Substances that enhance the migration ofmesenchymal stem cells to damaged sites have the potential to improve the effectiveness of tissue repair.We previously found that ethanol extracts of Mallotus philippinensis bark promoted migration ofmesenchymal stem cells and improved wound healing in a mouse model.We also demonstrated that bark extracts contain cinnamtannin B-1, a flavonoid with in vitro migratory activity against mesenchymal stem cells. However, the in vivo effects of cinnamtannin B-1 on the migration of mesenchymal stem cells and underlying mechanism of this action remain unknown. Therefore, we examined the effects of cinnamtannin B-1 on in vivo migration ofmesenchymal stem cells and wound healing in mice. In addition, we characterized cinnamtannin B-1-induced migration of mesenchymal stemcells pharmacologically and structurally. The mobilization of endogenous mesenchymal stemcells into the blood circulation was enhanced in cinnamtannin B-1-Treated mice as shown by flow cytometric analysis of peripheral blood cells. Whole animal imaging analysis using luciferase-expressing mesenchymal stemcells as a tracer revealed that cinnamtannin B-1 increased the homing of mesenchymal stemcells to wounds and accelerated healing in a diabetic mouse model. Additionally, the cinnamtannin B-1-induced migration of mesenchymal stemcells was pharmacologically susceptible to inhibitors of phosphatidylinositol 3-kinase, phospholipase C, lipoxygenase, and purines. Furthermore, biflavonoids with similar structural features to cinnamtannin B-1 also augmented the migration of mesenchymal stem cells by similar pharmacological mechanisms. These results demonstrate that cinnamtannin B-1 promotedmesenchymal stem cell migration in vivo and improved wound healing in mice. Furthermore, the results reveal that cinnamtannin B-1-induced migration ofmesenchymal stemcells may bemediated by specific signaling pathways, and the flavonoid skeleton may be relevant to its effects onmesenchymal stem cell migration.
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