PT  - JOURNAL ARTICLE
AU  - Nemoto, Yasuhiro
AU  - Kanai, Takanori
AU  - Takahara, Masahiro
AU  - Oshima, Shigeru
AU  - Nakamura, Tetsuya
AU  - Okamoto, Ryuichi
AU  - Tsuchiya, Kiichiro
AU  - Watanabe, Mamoru
TI  - Bone marrow-mesenchymal stem cells are a major source of interleukin-7 and sustain colitis by forming the niche for colitogenic CD4 memory T cells
AID  - 10.1136/gutjnl-2012-302029
DP  - 2013 Aug 01
TA  - Gut
PG  - 1142--1152
VI  - 62
IP  - 8
4099  - http://gut.bmj.com/content/62/8/1142.short
4100  - http://gut.bmj.com/content/62/8/1142.full
SO  - Gut2013 Aug 01; 62
AB  - Objective Interleukin (IL)-7 is mainly produced in bone marrow (BM) that forms the niche for B cells. We previously demonstrated that BM also retains pathogenic memory CD4 T cells in murine models of inflammatory bowel disease (IBD). However, it remains unknown whether BM-derived IL-7 is sufficient for the development of IBD and which cells form the niche for colitogenic memory CD4 T cells in BM. Design To address these questions, we developed mice in which IL-7 expression was specific for BM, and identified colitis-associated IL-7-expressing mesenchymal stem cells (MSC) in the BM. Results IL-7–/–×RAG-1–/– mice injected with BM cells from IL-7+/+×RAG-1–/– mice, but not from IL-7–/–×RAG-1–/– mice, expressed IL-7 in BM, but not in their colon, and developed colitis when injected with CD4+CD45RBhigh T cells. Cultured BM MSC stably expressed a higher level of IL-7 than that of primary BM cells. IL-7-sufficient, but not IL-7-deficient, BM MSC supported upregulation of Bcl-2 in, and homeostatic proliferation of, colitogenic memory CD4 T cells in vitro. Notably, IL-7–/–×RAG-1–/– mice transplanted with IL-7-sufficient, but not IL-7-deficient, BM MSC expressed IL-7 in BM, but not in their colon, and developed colitis when transplanted with CD4+CD45RBhigh T cells. Conclusions We demonstrate for the first time that BM MSC are a major source of IL-7 and play a pathological role in IBD by forming the niche for colitogenic CD4 memory T cells in BM.