Skip to main content

Advertisement

SpringerLink
Log in

M1 macrophages-derived exosomes miR-34c-5p regulates interstitial cells of Cajal through targeting SCF

  • Published:
Journal of Biosciences Aims and scope Submit manuscript

Abstract

Slow transit constipation (STC) is a gastrointestinal disorder characterized by abnormal prolonged colonic transit time, which affects the life quality of many people. The decrease number of interstitial cells of Cajal (ICCs) is involved in the pathogenesis of STC. However, the molecular mechanism of loss of ICCs in STC remains unclear, making it difficult to develop new agents for the disease. In this study, we investigated the mechanism of decreasing ICCs in the pathogenesis of STC. We constructed the STC model rats by using atropine and diphenoxylate. A series of methods were used including immunofluorescence and immunochemistry staining, western blot, qRT-PCR, exosomes extraction and exosomes labeling. The results indicate that ICCs decreased in the STC rats accompanied with the macrophages activation. Further studies suggested that macrophages decreased the cell viability of ICCs by secretion exosomes containing miR-34c-5p. miR-34c-5p targeted the 3′-UTR of stem cell factor(SCF) mRNA and regulated the expression of SCF negatively. In conclusion, we demonstrated a novel regulatory mechanism of ICCs cell viability in STC. We found that exosome miR-34c-5p mediate macrophage-ICCs cross-talk. M1 macrophages derived exosomes miR-34c-5p decreased ICCs cell viability by directly targeting SCF.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Bharucha AE and Lacy BE 2020 Mechanisms, evaluation, and management of chronic constipation. Gastroenterology 158 1232–1249

    Article  CAS  Google Scholar 

  • Choe N, Kwon JS, Kim YS, Eom GH, Ahn YK, et al. 2015 The microRNA miR-34c inhibits vascular smooth muscle cell proliferation and neointimal hyperplasia by targeting stem cell factor. Cell Signal. 27 1056–1065

    Article  CAS  Google Scholar 

  • Clément T, Salone V and Rederstorff M 2015 Dual luciferase gene reporter assays to study miRNA function. Methods Mol. Biol. 1296 187–198

    Article  Google Scholar 

  • Correia de Sousa M, Gjorgjieva M, Dolicka D, Sobolewski C and Foti M 2019 Deciphering miRNAs’ action through miRNA editing. Int. J. Mol. Sci. 20 6249

    Article  Google Scholar 

  • Fan Y, Wu SD, Fu BB, Weng C and Wang XP 2014 Decreased number of interstitial cells of Cajal play an important role in the declined intestinal transit during cholesterol gallstone formation in guinea pigs fed on high cholesterol diet. Int. J. Clin. Exp. Med. 7 1262–1268

    PubMed  PubMed Central  Google Scholar 

  • Gordon M, MacDonald JK, Parker CE, Akobeng AK and Thomas AG 2016 Osmotic and stimulant laxatives for the management of childhood constipation. Cochrane Database Syst. Rev. 2016 Cd009118

    PubMed Central  Google Scholar 

  • Heemskerk SCM and Rotteveel AH 2020 Heterogeneous outcome reporting in adult slow-transit constipation studies: Systematic review towards a core outcome set. J Gastroenterol. Hepatol. 35 192–203

    Article  Google Scholar 

  • Hu J, Hu X and Kan T 2019 MiR-34c Participates in Diabetic Corneal Neuropathy Via Regulation of Autophagy. Invest. Ophthalmol. vis. Sci. 60 16–25

    Article  CAS  Google Scholar 

  • Iino S, Horiguchi K and Horiguchi S 2020 c-Kit-stem cell factor signal-independent development of interstitial cells of Cajal in murine small intestine. Cell Tiss. Res. 379 121–129

    Article  CAS  Google Scholar 

  • Jani B and Marsicano E 2018 Constipation: Evaluation and management. Mol. Med. 115 236–240

    Google Scholar 

  • Jiang F, Zhou JY, Wu J, Tian F, Zhu XX, et al. 2017 Yangyin Runchang decoction improves intestinal motility in mice with atropine/diphenoxylate-induced slow-transit constipation. Evid. Based Complement. Alternat. Med. 2017 4249016

    PubMed  PubMed Central  Google Scholar 

  • Kabekkodu SP, Shukla V, Varghese VK, D’Souza S, Chakrabarty S, et al. 2018 Clustered miRNAs and their role in biological functions and diseases. Biol. Rev. Camb. Philos. Soc. 93 1955–1986

    Article  Google Scholar 

  • Kaji N, Horiguchi K, Iino S, Nakayama S, Ohwada T, et al. 2016 Nitric oxide-induced oxidative stress impairs pacemaker function of murine interstitial cells of Cajal during inflammation. Pharmacol. Res. 111 838–848

    Article  CAS  Google Scholar 

  • Li Q, Li B, Li Q, Wei S, He Z, et al. 2018 Exosomal miR-21-5p derived from gastric cancer promotes peritoneal metastasis via mesothelial-to-mesenchymal transition. Cell Death Dis. 9 854

    Article  Google Scholar 

  • Lin ZL, Chen QY, Tian HL, Yang B, Zhao D, et al. 2020 Effect of fecal bacterial preservation time on the outcomes of fecal microbiota transplantation for slow transit constipation. Zhonghua Wei Chang Wai Ke Za Zhi 23 56–62

    CAS  PubMed  Google Scholar 

  • Liu W, Zhang Q, Li S, Li L, Ding Z, et al. 2015 The relationship between colonic macrophages and MicroRNA-128 in the pathogenesis of slow transit constipation. Dig. Dis. Sci. 60 2304–2315

    Article  CAS  Google Scholar 

  • Lu TX and Rothenberg ME 2018 MicroRNA. J. Allergy Clin. Immunol. 141 1202–1207

    Article  CAS  Google Scholar 

  • Ma Y, Chen Y, Zheng Y, Wen Y, Li Y, et al. 2020 SCF/c-kit signaling pathway participates in ICC damage in neurogenic bladder. Cell Cycle 19 2074–2080

    Article  CAS  Google Scholar 

  • Mazzone A, Strege PR and Gibbons SJ 2020 microRNA overexpression in slow transit constipation leads to reduced Na(V)1.5 current and altered smooth muscle contractility. Gut 69 868–876

    Article  Google Scholar 

  • Orecchioni M, Ghosheh Y, Pramod AB and Ley K 2019 Macrophage polarization: different gene signatures in M1(LPS+) vs. classically and M2(LPS-) vs. Alternatively activated macrophages. Front. Immunol. 10 1084

    Article  CAS  Google Scholar 

  • Pegtel DM and Gould SJ 2019 Exosomes. Annu. Rev. Biochem. 88 487–514

    Article  CAS  Google Scholar 

  • Radetic M and Kamal A 2021 Severe gastroparesis is associated with an increased incidence of slow-transit constipation as measured by wireless motility capsule. Neurogastroenterol. Motil. 33 e14045

    Article  Google Scholar 

  • Raziq K, Cai M, Dong K, Wang P, Afrifa J, et al. 2020 Competitive endogenous network of lncRNA, miRNA, and mRNA in the chemoresistance of gastrointestinal tract adenocarcinomas. Biomed. Pharmacother. 130 110570

    Article  CAS  Google Scholar 

  • Sailer M 2019 Slow transit constipation. Zentralbl Chir 144 179–189

    Article  Google Scholar 

  • Sanders KM 2019 Spontaneous electrical activity and rhythmicity in gastrointestinal smooth muscles. Adv. Exp. Med. Biol. 1124 3–46

    Article  CAS  Google Scholar 

  • Saravanaperumal SA and Gibbons SJ 2018 Extracellular Cl(-) regulates electrical slow waves and setting of smooth muscle membrane potential by interstitial cells of Cajal in mouse jejunum. Exp. Physiol. 103 40–57

    Article  CAS  Google Scholar 

  • Shi Z, Zhang K, Zhou H, Jiang L, Xie B, et al. 2020 Increased miR-34c mediates synaptic deficits by targeting synaptotagmin 1 through ROS-JNK-p53 pathway in Alzheimer’s disease. Aging Cell 19 e13125

    Article  CAS  Google Scholar 

  • Vriesman MH, Koppen IJN, Camilleri M, Di Lorenzo C and Benninga MA 2020 Management of functional constipation in children and adults. Nat. Rev. Gastroenterol. Hepatol. 17 21–39

    Article  Google Scholar 

  • Wang YB, Ling J, Zhang WZ, Li G, Qiu W, et al. 2018 Effect of bisacodyl on rats with slow transit constipation. Braz. J. Med. Biol. Res. 51 e7372

    Article  Google Scholar 

  • Wang Z, Zhu H, Shi H, Zhao H, Gao R, et al. 2019 Exosomes derived from M1 macrophages aggravate neointimal hyperplasia following carotid artery injuries in mice through miR-222/CDKN1B/CDKN1C pathway. Cell Death Dis. 10 422

    Article  Google Scholar 

  • Ward SM and Sanders KM 2006 Involvement of intramuscular interstitial cells of Cajal in neuroeffector transmission in the gastrointestinal tract. J. Physiol. 576 675–682

  • Wei J, Li N, Xia X, Chen X, Peng F, et al. 2014 Effects of lipopolysaccharide-induced inflammation on the interstitial cells of Cajal. Cell Tiss. Res. 356 29–37

    Article  CAS  Google Scholar 

  • Xue H, Wang FY, Kang Q and Tang XD 2018 c-Kit mutation reduce intestinal epithelial cell proliferation and migration, but not influence intestinal permeability stimulated by lipopolysaccharide. Acta Histochem. 120 534–541

    Article  CAS  Google Scholar 

  • Yang S, Li WS, Dong F, Sun HM, Wu B, et al. 2014 KITLG is a novel target of miR-34c that is associated with the inhibition of growth and invasion in colorectal cancer cells. J. Cell Mol. Med. 18 2092–2102

    Article  CAS  Google Scholar 

  • Yu C, Zang L, Feng B, Zhang L, Xue P, et al. 2020 Co-expression network analysis identified specific miRNAs and genes in association with slow-transit constipation. Mol. Med. Rep. 22 4696–4706

    Article  CAS  Google Scholar 

  • Yunna C, Mengru H, Lei W and Weidong C 2020 Macrophage M1/M2 polarization. Eur. J. Pharmacol. 877 173090

    Article  Google Scholar 

  • Zhao S and Chen Q 2018 Aberrantly Expressed Genes and miRNAs in Slow Transit Constipation Based on RNA-Seq Analysis. Biomed. Res. Int. 2018 2617432

    PubMed  PubMed Central  Google Scholar 

  • Zheng H, Liu YJ, Chen ZC and Fan GQ 2021 miR-222 regulates cell growth, apoptosis, and autophagy of interstitial cells of Cajal isolated from slow transit constipation rats by targeting c-kit. Indian J. Gastroenterol. 40 198–208

    Article  Google Scholar 

  • Zhou X, Brown BA and Siegel AP 2020a Exosome-mediated crosstalk between keratinocytes and macrophages in cutaneous wound healing. ACS Nano 14 12732–12748

    Article  CAS  Google Scholar 

  • Zhou X, Qian H, Zhang D and Zeng L 2020b Inhibition of autophagy of Cajal mesenchymal cells by gavage of tong bian decoction based on the rat model of chronic transit constipation. Saudi J. Biol. Sci. 27 623–628

    Article  CAS  Google Scholar 

  • Zhu F, Xu S, Zhang Y, Chen F, Ji J, et al. 2016 Total Glucosides of paeony promote intestinal motility in slow transit constipation rats through amelioration of interstitial cells of Cajal. PLoS One 11 e0160398

    Article  Google Scholar 

Download references

Acknowledgements

This study was supported by research grants from the Six Talent Peaks Project in Jiangsu Province (WSN-239). We would like to thank all the researchers and study participants for their contributions.

Author information

Author notes

  1. Su Xu and Jinhai Zhai are co-first authors.

Authors and Affiliations

  1. Department of Anorectal Surgery, Yancheng Hospital of Traditional Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Yancheng, 224001, Jiangsu, China

    Su Xu, Ke Xu, Chenghua Wu & Tao Lin

  2. Department of Gastroenterology, The Jiangyin Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangyin, 214000, China

    Jinhai Zhai

  3. Department of Anorectal Surgery, Binhai County Hospital of traditional Chinese Medicine, Yancheng, 224500, Jiangsu, China

    Xingguo Zuo

  4. First Clinical Medical College, Nanjing University of Chinese Medicine, No. 138 Xianlin Avenue, Nanjing, 210023, China

    Li Zeng

Authors
  1. Su Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jinhai Zhai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ke Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xingguo Zuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chenghua Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tao Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Li Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Su Xu or Li Zeng.

Additional information

Comunicated by Kundan Sengupta.

Corresponding editor: Kundan Sengupta

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, S., Zhai, J., Xu, K. et al. M1 macrophages-derived exosomes miR-34c-5p regulates interstitial cells of Cajal through targeting SCF. J Biosci 46, 90 (2021). https://doi.org/10.1007/s12038-021-00212-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12038-021-00212-z

Keywords

Search

Navigation