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Cultured bone marrow cell local implantation accelerates healing of ulcers in mice

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Abstract

Background

The therapeutic potential of bone marrow (BM)-derived cells in ulcers is not known. This study aimed to clarify (1) cell types that are derived from the BM which infiltrate ulcers; (2) whether BM-derived cells or gastric myofibroblasts can be used for cell transplantation to treat ulcers; and (3) the phenotypes of such transplantable cells.

Methods

(1) Wild-type mice were transplanted with BM cells of green fluorescent protein (GFP)-transgenic mice. Acetic acid-induced gastric ulcers were produced in mice after BM transplantation. (2) BM cells and gastric myofibroblasts were isolated from GFP-transgenic mice. Bone marrow cells attached to plastic dishes were selected for expansion. Gastric ulcers were induced, and BM-derived cells, myofibroblasts, or phosphate-buffered saline were injected around ulcers. The ulcer healing process was examined macroscopically and histologically. (3) Expression of growth factors and cytokines in transplantable cells was examined by reverse transcriptase-polymerase chain reaction.

Results

(1) GFP-positive cells with interstitial phenotypes were observed at the ulcerated area. (2) Ulcer healing was significantly promoted by the injection of BM-derived cells compared to controls on day 7, but not on day 3. The BM-derived cells were observed in the tissue surrounding the ulcer. However, myofibroblasts were not found. (3) The BM-derived cells expressed hepatocyte growth factor, transforming growth factor-β1, and other stromal factors before transplantation, and had mesenchymal phenotypes after transplantation.

Conclusions

BM-derived cells are involved in the ulcer healing. BM-derived cells, but not myofibroblasts, are locally implantable to ulcers. Thus, BM-derived cells can be transplanted to accelerate ulcer healing.

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References

  1. Gabbiani G. The myofibroblast in wound healing and fibrocontractive diseases. J Pathol 2003;200:500–503.

    Article  PubMed  CAS  Google Scholar 

  2. Lorena D, Uchio K, Costa AM, Desmouliere A. Normal scarring: importance of myofibroblasts. Wound Repair Regen 2002;10:86–92.

    Article  PubMed  Google Scholar 

  3. Grinnell F. Fibroblasts, myofibroblasts, and wound contraction. J Cell Biol 1994;124:401–404.

    Article  PubMed  CAS  Google Scholar 

  4. Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 2002;3:349–363.

    Article  PubMed  CAS  Google Scholar 

  5. Desmouliere A, Redard M, Darby I, Gabbiani G. Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am J Pathol 1995;146:56–66.

    PubMed  CAS  Google Scholar 

  6. Nishida T, Tsuji S, Kimura A, Tsujii M, Ishii S, Yoshio T, et al. Endothelin-1, an ulcer inducer, promotes gastric ulcer healing via mobilizing gastric myofibroblasts and stimulates production of stroma-derived factors. Am J Physiol Gastrointest Liver Physiol 2006;290:G1041–G1050.

    Article  PubMed  CAS  Google Scholar 

  7. 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;8:1011–1017.

    Article  PubMed  CAS  Google Scholar 

  8. Petersen BE, Bowen WC, Patrene KD, Mars WM, Sullivan AK, et al. Bone marrow as a potential source of hepatic oval cells. Science 1999;284:1168–1170.

    Article  PubMed  CAS  Google Scholar 

  9. 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 Repair Regen 2005;13:109–118.

    Article  PubMed  Google Scholar 

  10. Komori M, Tsuji S, Tsujii M, Murata H, Iijima H, Yasumaru M, et al. Efficiency of bone marrow-derived cells in regeneration of the stomach after induction of ethanol-induced ulcers in rats. J Gastroenterol 2005;40:591–599.

    Article  PubMed  Google Scholar 

  11. Direkze NC, Forbes SJ, Brittan M, Hunt T, Jeffery R, Preston SL, et al. Multiple organ engraftment by bone-marrow-derived myofibroblasts and fibroblasts in bone-marrow-transplanted mice. Stem Cells 2003;21:514–520.

    Article  PubMed  Google Scholar 

  12. Okabe M, Ikawa M, Kominami K, Nakanishi T, Nishimune Y. ’Green mice’ as a source of ubiquitous green cells. FEBS Lett 1997;407:313–319.

    Article  PubMed  CAS  Google Scholar 

  13. Okabe S, Saziki R, Takagi K. Cortisone acetate and stress on the healing process of chronic gastric ulcer in rats. J Appl Physiol 1971;30:793–796.

    PubMed  CAS  Google Scholar 

  14. Bianchi G, Muraglia A, Daga A, Corte G, Cancedda R, Quarto R. Microenvironment and stem properties of bone marrow-derived mesenchymal cells. Wound Repair Regen 2001;9:460–466.

    Article  PubMed  CAS  Google Scholar 

  15. Bianco P, Riminucci M, Gronthos S, Robey PG. Bone marrow stromal stem cells: nature, biology, and potential applications. Stem Cells 2001;19:180–192.

    Article  PubMed  CAS  Google Scholar 

  16. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature (Lond) 2002;418:41–49.

    Article  CAS  Google Scholar 

  17. Tsuji S, Kawano S, Tsujii M, Fusamoto H, Kamada T. Roles of hepatocyte growth factor and its receptor in gastric mucosa. A cell biological and molecular biological study. Dig Dis Sci 1995;40:1132–1139.

    Article  PubMed  CAS  Google Scholar 

  18. Sun WH, Tsuji S, Tsujii M, Gunawan ES, Sawaoka H, Kawai N, et al. Cyclo-oxygenase-2 inhibitors suppress epithelial cell kinetics and delay gastric wound healing in rats. J Gastroenterol Hepatol 2000;15:752–761.

    Article  PubMed  CAS  Google Scholar 

  19. Ernst H, Konturek PC, Hahn EG, Stosiek HP, Brzozowski T, Konturek SJ. Effect of local injection with basic fibroblast growth factor (BFGF) and neutralizing antibody to BFGF on gastric ulcer healing, gastric secretion, angiogenesis and gastric blood flow. J Physiol Pharmacol 2001;52:377–390.

    PubMed  CAS  Google Scholar 

  20. Chai J, Jones MK, Tarnawski AS. Serum response factor is a critical requirement for VEGF signaling in endothelial cells and VEGF-induced angiogenesis. FASEB J 2004;18:1264–1266.

    PubMed  CAS  Google Scholar 

  21. Bajaj-Elliott M, Breese E, Poulsom R, Fairclough PD, MacDonald TT. Keratinocyte growth factor in inflammatory bowel disease. Increased mRNA transcripts in ulcerative colitis compared with Crohn’s disease in biopsies and isolated mucosal myofibroblasts. Am J Pathol 1997;151:1469–1476.

    PubMed  CAS  Google Scholar 

  22. Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringden O. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol 2003;57:11–20.

    Article  PubMed  Google Scholar 

  23. Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, et al. Human bone marrow stromal cells suppress Tlymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002;99:3838–3843.

    Article  PubMed  Google Scholar 

  24. Deans RJ, Moseley AB. Mesenchymal stem cells: biology and potential clinical uses. Exp Hematol 2000;28:875–884.

    Article  PubMed  CAS  Google Scholar 

  25. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005;105:1815–1822.

    Article  PubMed  CAS  Google Scholar 

  26. Ferrari G, Cusella-De Angelis G, Coletta M, Paolucci E, Stornaiuolo A, Cossu G, Mavilio F. Muscle regeneration by bone marrow-derived myogenic progenitors. Science 1998;279:1528–1530.

    Article  PubMed  CAS  Google Scholar 

  27. Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, et al. Bone marrow cells regenerate infarcted myocardium. Nature (Lond) 2001;410:701–705.

    Article  CAS  Google Scholar 

  28. Eglitis MA, Mezey E. Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. Proc Natl Acad Sci USA 1997;94:4080–4085.

    Article  PubMed  CAS  Google Scholar 

  29. Shen CN, Slack JM, Tosh D. Molecular basis of transdifferentiation of pancreas to liver. Nat Cell Biol 2000;2:879–887.

    Article  PubMed  CAS  Google Scholar 

  30. Alison MR, Poulsom R, Jeffery R, Dhillon AP, Quaglia A, Jacob J, et al. Hepatocytes from non-hepatic adult stem cells. Nature (Lond) 2000;406:257.

    Article  CAS  Google Scholar 

  31. Krause DS, Theise ND, Collector MI, Henegariu O, Hwang S, Gardner R, et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 2001;105:369–377.

    Article  PubMed  CAS  Google Scholar 

  32. Jackson KA, Majka SM, Wang H, Pocius J, Hartley CJ, Majesky MW, et al. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest 2001;107:1395–1402.

    Article  PubMed  CAS  Google Scholar 

  33. Ohana M, Okazaki K, Oshima C, Andra’s D, Nishi T, Uchida K, et al. A critical role for IL-7R signaling in the development of Helicobacter felis-induced gastritis in mice. Gastroenterology 2001;121:329–336.

    Article  PubMed  CAS  Google Scholar 

  34. Muller-Decker K, Leder C, Neumann M, Neufang G, Bayerl C, Schweizer J, et al. Expression of cyclooxygenase isozymes during morphogenesis and cycling of pelage hair follicles in mouse skin: precocious onset of the first catagen phase and alopecia upon cyclooxygenase-2 overexpression. J Invest Dermatol 2003;121:661–668.

    Article  PubMed  Google Scholar 

  35. Amano O, Koshimizu U, Nakamura T, Iseki S. Enhancement by hepatocyte growth factor of bone and cartilage formation during embryonic mouse mandibular development in vitro. Arch Oral Biol 1999;44:935–946.

    Article  PubMed  CAS  Google Scholar 

  36. Jeong HJ, Kim JB, Hong SH, An NH, Kim MS, Park BR, et al. Vascular endothelial growth factor is regulated by hypoxic stress via MAPK and HIF-1 alpha in the inner ear. J Neuroimmunol 2005;163:84–91.

    Article  PubMed  CAS  Google Scholar 

  37. Mori I, Goshima F, Koshizuka T, Imai Y, Kohsaka S, Koide N, et al. Iba1-expressing microglia respond to herpes simplex virus infection in the mouse trigeminal ganglion. Brain Res Mol Brain Res 2003;120:52–56.

    Article  PubMed  CAS  Google Scholar 

  38. Machida H, Ogawa K, Funaba M, Mizutani T, Tsujimoto M. mRNA expression of type I and type II receptors for activin, transforming growth factor-beta, and bone morphogenetic protein in the murine erythroleukemic cell line, F5-5.fl. Eur J Endocrinol 2000;143:705–710.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Clinical Research Building (K1), Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, 565-0871, Japan

    Tsutomu Nishida, Shingo Tsuji, Masahiko Tsujii, Shuji Ishii, Toshiyuki Yoshio, Shinichiro Shinzaki, Satoshi Egawa, Takanobu Irie, Yoshimi Kakiuchi, Masakazu Yasumaru, Hideki Iijima, Shusaku Tsutsui & Norio Hayashi

  2. Department of Clinical Laboratory Science, Osaka University Graduate School of Medicine, Osaka, Japan

    Sunao Kawano

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  1. Tsutomu Nishida
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  2. Shingo Tsuji
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  3. Masahiko Tsujii
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Nishida, T., Tsuji, S., Tsujii, M. et al. Cultured bone marrow cell local implantation accelerates healing of ulcers in mice. J Gastroenterol 43, 124–135 (2008). https://doi.org/10.1007/s00535-007-2137-6

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  • DOI: https://doi.org/10.1007/s00535-007-2137-6

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