Conditioned mesenchymal stem cells produce pleiotropic gut trophic factors.
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.
Department of Gastroenterology, Rheumatology, and Clinical Immunology, Sapporo Medical University, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan.
Shuhei
S
Watanabe
Yoshiaki
Y
Arimura
Kanna
K
Nagaishi
Hiroyuki
H
Isshiki
Kei
K
Onodera
Masanao
M
Nasuno
Kentaro
K
Yamashita
Masashi
M
Idogawa
Yasuyoshi
Y
Naishiro
Masaki
M
Murata
Yasushi
Y
Adachi
Mineko
M
Fujimiya
Kohzoh
K
Imai
Yasuhisa
Y
Shinomura
D000818:Animals; D017209:Apoptosis; D018938:Caco-2 Cells; D002453:Cell Cycle / Q000187:drug effects; D015687:Cell Hypoxia; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018932:Chemokine CCL2 / Q000032:analysis; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000494:pharmacology*; D016207:Cytokines / Q000032:analysis / Q000378:metabolism*; D016264:Dextran Sulfate; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D040081:Protein Array Analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D014302:Trinitrobenzenesulfonic Acid; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis; D051153:Wnt Proteins / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics; D000094742:Secreted Frizzled-Related Proteins
D018932:Chemokine CCL2; D017077:Culture Media, Conditioned; D016207:Cytokines; D016264:Dextran Sulfate; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D014302:Trinitrobenzenesulfonic Acid; D042461:Vascular Endothelial Growth Factor A; D051153:Wnt Proteins; C500646:Sfrp1 protein, rat; D000094742:Secreted Frizzled-Related Proteins; C498455:Sfrp4 protein, rat; C502412:Wnt11 protein, rat; C502524:Wnt5b protein, rat