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

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.

Recruitment of Mesenchymal Stem Cells to Damaged Sites by Plant-Derived Components

“…For example, although PCA was only found to be effective at high doses, its potential has been demonstrated and has been suggested to function by increasing the expression and activation of MMPs, which then degrade the ECM to enhance MSC invasion into tissues (Wang et al, 2008). Studies on cinnamtannin B-1 have shown that structurally related flavonoids also have MSC migration activity (Fujita et al, 2015). Thus, expanding upon this structural framework offers the potential to develop more active compounds through structure-based drug development.…”

“…Thus, expanding upon this structural framework offers the potential to develop more active compounds through structure-based drug development. Since CBD, a non-psychoactive cannabinoid, can promote MSC Anti-oxidant, Anti-inflammatory, Anti-thrombotic López et al, 2008, Neuro-protective Chi et al, 2013, Pancreatic-protective Rivera-Barreno et al, 2010, Anti-cancer Carriere et al, 2018, Wound healing Gangwar et al, 2015Migration Furumoto et al, 2014Fujita et al, 2015 Wound healing Fujita et al, 2015 Cannabinoids Cannabis sativa (Cannabaceae) Grof, 2018…”

“…Cinnamtannin B-1 has also been shown to promote BMSC migration when administered within the range of 0.8-2 µg/ml, and enhanced wound healing in a mouse model following topical administration (1.2 and 2.4 µg/wound) (Fujita et al, 2015). Further, examination of BMSC recruitment in blood circulation via cell marker analysis showed that mobilization of endogenous MSCs into the blood increased following cinnamtannin B-1 treatment.…”

From Inflammation to Current and Alternative Therapies Involved in Wound Healing

“…It is noted that the pharmacological effects on healing observed in the plants described in the table may be related to secondary metabolites presence found in these plant materials, since several studies have shown that mainly tannins [ 213 ], flavonoids [ 214 ], triterpenes [ 215 ], and essential oils [ 216 ] may be associated with such activity.…”

Tunable biomaterials for myocardial tissue regeneration: promising new strategies for advanced biointerface control and improved therapeutic outcomes

“…182 Recent studies demonstrated that other signaling interactions, such as CCL27-CCR10 and CCL21-CCR7 also mediate stem cell homing. 183 Other homing factors include SCF, transforming growth factor (TGF)-β3, 184 MCP-1, 185 platelet-derived growth factor (PDGF), 186 macrophage inflammatory protein-3alpha (MIP-3α) and interleukin-8, 187 as well as a number of other therapeutic agents, such as antioxidants, the platelet aggregation inhibitor cinnamtannin B-1, 188 flavonoids, and the Wnt inhibitor sclerostin. 189 Exploiting these results, scaffolds have been loaded with these chemoattractants to direct endogenous stem cell homing and recruitment.…”