MenSCs ameliorate experimental colitis by protecting intestinal barrier integrity by inhibiting the NF-κB/Snail signaling pathway

doi:10.21203/rs.3.rs-4203502/v1

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MenSCs ameliorate experimental colitis by protecting intestinal barrier integrity by inhibiting the NF-κB/Snail signaling pathway

https://doi.org/10.21203/rs.3.rs-4203502/v1

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Background: Inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC) are chronic recurrent nonspecific intestinal disease that are characterized by intestinal epithelial barrier dysfunction and excessive activation of the mucosal immune system. In this study, we aimed to investigate the effects and mechanisms of menstrual blood-derived stem cells(MenSCs) against colon inflammation and mucosal tissue repair.

Methods: LPS-exposed human colonic epithelial cancer cell line Caco2, and HT29. Tight junction(TJ) proteins and the level of inflammatory factors were assessed by Western blot and qRT-PCR. MenSCswere co-cultured with LPS-exposed human colonic epithelial cancer cell line, HT29, dextran sulfate sodium (DSS)-induced IBD

mouse models were intravenously administered MenSCs. Effects of MenSCs on intestinal inflammation, and colon barrier function were investigated. Finally, NF-κB-snail signaling pathway were assessed by western blot.

Results: LPS downregulates intercellular junction proteins, and induces the production of inflammatory cytokines in intestinal epithelial cells. MenSCs mitigated DSS-induced colitis in mice, by reducing body weight loss, colonic shortening, and disease activity index scores and by inhibiting the expressions of the proinflammatory cytokines IL-1β, IL-6, and TNF-α. MenSCs increased the expression of TJ proteins, improved the destruction of tight junction (TJ) structures and reduced intestinal epithelial permeability. Furthermore, MenSCs could inhibit NF-κB p65 phosphorylation and the expression of Snail and prevent Snail nuclear localization, thereby maintaining tight and adherens junctions.

Conclusions: Our data demonstrate that MenSCsalleviates gut inflammation, protects intestinal mucosal barrier by inhibiting the NF-κB /Snail signaling pathway.

Inflammatory bowel disease

Ulcerative colitis

MenSCs

Tight junction

Intestinal barrier

NF-κB/Snail

Inflammatory bowel diseases are chronic, idiopathic intestinal inflammatory diseases, that mainly include ulcerative colitis (UC) and Crohn’s disease (CD)[1]. The incidence of IBD in Asia has been increasing in recent years. The pathogenesis of IBD is not fully understood, but is attributed to a variety of factors, including genetic predisposition, changes in the gut microbiome, innate and adaptive immune system deficiencies, and various environmental factors. In addition, IBD is caused by the inappropriate immune response of genetically susceptible hosts to pathogens[2], and its characteristics include an abnormal mucosal immune response and intestinal barrier function disorders[3]. Current pharmaceutical treatments for IBD broadly or selectively mainly target inflammatory processes, and include 5-aminosalicylic acid, steroids, antimicrobial agents, immunomodulators and monoclonal antibodies [4]. With the increasing incidence of IBD, existing therapies cannot meet clinical needs [5]. Accordingly, the development of safe and effective treatments against IBD is necessary.

The intestinal epithelial barrier is an anatomical and functional structure that segregates the internal environment from the luminal milieu, by protecting against invasion of antigens and microorganisms and absorbing essential fluids and nutrients[6, 7]. As a major component of this physical barrier, tight junctions (TJs) act as a circumferential belt to seal the paracellular space, thus inhibiting the penetration of specific substances across the epithelium. TJs mainly consist of three integral transmembrane proteins, occludin[8], claudins[9], and junctional adhesion molecule[10], which interact with zonula occludens (ZO) proteins[11, 12]. Therefore, targeting epithelial barrier function may be an effective approach for treating IBD.

Mesenchymal stem cells (MSCs) are multipotent progenitors with differentiation capabilities, which can be isolated from different tissue, such as adipose, umbilical cord, and bone marrow[13]. MSCs can be induced to differentiate into fat, bone, cartilage and other types of cells in vitro. At present, MSCs have shown good application prospects in the treatment of various diseases by secreting cytokines and mediating immune regulation[14]. Because of their advantages such as non-invasive sample collection, multiple collection from the same donor, access to a large number of seed cells with the same genetic background, and autotransplantation, blood derived endometrial stem cells (MenSCs) have gradually become an important cell source for stem cell therapy[15]. However, whether MenSCs play a critical role in intestinal barrier maintenance is still unknown. This study aimed to establish a model of intestinal epithelial cell injury and a mouse colitis model based on the structural damage of the intestinal epithelial barrier, to confirm that MenSCs can restore the function of the epithelial barrier and alleviate intestinal injury by repairing the tight junction structure of the intestinal epithelium, further explore the specific mechanism by whcich MenSCs repair intestinal epithelial barrier function in the treatment of colitis, and provide a feasible strategy for the treatment of clinical ulcerative colitis.

Reagents. Lipopolysaccharide (LPS) was purchased from Sigma (St. Louis, MO).Antibodies against E-cadherin, occludin, Claudin-1, ZO-1, AKTS473, and AKT were purchased from Cell Signaling Technology (Danvers, MA). Actin was obtained from Santa Cruz Biotechnology Inc. (San Diego, CA, USA) Alexa Fluor® 488 anti-rabbit IgG and Alexa Fluor® 488 anti-mouse IgG were purchased from Jackson ImmunoResearch Laboratories, Inc. (West Grove, PA, USA).

Cell culture. Caco-2, and HT-29 cells were purchased from the American Tissue Culture Collection (Manassas, VA). The cells were grown in complete DMEM supplemented with 10% fetal bovine serum, streptomycin, penicillin, and L-glutamine.

Animals. The use of animals was approved by the Institutional Animal Care and Use Committee of Xinxiang University and were carried out according to the Guide for the Care and Use of Laboratory Animals by the National Research Council. Female BALB/c mice (aged 6–8 weeks) were obtained from Vital River Laboratories [Beijing, China; license no. SCXK (Beijing) 2012-0001] and maintained in SPF facilities at Xinxiang University. The mice were administered 3% dextran sulfate sodium salt (DSS; 0216011080, MP Biomedicals) daily in drinking water for 7 days to induce the colitis. The mice in the MSC treatment group were injected with 1 × 10⁶ cells (suspended in 200 µL of saline) via the tail vein on Days 7, and 14. The mice in the PBS treatment group received an equal amount of saline. The mice were weighed, at the end of the experiment (Day 14), the mice were sacrificed, and their sera, and colon were harvested for further examination.

Real-time quantitative PCR. Total RNA was extracted from cells and tissues using the RNeasy Mini Kit (Qiagen). Reverse transcription and quantitative PCR were carried out using a PrimeScript RT reagent kit and SYBR Green Supermix (Takara, Dalian, China). Primers for,occludin, claudin-1, ZO-1, and GAPDH were obtained from GENEWIZ(Suzhou, China). The primer sequences are shown in Supplementary Table 1. The relative amount of each gene was normalized to that of GAPDH. The fold change was calculated by the ΔΔCT method. The percent expression was calculated as the ratio of the normalized value of each sample to that of the corresponding untreated control sample. All real-time RT-PCR analyses were performed in triplicate.

Western blot analysis. Cells were grown in 12-well plates, harvested and lysed in RIPA lysis buffer (P0013B, Beyotime). After being incubated on ice for 30 min, the cell lysates were centrifuged at 4°C, and 15,000 rpm for 15 min. The lysates were analyzed by Western blotting with antibodies (1:1000 or 1:2000) against the proteins of interest, followed by horseradish peroxidase-conjugated goat anti-rabbit or anti-mouse IgG (1:3000) and SuperSignal Western Pico enhanced chemiluminescence substrate (Pierce Chemical Co., Rockford, IL). The density of the bands was analyzed by using ImageJ software (NIH, Bethesda, MD, USA) (https://imagej.nih.gov/ij/) and normalized to their corresponding total proteins or β-actin as indicated. The quantified results are presented as the mean ± standard deviation (SD) from three experiments in bar graphs.

Immunofluorescence staining. Caco-2 cells were seeded on coverslips in 24-well flat-bottomed plates and treated with LPS for 24 h. The cells were fixed with 100% methanol at -20°C for 20 min. The cells were permeabilized with 0.25% Triton X-100 in PBS for 20 min and washed three times with PBS. The fixed cells were incubated with 5% bovine serum albumin (BSA) in PBS for 30 min at room temperature, and then with anti-occludin and anti-claudin-1 antibodies (1:100) in PBS overnight at 4°C. After being incubated, the cells were washed in blocking buffer and stained with Alexa488-conjugated anti-mouse and anti-rabbit IgG (1:100), for 1 h at room temperature. Finally, the cells were stained with 10 µΜ DAPI (4’,6-diamidino-2-phenylindole) for 5 min. After the cells were washed in PBS, fluorescent images were captured under a Nikon fluorescence microscope.

Statistical analysis. The differences in the mRNA levels and Western blot band densities in the cells exposed to LPS in the absence or presence of various treatments were statistically analyzed by using unpaired Student’s t tests. The data are presented as the mean ± SD of three independent experiments. A p value of < 0.05 was considered statistically significant. All statistical analyses were performed with GraphPad Prism (GraphPad software 8.0 (https://www.graphpad.com/scientific-software/prism).

LPS downregulates intercellular junction proteins. We investigated whether LPS could suppress intercellular junction protein expression. LPS decreased the levels of E-cadherin, occludin, claudin-1 and ZO-1 in a dose- and time-dependent manner in Caco2, and HT29 cells (Fig. 1A-D). We next determined whether LPS downregulated the expression of intercellular junctions at the transcriptional level. As shown in Fig. 2A-D, LPS significantly decreased the mRNA levels of E-cadherin, occludin, claudin-1 and ZO-1 in a dose-dependent manner.

LPS induces the production of inflammatory cytokines in intestinal epithelial cells. In Caco-2 cells stimulated with or without LPS, IL-1β, TNF-α, and IL-6 mRNA and protein expression were increased. Our results showed that LPS significantly increased IL-1β, TNF-α, and IL-6 levels(Fig. 3A, B). Western blot analysis revealed that the protein expression levels of L-1β, TNF-α, and IL-6 in the LPS group were significantly increased(Fig. 3C).

DSS downregulates the levels of intercellular junction proteins in the intestinal tissue of mice. We investigated whether DSS impairs intestinal epithelial barrier and downregulates the expression of tight junction protein. As shown in Fig. 4B, C, H&E staining revealed widespread edema and inflammatory cell infiltration in intestinal tissue. The pathological scores were significantly higher in the colitis mice than in the controls. The qPCR results demonstrated the upregulation of inflammatory factors, such as IL-1β, TNF-α, IL-6 in the intestinal tissue of colitis mice (Fig. 4D). DSS significantly decreased the levels of E-cadherin, occludin, claudin-1 and ZO-1 in the intestinal tissue of colitis mice (Fig. 4E). Immunofluorescence staining revealed that E-cadherin, occludin and claudin-1 expression was significantly decreased in the intercellular junctions of intestinal pithelial cells in colitis mice (Fig. 4F).

MenSCs alleviate LPS-induced tight junction structural damage. The therapeutic effects of MenSCs on tight junction structural damage were examined in intestinal epithelial cells stimulated with or without LPS. MenSCs effectively restored the levels of E-cadherin, occludin and claudin-1 in LPS-stimulated cells(Fig. 5A). Similarly, MenSCs effectively restored the E-cadherin, occludin and claudin-1 mRNA levels in LPS stimulated HT29 cells(Fig. 5B). The qPCR results demonstrated that MenSCs significantly decreased the levels of the inflammatory factors IL-1β, TNF-α, IL-6 (Fig. 5C). The transepithelial electrical resistance (TEER) assay revealed that MenSCs moderately prevented the decrease in electric resistance in LPS stimulated Caco-2 cells (Fig. 5D).

MenSCs attenuated chemically induced colitis in mice. The therapeutic effects of MenSCs on IBD were examined in DSS-induced colitis. The survival rate of mice with DSS-induced colitis that were treated with MenSCs (DSS + MenSCs) was significantly higher than that of mice treated with DSS on day 10 (Fig. 6B). Moreover, the DSS group exhibited lower body weights and higher DAI scores than the DSS + MenSCs group (Fig. 6C). On the 10th day of treatment, the colon length in the DSS group was shorter than that in the DSS + MenSCs group (Fig. 6D). Histological scoring revealed that MenSCs reduced the structural destruction of colon tissue, and inhibited inflammatory cell infiltration, and crypt loss(Fig. 6E). The qPCR results showed decreased levels of the inflammatory factors IL-1β, TNF-α, and IL-6 (Fig. 6F).

MenSCs alleviate intestinal mucosal barrier dysfunction in colitis mice. The concentration of FITC-dextran in serum was quantified to determine intestinal barrier permeability after DSS administration. The results demonstrated that permeability was significantly higher in the DSS group than that in the DSS + MenSCs group (Fig. 7A). The expression of the TJ proteins E-cadherin, ZO-1, Occludin, and claudin-1 in intestinal epithelial cells was determined by Western blotting and immunohistochemical staining. As shown in Fig. 7B-C, the Western blotting and immunohistochemistry results showed significantly higher protein expression of E-cadherin, ZO-1, Occludin, and claudin-1 in the DSS + MenSCs group than in the DSS group. Similarly, MenSCs effectively restored E-cadherin, occludin and claudin-1 mRNA levels compared to those in DSS mice (Fig. 7D).

MenSCs protect tight and adherens junctions by inhibiting the activation of the NF-κB/Snail signaling pathway. Snail is a transcriptional inhibitor that can directly inhibit the expression of many genes encoding epithelial junction proteins such as E-cadherin, ZO-1, and claudin-1[16–18].NF-κB is a critical transcription factor involved in the regulation of many signaling pathways that are important in inflammation, the immune response and cancer development[19, 20]. One of the reported mechanisms by which NF-κB downregulates E-cadherin is through Snail activation and stabilization[21]. Our results showed that the expression of phosphorylated NF-κB p65 and Snail protein in HT29 cells increased significantly after LPS stimulation, however, this increase was reversed by MenSC treatment (Fig. 8A, B). These findings indicated that MenSCs could reduce the expression of Snail by inhibiting the phosphorylation of NF-κB p65, thereby increasing the expression levels of E-cadherin, occludin, claudin, and ZO-1, and protecting intestinal epithelial cell junctions. To confirm this hypothesis, we also examined changes in NF-κB and Snail in mice (Fig. 8D and E). The results showed that compared with that in normal control group, the protein expression of NF-κB p65 and Snail in the colon tissue of DSS-induced colitis mice was upregulated, while MenSC treatment significantly inhibited the expression of NF-κB p65 and Snail, indicating that MenSCs could regulate tight and adherens junction proteins by inhibiting the activation of the NF-κB/Snail signaling pathway, thereby protecting the intestinal barrier function.

Our study focused on the mechanisms of the therapeutic effect of MSCs against colon inflammation and the repair of mucosal tissue. According to our results, intercellular junction protein expression was downregulated in intestinal epithelial cells in vitro and in vivo. The levels of the proinflammatory cytokines IL-1β, TNF-α, and IL-6 were increased. MenSC treatment restored intercellular junction structure and function in vitro and in vivo, decreased the levels of the proinflammatory cytokines IL-1β, TNF-α, and IL-6, and repaired the intestinal barrier. Our findings indicated that MenSCs are a promising candidate for UC treatment that can protect the intestinal barrier and modulate the immune response.

Inflammatory bowel disease (IBD) is a chronic and nonspecific inflammatory gastrointestinal disease, and ulcerative colitis (UC) and Crohn’s disease (CD) are the common subtypes of IBD[2]. A recent report showed that DSS increased intestinal permeability suggesting that DSS can contribute to disease development by disrupting barrier function[22]. Our study demonstrated that ZO-1, Occludin, and Claudin-1 are the key members in the TJ protein family, and are pivotal for maintaining the function and integrity of the intestinal barrier. We found that LPS downregulated E-cadherin, ZO-1, and Occludin expression, and increased the levels of the proinflammatory cytokines IL-1β and TNF-α in Caco2 cells and HT29 cells, DSS-induced IBD mice exhibited downregulated E-cadherin, ZO-1, and Occludin expression, and disruption of the intestinal barrier increased intestinal mucosal permeability, and the levels of the proinflammatory cytokines IL-1β, and TNF-α.

Additionally, MSC transplantation has been considered a novel therapeutic approach for IBD with the potential to regulate the immune response and promote tissue regeneration[23]. In addition to the frequently used UcMSCs, MenSCs have attracted notable attention as a promising alternative stem cell based therapy for various diseases based on their wide-ranging advantages, such as their regular and noninvasive collection method, abundant availability, superior proliferative capacity and autologous transplantation potential[24]. A subsequent clinical report also confirmed the therapeutic effects and safety of autologous MenSC transplantation for patients with Asherman’s syndrome[25]. Additionally, six clinical studies on MenSC-based therapies have been officially approved by the National Health Commission of the People's Republic of China due to the superior biological characteristics of MenSCs.

Currently, various animal experiments have shown that MSCs exert therapeutic effects on colitis[26, 27], but only a single type of MSCs was used in most of these studies. MSC have been reported to stimulate the regeneration of epithelial cells in vitro[28], but their protective effect on the intestinal mucosal barrier in vivo remains unclear. The intestinal barrier protects against pathogen invasion, and intestinal barrier dysfunction contributes to IBD. The mechanical barrier is composed of TJs from the intestinal epithelial cells (IECs) and the mucus layer[29]. Previous studies on TJs showed that once the tight junction structure of the intestine is destroyed, it can cause the infiltration of harmful substances and foreign pathogens into the intestine, which in turn will lead to inflammatory reactions and disruption of the mucosal system and cause a variety of intestinal diseases[30, 31]. Our results indicated that MenSCs significantly reduced the permeability of LPS-induced intestinal epithelial cells and mice with DSS-induced colitis. These results substantiate the r reparative effect of MSCs on intestinal damage.

Snail is a transcription factor that regulates gene expression by binding to the E-box motif in the promoter of the target gene. As a transcriptional repressor, Snail can negatively regulate the expression of a variety of epithelial junction protein genes, including E-cadherin and occludin [17, 32]. Studies have shown that ectopic Snail expression downregulates the expression of tight junction and adherens junction proteins[32]. Studies have shown that nuclear factor-κB (NF-κB)-mediated activation of Snail transcription plays an important role in the regulation of EMT in tumor cells[33–35]. The NF-κB pathway regulates Snail expression through transcriptional and posttranslational mechanisms, and NF-κB increases the transcription of Snail [36]. Our study showed that DSS stimulated intestinal epithelial cells to increase the phosphorylation of NF-κB, which in turn increased Snail expression and nuclear translocation. The colon tissue of mice with DSS-induced colitis also showed a trend of increases in the phosphorylation of NF-κB and Snail. MenSCs significantly inhibited the phosphorylation of NF-κB and the expression of Snail, thereby regulating the expression of tight junction and adherens junction proteins, and protecting the intestinal barrier.

In conclusion, MenSCs effectively improves the symptoms of DSS-induced colitis in mice, protects the intestinal epithelial barrier by inhibiting the NF-κB /Snail signaling pathway, and may be a novel therapeutic approach for colitis treatment.

MSC

Mesenchymal stem cells

MenSCs

Menstrual blood-derived stem cells

IBD

Inflammatory bowel disease

Ulcerative colitis DSS:Dextran sulfate sodium

Tight junctions

PVDF

Polyvinylidene difluoride

H&E

Hematoxylin and eosin.

Acknowledgments

Not applicable.

Author contributions

Tao Ruan and Chengxu Xue designed and conducted the experiments and performed the data analysis. Jiaming Han administered the project. Tao Ruan wrote the manuscript. Juntang Lin were responsible for overall supervision. All the authors read and approved the fnal manuscript.

Funding

This work was supported by the Scientific and Technological Foundation of Henan Province in China (222102310382, and 222102310383 ) and Key Research Projects in the Colleges of Henan Province (23A180019).

Availability of data and materials

The datasets in this study are available from the corresponding authors upon request.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Xinxiang Medical University (approval number: XYLL-2021041) on 18nd March 2021. The approved title is: The mechanism of extracellular vesicles derived from menstrual blood ameliorate experimental colitis by protecting intestinal barrier integrity. All animal procedures were performed in agreement with the National Institutes of Health guidelines. Written informed consent was obtained from all menstrual blood donors involved in this study.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Author details

¹Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, China. ²School of Public Health, Xinxiang Medical University, Xinxiang,453003, China.

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MenSCs ameliorate experimental colitis by protecting intestinal barrier integrity by inhibiting the NF-κB/Snail signaling pathway

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