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

Yasuhiro Nemoto, Takanori Kanai, Masahiro Takahara, Shigeru Oshima, Tetsuya Nakamura, Ryuichi Okamoto, Kiichiro Tsuchiya, Mamoru Watanabe

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1142-1152
Number of pages11
JournalGut
Volume62
Issue number8
DOIs
Publication statusPublished - Aug 1 2013
Externally publishedYes

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Interleukin-7
Colitis
Mesenchymal Stromal Cells
Bone Marrow
T-Lymphocytes
Inflammatory Bowel Diseases
Bone Marrow Cells
Colon

ASJC Scopus subject areas

  • Gastroenterology

Cite this

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. / Nemoto, Yasuhiro; Kanai, Takanori; Takahara, Masahiro; Oshima, Shigeru; Nakamura, Tetsuya; Okamoto, Ryuichi; Tsuchiya, Kiichiro; Watanabe, Mamoru.

In: Gut, Vol. 62, No. 8, 01.08.2013, p. 1142-1152.

Research output: Contribution to journalArticle

Nemoto, Y, Kanai, T, Takahara, M, Oshima, S, Nakamura, T, Okamoto, R, Tsuchiya, K & Watanabe, M 2013, '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', Gut, vol. 62, no. 8, pp. 1142-1152. https://doi.org/10.1136/gutjnl-2012-302029
Nemoto, Yasuhiro ; Kanai, Takanori ; Takahara, Masahiro ; Oshima, Shigeru ; Nakamura, Tetsuya ; Okamoto, Ryuichi ; Tsuchiya, Kiichiro ; Watanabe, Mamoru. / 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. In: Gut. 2013 ; Vol. 62, No. 8. pp. 1142-1152.
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abstract = "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.",
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T1 - 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

AU - Nemoto, Yasuhiro

AU - Kanai, Takanori

AU - Takahara, Masahiro

AU - Oshima, Shigeru

AU - Nakamura, Tetsuya

AU - Okamoto, Ryuichi

AU - Tsuchiya, Kiichiro

AU - Watanabe, Mamoru

PY - 2013/8/1

Y1 - 2013/8/1

N2 - 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.

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.

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