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Human Umbilical Cord Mesenchymal Stem Cell Therapy Mitigates Interstitial Cystitis by Inhibiting Mast Cells.

ABSTRACT: BACKGROUND Interstitial cystitis (IC) is a recurrent and chronic inflammatory disease that compromises patients' quality of life. Effective treatments for IC are limited. This study aimed to evaluate the therapeutic potency of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) in an IC-induced rat model and investigate the potential molecular mechanism in a mast cell model (rat basophilic leukemia cells, RBL-2H3) in treating IC in a coculture system. MATERIAL AND METHODS The rat model of IC was induced by cyclophosphamide (CYP). Rats were randomly divided into 3 groups: sham, IC+PBS, and IC+MSC. In the coculture system, RBL-2H3 cells were sensitized overnight to Compound 48/80 (C48/80), cocultured with UC-MSCs for 3 days, and collected for subsequent experiments. RBL-2H3 cells were randomly divided into 3 groups: sham, C48, and UC-MSCs (C48+MSC). RESULTS The UC-MSCs marked by thymidine analog 5-ethynyl-2-deoxyuridine (EdU) were transplanted in the treatment group, and were densely distributed in the bladder. Accordingly, the conscious cystometry was measured and the bladder tissues were harvested. Compared with the sham group, the treated IC rats exhibited shorter bladder voiding intervals (307±35 vs 217±37 s; P<0.01), more integral epithelia, and less collagen fiber aggregation, infiltration and degranulation of mast cells, and inflammatory cytokines in the bladder tissue. In the coculture system, compared with the C48 group, the UC-MSC-treated RBL-2H3 cells had suppressed degranulation. CONCLUSIONS UC-MSCs treatment showed a promising therapeutic effect on treating IC in vivo and in vitro. UC-MSCs inhibit mast cell degranulation in IC and could be a potential therapeutic target to ameliorate inflammation in IC.

SUBMITTER: Xu Y

PROVIDER: S-EPMC8353995 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:OBJECTIVE:Interstitial cystitis (IC) is a chronic intractable disease. Recently, the potential application of stem cell (SC) therapy was suggested for IC management. This study aimed to establish an optimal SC source and verify the efficacy and safety of SC injection therapy in an IC rat model. DESIGN:After IC animal model induction, urine-derived stem cells (USCs), adipose tissue-derived stem cells (ADSCs), bone marrow-derived stem cells (BMSCs) and amniotic fluid-derived stem cells (AFSCs) were injected into the bladder submucosa. The following parameters were analysed: 1) functional improvement of bladder via cystometry, 2) histological changes and 3) inflammatory gene expression and regenerative potential of damaged bladder tissues. Additionally, an optimal method for SC introduction in terms of effective bladder regeneration was analysed. RESULTS:Intercontraction interval was significantly increased and inflammatory reactions and fibrotic changes were decreased in all of the SC-injected groups than in the control group. PCR analysis revealed that inflammatory gene expression significantly decreased in the USC-treated group than in the other groups. To confirm the optimal SC injection route in the IC rat model, group was divided according to the following criteria: 1) direction of SC injection into the bladder submucosa, 2) injection via tail vein, 3) transurethral instillation. In each analysis, the groups in which SCs were injected into the bladder submucosa showed significantly longer intercontraction interval, better morphologic regeneration and inhibition of bladder inflammatory reaction compared with the other groups. CONCLUSION:Regardless of the cell source, human tissue-derived mesenchymal SCs regenerated damaged bladder tissue, promoted functional recovery and inhibited inflammatory cell accumulation in an IC rat model; particularly, USC had the highest inhibitory effect on inflammation. Additionally, direct USC injection into the bladder submucosa was expected to have the best therapeutic effect, which will be an important factor for clinical applications in the future.

Project description:OBJECTIVE:To study the anti- fibrotic effect of human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-EXOs) and explore the mechanism. METHODS:Twenty-four C57 BL/6 mice were divided into 4 groups (n=6), including the control group treated with intratracheal injection of saline (3 mg/kg); lung fibrosis model group with intratracheal injection of 1.5 mg/mL bleomycin solution (prepared with saline, 3 mg/kg); EXOs1 group with intratracheal injection of 1.5 mg/mL bleomycin solution (3 mg/kg) and hUCMSC-EXOs (100 ?g/250 ?L, given by tail vein injection on the next day after modeling); and EXOs2 group with intratracheal injection of 1.5 mg/mL bleomycin solution (3 mg/kg) and hUCMSC-EXOs (100 ?g/250 ?L, given by tail vein injection on the 10th day after modeling). At 21 days after modeling, pulmonary index, lung tissue pathology and collagen deposition in the mice were assessed using HE staining and Masson staining. The expression level of TGF-?1 was detected using ELISA, and vimentin, E-cadherin and phosphorylated Smad2/3 (p-Smad2/3) were detected using immunohistochemical staining. CCK8 assay was used to evaluate the effect of hUCMSCEXOs on the viability of A549 cells, and Western blotting was used to detect the expression levels of p-Smad2/3, vimentin, and E-cadherin in the cells. RESULTS:Compared with those in the model group, the mice treated with hUCMSC-EXOs showed significantly reduced the pulmonary index (P < 0.05), collagen deposition, lung tissue pathologies, lowered expressions of TGF-?1 (P < 0.05), vimentin, and p-Smad2/3 and increased expression of E-cadherin. hUCMSC-EXOs given on the second day produced more pronounced effect than that given on the 11th day (P < 0.05). CCK8 assay results showed that hUCMSC-EXOs had no toxic effects on A549 cells (P > 0.05). Western blotting results showed that hUCMSC-EXOs treatment significantly increased the expression of E-cadherin and decreased the expressions of p-Smad2/3 and vimentin in the cells. CONCLUSIONS:hUCMSC-EXOs can alleviate pulmonary fibrosis in mice by inhibiting epithelialmesenchymal transition activated by the TGF-?1/Smad2/3 signaling pathway, and the inhibitory effect is more obvious when it is administered on the second day after modeling.

Project description:BackgroundHuman umbilical cord mesenchymal stem cells (UC-MSCs) are multipotent progenitor cells representing an attractive therapeutic tool for tissue damage and inflammation owing to their unique immunomodulatory properties. This study was designed to determine the protective effects and underlying mechanisms of UC-MSCs on acute liver failure (ALF).MethodsALF was induced in mice by intraperitoneal injection of D-galactosamine (D-GalN) and lipopolysaccharide (LPS). Mice were intravenously injected with 1×106 UC-MSCs one hour before or six hours after D-GalN/LPS injection. Liver function was valued by serum biochemical parameters and hematoxylin-eosin staining. Inflammatory cytokine and chemokine levels were measured by real-time PCR, and inflammatory cells infiltration was observed by immunofluorescence staining. Hepatocyte apoptosis and pyroptosis related proteins were detected by western blot. Murine macrophage Raw264.7 in the presentation of LPS was treated with the UC-MSCs condition medium (UC-MSCs-CM), and then the levels of inflammatory cytokines and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in Raw264.7 were measured.ResultsUC-MSCs significantly reduced the mortality, decreased serum alanine aminotransferase and aspartate aminotransferase levels, and improved the pathological damage. Moreover, UC-MSCs inhibited inflammatory cytokine and chemokine levels, especially TNF-α, interleukins-6 (IL-6), IL-1β, monocyte chemoattractant protein (MCP-1), CC-chemokines ligand 2 (CCL2), C-X-C motif ligand 2 (CXCL2), and reduced macrophage, neutrophil and T lymphocyte infiltration into the liver tissue. UC-MSCs also attenuated hepatocyte apoptosis, as evidenced by decreased TUNEL positive cells, increased Bcl-xl/Bax protein ratio and downregulated cleaved caspase 3 levels. NLRP3 inflammasome activation, IL-1β maturation and cleaved caspase1 were suppressed by UC-MSC administration. Furthermore, the UC-MSCs-CM reduced the levels of inflammatory cytokines and the activation of NLRP3 inflammasome in Raw264.7.ConclusionsOur results demonstrated that UC-MSCs exerted therapeutic effects on ALF by inhibiting apoptosis, inflammation, and pyroptosis.

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Human Umbilical Cord Mesenchymal Stem Cell Therapy Mitigates Interstitial Cystitis by Inhibiting Mast Cells.

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