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TMF and glycitin act synergistically on keratinocytes and fibroblasts to promote wound healing and anti-scarring activity

View Article: PubMed Central - PubMed

ABSTRACT

Keratinocyte-fibroblast interactions are critical for skin repair after injury. During the proliferative phase of wound healing, proliferation, migration and differentiation of these cells are the major mechanisms leading to tissue remodeling. We have previously reported that glycitin, a major soy isoflavone, stimulates dermal fibroblast proliferation; and the phytochemical, 4′,6,7-trimethoxyisoflavone (TMF), induces migration of HaCaT keratinocyte cells. We therefore investigated whether these compounds display synergistic effects on skin cells during wound healing in vitro and in vivo. Co-treatment with TMF and glycitin synergistically promotes the proliferation and migration of both keratinocytes and dermal fibroblasts, with a 1:1 ratio of these compounds showing the greatest efficacy in our co-culture system. This keratinocyte-fibroblast interaction occurred via the secretion of TGF-β, and the induction of differentiation and proliferation was confirmed in both indirect and direct co-culture assays. In an excisional and burn wound animal model, mice treated with a 1:1 ratio of TMF and glycitin showed faster wound closure, regeneration and scar reduction than even the positive control drug. These data indicate that two isoflavones, TMF and glycitin, act synergistically to promote wound healing and anti-scarring and could potentially be developed together as a bioactive therapeutic for wound treatment.

No MeSH data available.


The chemical structure of TMF and glycitin. (a) TMF (4′,6,7-trimethoxyisoflavone). (b) Glycitin (4′-hydroxy-6-methoxyisoflavone-7-D-glucoside). TMF, 4′,6,7-trimethoxyisoflavone.
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fig1: The chemical structure of TMF and glycitin. (a) TMF (4′,6,7-trimethoxyisoflavone). (b) Glycitin (4′-hydroxy-6-methoxyisoflavone-7-D-glucoside). TMF, 4′,6,7-trimethoxyisoflavone.

Mentions: We previously reported that glycitin (4′-hydroxy-6-methoxyisoflavone-7-D-glucose, Figure 1a) induces the proliferation and migration of fibroblasts,1, 9 whereas TMF (Figure 1b) promotes HaCaT keratinocyte migration, but not proliferation.2 In an excisional wound experiment, we found that TMF accelerates re-epithelialization, and appendages were formed along the epidermis at 15 days after the wounding event. By contrast, groups receiving other treatments had a thick epidermis and less differentiating appendages than those treated with TMF (Supplementary Data 1). Because wound closure involves closure of the epidermis, known as re-epithelialization, as well as dermal closure, which requires both fibroblast cells and collagens, we hypothesized that a mixture of glycitin and TMF may enhance the wound healing process by synergistically stimulating cells in both the epidermis and dermis.


TMF and glycitin act synergistically on keratinocytes and fibroblasts to promote wound healing and anti-scarring activity
The chemical structure of TMF and glycitin. (a) TMF (4′,6,7-trimethoxyisoflavone). (b) Glycitin (4′-hydroxy-6-methoxyisoflavone-7-D-glucoside). TMF, 4′,6,7-trimethoxyisoflavone.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5382558&req=5

fig1: The chemical structure of TMF and glycitin. (a) TMF (4′,6,7-trimethoxyisoflavone). (b) Glycitin (4′-hydroxy-6-methoxyisoflavone-7-D-glucoside). TMF, 4′,6,7-trimethoxyisoflavone.
Mentions: We previously reported that glycitin (4′-hydroxy-6-methoxyisoflavone-7-D-glucose, Figure 1a) induces the proliferation and migration of fibroblasts,1, 9 whereas TMF (Figure 1b) promotes HaCaT keratinocyte migration, but not proliferation.2 In an excisional wound experiment, we found that TMF accelerates re-epithelialization, and appendages were formed along the epidermis at 15 days after the wounding event. By contrast, groups receiving other treatments had a thick epidermis and less differentiating appendages than those treated with TMF (Supplementary Data 1). Because wound closure involves closure of the epidermis, known as re-epithelialization, as well as dermal closure, which requires both fibroblast cells and collagens, we hypothesized that a mixture of glycitin and TMF may enhance the wound healing process by synergistically stimulating cells in both the epidermis and dermis.

View Article: PubMed Central - PubMed

ABSTRACT

Keratinocyte-fibroblast interactions are critical for skin repair after injury. During the proliferative phase of wound healing, proliferation, migration and differentiation of these cells are the major mechanisms leading to tissue remodeling. We have previously reported that glycitin, a major soy isoflavone, stimulates dermal fibroblast proliferation; and the phytochemical, 4′,6,7-trimethoxyisoflavone (TMF), induces migration of HaCaT keratinocyte cells. We therefore investigated whether these compounds display synergistic effects on skin cells during wound healing in vitro and in vivo. Co-treatment with TMF and glycitin synergistically promotes the proliferation and migration of both keratinocytes and dermal fibroblasts, with a 1:1 ratio of these compounds showing the greatest efficacy in our co-culture system. This keratinocyte-fibroblast interaction occurred via the secretion of TGF-β, and the induction of differentiation and proliferation was confirmed in both indirect and direct co-culture assays. In an excisional and burn wound animal model, mice treated with a 1:1 ratio of TMF and glycitin showed faster wound closure, regeneration and scar reduction than even the positive control drug. These data indicate that two isoflavones, TMF and glycitin, act synergistically to promote wound healing and anti-scarring and could potentially be developed together as a bioactive therapeutic for wound treatment.

No MeSH data available.