Skip to main content

Advertisement

SpringerLink
Log in

Myogenic lineage differentiated mesenchymal stem cells enhance recovery from dextran sulfate sodium-induced colitis in the rat

  • Original Article—Alimentary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

Although mounting evidence implicates mesenchymal stem cells (MSCs) in intestinal tissue repair, uncertainty remains concerning the distribution, function, and fate of repopulating MSCs in recipient colonic tissues. Therefore, we investigated the role of transplanted MSCs in the repair phase of DSS colitis.

Methods

LacZ-labeled rat MSCs were transplanted into rats with colitis induced by 4% DSS on day 2. Regular water replaced the DSS solution on day 6. Therapeutic effect was evaluated on day 9 by clinicopathologic and growth factor/cytokine expression profiles. We analyzed the Notch signaling pathway by Western blotting and characterized immunofluorescence of lacZ-labeled MSCs with confocal laser microscopy. In vivo differentiation of MSC was confirmed by transmission electron microscopy (TEM).

Results

Recovery of colitis was modestly but significantly promoted by MSC transplantation due to proceeding cell cycle and inhibiting apoptosis in the epithelia. Tgfa mRNA expression increased significantly, while Notch signaling was inhibited in the colonic tissues with MSC transplantation. β-Galactosidase-positive cells, which expressed α-SMA, desmin, and vimentin, were infrequently detected in the lamina propria stroma. DSS exposure in vitro proved to be the most potent inducer for α-SMA in MSCs where TEM demonstrated myogenic lineage differentiation.

Conclusions

We found that MSCs transplantation modestly promoted the repair of DSS colitis. The donor-derived MSCs were likely reprogrammed to differentiate to myogenic lineage cells by cues from the micro milieu. Further characterization of these cells is warranted as a basis for applying cell-based therapy for inflammatory bowel disease.

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

  1. Okayasu I, Hatakeyama S, Yamada M, Ohkusa T, Inagaki Y, Nakaya R. A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology. 1990;98:694–702.

    CAS  PubMed  Google Scholar 

  2. Watt J, Marcus R. Experimental ulcerative disease of the colon. Methods Achiev Exp Pathol. 1975;7:56–71.

    CAS  PubMed  Google Scholar 

  3. Egger B, Bajaj-Elliott M, MacDonald TT, Inglin R, Eysselein VE, Buchler MW. Characterization of acute murine dextran sodium sulphate colitis: cytokine profile and dose dependency. Digestion. 2000;62:240–8.

    Article  CAS  PubMed  Google Scholar 

  4. Cooper HS, Murthy SNS, Shah RS, Sedergran DJ. Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab Invest. 1993;69:238–49.

    CAS  PubMed  Google Scholar 

  5. Sturm A, Dignass AU. Epithelial restitution and wound healing in inflammatory bowel disease. World J Gastroenterol. 2008;14:348–53.

    Article  CAS  PubMed  Google Scholar 

  6. Taupin D, Podolsky DK. Trefoil factors: initiators of mucosal healing. Nat Rev Mol Cell Biol. 2003;4:721–32.

    Article  CAS  PubMed  Google Scholar 

  7. Dignass AU, Tsunekawa S, Podolsky DK. Fibroblast growth factors modulate intestinal epithelial cell growth and migration. Gastroenterology. 1994;106:1254–62.

    CAS  PubMed  Google Scholar 

  8. Scoville DH, Sato T, He XC, Li L. Current view: intestinal stem cells and signaling. Gastroenterology. 2008;134:849–64.

    Article  CAS  PubMed  Google Scholar 

  9. Williams KL, Fuller CR, Dieleman LA, DaCosta CM, Haldeman KM, Sartor RB, et al. Enhanced survival and mucosal repair after dextran sodium sulfate-induced colitis in transgenic mice that overexpress growth hormone. Gastroenterology. 2001;120:925–37.

    Article  CAS  PubMed  Google Scholar 

  10. Komori M, Tsuji S, Tsujii M, Murata H, Iijima H, Yasumaru M, et al. Involvement of bone marrow-derived cells in healing of experimental colitis in rats. Wound Rep Reg. 2005;13:109–18.

    Article  Google Scholar 

  11. Okamoto R, Yajima T, Yamazaki M, Kanai T, Mukai M, Okamoto S, et al. Damaged epithelia regenerated by bone marrow-derived cells in the human gastrointestinal tract. Nat Med. 2002;8:1011–7.

    Article  CAS  PubMed  Google Scholar 

  12. Matsumoto T, Okamoto R, Yajima T, Mori T, Okamoto S, Ikeda Y, et al. Increase of bone marrow-derived secretory lineage epithelial cells during regeneration in the human intestine. Gastroenterology. 2005;128:1851–67.

    Article  CAS  PubMed  Google Scholar 

  13. Brittan M, Chance V, Elia G, Poulsom R, Alison MR, MacDonald TT, et al. A regenerative role for bone marrow following experimental colitis: contribution to neovasculogenesis and myofibroblasts. Gastroenterology. 2005;128:1984–95.

    Article  PubMed  Google Scholar 

  14. Brittan M, Hunt T, Jeffery R, Poulsom R, Forbes SJ, Hodivala-Dilke K, et al. Bone marrow derivation of pericryptal myofibroblasts in the mouse and human small intestine and colon. Gut. 2002;50:752–7.

    Article  CAS  PubMed  Google Scholar 

  15. Bamba S, Lee C-Y, Brittan M, Preston SL, Direkze NC, Poulsom R, et al. Bone marrow transplantation ameliorates pathology in interleukin-10 knockout colitic mice. J Pathol. 2006;209:265–73.

    Article  CAS  PubMed  Google Scholar 

  16. Hayashi Y, Tsuji S, Tsujii M, Nishida T, Ishii S, Nakamura T, et al. The transdifferentiation of bone-marrow-derived cells in colonic mucosal regeneration after dextran-sulfate-sodium-induced colitis in mice. Pharmacology. 2007;80:193–9.

    Article  CAS  PubMed  Google Scholar 

  17. Jiang S, Walker L, Afentoulis M, Anderson DA, Jauron-Mills L, Corless CL, et al. Transplanted human bone marrow contributes to vascular endothelium. Proc Natl Acad Sci. 2004;101:16891–6.

    Article  CAS  PubMed  Google Scholar 

  18. Beck PL, Li Y, Wong J, Chen CW, Keenan CM, Sharkey KA, et al. Inducible nitric oxide synthase from bone marrow-derived cells plays a critical role in regulating colonic inflammation. Gastroenterology. 2007;132:1778–90.

    Article  CAS  PubMed  Google Scholar 

  19. Yabana T, Arimura Y, Tanaka H, Goto A, Hosokawa M, Nagaishi K, et al. Enhancing epithelial engraftment of rat mesenchymal stem cells restores epithelial barrier integrity. J Pathol. 2009;218:350–9.

    Article  CAS  PubMed  Google Scholar 

  20. Hayashi Y, Tsuji S, Tsuji M, Tsujii M, Nishida T, Iijima H, et al. Topical implantation of Mesenchymal stem cells has beneficial effects on healing of experimental colitis in rats. J Pharmacol Exp Ther. 2008;326:523–31.

    Article  CAS  PubMed  Google Scholar 

  21. Ando Y, Inaba M, Sakaguchi Y, Tsuda M, Quan GK, Omae M, et al. 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. 2008;14:826–38.

    Article  PubMed  Google Scholar 

  22. Khalil PN, Weiler V, Nelson PJ, Khalil MN, Moosmann S, Mutschler WE, et al. Nonmyeloablative stem cell therapy enhances microcirculation and tissue regeneration in murine inflammatory bowel disease. Gastroenterology. 2007;132:944–54.

    Article  PubMed  Google Scholar 

  23. Zhang Q, Shi S, Liu Y, Uyanne J, Shi Y, Le AD. Mesenchymal stem cells derived from human gingiva are capable of immunomodulatory functions and ameliorate inflammation-related tissue destruction in experimental colitis. J Immunol. 2009;183:7787–98.

    Article  CAS  PubMed  Google Scholar 

  24. Gonzalez-Rey E, Anderson P, González MA, Rico L, Buscher D, Delgado M. Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut. 2009;58:929–39.

    Article  CAS  PubMed  Google Scholar 

  25. Tanaka F, Tominaga K, Ochi M, Tanigawa T, Watanabe T, Fujiwara Y, et al. Exogenous administration of mesenchymal stem cells ameliorates dextran sulfate sodium-induced colitis via anti-inflammatory action in damaged tissue in rats. Life Sci. 2008;83:771–9.

    Article  CAS  PubMed  Google Scholar 

  26. Inoue H, Ohsawa I, Murakami T, Kimura A, Hakamata Y, Sato Y, et al. Development of new inbred transgenic strains of rats with LacZ or GFP. Biochem Biophys Res Commun. 2005;329:288–95.

    Article  CAS  PubMed  Google Scholar 

  27. Javazon EH, Colter DC, Schwarz EJ, Prockop DJ. Rat marrow stromal cells are more sensitive to plating density and expand more rapidly from single-cell-derived colonies than human marrow stromal cells. Stem Cells. 2001;19:219–25.

    Article  CAS  PubMed  Google Scholar 

  28. Romanov YA, Svintsitskaya VA, Smirnov VN. Searching for alternative sources of postnatal human mesenchymal stem cells: candidate MSC-Like cells from umbilical cord. Stem Cells. 2003;21:105–10.

    Article  PubMed  Google Scholar 

  29. Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Nakatani T, et al. Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats. Hepatology. 2001;34:745–50.

    Article  CAS  PubMed  Google Scholar 

  30. Iyonaga K, Takeya M, Yamamoto T, Ando M, Takahashi K. A novel monoclonal antibody, RM-4, specifically recognizes rat macrophages and dendritic cells in formalin-fixed, paraffin-embedded tissues. Histochem J. 1997;29:105–16.

    Article  CAS  PubMed  Google Scholar 

  31. Rieder F, Brenmoehl J, Leeb S, et al. Wound healing and fibrosis in intestinal disease. Gut. 2007;56:130–9.

    Article  CAS  PubMed  Google Scholar 

  32. Barnard JA, Beauchamp RD, Russell WE, Scholmerich J, Rogler G, et al. Epidermal growth factor-related peptides and their relevance to gastrointestinal pathophysiology. Gastroenterology. 1995;108:564–80.

    Article  CAS  PubMed  Google Scholar 

  33. Xian CJ, Cool JC, Howarth GS, Read LC. Effects of TGF-alpha gene knockout on epithelial cell kinetics and repair of methotrexate-induced damage in mouse small intestine. J Cell Physiol. 2002;191:105–15.

    Article  CAS  PubMed  Google Scholar 

  34. Yang Q, Bermingham NA, Finegold MJ, Zoghbi HY. Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science. 2001;294:2155–8.

    Article  CAS  PubMed  Google Scholar 

  35. Okamoto R, Tsuchiya K, Nemoto Y, Akiyama J, Nakamura T, Kanai T, et al. Requirement of Notch activation during regeneration of the intestinal epithelia. Am J Physiol Gastrointest Liver Physiol. 2009;296:23–35.

    Article  Google Scholar 

  36. González MA, Gonzalez-Rey E, Rico L, Buscher D, Delgado M. Adipose-derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses. Gastroenterology. 2009;136:978–89.

    Article  PubMed  Google Scholar 

  37. Wei Y, Nie Y, Lai J, Wan YJ, Li Y. Comparison of the population capacity of hematopoietic and mesenchymal stem cells in experimental colitis rat model. Transplantation. 2009;88:42–8.

    Article  PubMed  Google Scholar 

  38. Hilton MJ, Tu X, Wu X, Bai S, Zhao H, Kobayashi T, et al. Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Nat Med. 2008;14:306–14.

    Article  CAS  PubMed  Google Scholar 

  39. Kinner B, Zaleskas JM, Spector M. Regulation of smooth muscle actin expression and contraction in adult human mesenchymal stem cells. Exp Cell Res. 2002;278:72–83.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We are very grateful to Dr. T Mitsuhashi, associate professor of the Department of Surgical Pathology, for assessment of colitis and Dr. M Murata, assistant professor of the Second Department of Pathology, Sapporo Medical University, for performing the electron microscopy studies. We are thankful to the National BioResource Project for the Rat in Japan (http://www.anim.med.kyoto-u.ac.jp/NBR/) for providing rat strains LEW-Tg (Gt (Rosa) 26Sor-lacZ) 44Jmsk. This work was supported in part by Health and Labor Sciences Research Grants for research on intractable diseases from Ministry of Health, Labor and Welfare of Japan (K.I.).

Conflict of interest

None of the authors has any conflicts of interest.

Author information

Authors and Affiliations

  1. First Department of Internal Medicine, Sapporo Medical University, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan

    Hiroki Tanaka, Yoshiaki Arimura, Takashi Yabana, Akira Goto, Masayo Hosokawa, Kanna Nagaishi, Kentaro Yamashita, Hiroyuki Yamamoto & Yasuhisa Shinomura

  2. Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan

    Yasushi Sasaki

  3. Department of Anatomy, Sapporo Medical University, Sapporo, Japan

    Mineko Fujimiya

  4. Sapporo Medical University, Sapporo, Japan

    Kohzoh Imai

Authors
  1. Hiroki Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yoshiaki Arimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takashi Yabana
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Akira Goto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Masayo Hosokawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kanna Nagaishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kentaro Yamashita
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hiroyuki Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yasushi Sasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mineko Fujimiya
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kohzoh Imai
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yasuhisa Shinomura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yoshiaki Arimura.

Electronic supplementary material

Below is the link to the electronic supplementary material.

535_2010_320_MOESM1_ESM.jpg

Supplementary Fig 1 DSS colitis. The rats were given drinking water containing 10% DSS ad libitum from day 0 until day 6, and were divided into four treatment groups (n = 10 per group), group 1 received an injection of 2×104 rMSCs/g on day 1; group 2 on day 2; and group 3 on day 3; while the control group received no rMSCs injection. For 4% DSS colitis, DSS was continuously administered from day 0 to day 6. The rats were divided into two groups of 10 each; in the treatment group rMSCs were transplanted on day 3, while the control group rats were treated similarly but without DSS administration (Supplementary Fig. 1 online). rMSC transplantation against 10% lethal and 4% DSS colitis. (a) Therapeutic protocol against 10% lethal DSS colitis. Each arrowhead represents the indicated rMSC injection dose in each group (day 1, 2, or 3 group). (b) Time course of body weight change. NS indicates no significance. (c) Overall survival analyzed by Kaplan-Meier estimate using log-rank (Mantel-Cox) test. (d) Therapeutic protocol against 4% DSS colitis. 4% DSS had been continuously administered for six days (day 0 to day 6). rMSCs transplantations were performed at day 3 (arrowheads). (e) Time course of body weight change. NS indicates no significance. (JPEG 624 kb)

Supplementary Table 1 (DOC 39 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tanaka, H., Arimura, Y., Yabana, T. et al. Myogenic lineage differentiated mesenchymal stem cells enhance recovery from dextran sulfate sodium-induced colitis in the rat. J Gastroenterol 46, 143–152 (2011). https://doi.org/10.1007/s00535-010-0320-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-010-0320-7

Keywords

Search

Navigation