymal stem cells

2021 ◽  
Author(s):  
Jinjie Wu ◽  
Yitao Tang ◽  
Ximing Pu ◽  
Menglu Wang ◽  
Fuying Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Inflammatory Response ◽  
Biphasic Calcium Phosphate ◽  
Inflammatory Responses ◽  
Mechanical Stimuli ◽  
Micro Vibration ◽  
Vibration Parameters

Despite in vitro studies have shown that biomaterials and mechanical stimuli can mediate the inflammatory response or regulate osteogenesis of MSCs, the underlying behaviour for inflammatory response of macrophages on...

scholarly journals BDNF-Overexpressing Engineered Mesenchymal Stem Cells Enhances Their Therapeutic Efficacy against Severe Neonatal Hypoxic Ischemic Brain Injury

2021 ◽  
Vol 22 (21) ◽  
pp. 11395
Author(s):  
So Yoon Ahn ◽  
Dong Kyung Sung ◽  
Yun Sil Chang ◽  
Se In Sung ◽  
Young Eun Kim ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Mesenchymal Stem Cells ◽  
Brain Injury ◽  
Therapeutic Efficacy ◽  
Inflammatory Responses ◽  
Apoptotic Cell ◽  
Glucose Deprivation

We investigated whether irradiated brain-derived neurotropic factor (BDNF)-overexpressing engineered human mesenchymal stem cells (BDNF-eMSCs) improve paracrine efficiency and, thus, the beneficial potency of naïve MSCs against severe hypoxic ischemic (HI) brain injury in newborn rats. Irradiated BDNF-eMSCs hyper-secreted BDNF > 10 fold and were >5 fold more effective than naïve MSCs in attenuating the oxygen-glucose deprivation-induced increase in cytotoxicity, oxidative stress, and cell death in vitro. Only the irradiated BDNF-eMSCs, but not naïve MSCs, showed significant attenuating effects on severe neonatal HI-induced short-term brain injury scores, long-term progress of brain infarct, increased apoptotic cell death, astrogliosis and inflammatory responses, and impaired negative geotaxis and rotarod tests in vivo. Our data, showing better paracrine potency and the resultant better therapeutic efficacy of the irradiated BDNF-eMSCs, compared to naïve MSCs, suggest that MSCs transfected with the BDNF gene might represent a better, new therapeutic strategy against severe neonatal HI brain injury.

scholarly journals Gingival Mesenchymal Stem Cells (GMSC)-derived Exosomes are more Immunosuppressive than GMSC in Ameliorating Collagen-induced Arthritis

2021 ◽  
Author(s):  
Xiaohong Tian ◽  
Wumei Wei ◽  
Yue Cao ◽  
Tianrang Ao ◽  
Feng Huang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Inflammatory Responses ◽  
Bone Erosion ◽  
T Cell Subsets ◽  
Dependent Manner ◽  
Collagen Induced Arthritis ◽  
Therapy Strategy ◽  
Th Cell

Abstract BackgroundRheumatoid arthritis (RA) is a chronic, progressive, and inflammatory autoimmune disease, and current approaches offer no cures for it. Although gingival mesenchymal stem cells (GMSC) have the potential to treat RA, MSC-based therapy faces many challenges such as immunogenicity and tumorigenicity. MSCs release extracellular vesicles (EVs) including exosomes that display a therapeutic effect in inflammatory disease models. However, the role of GMSC-derived exosomes (GMSC-Exo) has never been reported in RA. We herein compare the immunomodulatory function of GMSC-Exo and GMSC in collagen-induced arthritis (CIA) model and explore the underlying mechanisms.MethodsGMSC-Exo was isolated by differential ultracentrifugation. CIA was induced with the immunization of type II collagen (CII) and complete freund's adjuvant (CFA) in DBA/1J mice. GMSC-Exo or GMSC were injected i.v. into mice on day 21 after immunization. Immunosuppressive effects of GMSC-Exo or GMSC were investigated on CD4+ Th cell subsets in vitro and in CIA model.ResultsSystemic infusion of GMSC-Exo or GMSC significantly attenuated the severity of arthritis, resumed the balance of Th cell subsets, and reduced level of NF-κB p65/p50 in CIA mice. GMSC-Exo or GMSC significantly up-regulated CD4+Treg percentages and IL-10 level in a dose-dependent manner, while down-regulated CD4+Th1 and CD4+Th17 percentages as well as levels of inflammatory cytokines (IFN-γ, IL-17A) in vitro. Importantly, GMSC-Exo showed stronger effects than GMSC in inhibiting IL-17A and promoting IL-10, reducing incidence and bone erosion of arthritis.ConclusionsThe present study demonstrates for the first time that GMSC-Exo can alleviate inflammatory responses and bone erosion in CIA mice, which might occur via regulating the ratio of CD4+ T cell subsets (Th1, Th17 and Treg) and/or inhibiting the IL-17RA-Act1-TRAF6-NF-κB signal pathway. In addition, our results suggest that GMSC-Exo has more advantages than GMSC in treating CIA, and may offer a promising new cell-free therapy strategy for RA and other autoimmune diseases.

Autologous transplantation of mesenchymal stem cells into the portal vein of the miniature pig; a preliminary experiment for NOTES approach

2019 ◽  
Vol 98 (9) ◽  
pp. 350-355
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cell Therapy ◽  
Portal Vein ◽  
Liver Parenchyma ◽  
Miniature Pig ◽  
Hepatic Diseases ◽  
Study Results

Introduction: There is evidence that mesenchymal stem cells (MSCs) could trans-differentiate into the liver cells in vitro and in vivo and thus may be used as an unfailing source for stem cell therapy of liver disease. Combination of MSCs (with or without their differentiation in vitro) and minimally invasive procedures as laparoscopy or Natural Orifice Transluminal Endoscopic Surgery (NOTES) represents a chance for many patients waiting for liver transplantation in vain. Methods: Over 30 millions of autologous MSCs at passage 3 were transplanted via the portal vein in an eight months old miniature pig. The deposition of transplanted cells in liver parenchyma was evaluated histologically and the trans-differential potential of CM-DiI labeled cells was assessed by expression of pig albumin using immunofluorescence. Results: Three weeks after transplantation we detected the labeled cells (solitary, small clusters) in all 10 samples (2 samples from each lobe) but no diffuse distribution in the samples. The localization of CM-DiI+ cells was predominantly observed around the portal triads. We also detected the localization of albumin signal in CM-DiI labeled cells. Conclusion: The study results showed that the autologous MSCs (without additional hepatic differentiation in vitro) transplantation through the portal vein led to successful infiltration of intact miniature pig liver parenchyma with detectable in vivo trans-differentiation. NOTES as well as other newly developed surgical approaches in combination with cell therapy seem to be very promising for the treatment of hepatic diseases in near future.

In vitro effect of prolactin on the osteogenic potential of bone marrow mesenchymal stem cells of rats

2013 ◽  
Author(s):  
Melo Ocarino Natalia de ◽  
Silvia Silva Santos ◽  
Lorena Rocha ◽  
Juneo Freitas ◽  
Reis Amanda Maria Sena ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Osteogenic Potential ◽  
Marrow Mesenchymal Stem Cells ◽  
Vitro Effect
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