Journal of Gastroenterology

, Volume 49, Issue 2, pp 270–282 | Cite as

Conditioned mesenchymal stem cells produce pleiotropic gut trophic factors

  • Shuhei Watanabe
  • Yoshiaki ArimuraEmail author
  • Kanna Nagaishi
  • Hiroyuki Isshiki
  • Kei Onodera
  • Masanao Nasuno
  • Kentaro Yamashita
  • Masashi Idogawa
  • Yasuyoshi Naishiro
  • Masaki Murata
  • Yasushi Adachi
  • Mineko Fujimiya
  • Kohzoh Imai
  • Yasuhisa Shinomura
Original Article—Alimentary Tract



Although mounting evidence implicates mesenchymal stem cells (MSCs) in intestinal tissue repair, controversy remains regarding the engraftment, proliferation, and differentiation for repopulating MSCs in recipient tissues. Therefore, we investigated the paracrine and/or endocrine role of MSCs in experimental colitis.


We analyzed the therapeutic effects of MSC-conditioned medium (MSC-CM) on dextran sulfate sodium (DSS)- or 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis. We investigated the effects of MSC-CM on the epithelial cell viability, mobility, cell cycle, and cytokine production in ex vivo lamina propria/mesenteric lymphocytes, a macrophage cell line, and the mixed lymphocyte reaction. An optimal regimen against colitis was explored. The contents of MSC-CM were analyzed using a WNT signaling pathway polymerase chain reaction array, an inflammatory cytokines antibody array, and liquid chromatography-tandem mass spectrometry analysis.


Independent of the systemic administration route, MSC-CM concentrates were effective for the inductive phase of TNBS-induced colitis and for the recovery phase of DSS-induced colitis. Hypoxia appeared to be one of the optimal preconditioning factors assessed by cell motility and viability through activating the PI3K-Akt pathway in rat small intestine epithelial cells, IEC-6. Thus, Hypoxia had profound effects on the contents of MSC-CM, which comprised pleiotropic gut trophic factors involved in each wound healing process, including the anti-inflammatory, proliferative, and tissue remodeling phases.


Identification and optimization of potential gut trophic factors in MSC-CM is urgently needed to form the basis for new drug discovery and for optimizing cell-based therapies for inflammatory bowel disease.


Mesenchymal stem cell Conditioned medium Dextran sulfate sodium colitis 2,4,6-Trinitrobenzenesulfonic acid Inflammatory bowel disease 



We would like to thank Ms. K Fujii, Research Assistant, Sapporo Medical University, for technical assistance. This work was supported in part by Health and Labor Sciences Research Grants for research on intractable diseases from the Ministry of Health, Labor and Welfare of Japan (to K.I.).

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

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Copyright information

© Springer Japan 2013

Authors and Affiliations

  • Shuhei Watanabe
    • 1
  • Yoshiaki Arimura
    • 1
    Email author
  • Kanna Nagaishi
    • 2
  • Hiroyuki Isshiki
    • 1
  • Kei Onodera
    • 1
  • Masanao Nasuno
    • 1
  • Kentaro Yamashita
    • 1
  • Masashi Idogawa
    • 3
  • Yasuyoshi Naishiro
    • 4
  • Masaki Murata
    • 5
  • Yasushi Adachi
    • 1
  • Mineko Fujimiya
    • 2
  • Kohzoh Imai
    • 6
  • Yasuhisa Shinomura
    • 1
  1. 1.Department of Gastroenterology, Rheumatology, and Clinical ImmunologySapporo Medical UniversitySapporoJapan
  2. 2.Department of AnatomySapporo Medical UniversitySapporoJapan
  3. 3.Department of Medical Genome Sciences, Research Institute for Frontier MedicineSapporo Medical UniversitySapporoJapan
  4. 4.Department of Educational DevelopmentSapporo Medical UniversitySapporoJapan
  5. 5.Department of PathologySapporo Medical UniversitySapporoJapan
  6. 6.Center for Antibody and Vaccine Therapy, Institute of Medical ScienceUniversity of TokyoTokyoJapan

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