Concise review: two negative feedback loops place mesenchymal stem/stromal cells at the center of early regulators of inflammation.

Recent data demonstrated that MSCs can be activated by proinflammatory signals to introduce two negative feedback loops into the generic pathway of inflammation. In one loop, the activated MSCs secrete PGE2 that drives resident macrophages with an M1 proinflammatory phenotype toward an M2 anti-inflammatory phenotype. In the second loop, the activated MSCs secrete TSG-6 that interacts with CD44 on resident macrophages to decrease TLR2/NFκ-B signaling and thereby decrease the secretion of proinflammatory mediators of inflammation. The PGE2 and TSG-6 negative feedback loops allow MSCs to serve as regulators of the very early phases of inflammation. These and many related observations suggest that the MSC-like cells found in most tissues may be part of the pantheon of cells that protect us from foreign invaders, tissue injury, and aging.