Induction of regulatory t cells and its regulation with insulin-like growth factor/insulin-like growth factor binding protein-4 by human mesenchymal stem cells

Ippei Miyagawa, Shingo Nakayamada, Kazuhisa Nakano, Kaoru Yamagata, Kei Sakata, Kunihiro Yamaoka, Yoshiya Tanaka

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Human mesenchymal stem cells (MSCs) are multipotent and exert anti-inflammatory effects, but the underlying mechanism remains to be elucidated. In the current study, we investigated the regulatory mechanism of regulatory T cell (Treg) induction through the growth factors released by human MSCs. Human naive CD4+ T cells were stimulated with anti-CD3/28 Abs and cocultured with human MSC culture supernatant for 48 h. The proliferation and cytokine production of CD4+ T cells and surface molecule expression on CD4+ T cells were evaluated. The proliferation of anti-CD3/28 Abs-stimulated CD4+ T cells was suppressed by the addition of human MSC culture supernatant; in addition, the production of IL-10 and IL-4 increased. The human MSC culture supernatant induced CD4+FOXP3+ Tregs that expressed CD25, CTLA-4, glucocorticoid-induced TNFR-related protein, insulinlike growth factor (IGF)-1R, and IGF-2R, showing antiproliferative activity against CD4+ T cells. In addition, the induction of Tregs by human MSC culture supernatant was enhanced by the addition of IGF and suppressed by the inhibition of IGF-1R. In contrast, a significant amount of IGF binding protein (IGFBP)-4, an inhibitor of IGF action, was detected in the human MSC culture supernatant. After neutralization of IGFBP-4 in the human MSC culture supernatant by anti-IGFBP-4 Ab, Treg numbers increased significantly. Thus, our results raise the possibility that human MSC actions also involve a negative-regulatory mechanism that suppresses Treg proliferation by releasing IGFBP-4. The results of this study suggest that regulation of IGF may be important for treatments using human MSCs.

Original languageEnglish
Pages (from-to)1616-1625
Number of pages10
JournalJournal of Immunology
Volume199
Issue number5
DOIs
Publication statusPublished - 2017 Sep 1

ASJC Scopus subject areas

  • Immunology

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