Cinnamtannin B-1 Promotes Migration of Mesenchymal Stem Cells and Accelerates Wound Healing in Mice

PLoS One. 2015 Dec 11;10(12):e0144166. doi: 10.1371/journal.pone.0144166. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Movement / drug effects*
  • Cell Proliferation / drug effects
  • Diabetes Mellitus, Experimental / pathology
  • Disease Models, Animal
  • Female
  • Flavonoids / pharmacology
  • Male
  • Mesenchymal Stem Cells / cytology*
  • Mesenchymal Stem Cells / drug effects
  • Mice
  • Polyphenols / pharmacology
  • Proanthocyanidins / pharmacology*
  • Wound Healing / drug effects*

Substances

  • Flavonoids
  • Polyphenols
  • Proanthocyanidins
  • cinnamtannin B-1

Grants and funding

This work was supported in part by Grants-in-Aid for Scientific Research (C,23618007) from the Ministry of Education, Culture, Sports, Science and Technology, and by Budget for Joint Research at the Osaka University (J119801020). The funders had no role in the study design, data collection, and analysis, decision to publish, or preparation of the manuscript. PIAS Corporation provided support in the form of salaries for authors NO, SS, KZ, KN, and KH, but did not have any additional role in the study design, data collection, and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are described in the author contributions section.