Mesenchymal stem cells and the immune system – Immunosuppression without drugs

2008 ◽  
Vol 149 (8) ◽  
pp. 339-346 ◽  
Author(s):  
Judit Kiss ◽  
Veronika Urbán S. ◽  
Valéria Dudics ◽  
Virág Vas ◽  
Ferenc Uher
Keyword(s):  
Rheumatoid Arthritis ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Immune System ◽  
Graft Versus Host

A mesenchymalis őssejteket (MSC-ket) már számos szövettípusból sikeresen izolálták. Ezek a sejtek terápiás felhasználás szempontjából különösen ígéretesnek tűnnek a felnőtt szöveti őssejtek közül, mivel könnyen izolálhatók, és viszonylag egyszerű a fenntartásuk és szaporításuk in vitro, valamint képesek számos sejttípussá, többek között csont-, porc-, ín-, izom- és zsírsejtekké alakulni. A szervezetben ezek a sejtek biztosítják azokat a növekedési faktorokat és cytokineket, amelyek a vérképző sejtek osztódását és differenciálódását szabályozzák. In vivo képesek lehetnek sérült szövetek regenerálására a vesében, szívben, májban, hasnyálmirigyben és az emésztőrendszerben. Emellett az MSC-k immunmoduláló és gyulladáscsökkentő hatással is rendelkeznek, és allogén szervezetben is csak minimális immunválaszt váltanak ki. Bár a folyamat háttere még nem teljesen ismert, az e sejtek immunszuppresszív hatásán alapuló módszerek már a klinikai kipróbálás fázisában vannak, és lehetséges, hogy a jövőben az MSC-k segítségével allograft-kilökődés, graft versus host betegség, rheumatoid arthritis, autoimmun eredetű ízületi gyulladás és más olyan betegségek lesznek kezelhetők, amelyek esetében immunszuppresszió és szöveti regeneráció is szükséges. A jelen összefoglaló célja a mesenchymalis őssejtekről szóló irodalom áttekintése, különös tekintettel azok immunmoduláló tulajdonságaira és jövőbeli lehetséges klinikai felhasználására.

scholarly journals The Therapeutic Effect of ICAM-1-Overexpressing Mesenchymal Stem Cells on Acute Graft-Versus-Host Disease

2018 ◽  
Vol 46 (6) ◽  
pp. 2624-2635 ◽  
Author(s):  
Bo Tang ◽  
Xue Li ◽  
Yuanlin Liu ◽  
Xiuhui Chen ◽  
Ximei Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
T Cell ◽  
Mouse Model ◽  
Graft Versus Host Disease ◽  
Culture Methods ◽  
Graft Versus Host

Background/Aims: Mesenchymal stem cells (MSCs) do not readily migrate to appropriate sites, and this creates a major obstacle for their use in the treatment of graft-versus-host disease (GVHD). Intercellular adhesion molecule-1 (ICAM-1) can guide the homing of various immune cells to the proper anatomical location within secondary lymphoid organs (SLOs), which are the major niches for generating immune responses or tolerance. MSCs rarely migrate to SLOs after intravenous infusion, and are constitutively low expression of ICAM-1. So in our previous work, ICAM-1 was engineered into a murine MSC line C3H10T1/2 by retrovirus transfection system (ICAM-1MSCs). Here, we hypothesized that ICAM-1highMSCs may significantly improve their immunomodulatory effect. Methods: We used different co-culture methods combined with real-time PCR and flow cytometry to evaluate ICAM-1highMSCs immunomodulatory effect on dendritic cells (DCs) and T cells in vitro and in vivo. MSCs were labeled with carboxyfluorescein diacetate succinimidylester (CFSE) to detect its distribution in mouse model. Results: Our in vitro analyses revealed ICAM-1 MSCs could suppress DCs maturation according to co-culture methods and suppress the T cell immune response according to the mixed lymphocyte response (MLR) and lymphoblast transformation test (LTT) tests. We found that infusion of ICAM-1highMSCs potently prolonged the survival of GVHD mouse model. The infused ICAM-1highMSCs migrate to SLOs in vivo, and suppressed DCs maturation, suppressed CD4+ T cell differentiation to Th1 cells, and increased the ratios of Treg cells. Conclusions: Taken together, these data demonstrate that ICAM-1highMSCs had an enhanced immunosuppressive effect on DCs and T cells, which may help explain the protective effect in a GVHD model. This exciting therapeutic strategy may improve the clinical efficacy of MSC-based therapy for GVHD.

scholarly journals Chronic Inflammation-Induced Senescence Impairs Immunomodulatory Properties of Synovial Fluid Mesenchymal Stem Cells in Rheumatoid Arthritis

2021 ◽  
Author(s):  
Hyeon-Jeong Lee ◽  
Won-Jae Lee ◽  
Sun-Chul Hwang ◽  
Yong-Ho Choi ◽  
Saetbyul Kim ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Synovial Fluid ◽  
Chronic Inflammation ◽  
Cellular Senescence ◽  
Average Duration ◽  
Duration Of Disease

Abstract BackgroundAlthough immunomodulation properties of mesenchymal stem cells (MSCs) has been highlighted as a new therapy for autoimmune diseases, including rheumatoid arthritis (RA), the alteration of disease-specific characteristics of MSCs derived from elderly RA patients are not well understood. MethodsWe established the MSCs derived from synovial fluid (SF) from age-matched early (average duration of disease: 1.7 years) and long-standing (average duration of disease: 13.8 years) RA patients (E-/L-SF-MSCs) and then comparatively analyzed the characteristics of MSCs such as stemness, proliferation, cellular senescence, in vitro differentiation and in vivo immunomodulation properties.ResultsThe presence of MSC populations in the SF from RA patients was identified and we found that L-SF-MSCs exhibited impaired proliferation, intensified cellular senescence, reduced immunomodulation properties and attenuation of anti-arthritic capacity in an RA animal model than E-SF-MSCs. In particular, E-SF-MSCs demonstrated cellular senescence progression and attenuation of immunomodulation properties at similar levels to that of L-SF-MSCs in an RA joint mimicking milieu due to hypoxia and pro-inflammatory cytokine exposure. Due to long-term exposure to the chronic inflammation milieu, the progression of cellular senescence, attenuation of immunomodulation properties and loss of anti-arthritic potentials are more often identified in SF-MSCs of long-standing RA than early RA. ConclusionWe conclude that a chronic RA inflammation milieu affected the potential of MSCs; therefore, this work addresses the importance of understanding MSC characteristics during disease states prior to their application in patients.

Murine Mesenchymal Stem Cells Fail To Suppress Acute Graft Versus Host Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5253-5253
Author(s):  
William H. Peranteau ◽  
Andrea T. Badillo ◽  
Keith Alcorn ◽  
Stephanie Filice ◽  
Alan W. Flake
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Weight Loss ◽  
Mesenchymal Stem Cells ◽  
Human Mscs ◽  
Post Injection ◽  
Spleen Cells ◽  
Graft Versus Host

Abstract Mesenchymal stem cells (MSCs) are multipotent cells of potential clinical interest given their capacity for in vitro expansion and intriguing immunologic properties. Studies using human and murine MSCs demonstrated their ability to suppress stimulated T cells in vitro. Consequently, much interest has been generated in the ability of MSCs to prevent graft versus host disease (GVHD). In fact, a limited number of case reports suggest a therapeutic role of human MSCs in the treatment of GVHD. Although encouraging, no systematic study has been performed to assess the ability of MSCs to suppress GVHD in vivo. In the current study we utilize a purified population of adult bone marrow derived murine MSCs previously shown to be immunosuppressive in vitro to evaluate the therapeutic potential in vivo of MSCs in an established model of murine GVHD. Methods: 8–12 week old C57Bl/6xBalb/c F1 mice were given 750cGy irradiation in a Cs135 gamma irradiator. 16–20 hours after irradiation, the mice received one of four groups of donor cells via lateral tail vein injection: 1) 10e6 C57Bl/6 (B6) bone marrow cells (BM) (n=5), 2) 10e6 B6 BM cells + 30e6 B6 spleen cells (n=12) (GVHD inoculum), 3) 10e6 B6 BM cells + 30e6 B6 spleen cells + 1e6 B6 MSCs (n=4) or 4) 10e6 B6 BM cells + 30e6 B6 spleen cells + 1.5e5 B6 MSCs (n=7). Mice were weighed and assessed for physical signs of GVHD such as ruffled fur, desquamation, diarrhea and hunching prior to receiving irradiation and on a weekly basis following irradiation and injection of the cellular inoculum. Results: In accordance with previous studies, the injection of 30e6 parental (B6) spleen cells combined with 10e6 (B6) parental BM cells into an F1 (B6xBalb/c) recipient following 750cGy irradiation resulted in a reliable model of GVHD. All mice receiving this inoculum demonstrated physical signs of GVHD including hunching and ruffled fur by three weeks post injection with the progression to desquamation and diarrhea by 5 weeks post injection. Similar to mice receiving the GVHD inoculum, mice receiving 30e6 B6 spleen cells + 10e6 B6 BM cells + either 1e6 B6 MSCs or 1.5e5 B6 MSCs demonstrated physical signs of GVHD by 3 weeks post injection. Control mice receiving only 10e6 B6 BM cells after 750cGy irradiation remained healthy and did not demonstrate any signs of GVHD. As demonstrated in figure 1, coinjection of either 1e6 B6 MSCs or 1.5e5 B6 MSCs with 30e6 B6 spleen cells + 10e6 B6 BM cells did not result in any significant change in weight loss compared to those mice receiving the GVHD inoculum. Similarly, the survival of mice receiving the GVHD inoculum was not improved by the coinjection of either 1e6 B6 MSCs or 1.5e5 B6 MSCs (25% vs 0% vs 28.57% at 6 weeks post injection). Conclusion: Previous studies have supported an in vitro immunosuppressive function of MSCs and a limited number of human studies have highlighted the potential ability of human MSCs to suppress GVHD. Despite these previous findings the current study demonstrates that the intravenous injection of MHC matched murine MSCs at the time of GVHD induction in an established murine model of GVHD does not affect the onset or severity of GVHD as measured by physical exam, weight loss and survival. Figure Figure

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.

Differentiation of mesenchymal stem cells from humans and animals into insulin-producing cells: An overview in vitro induction forms

2020 ◽  
Vol 16 ◽  
Author(s):  
Bruna O. S. Câmara ◽  
Bruno M. Bertassoli ◽  
Natália M. Ocarino ◽  
Rogéria Serakides
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Culture Medium ◽  
Adipogenic Differentiation ◽  
Medium Composition ◽  
Cell Therapies ◽  
Insulin Producing Cells ◽  
Msc Differentiation

The use of stem cells in cell therapies has shown promising results in the treatment of several diseases, including diabetes mellitus, in both humans and animals. Mesenchymal stem cells (MSCs) can be isolated from various locations, including bone marrow, adipose tissues, synovia, muscles, dental pulp, umbilical cords, and the placenta. In vitro, by manipulating the composition of the culture medium or transfection, MSCs can differentiate into several cell lineages, including insulin-producing cells (IPCs). Unlike osteogenic, chondrogenic, and adipogenic differentiation, for which the culture medium and time are similar between studies, studies involving the induction of MSC differentiation in IPCs differ greatly. This divergence is usually evident in relation to the differentiation technique used, the composition of the culture medium, the cultivation time, which can vary from a few hours to several months, and the number of steps to complete differentiation. However, although there is no “gold standard” differentiation medium composition, most prominent studies mention the use of nicotinamide, exedin-4, ß-mercaptoethanol, fibroblast growth factor b (FGFb), and glucose in the culture medium to promote the differentiation of MSCs into IPCs. Therefore, the purpose of this review is to investigate the stages of MSC differentiation into IPCs both in vivo and in vitro, as well as address differentiation techniques and molecular actions and mechanisms by which some substances, such as nicotinamide, exedin-4, ßmercaptoethanol, FGFb, and glucose, participate in the differentiation process.

scholarly journals Lithium-Doped Biological-Derived Hydroxyapatite Coatings Sustain In Vitro Differentiation of Human Primary Mesenchymal Stem Cells to Osteoblasts

Coatings ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 781 ◽  
Author(s):  
Paula E. Florian ◽  
Liviu Duta ◽  
Valentina Grumezescu ◽  
Gianina Popescu-Pelin ◽  
Andrei C. Popescu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Doping Agent ◽  
Hydroxyapatite Coatings ◽  
3D Network ◽  
Immunofluorescence Labelling ◽  
Good Biocompatibility ◽  
Adhesion Process

This study is focused on the adhesion and differentiation of the human primary mesenchymal stem cells (hMSC) to osteoblasts lineage on biological-derived hydroxyapatite (BHA) and lithium-doped BHA (BHA:LiP) coatings synthesized by Pulsed Laser Deposition. An optimum adhesion of the cells on the surface of BHA:LiP coatings compared to control (uncoated Ti) was demonstrated using immunofluorescence labelling of actin and vinculin, two proteins involved in the initiation of the cell adhesion process. BHA:LiP coatings were also found to favor the differentiation of the hMSC towards an osteoblastic phenotype in the presence of osteoinductive medium, as revealed by the evaluation of osteoblast-specific markers, osteocalcin and alkaline phosphatase. Numerous nodules of mineralization secreted from osteoblast cells grown on the surface of BHA:LiP coatings and a 3D network-like organization of cells interconnected into the extracellular matrix were evidenced. These findings highlight the good biocompatibility of the BHA coatings and demonstrate that the use of lithium as a doping agent results in an enhanced osteointegration potential of the synthesized biomaterials, which might therefore represent viable candidates for future in vivo applications.

scholarly journals Comparative analysis of mouse bone marrow and adipose tissue mesenchymal stem cells for critical limb ischemia cell therapy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Pegah Nammian ◽  
Seyedeh-Leili Asadi-Yousefabad ◽  
Sajad Daneshi ◽  
Mohammad Hasan Sheikhha ◽  
Seyed Mohammad Bagher Tabei ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Adipose Tissue ◽  
Cell Therapy ◽  
Femoral Artery ◽  
Critical Limb Ischemia ◽  
Limb Ischemia

Abstract Introduction Critical limb ischemia (CLI) is the most advanced form of peripheral arterial disease (PAD) characterized by ischemic rest pain and non-healing ulcers. Currently, the standard therapy for CLI is the surgical reconstruction and endovascular therapy or limb amputation for patients with no treatment options. Neovasculogenesis induced by mesenchymal stem cells (MSCs) therapy is a promising approach to improve CLI. Owing to their angiogenic and immunomodulatory potential, MSCs are perfect candidates for the treatment of CLI. The purpose of this study was to determine and compare the in vitro and in vivo effects of allogeneic bone marrow mesenchymal stem cells (BM-MSCs) and adipose tissue mesenchymal stem cells (AT-MSCs) on CLI treatment. Methods For the first step, BM-MSCs and AT-MSCs were isolated and characterized for the characteristic MSC phenotypes. Then, femoral artery ligation and total excision of the femoral artery were performed on C57BL/6 mice to create a CLI model. The cells were evaluated for their in vitro and in vivo biological characteristics for CLI cell therapy. In order to determine these characteristics, the following tests were performed: morphology, flow cytometry, differentiation to osteocyte and adipocyte, wound healing assay, and behavioral tests including Tarlov, Ischemia, Modified ischemia, Function and the grade of limb necrosis scores, donor cell survival assay, and histological analysis. Results Our cellular and functional tests indicated that during 28 days after cell transplantation, BM-MSCs had a great effect on endothelial cell migration, muscle restructure, functional improvements, and neovascularization in ischemic tissues compared with AT-MSCs and control groups. Conclusions Allogeneic BM-MSC transplantation resulted in a more effective recovery from critical limb ischemia compared to AT-MSCs transplantation. In fact, BM-MSC transplantation could be considered as a promising therapy for diseases with insufficient angiogenesis including hindlimb ischemia.

scholarly journals Adropin-based dual treatment enhances the therapeutic potential of mesenchymal stem cells in rat myocardial infarction

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
HuiYa Li ◽  
DanQing Hu ◽  
Guilin Chen ◽  
DeDong Zheng ◽  
ShuMei Li ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Therapeutic Potential ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Paracrine Factors ◽  
Dual Treatment

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.

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.

Combined Effects of Bone Marrow-Derived Mesenchymal Stem Cells and PLGA-PEG-PLGA Scaffolds on Repair of Articular Cartilage Defect

2013 ◽  
Vol 815 ◽  
pp. 345-349 ◽  
Author(s):  
Ching Wen Hsu ◽  
Ping Liu ◽  
Song Song Zhu ◽  
Feng Deng ◽  
Bi Zhang
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Articular Cartilage ◽  
Growth Factor ◽  
Cartilage Defect ◽  
Cartilage Regeneration ◽  
Tissue Growth ◽  
Cartilage Defects

Here we reported a combined technique for articular cartilage repair, consisting of bone arrow mesenchymal stem cells (BMMSCs) and poly (dl-lactide-co-glycolide-b-ethylene glycol-b-dl-lactide-co-glycolide) (PLGA-PEG-PLGA) triblock copolymers carried with tissue growth factor (TGF-belat1). In the present study, BMMSCs seeded on PLGA-PEG-PLGA with were incubated in vitro, carried or not TGF-belta1, Then the effects of the composite on repair of cartilage defect were evaluated in rabbit knee joints in vivo. Full-thickness cartilage defects (diameter: 5 mm; depth: 3 mm) in the patellar groove were either left empty (n=18), implanted with BMMSCs/PLGA (n=18), TGF-belta1 modified BMMSCs/PLGA-PEG-PLGA. The defect area was examined grossly, histologically at 6, 24 weeks postoperatively. After implantation, the BMMSCs /PLGA-PEG-PLGA with TGF-belta1 group showed successful hyaline-like cartilage regeneration similar to normal cartilage, which was superior to the other groups using gross examination, qualitative and quantitative histology. These findings suggested that a combination of BMMSCs/PLGA-PEG-PLGA carried with tissue growth factor (TGF-belat1) may be an alternative treatment for large osteochondral defects in high loading sites.

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