HucMSC-Ex alleviates inflammatory bowel disease via the lnc78583-mediated miR3202/HOXB13 pathway

HucMSC-Ex alleviates inflammatory bowel disease via the lnc78583-mediated miR3202/HOXB13 pathway HucMSC-Ex通过调控lnc78583介导的miR3202/HOXB13通路缓解炎症性肠病 1 equal first-author 2 equal 1 3 1 4 1 1 1 5 corresp Zhaoyang ZHANG, Zhangcy19791216@163.com Zhaoyang ZHANG, Zhangcy19791216@163.com Zhangcy19791216@163.com https://orcid.org/0000-0003-0288-7103 1 corresp corresp Zhaoyang ZHANG, Zhangcy19791216@163.com Zhaoyang ZHANG, Zhangcy19791216@163.com Fei MAO, maofei2003@ujs.edu.cn Fei MAO, maofei2003@ujs.edu.cn maofei2003@ujs.edu.cn https://orcid.org/0000-0001 Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang 212013, China Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang 212013, China Nanjing Lishui People’s Hospital, Zhongda Hospital Lishui Branch, Southeast University, Nanjing 211200, China Nanjing Lishui People’s Hospital, Zhongda Hospital Lishui Branch, Southeast University, Nanjing 211200, China Directorate of University Health Services, University of Cape Coast, Cape Coast, Ghana Directorate of University Health Services, University of Cape Coast, Cape Coast, Ghana Department of Gastroenterology, the Second People’s Hospital of Zhenjiang, Zhenjiang 212000, China Department of Gastroenterology, the Second People’s Hospital of Zhenjiang, Zhenjiang 212000, China Clinical Lab, Taicang Hospital of Traditional Chinese Medicine, Suzhou 215400, China Clinical Lab, Taicang Hospital of Traditional Chinese Medicine, Suzhou 215400, China 炎症性肠病（IBD）是一组慢性、复发性肠道炎症，主要包括溃疡性结肠炎（UC）和克罗恩病（CD）。IBD的发病机制很复杂，其潜在机制仍不清楚。近年来，人们对长链非编码RNA（lncRNA）进行了研究，并将其确定为IBD的潜在生物标志物。在本研究中，通过使用高通量RNA测序筛选出一种新的lncRNA-lnc78583。前期荧光定量聚合酶链式反应（qRT-PCR）分析结果表明，lnc78583和同源框B13（HOXB13）的mRNA表达水平在IBD患者和炎症状态下的人结直肠黏膜上皮细胞（FHC）中显著降低。为了探索lnc78583在肠道炎症环境中的作用机制，我们通过对FHC进行lnc78583过表达处理，发现不仅增加了HOXB13和IL-10的表达，而且增强了细胞活力，降低了LDH的释放和p-NF-κB的激活。随后，我们用人脐带间充质干细胞来源的外泌体（hucMSC-Ex）处理FHC，结果表明其上调了lnc78583和HOXB13的表达。此外，进一步预测到miR3202在FHC中和lnc78583以及HOXB13呈负相关作用。lnc78583的过表达下调miR3202，而miR3202模拟物显着降低HOXB13的表达水平。综上，我们的研究初步证明hucMSC-Ex通过lnc78583介导的miR3202/HOXB13通路调节IBD的炎症进程，从而为IBD提供新的诊断方案和治疗策略。 炎症性肠病 长链非编码RNA（lncRNA） HOXB13 miR3202 间充质干细胞 外泌体 As a group of nonspecific inflammatory diseases affecting the intestine, inflammatory bowel disease (IBD) exhibits the characteristics of chronic recurring inflammation, and was proven to be increasing in incidence ( Kaplan, 2015 Kaplan, 2015 ). IBD induced by genetic background, environmental changes, immune functions, microbial composition, and toxin exposures ( Sassonet al., 2021 Sasson et al., 2021 ) primarily includes ulcerative colitis (UC) and Crohn's disease (CD) with complicated clinical symptoms featured by abdominal pain, diarrhea, and even blood in stools ( Fan et al., 2021 Fan et al., 2021 ; Huang et al., 2021 Huang et al., 2021 ). UC is mainly limited to the rectum and the colon, while CD usually impacts the terminal ileum and colon in a discontinuous manner ( Ordás et al., 2012 Ordás et al., 2012 ; Panés and Rimola, 2017 Panés and Rimola, 2017 ). In recent years, many studies have suggested the lack of effective measures in the diagnosis and treatment of IBD, prompting an urgent need for new strategies to understand the mechanisms of and offer promising therapies for IBD. Although traditional approaches have focused on protein-coding RNAs (messenger RNAs (mRNAs)), the existing evidence is highly suggestive that non-coding RNAs, mainly including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and ribosomal RNAs (rRNAs), have potential functions in IBD ( Esteller, 2011 Esteller, 2011 ). Initially considered as "dark matter" and the transcriptional noise of genes, lncRNAs are a class of transcript RNA that are more than 200 nucleotides in length without protein-coding capacity ( Jatharet al., 2017 Jathar et al., 2017 ). As lncRNAs are involved in chromatin modification, gene transcriptional regulation, protein post-translational regulation, and miRNA regulation ( Qian et al., 2019 Qian et al., 2019 ), with the increasing development of high-throughput sequencing, there is now emerging evidence that sheds light on the importance of lncRNAs. LncRNAs exhibit specific expression in different cells, tissues, and organs, thereby affecting cell proliferation, differentiation, apoptosis, and migration. Previous studies have indicated the marked roles of lncRNAs in cancers, inflammation, and other diseases. For example, one of the most often investigated lncRNAs, H19 participates in the onset and progression of lung cancer ( Huanget al., 2018 Huang et al., 2018 ), ovarian cancer ( Barnhoorn et al., 2018 Barnhoorn et al., 2018 ), gastric cancer ( Ganet al., 2019 Gan et al., 2019 ), and Parkinson's disease ( Jianget al., 2020 Jiang et al., 2020 ) through different pathways. A recent study also elucidated that lncRNA small nucleolar RNA host gene 6 (SNHG6) can promote hepatocellular carcinoma progression by interacting with heterogeneous nuclear ribonucleoprotein L/polypyrimidine tract-binding protein 1 (HNRNPL/PTBP1) to facilitate SET domain containing 7/leucine zipper transcription factor-like 1 (SETD7/LZTFL1) mRNA destabilization ( Wanget al., 2021 Wang et al., 2021 ). Moreover, further studies have provided insights into the association between lncRNAs and exosomes. Liu et al. (2021) Liu et al. (2021) found that exosomes in the pericardial fluid carry linc00636 to promote cardiac fibrosis in patients with atrial fibrillation through the miRNA-450a-2-3p/mitogen-activated protein kinase (miR-450a-2-3p/MAPK) signaling pathway. Concerning IBD, there is also an increasing recognition of the significance of lncRNAs. For instance, the lncRNA DQ786243 was found to be overexpressed in CD patients positively linked to cyclic adenosine monophosphate (cAMP)‍-response element-binding protein (CREB) and forkhead transcription factor protein P3 (Foxp3) ( Qiaoet al., 2013 Qiao et al., 2013 ). BC012900 and inter‍feron γ‍-antisense RNA1 (IFNG-AS1) were proposed to be key enhancers of UC ( Paduaet al., 2016 Padua et al., 2016 ; Wu et al., 2016 Wu et al., 2016 ). Besides, lncRNA growth arrest-specific transcript 5 (GAS5) was indicated to be beneficial for pediatric IBD therapy via reducing the expression of matrix metallopeptidase 2 (MMP2) and MMP9 ( Lucafò et al., 2019 Lucafò et al., 2019 ). In addition, lncRNAs have been shown to be involved in the regulation of intestinal epithelial cells, thereby improving inflammation and the functional regulation of regulatory T cells ( Yaraniet al., 2018 Yarani et al., 2018 ). The inhibition of lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) suppresses the inflammatory response in IBD by modulating the intestinal epithelial barrier and through the exosome-mediated polarization of macrophages ( Liu et al., 2018 Liu et al., 2018 ). This indicates the negative effects of NEAT1, as it enhances inflammation and disrupts the intestinal epithelial barrier function. Furthermore, lncRNA NEAT1 was proven to regulate IBD in various ways involving an exosome-mediated pathway ( Jiaet al., 2018 Jia et al., 2018 ). In our study, high-throughput sequencing was applied to determine the different expression levels of lncRNAs between two pairs of colon tissues from IBD patients and their matched health controls (HCs). The lncRNA sequencing information analysis process mainly included the quality control of sequencing data, data comparison analysis, quantification of expression, identification of novel lncRNAs, analysis of differential expression, feature analysis, and target prediction of novel lncRNAs. The raw data have been uploaded to the National Center for Biotechnology Information (NCBI) platform (SUB10893884). A total of 1344 IBD-related RNAs were detected, as presented in the heatmaps (Figs. 1a 1a and 1b 1b ) and Jensen-Shannon (JS) score ( Fig. 1 Fig. 1 c), among which 618 were lncRNAs and 726 were mRNAs. The JS scores showed a positive relationship with tissue specificity. After excluding lncRNAs with a |log 2 Ratio| lower than 1 and a P -value greater than 0.05, we identified 72 differentially expressed lncRNAs including 31 known lncRNAs and 41 novel lncRNAs named after MSTRG, as well as 325 differentially expressed mRNAs ( Figs. 1 Figs. 1 d‍‒‍1f). Among these RNAs, 18 known lncRNAs, 15 novel lncRNAs, and 251 mRNAs were upregulated, while 13 known lncRNAs, 26 novel lncRNAs, and 74 mRNAs were downregulated ( Fig. 1 Fig. 1 g). Herein, we focused on the novel lncRNAs that have been classified into long intergenic non-coding RNAs (lincRNAs) (49%), intronic lncRNAs (34%), and antisense lncRNAs (17%) according to their locations ( Fig. 1 Fig. 1 h). Next, we verified the novel lncRNAs by quantitative real time-polymerase chain reaction (qRT-PCR) in human colorectal mucosa cells (fetal human cells (FHCs)) and found that eight lncRNAs were consistent with the findings of RNA sequencing (RNA-seq), which included five upregulated MSTRG genes (117344, 153448, 83406, 151143, and 182523), as well as three downregulated MSTRG genes (24161, 78583, and 185073). The results are presented in Figs. 2a 2a and 2b 2b . Given the outcome of the cell experiments, we further tested the expression levels of these lncRNAs by collecting more human tissues. The results of qRT-PCR showed that the MSTRG.78583 was significantly decreased in IBD patients ( Fig. 2 Fig. 2 c). Because the high-throughput sequencing results detected one of the targeted mRNAs of MSTRG.‍78583, homeobox B13 (HOXB13), which showed significantly decreased expression, we also tested HOXB13 expression in IBD patients. Both qRT-PCR and immunohistochemistry (IHC) provided the same results that the mRNA and protein levels of HOXB13 were significantly reduced in IBD ( Figs. 2 Figs. 2 d‍‒‍2f). Under this circumstance, we chose MSTRG.78583 as our target for further studies and renamed it as lnc78583. In order to explore the effect of lnc78583 on lipopolysaccharide (LPS)‍-induced colorectal cell inflammation, we performed the next stage of the experiment using FHC. Firstly, we found that lnc78583 was decreased after a low concentration of under 500 ng/mL LPS treatment, and showed a dependence on concentration ( Fig. 3 Fig. 3 a). Based on the results, we selected 100 ng/mL as our key concentration and determined the expression levels of mRNAs of inflammatory factors in addition to lnc78583 and HOXB13. The qTR-PCR analysis indicated that lnc78583 and HOXB13 were significantly decreased in the LPS group (Figs. 3b 3b and 3c 3c ). Moreover, the pro-inflammatory factors, tumor necrosis factor-‍α (TNF-‍α) and interleukin-6 (IL-6) were highly expressed, while an anti-inflammatory factor, IL-10, was lowly expressed in the LPS group ( Figs. 3 Figs. 3 d‍‒‍3f). Altogether, these data demonstrated that lnc78583 and HOXB13 had a negative relationship with inflammation of FHC. Furthermore, we successfully overexpressed lnc78583 in FHC ( Fig. 3 Fig. 3 g). The qRT-PCR analysis showed that the overexpression of lnc78583 upregulated HOXB13 and IL-10 to inhibit inflammation (Figs. 3h 3h and 3i 3i ). Western blot analysis confirmed the increased expression of HOXB13, whereas the activation of nuclear factor-‍‍κB (NF-‍κB), which mainly mediates inflammation, was also partially inhibited ( Fig. 3 Fig. 3 j). We used an image processing software, ImageJ, to clearly present our results (Figs. 3k 3k and 3l 3l ). In addition, the cell counting kit-8 (CCK8) assay indicated enhanced cell viability through the overexpression of lnc78583, which again contributed to a reduced lactic dehydrogenase (LDH) release (Figs. 3m 3m and 3n 3n ). In conclusion, lnc78583 exerted a protective effect on LPS-induced FHC inflammation through targeting HOXB13. Given that many previous studies have revealed the damage-repairing roles of human umbilical cord mesenchymal stem cells-derived exosome (hucMSC-Ex) in many diseases including IBD, in the present study, we explored whether hucMSC-Ex regulates lnc78583 during IBD mitigation. Firstly, we examined hucMSC-Ex by nanoparticle tracking analysis (NTA) and western blot, which showed a peak exosome diameter of about 167.2 nm with the positive expression of cluster of differentiation 9 (CD9), CD63, and heat shock protein 70 (HSP70) (Figs. 4a 4a and 4b 4b ). In addition, an electron microscope was used to observe and confirm the exosomes ( Fig. 4 Fig. 4 c). As predicted, the cell viability of FHC was improved in the hucMSC-Ex+LPS group compared with the LPS-untreated group as analyzed through the CCK8 kit ( Fig. 4 Fig. 4 d). Meanwhile, the LDH released in the hucMSC-Ex was significantly reduced ( Fig. 4 Fig. 4 e). Furthermore, a qRT-PCR assay was conducted, which showed that hucMSC-Ex elevated the expression levels of lnc78583, HOXB13, and IL-10, as compared with LPS stimulation ( Figs. 4 Figs. 4 f‍‒‍4h). In addition to mRNA levels, the western blot analysis indicated that the protein level of HOXB13 was increased in the hucMSC-Ex+LPS group with a decreasing activated expression level of phosphorylated NF‍-‍κB (p-NF-‍κB) ( Fig. 4 Fig. 4 i). We also used ImageJ to clearly represent our results (Figs. 4j 4j and 4k 4k ). Altogether, these observations provide evidence that hucMSC-Ex alleviates LPS-induced FHC inflammation by regulating the lnc78583/HOXB13 axis. Since multiple studies have evidenced the lncRNA-miRNA-mRNA relationship network, we explored the miRNA that possibly engages lnc78583 and HOXB13. We first predicted their target genes in the miRDB database ( http://mirdb. http://mirdb. ‍org) and found that the miRNA miR3202 had binding sites with lnc78583 and HOXB13 as depicted in Fig. 5 Fig. 5 a. Subsequently, we estimated the expression level of miR3202 in FHC by qRT-PCR, and found that miR3202 was upregulated after LPS stimulation, indicating a negative relation with lnc78583 and HOXB13 in FHC ( Fig. 5 Fig. 5 b). Next, we transfected FHC with lnc78583 ( Fig. 5 Fig. 5 c) and the results indicated that the overexpression of lnc78583 significantly inhibited miR3202 expression ( Fig. 5 Fig. 5 d). Then, to verify the relation of miR3202 with HOXB13, we transfected FHC with miR3202 mimics and miR3202 inhibitor ( Fig. 5 Fig. 5 e), and found HOXB13 to be significantly decreased in the miR3202 mimics group ( Fig. 5 Fig. 5 f). Finally, we detected the expression of miR3202 in hucMSC-Ex-treated FHC and indicated a consistent outcome, as hucMSC-Ex reduced the miR3202 level under inflammation ( Fig. 5 Fig. 5 g). Furthermore, the western blot analysis illustrated that miR3202 had an inverse role in activating NF-‍κB compared with lnc78583 ( Fig. 5 Fig. 5 h). The ImageJ software was similarly applied to clearly demonstrate the results of western blot ( Fig. 5 Fig. 5 i). In conclusion, through high-throughput sequencing, we found a novel lncRNA, lnc78583, located at chromosome 17 (chr17): 48752528‍‒‍48755853 near HOXB13, and proved that hucMSC-Ex alleviates inflammation through the lnc78583-mediated miR3202/HOXB13 pathway ( Fig. 6 Fig. 6 ). Materials and methods 1 Detailed methods are provided in the electronic supplementary materials of this paper. References Barnhoorn M , de Jonge-Muller E , Molendijk I , et al. , 2018 . Endoscopic administration of mesenchymal stromal cells reduces inflammation in experimental colitis . Inflamm Bowel Dis , 24 ( 8 ): 1755 - 1767 . https://doi.org/10.1093/ibd/izy130 https://doi.org/10.1093/ibd/izy130 Endoscopic administration of mesenchymal stromal cells reduces inflammation in experimental colitis Esteller M , 2011 . Non-coding RNAs in human disease . 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All authors have read and approved the final version of the article, and therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data. 10.1631/jzus.B2100793 1673-1581（2022）05-0423-09 This work was supported by the Zhenjiang Key Research and Development Plan (Social Development) (No. SH2021066), the Clinical Medical Science and Technology Development Fund Project of Jiangsu University in 2018 (No. JLY20180031), and the Taicang Science and Technology Planning Project (No. TC2020JCYL17), China. 2021-09-15 2022-01-27 2022-05-15 2022-12-27 2022-04-15 Copyright © Zhejiang University and Springer-Verlag GmbH Germany, part of Springer Nature 2022 2022 浙江大学出版社 Yuting XU, Li ZHANG, Dickson Kofi Wiredu OCANSEY, Bo WANG, Yilin HOU, Rong MEI, Yongmin YAN, Xu ZHANG, Zhaoyang ZHANG, and Fei MAO declare that they have no conflict of interest. All participants gave informed consent and this research was performed with the permission of institutions involved and approval from the Ethical Committee of Jiangsu University (No. 2014280). Compliance with ethics guidelines Supplementary information 1 Materials and methods 浙江大学学报（英文版）（B辑：生物医学和生物技术） 5 23