Comparison of therapeutic effects of different mesenchymal stem cells on rheumatoid arthritis in mice

Background Rheumatoid arthritis (RA) is a chronic and nonspecific autoimmune disease, which leads to joint destruction and deformity. To investigate the potential of human mesenchymal stem cells (MSCs) as a new therapeutic strategy for patients with RA, we compared the therapeutic effects of bone marrow derived MSCs (BMSCs), umbilical cord derived MSCs (UCs), and stem cells derived from human exfoliated deciduous teeth (SHED) on collagen-induced arthritis (CIA) in mice. Methods A total of 24 DBA/1 mice were infused with type II collagen to induce RA in the experimental model. MSC-treated mice were infused with UCs, BMSCs, and SHED, respectively. Bone erosion and joint destruction were measured by micro-computed tomographic (micro-CT) analysis and hematoxylin and eosin staining. The levels of tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β) were measured by immunohistochemistry and Enzyme-Linked Immunosorbent Assay (ELISA). Results Systemic delivery of MSCs significantly improved the severity of the symptoms related to CIA to greater extent compared with the untreated control group. Micro-CT revealed reduced bone erosions in the metatarsophalangeal joints upon treatment with MSCs. Additionally, according to histologic evaluation, reduced synovitis and articular destruction were observed in MSC-treated groups. The levels of TNF-α and IL-1β in the serum and joints decreased with treatment by MSCs. Conclusion Our findings suggest that systemic infusion of UCs, BMSCs, and SHED may significantly alleviate the effects of RA. The therapeutic effect of BMSCs was greater than that of SHED, while the UCs were shown to have the best therapeutic effect on CIA mice. In conclusion, compared with BMSCs and SHED, UCs may be a more suitable source of MSCs for the treatment of patients with RA.

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Therapeutic Effects and Repair Mechanism of HGF Gene Transfected Mesenchymal Stem Cells on Injured Endometrium via Activating Phosphorylated c-Met

10.21203/rs.3.rs-466396/v1 ◽

2021 ◽

Author(s):

Xuan Xu ◽

Jianye Wang ◽

Liu Dong ◽

Qiong Xing ◽

Ying Wang ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Quantitative Polymerase Chain Reaction ◽

Akt Signaling ◽

Enzyme Linked Immunosorbent Assay ◽

Control Group ◽

Therapeutic Effects ◽

Related Factors ◽

Paracrine Factors ◽

Endometrial Epithelium

Abstract BackgroundThere are many studies on the advantages of mesenchymal stem cells (MSCs) that could secret various paracrine factors in repairing endometrial injury. It is necessary to improve the stability and effectiveness of MSCs. Hepatocyte growth factor (HGF), as one of the cytokines secreted by MSCs, plays a significant role in vascular repair and mesenchymal to epithelial transformation (MET). It can be deduced that HGF is closely related to the repair process of endometrium.Therefore, we aim to investigate the effect and mechanism of MSCs from umbilical cord transfected with HGF gene in the damaged mouse endometrium.MethodsHGF gene transfected MSCs were prepared by electroporation. After determining the cell characteristics and cell activity of HGF gene transfected MSCs, the ability of HGF gene transfected MSCs to express HGF was detected by enzyme-linked immunosorbent assay. Totally, 60 female mice were randomly divided into Control group, Saline group, MSCs group , and HGF gene-transfected MSCs (MSCshgf) group. Each group of mice received treatment after injury. HE staining were used to evaluate the changes in the thickness of endometrial epithelium and the number of endometrial glands. Immunofluorescence was used to evaluate the molecular repair effect. Real time fluorescent quantitative polymerase chain reaction was used to compare the expression of angiogenesis related factors. Western blot was used to detect the activation of HGF/c-Met and AKT signaling pathways.ResultsHGF gene transfected MSCs retained the characteristics of original MSCs, and the concentration of HGF secreted by MSCs transfected with HGF gene was higher than that of normal MSCs. Compared with normal MSCs, HGF gene transfected MSCs have a more effect in promoting the repair of damaged endometrial epithelium, mainly in significantly increasing the thickness of damaged endometrial epithelium, increasing the number of glands and proliferating cells(p<0.01). Meanwhile, HGF gene transfected MSCs can improve the expression level of endometrial vascular growth related factors and promote the MET process (p<0.01). At the same time, Western blotting confirmed that these repair effects were related to HGF activation of its receptor c-Met and downstream AKT signaling pathway.ConclusionsCompared with normal MSCs, HGF gene transfected MSCs have a more significant effect in repairing the damaged endometrial epithelium. This effect is achieved by activating the receptor c-Met of HGF and downstream AKT pathway.

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Mesenchymal Stem Cells Enhance Therapeutic Effect and Prevent Adverse Gastrointestinal Reaction of Methotrexate Treatment in Collagen-Induced Arthritis

Stem Cells International ◽

10.1155/2021/8850820 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Qiming Zhai ◽

Jiayi Dong ◽

Xuesi Zhang ◽

Xiaoning He ◽

Dongdong Fei ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Side Effects ◽

Adverse Events ◽

Therapeutic Effect ◽

Therapeutic Effects ◽

Collagen Induced Arthritis ◽

Combined Application ◽

Raw264.7 Macrophages

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by articular destruction and functional loss. Methotrexate (MTX) is effective in RA treatment. However, MTX induces several adverse events and 20%-30% of patients do not respond to MTX. Thus, it is urgent to enhance the therapeutic effects and reduce the side effects of MTX. Recent studies showed that mesenchymal stem cells (MSCs) were participants in anti-inflammation, immunoregulation, and tissue regeneration. However, whether the combined application of MSCs and MTX promotes the therapeutic effects and reduces the side effects of MTX has not been studied. In this study, we used bovine type II collagen to induce rheumatoid arthritis in mice (collagen-induced arthritis, CIA). Then, CIA mice were subjected to MTX or MSC treatment, or both. The therapeutic effect and adverse events of different treatments on RA were evaluated with micro-CT, HE staining, and immunohistochemistry in vivo. Apoptosis and proliferation of MODE-K cells were measured after treated with MTX or/and cocultured with UCs. To test M2 polarization, Raw264.7 macrophages were stimulated by MTX with different concentrations or cocultured with UCs. We found that the combined application of MSCs and MTX increased the therapeutic effects on RA, as evidenced by decreased arthritis score, inflammatory responses, and mortality. Moreover, in this combination remedy, MTX prefers to suppress inflammation by facilitating macrophage polarization to M2 type while UCs prefer to eliminate gastrointestinal side effects of MTX via mitigating the apoptosis of intestinal epithelial cells. Thus, a combination of MTX and UCs is a promising strategy for RA treatment.

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

Stem Cell Research & Therapy ◽

10.1186/s13287-020-02118-3 ◽

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.

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Intra-Articular Injection of Umbilical Cord Mesenchymal Stem Cells Loaded With Graphene Oxide Granular Lubrication Ameliorates Inflammatory Responses and Osteoporosis of the Subchondral Bone in Rabbits of Modified Papain-Induced Osteoarthritis

Frontiers in Endocrinology ◽

10.3389/fendo.2021.822294 ◽

2022 ◽

Vol 12 ◽

Author(s):

Aifeng Liu ◽

Jixin Chen ◽

Juntao Zhang ◽

Chao Zhang ◽

Qinxin Zhou ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Graphene Oxide ◽

Animal Models ◽

Cartilage Repair ◽

Subchondral Bone ◽

Inflammatory Responses ◽

Micro Ct ◽

Tnf Α ◽

Femoral Condyles

AimThis study is to investigate the effects of umbilical cord mesenchymal stem cells (UCMSCs) loaded with the graphene oxide (GO) granular lubrication on ameliorating inflammatory responses and osteoporosis of the subchondral bone in knee osteoarthritis (KOA) animal models.MethodsThe KOA animal models were established using modified papain joint injection. 24 male New Zealand rabbits were classified into the blank control group, GO group, UCMSCs group, and GO + UCMSCs group, respectively. The concentration in serum and articular fluid nitric oxide (NO), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), type II collagen (COL-II), and glycosaminoglycan (GAG) was detected using ELISA, followed by the dissection of femoral condyles and staining of HE and Micro-CT for observation via the microscope.ResultsGO granular lubrication and UCMSCs repaired the KOA animal models. NO, IL-6, TNF-α, GAG, and COL-II showed optimal improvement performance in the GO + UCMSCs group, with statistical significance in contrast to the blank group (P <0.01). Whereas, there was a great difference in levels of inflammatory factors in serum and joint fluid. Micro-CT scan results revealed the greatest efficacy of the GO + UCMSCs group in improving joint surface damage and subchondral bone osteoporosis. HE staining pathology for femoral condyles revealed that the cartilage repair effect in GO + UCMSCs, UCMSCs, GO, and blank groups were graded down.ConclusionUCMSCs loaded with graphene oxide granular lubrication can promote the secretion of chondrocytes, reduce the level of joint inflammation, ameliorate osteoporosis of the subchondral bone, and facilitate cartilage repair.

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Suppression of transforming growth factor-β by mesenchymal stem-cells accelerates liver regeneration in liver fibrosis animal model

Zinc supplementation improves heme biosynthesis in rats exposed to lead ◽

10.18051/univmed.2021.v40.29-35 ◽

2021 ◽

Vol 40 (1) ◽

pp. 29

Author(s):

Nur Anna C Sa’dyah ◽

Agung Putra ◽

Bayu Tirta Dirja ◽

Nurul Hidayah ◽

Salma Yasmine Azzahara ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Growth Factor ◽

Liver Fibrosis ◽

Transforming Growth Factor ◽

Healing Process ◽

Enzyme Linked Immunosorbent Assay ◽

Control Group ◽

Significant Difference ◽

T1 And T2

Introduction Liver fibrosis (LF) results from the unregulated chronic wound healing process in liver tissue. Transforming growth factor-beta (TGF-β) is the major contributing cytokine of LF promotion through activation of quiescent hepatic stellate cells (HSCs) into myofibroblasts (MFs) and increased extracellular matrix (ECM) deposition such as collagen leading to scar tissue development. Mesenchymal stem cells (MSCs) have an immunomodulatory capability that could be used as a new treatment for repairing and regenerating LF through suppression of TGF-β. This study aimed to examine the role of MSCs in liver fibrosis animal models through suppression of TGF-β levels without scar formation particularly in the proliferation phase. Methods In this study, a completely randomized design was used with sample size of 24. Male Sprague Dawley rats were injected intraperitoneally (IP) with carbon tetrachloride (CCl4), twice weekly, for eight weeks to induce LF. Rats were randomly assigned to four groups: negative control, CCl4 group, and CCL4 + MSC-treated groups T1 and T2, at doses of 1 x 106 and 2x106 cells, respectively. TGF-β levels were analyzed by enzyme-linked immunosorbent assay (ELISA). One-way ANOVA and a least significant difference (LSD) was used to analyse the data. Results The TGF levels of LF rat models decreased on day 7 after MSC administration. The levels of TGF-β in both MSC groups T1 and T2 decreased significantly compared with the control group (p<0.05). The TGF-β suppression capability of T2 was optimal and more significant than that of T1. Conclusion MSCs can suppress TGF levels in liver fibrosis induced rats.

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Infusion of Bone Marrow Mesenchymal Stem Cells Attenuates Experimental Severe Acute Pancreatitis in Rats

Stem Cells International ◽

10.1155/2016/7174319 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 6

Author(s):

Hang Zhao ◽

Zhiying He ◽

Dandan Huang ◽

Jun Gao ◽

Yanfang Gong ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Acute Pancreatitis ◽

Mesenchymal Stem Cells ◽

Survival Rate ◽

Severe Acute Pancreatitis ◽

Control Group ◽

Therapeutic Effects ◽

Isolation And Characterization ◽

Marrow Mesenchymal Stem Cells

Background & Aims. Severe acute pancreatitis (SAP) remains a high-mortality disease. Bone marrow (BM) mesenchymal stem cells (MSCs) have been demonstrated to have plasticity of transdifferentiation and to have immunomodulatory functions. In the present study, we assessed the roles of MSCs in SAP and the therapeutic effects of MSC on SAP after transplantation.Methods. A pancreatitis rat model was induced by the injection of taurocholic acid (TCA) into the pancreatic duct. After isolation and characterization of MSC from BM, MSC transplantation was conducted 24 hrs after SAP induction by tail vein injection. The survival rate was observed and MSCs were traced after transplantation. The expression of TNF-αand IL-1βmRNA in the transplantation group was also analyzed.Results. The survival rate of the transplantation group was significantly higher compared to the control group (p<0.05). Infused MSCs were detected in the pancreas and BM 3 days after transplantation. The expression of TNF-αand IL-1βmRNA in the transplantation group was significantly lower than in the control group in both the pancreas and the lungs (p<0.05).Conclusions. MSC transplantation could improve the prognosis of SAP rats. Engrafted MSCs have the capacity of homing, migration, and planting during the treatment of SAP.

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Therapeutic Benefits by Human Mesenchymal Stem Cells (hMSCs) and Ang-1 Gene-Modified hMSCs after Cerebral Ischemia

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9600527 ◽

2007 ◽

Vol 28 (2) ◽

pp. 329-340 ◽

Cited By ~ 156

Author(s):

Toshiyuki Onda ◽

Osamu Honmou ◽

Kuniaki Harada ◽

Kiyohiro Houkin ◽

Hirofumi Hamada ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cerebral Artery ◽

Human Mesenchymal Stem Cells ◽

Artery Occlusion ◽

Control Group ◽

Therapeutic Effects ◽

Lesion Volume ◽

Therapeutic Benefits ◽

Cerebral Artery Occlusion

Transplantation of human mesenchymal stem cells (hMSCs) prepared from adult bone marrow has been reported to ameliorate functional deficits after cerebral artery occlusion in rats. Although several hypotheses to account for these therapeutic effects have been suggested, current thinking is that both neuroprotection and angiogenesis are primarily responsible. In this study, we compared the effects of hMSCs and angiopoietin-1 gene-modified hMSCs (Ang-hMSCs) intravenously infused into rats 6 h after permanent middle cerebral artery occlusion. Magnetic resonance imaging and histologic analyses revealed that rats receiving hMSCs or Ang-hMSCs exhibited comparable reduction in gross lesion volume as compared with the control group. Although both cell types indeed improved angiogenesis near the border of the ischemic lesions, neovascularization and regional cerebral blood flow were greater in some border areas in Ang-hMSC group. Both hMSC- and Ang-hMSC-treated rats showed greater improved functional recovery in the treadmill stress test than did control rats, but the Ang-hMSC group was greater. These results indicate the intravenous administration of genetically modified hMSCs to express angiopoietin has a similar effect on reducing lesion volume as hMSCs, but the Ang-hMSC group showed enhanced regions of increased angiogenesis at the lesion border, and modest additional improvement in functional outcome.

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Therapeutic effect of various ginsenosides on rheumatoid arthritis

BMC Complementary Medicine and Therapies ◽

10.1186/s12906-021-03302-5 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Meng Zhang ◽

Hongwei Ren ◽

Kun Li ◽

Shengsheng Xie ◽

Ru Zhang ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Flow Cytometry ◽

T Cell ◽

Therapeutic Effect ◽

Negative Control Group ◽

Negative Control ◽

Control Group ◽

Potential Candidate ◽

Tnf Α ◽

Huvec Cells

Abstract Background Rheumatoid arthritis (RA) is an autoimmune disease which causes disability and threatens the health of humans. Therefore, it is of great significance to seek novel effective drugs for RA. It has been reported that various ginsenoside monomers are able to treat RA. However, it is still unclear which ginsenoside is the most effective and has the potential to be developed into an anti-RA drug. Methods The ginsenosides, including Rg1, Rg3, Rg5, Rb1, Rh2 and CK, were evaluated and compared for their therapeutic effect on RA. In in vitro cell studies, methotrexate (MTX) and 0.05% dimethyl sulfoxide (DMSO) was set as a positive control group and a negative control group, respectively. LPS-induced RAW264.7 cells and TNF-α-induced HUVEC cells were cultured with MTX, DMSO and six ginsenosides, respectively. Cell proliferation was analyzed by MTT assay and cell apoptosis was carried out by flow cytometry. CIA mice model was developed to evaluate the therapeutic efficacy of ginsenosides. The analysis of histology, immunohistochemistry, flow cytometry and cytokine detections of the joint tissues were performed to elucidate the action mechanisms of ginsenosides. Results All six ginsenosides showed good therapeutic effect on acute arthritis compared with the negative control group, Ginsenoside CK provided the most effective treatment ability. It could significantly inhibit the proliferation and promote the apoptosis of RAW 264.7 and HUVEC cells, and substantially reduce the swelling, redness, functional impairment of joints and the pathological changes of CIA mice. Meanwhile, CK could increase CD8 + T cell to down-regulate the immune response, decrease the number of activated CD4 + T cell and proinflammatory M1-macrophages, thus resulting in the inhibition of the secretion of proinflammatory cytokine such as TNF-α and IL-6. Conclusion Ginsenoside CK was proved to be a most potential candidate among the tested ginsenosides for the treatment of RA, with a strong anti-inflammation and immune modulating capabilities.

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