Abstract
Substances that enhance the migration of mesenchymal 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 of mesenchymal 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 of mesenchymal stem cells and wound healing in mice. In addition, we characterized cinnamtannin B-1-induced migration of mesenchymal stem cells pharmacologically and structurally. The mobilization of endogenous mesenchymal stem cells 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 stem cells as a tracer revealed that cinnamtannin B-1 increased the homing of mesenchymal stem cells to wounds and accelerated healing in a diabetic mouse model. Additionally, the cinnamtannin B-1-induced migration of mesenchymal stem cells 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 promoted mesenchymal stem cell migration in vivo and improved wound healing in mice. Furthermore, the results reveal that cinnamtannin B-1-induced migration of mesenchymal stem cells may be mediated by specific signaling pathways, and the flavonoid skeleton may be relevant to its effects on mesenchymal stem cell migration.
Highlights
Mesenchymal stem cells (MSCs) have the ability to differentiate into various cell types and secrete proregenerative factors that contribute to tissue repair [1,2]
We evaluated the effects of cinnamtannin B-1 on the in vivo migration of endogenous MSCs to the blood circulation as well as their homing to wounds
Flow cytometric analysis revealed that the population of lineage-negative, PDGFRα+, and Sca-1+ (Lin-/PDGFRα+/Sca1+) cells was increased in cinnamtannin B-1-treated mice compared with the control (Fig 1A)
Summary
Mesenchymal stem cells (MSCs) have the ability to differentiate into various cell types and secrete proregenerative factors that contribute to tissue repair [1,2]. Several studies have indicated that MSCs migrate to the wound site during the healing process [3,4]. Enhancing the mobilization of endogenous MSCs to wound sites has the potential to improve the healing process [9,10]. The development of methods to enhance the homing of the stem cells to specific tissues is required in cell therapy and, various approaches have been used in an attempt to achieve this in animal models [11]. The identification of new materials that enhance the mobilization of resident MSCs or the homing of circulating MSCs in the peripheral blood may improve current therapeutic approaches
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