Miyagawa Ippei, Nakayamada Shingo, Kondo Masahiro, Tanaka Yoshiya
The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyusyu, Japan.
Mitsubishi Tanabe Pharma Research Institute, Yokohama, Japan.
Crit Rev Immunol. 2018;38(6):471-478. doi: 10.1615/CritRevImmunol.2018027821.
Mesenchymal stem cells (MSCs) undergo self-renewal and differentiation into multiple lineages. They exert anti-inflammatory and immunomodulatory effects via either cell-cell contact or via the production of soluble factors. Various anti-inflammatory and immunomodulatory mechanisms have been identified using experimental murine MSCs. The most representative mechanism is the induction of FOXP3+ regulatory T cells (Treg cells) via the production of transforming growth factor (TGF)-β, which has also been reported in human MSCs. Recent studies have demonstrated that insulin-like growth factor (IGF) is also involved in the induction of FOXP3+ Treg cells. We previously demonstrated that the induction of FOXP3+ Treg cells by IGF is suppressed by the expression of IGF-binding protein-4 (IGFBP-4), which is an inhibitor of IGF. Because human MSCs produce both IGFs and IGFBP4, they may be considered to maintain immunological homeostasis by positive regulation of Treg cells through the production of growth factors as well as by a negative regulatory mechanism. Although human MSCs have already been applied in regenerative therapy and autoimmune disease treatment, control of their positive and negative regulatory mechanisms is expected to lead to more efficient clinical applications.
间充质干细胞（MSCs）能够自我更新并分化为多种细胞谱系。它们通过细胞间接触或分泌可溶性因子发挥抗炎和免疫调节作用。利用实验性小鼠MSCs已确定了多种抗炎和免疫调节机制。最具代表性的机制是通过产生转化生长因子（TGF）-β诱导FOXP3 +调节性T细胞（Treg细胞），这在人MSCs中也有报道。最近的研究表明，胰岛素样生长因子（IGF）也参与了FOXP3 + Treg细胞的诱导。我们之前证明，IGF对FOXP3 + Treg细胞的诱导作用会被IGF结合蛋白-4（IGFBP-4，一种IGF抑制剂）的表达所抑制。由于人MSCs既能产生IGFs又能产生IGFBP4，它们可能被认为通过产生生长因子对Treg细胞进行正向调节以及通过负向调节机制来维持免疫稳态。尽管人MSCs已被应用于再生治疗和自身免疫性疾病治疗，但对其正负调节机制的控制有望带来更有效的临床应用。
