Skip to main content

Advertisement

SpringerLink
Log in

Over-expression of CXCR4 on mesenchymal stem cells protect against experimental colitis via immunomodulatory functions in impaired tissue

  • Original Paper
  • Published:
Journal of Molecular Histology Aims and scope Submit manuscript

Abstract

Bone marrow-derived mesenchymal stem cells (BMSCs) are attractive candidates for tissue regeneration and immunoregulation in inflammatory bowel disease. However, their in vivo reparative capability is limited owing to barren efficiency of BMSCs to injury region. Stromal cell-derived factor (SDF-1) plays an important role in chemotaxis and stem cell homing through interaction with its specific receptor CXC chemokine receptor 4 (CXCR4). The present study was designed to investigate the role of SDF-1α/CXCR4 axis in the therapeutic effects of lentivirus-preconditioned BMSCs for 2,4,6-trinitrobenzene sulfonic acid (TNBS)-colitis rats. BMSCs were isolated from female Sprague–Dawley rats and identified by flow cytometry. Lentiviral transduction was applied to over-express CXCR4/GFP (Ad-CXCR4-BMSCs) or null/GFP (Ad-GFP-BMSCs). Efficacy of engraftment was determined by the presence of enhanced green fluorescent protein (GFP) positive cells. One week after intravenous administration, Ad-GFP-BMSCs failed to colonize in the inflamed colon and had no beneficial effect in TNBS-induced colitis. Instead, Ad-CXCR4-BMSCs signally ameliorated both clinical and microanatomical severity of colitis. Immunofluorescence and western blotting showed that Ad-CXCR4-BMSCs migrated toward inflamed colon was more efficient than Ad-GFP-BMSCs. The therapeutic effect of Ad-CXCR4-BMSCs was mediated by the suppression of pro-inflammatory cytokines and STAT3 phosphorylation in injured colon. Collectively, our data indicated that over-expression CXCR4 led to enhance in vivo mobilization and engraftment of BMSCs into inflamed colon where these cells can function as an anti-inflammatory and immunomodulatory component of the immune system in TNBS-induced colitis.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Ando Y, Inaba M, Sakaguchi Y, Tsuda M, Quan GK, Omae M, Okazaki K, Ikehara S (2008) Subcutaneous adipose tissue-derived stem cells facilitate colonic mucosal recovery from 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. Inflamm Bowel Dis 14(6):826–838

    Article  PubMed  Google Scholar 

  • Andoh A, Bamba S, Fujiyama Y, Brittan M, Wright NA (2005) Colonic subepithelial myofibroblasts in mucosal inflammation and repair: contribution of bone marrow-derived stem cells to the gut regenerative response. J Gastroenterol 40(12):1089–1099

    Article  PubMed  Google Scholar 

  • Andoh A, Shioya M, Nishida A, Bamba S, Tsujikawa T, Kim-Mitsuyama S, Fujiyama Y (2009) Expression of IL-24, an activator of the JAK1/STAT3/SOCS3 cascade, is enhanced in inflammatory bowel disease. J Immunol 183(1):687–695

    Article  CAS  PubMed  Google Scholar 

  • Castelo-Branco MTL, Soares IDP, Lopes DV, Buongusto F, Martinusso CA, do Rosario A Jr, Souza SAL, Gutfilen B, Fonseca LMB, Elia C, Madi K, Schanaider A, Rossi MID, Souza HSP et al (2012) Intraperitoneal but not intravenous cryopreserved mesenchymal stromal cells home to the inflamed colon and ameliorate experimental colitis. PLoS One 7(3):e33360

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chen QQ, Yan L, Wang CZ, Wang WH, Shi H, Su BB, Zeng QH, Du HT, Wan J (2013) Mesenchymal stem cells alleviate TNBS-induced colitis by modulating inflammatory and autoimmune responses. World J Gastroenterol 19(29):4702–4717

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Davaatseren M, Hwang JT, Park JH, Kim MS, Wang S, Sung MJ (2013) Poly-γ-glutamic acid attenuates angiogenesis and inflammation in experimental colitis. Mediators Inflamm 2013:982383

    Article  PubMed Central  PubMed  Google Scholar 

  • de Faria FM, Luiz-Ferreira A, Socca EA, de Almeida AC, Dunder RJ, Manzo LP, da Silva MA, Vilegas W, Rozza AL, Pellizzon CH, Dos Santos LC, Souza Brito AR (2012) Effects of rhizophora mangle on experimental colitis induced by TNBS in rats. Evid Based Complement Alternat Med 2012:753971

    Article  PubMed Central  PubMed  Google Scholar 

  • François S, Bensidhoum M, Mouiseddine M, Mazurier C, Allenet B, Semont A, Frick J, Saché A, Bouchet S, Thierry D, Gourmelon P, Gorin NC, Chapel A (2006) Local irradiation not only induces homing of human mesenchymal stem cells at exposed sites but promotes their widespread engraftment to multiple organs: a study of their quantitative distribution after irradiation damage. Stem Cells 24(4):1020–1029

    Article  PubMed  Google Scholar 

  • Gonzalez-Rey E, Anderson P, González MA, Rico L, Büscher D, Delgado M (2009) Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut 58(7):929–939

    Article  CAS  PubMed  Google Scholar 

  • Hosomi S, Oshitani N, Kamata N, Sogawa M, Okazaki H, Tanigawa T, Yamagami H, Watanabe K, Tominaga K, Watanabe T, Fujiwara Y, Maeda K, Hirakawa K, Arakawa T (2011) Increased numbers of immature plasma cells in peripheral blood specifically overexpress chemokine receptor CXCR3 and CXCR4 in patients with ulcerative colitis. Clin Exp Immunol 163(2):215–224

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jiang J, Huang L, Yu W, Wu X, Zhou P, Li X (2012) Overexpression of HTRA1 leads to down-regulation of fibronectin and functional changes in RF/6A cells and HUVECs. PLoS One 7(10):e46115

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Karp JM, Leng Teo GS (2009) Mesenchymal stem cell homing: the devil is in the details. Cell Stem Cell 4(3):206–216

    Article  CAS  PubMed  Google Scholar 

  • Katsuta T, Lim C, Shimoda K, Shibuta K, Mitra P, Banner BF, Mori M, Barnard GF (2000) Interleukin-8 and SDF1-alpha mRNA expression in colonic biopsies from patients with inflammatory bowel disease. Am J Gastroenterol 95(11):3157–3164

    CAS  PubMed  Google Scholar 

  • Ko IK, Kim Byung-Gyu, Awadallah Amad, Mikulan Jenifer, Lin Paul, Letterio JJ, Dennis JE (2010) Targeting improves MSC treatment of inflammatory bowel disease. Mol Ther 18(7):1365–1372

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kortesidis A, Zannettino A, Isenmann S, Shi S, Lapidot T, Gronthos S (2005) Stromal-derived factor-1 promotes the growth, survival, and development of human bone marrow stromal stem cells. Blood 15:3793–3801

    Article  Google Scholar 

  • Lee MJ, Lee JK, Choi JW, Lee CS, Sim JH, Cho CH, Lee KH, Cho IH, Chung MH, Kim HR, Ye SK (2012) Interleukin-6 induces S100A9 expression in colonic epithelial cells through STAT3 activation in experimental ulcerative colitis. PLoS One 7(9):e38801

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Li M, Yu J, Li Y, Li D, Yan D, Qu Z, Ruan Q (2012) CXCR4 positive bone mesenchymal stem cells migrate to human endothelial cell stimulated by ox-LDL via SDF-1alpha/CXCR4 signaling axis. Exp Mol Pathol 88(2):250–255

    Article  Google Scholar 

  • Liang Jialiang, Huang Wei, Yu X, Ashraf A, Wary KK, Xu M, Millard RW, Ashraf M, Wang Y (2012) Suicide gene reveals the myocardial neovascularization role of mesenchymal stem cells overexpressing CXCR4 (MSCCXCR4). PLoS One 7(9):e46158

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Liu Hongbao, Liu Shuibing, Li Yang, Wang Xiaohong, Xue Wujun, Ge Guanqun, Luo Xiaohui (2012) The role of SDF-1-CXCR4/CXCR7 axis in the therapeutic effects of hypoxia-preconditioned mesenchymal stem cells for renal ischemia/reperfusion injury. PLoS One 7(4):e34608

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ma J, Ge J, Zhang S, Sun A, Shen J, Chen L, Wang K, Zou Y (2005) Time course of myocardial stromal cell-derived factor 1 expression and beneficial effects of intravenously administered bone marrow stem cells in rats with experimental myocardial infarction. Basic Res Cardiol 100(3):217–223

    Article  CAS  PubMed  Google Scholar 

  • Matsumoto T, Okamoto R, Yajima T, Mori T, Okamoto S, Ikeda Y, Mukai M, Yamazaki M, Oshima S, Tsuchiya K, Nakamura T, Kanai T, Okano H, Inazawa J, Hibi T, Watanabe M (2005) Increase of bone marrow-derived secretory lineage epithelial cells during regeneration in the human intestine. Gastroenterology 128(7):1851–1867

    Article  CAS  PubMed  Google Scholar 

  • Mitsuyama K, Matsumoto S, Rose-John S, Suzuki A, Hara T, Tomiyasu N, Handa K, Tsuruta O, Funabashi H, Scheller J, Toyonaga A, Sata M (2006) STAT3 activation via interleukin 6 trans-signalling contributes to ileitis in SAMP1/Yit mice. Gut 55(9):1263–1269

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mokbel AN, El Tookhy OS, Shamaa AA, Rashed LA, Sabry D, El Sayed AM (2011) Homing and reparative effect of intra-articular injection of autologus mesenchymal stem cells in osteoarthritic animal model. BMC Musculoskelet Disord 15(12):259

    Article  Google Scholar 

  • Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, Benchimol EI, Panaccione R, Ghosh S, Barkema HW, Kaplan GG (2012) Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 142(1):46–54

    Article  PubMed  Google Scholar 

  • Musso A, Dentelli P, Carlino A, Chiusa L, Repici A, Sturm A, Fiocchi C, Rizzetto M, Pegoraro L, Sategna-Guidetti C, Brizzi MF (2005) Signal transducers and activators of transcription 3 signaling pathway: an essential mediator of inflammatory bowel disease and other forms of intestinal inflammation. Inflamm Bowel Dis 11:91–98

    Article  PubMed  Google Scholar 

  • Nasef A, Mathieu N, Chapel A, Frick J, François S, Mazurier C, Boutarfa A, Bouchet S, Gorin NC, Thierry D, Fouillard L (2007) Immunosuppressive effects of mesenchymal stem cells: involvement of HLA-G. Transplantation 84(2):231–237

    Article  CAS  PubMed  Google Scholar 

  • Neufert C, Pickert G, Zheng Y, Wittkopf N, Warntjen M, Nikolaev A, Ouyang W, Neurath MF, Becker C (2010) Activation of epithelial STAT3 regulates intestinal homeostasis. Cell Cycle 9(4):652–655

    Article  CAS  PubMed  Google Scholar 

  • Neurath MF, Finotto S, Fuss I, Boirivant M, Galle PR, Strober W (2001) Regulation of T-cell apoptosis in inflammatory bowel disease: to die or not to die, that is the mucosal question. Trends Immunol 22(1):21–26

    Article  CAS  PubMed  Google Scholar 

  • Newman R, Cuan N, Hampartzoumian T, Connor SJ, Lloyd AR, Grimm MC (2005) Vasoactive intestinal peptide impairs leucocyte migration but fails to modify experimental murine colitis. Clin Exp Immunol 139(3):411–420

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Paiotti AP, Ribeiro DA, Silva RM, Marchi P, Oshima CT, Neto RA, Miszputen SJ, Franco M (2012) Effect of COX-2 inhibitor lumiracoxib and the TNF-α antagonist etanercept on TNBS-induced colitis in Wistar rats. J Mol Histol 43(3):307–317

    Article  CAS  PubMed  Google Scholar 

  • Parekkadan B, Upadhyay R, Dunham J, Iwamoto Y, Mizoguchi E, Mizoguchi A, Weissleder R, Yarmush ML (2011) Bone marrow stromal cell transplants prevent experimental enterocolitis and require host CD11b+ splenocytes. Gastroenterology 140(3):966–975

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Polgar N, Csongei V, Szabo M, Zambo V, Melegh BI, Sumegi K, Nagy G, Tulassay Z, Melegh B (2012) Investigation of JAK2, STAT3 and CCR6 polymorphisms and their gene–gene interactions in inflammatory bowel disease. Int J Immunogenet 39(3):247–252

    Article  CAS  PubMed  Google Scholar 

  • Ponomaryov T, Peled A, Petit I, Taichman RS, Habler L, Sandbank J, Arenzana-Seisdedos F, Magerus A, Caruz A, Fujii N, Nagler A, Lahav M, Szyper-Kravitz M, Zipori D, Lapidot T (2000) Induction of the chemokine stromal-derived factor-1 following DNA damage improves human stem cell function. J Clin Invest 106(11):1331–1339

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Schrepfer S, Deuse T, Reichenspurner H, Fischbein MP, Robbins RC, Pelletier MP (2007) Stem cell transplantation: the lung barrier. Transplant Proc 39(2):573–576

    Article  CAS  PubMed  Google Scholar 

  • Sémont A, François S, Mouiseddine M, François A, Saché A, Frick J, Thierry D, Chapel A (2006) Mesenchymal stem cells increase self-renewal of small intestinal epithelium and accelerate structural recovery after radiation injury. Adv Exp Med Biol 585:19–30

    Article  PubMed  Google Scholar 

  • Shi M, Li J, Liao L, Chen B, Li B, Chen L, Jia H, Zhao RC (2007) Regulation of CXCR4 expression in human mesenchymal stem cells by cytokine treatment: role in homing efficiency in NOD/SCID. Haematologica 92(7):897–904

    Article  PubMed  Google Scholar 

  • Strober W, Fuss IJ (2011) Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases. Gastroenterology 140(6):1756–1767

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sugimoto K (2008) Role of STAT3 in inflammatory bowel disease. World J Gastroenterol 14(33):5110–5114

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sugimoto K, Ogawa A, Mizoguchi E, Shimomura Y, Andoh A, Bhan AK, Blumberg RS, Xavier RJ, Mizoguchi A (2008) IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Invest 118(2):534–544

    CAS  PubMed Central  PubMed  Google Scholar 

  • Tanaka F, Tominaga K, Ochi M, Tanigawa T, Watanabe T, Fujiwara Y, Ohta K, Oshitani N, Higuchi K, Arakawa T (2008) Exogenous administration of mesenchymal stem cells ameliorates dextran sulfate sodium-induced colitis via anti-inflammatory action in damaged tissue in rats. Life Sci 83(23–24):771–779

    Article  CAS  PubMed  Google Scholar 

  • Teicher BA, Fricker SP (2010) CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin Cancer Res 16:2927–2931

    Article  CAS  PubMed  Google Scholar 

  • Valcz G, Krenács T, Sipos F, Leiszter K, Tóth K, Balogh Z, Csizmadia A, Muzes G, Molnár B, Tulassay Z (2011) The role of the bone marrow derived mesenchymal stem cells in colonic epithelial regeneration. Pathol Oncol Res 17(1):11–16

    Article  CAS  PubMed  Google Scholar 

  • Voswinkel J, Francois S, Simon JM, Benderitter M, Gorin NC, Mohty M, Fouillard L, Chapel A et al (2013) Use of mesenchymal stem cells (MSC) in chronic inflammatory fistulizing and fibrotic diseases: a comprehensive review. Clin Rev Allergy Immunol 45(2):180–192

    Google Scholar 

  • Xavier RJ, Podolsky DK (2007) Unravelling the pathogenesis of inflammatory bowel disease. Nature 448(7152):427–434

    Article  CAS  PubMed  Google Scholar 

  • Yabana T, Arimura Y, Tanaka H, Goto A, Hosokawa M, Nagaishi K, Yamashita K, Yamamoto H, Adachi Y, Sasaki Y, Isobe M, Fujimiya M, Imai K, Shinomura Y (2009) Enhancing epithelial engraftment of rat mesenchymal stem cells restores epithelial barrier integrity. J Pathol 218(3):350–359

    Article  CAS  PubMed  Google Scholar 

  • Yu J, Li M, Qu Z, Yan D, Li D, Ruan Q (2010) SDF-1/CXCR4-mediated migration of transplanted bone marrow stromal cells toward areas of heart myocardial infarction through activation of PI3 K/Akt. J Cardiovasc Pharmacol 55(5):496–505

    CAS  PubMed  Google Scholar 

  • Zhang L, Liu Hou-jia, Li Tie-jun, Yang Y, Guo Xian-ling, Wu Meng-chao, Rui Yao-cheng, Wei Li-xin (2008a) Lentiviral vector-mediated siRNA knockdown of SR-PSOX inhibits foam cell formation in vitro. Acta Pharmacol Sin 29(7):847–852

    Article  CAS  PubMed  Google Scholar 

  • Zhang D, Fan GC, Zhou X, Zhao T, Pasha Z, Xu M, Zhu Y, Ashraf M, Wang Y (2008b) Over-expression of CXCR4 on mesenchymal stem cells augments myoangiogenesis in the infarcted myocardium. J Mol Cell Cardiol 44(2):281–292

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

The authors acknowledge the technical assistance of Qiong Yuan and Dongliang He. This work was supported by Grants form National Natural Science Foundation of China (No. 81273906).

Author information

Authors and Affiliations

  1. Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China

    Xingxing Liu, Dongmei Zuo, Heng Fan, Qing Tang, Zhexing Shou, Dan Cao & Zhou Zou

Authors
  1. Xingxing Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dongmei Zuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Heng Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qing Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhexing Shou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dan Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zhou Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Heng Fan.

Additional information

Xingxing Liu and Dongmei Zuo contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, X., Zuo, D., Fan, H. et al. Over-expression of CXCR4 on mesenchymal stem cells protect against experimental colitis via immunomodulatory functions in impaired tissue. J Mol Hist 45, 181–193 (2014). https://doi.org/10.1007/s10735-013-9541-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10735-013-9541-4

Keywords

Search

Navigation