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Conditioned mesenchymal stem cells produce pleiotropic gut trophic factors

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Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

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Acknowledgments

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.

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Authors and Affiliations

  1. Department of Gastroenterology, Rheumatology, and Clinical Immunology, Sapporo Medical University, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan

    Shuhei Watanabe, Yoshiaki Arimura, Hiroyuki Isshiki, Kei Onodera, Masanao Nasuno, Kentaro Yamashita, Yasushi Adachi & Yasuhisa Shinomura

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

    Kanna Nagaishi & Mineko Fujimiya

  3. Department of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, Japan

    Masashi Idogawa

  4. Department of Educational Development, Sapporo Medical University, Sapporo, Japan

    Yasuyoshi Naishiro

  5. Department of Pathology, Sapporo Medical University, Sapporo, Japan

    Masaki Murata

  6. Center for Antibody and Vaccine Therapy, Institute of Medical Science, University of Tokyo, Tokyo, Japan

    Kohzoh Imai

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  1. Shuhei Watanabe
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  2. Yoshiaki Arimura
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  9. Yasuyoshi Naishiro
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  13. Kohzoh Imai
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  14. Yasuhisa Shinomura
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Correspondence to Yoshiaki Arimura.

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Watanabe, S., Arimura, Y., Nagaishi, K. et al. Conditioned mesenchymal stem cells produce pleiotropic gut trophic factors. J Gastroenterol 49, 270–282 (2014). https://doi.org/10.1007/s00535-013-0901-3

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