Macrophages Regulate Smooth Muscle Differentiation of Mesenchymal Stem Cells via a Prostaglandin F2α-Mediated Paracrine Mechanism

Objective-Mesenchymal stem cells are useful for vascular regeneration of injured tissues. Macrophages are involved in acute or chronic inflammatory diseases, and interleukin-1 beta (IL-1 beta), a proinflammatory cytokine, plays a key role in the activation of macrophages within injured tissues. To explore the role of macrophages on mesenchymal stem cellmediated vascular regeneration, we examined the effects of IL-1 beta-activated macrophages on differentiation of human adipose tissue-derived mesenchymal stem cells (hASCs) to smooth muscle cells (SMCs) and the vascular regenerative capacity of the differentiated SMCs in a hindlimb ischemia animal model. Methods and Results-We demonstrate that IL-1 beta-conditioned medium from RAW 264.7 macrophages induces differentiation of human adipose tissue-derived mesenchymal stem cells to alpha-smooth muscle actin-positive SMCs, and the differentiated SMCs exhibited increased contractility in response to KCl and carbachol treatment. Transplantation of the differentiated SMCs attenuated severe hindlimb ischemia and promoted vascular regeneration. IL-1 beta treatment stimulated secretion of prostaglandin F-2 alpha from RAW 264.7 cells. Small interfering RNA-mediated silencing of the prostaglandin F-2 alpha receptor completely abrogated IL-1 beta conditioned medium-stimulated alpha-smooth muscle actin expression. Moreover, prostaglandin F-2 alpha treatment stimulated expression of alpha-smooth muscle actin in human adipose tissue-derived mesenchymal stem cells. Conclusion-These results suggest that IL-1 beta-activated macrophages promote differentiation of human adipose tissuederived mesenchymal stem cells to SMCs through a prostaglandin F-2 alpha-mediated paracrine mechanism. (Arterioscler Thromb Vasc Biol. 2012; 32: 2733-2740.)