Regulatory Mechanism of The Induction of Regulatory T Cells through Growth Factors Released by Human Mesenchymal Stem Cells

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)-beta, 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.