The Antimicrobial Peptide Human β-Defensin-3 Accelerates Wound Healing by Promoting Angiogenesis, Cell Migration, and Proliferation Through the FGFR/JAK2/STAT3 Signaling Pathway

Abstract

In addition to its antimicrobial activity, the skin-derived antimicrobial peptide human β-defensin-3 (hBD-3) promotes keratinocyte proliferation and migration to initiate the wound healing process; however, its effects on fibroblasts, which are the major cell type responsible for wound healing, remain unclear. We investigated the role of hBD-3 in cell migration, proliferation and production of angiogenic growth factors in human fibroblasts and evaluated the in vivo effect of hBD-3 on promoting wound healing and angiogenesis. Following hBD-3 treatment, the mouse wounds healed faster and showed accumulation of neutrophils and macrophages in the early phase of wound healing and reduction of these phagocytes 4 days later. hBD-3-treated wounds also displayed an increased number of fibroblasts and newly formed vessels compared to those of the control mice. Furthermore, the expression of various angiogenic growth factors was increased in the hBD-3-treated wounds. Additionally, in vitro studies demonstrated that hBD-3 enhanced the secretion of angiogenic growth factors such as fibroblast growth factor, platelet-derived growth factor and vascular endothelial growth factor and induced the migration and proliferation of human fibroblasts. The hBD-3-mediated activation of fibroblasts involves the fibroblast growth factor receptor 1 (FGFR1)/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathways, as evidenced by the inhibitory effects of pathway-specific inhibitors. We indeed confirmed that hBD-3 enhanced the phosphorylation of FGFR1, JAK2 and STAT3. Collectively, the current study provides novel evidence that hBD-3 might be a potential candidate for the treatment of wounds through its ability to promote wound healing, angiogenesis and fibroblast activation.

The Antimicrobial Peptides Human β-Defensins Induce the Secretion of Angiogenin in Human Dermal Fibroblasts

“…The levels of angiogenic factors have been shown to be downregulated in nonhealing chronic wounds [ 44 ]. As a recent study indicated that hBD-3 induced the production of angiogenic factors, such as VEGF, PDGF, and FGF2, by dermal fibroblasts [ 10 ], and because this report demonstrated that hBDs promote ANG secretion by fibroblasts, these findings indicate that hBDs may contribute to angiogenesis, in addition to their antimicrobial and other immunomodulatory activities. Therefore, it is hypothesized that promoting the production or receptor activation of angiogenic factors may be a useful treatment strategy for chronic wounds.…”

“…A recent study indicated that the skin-derived antimicrobial peptide hBD-3 promoted wound healing, angiogenesis, proliferation, and migration in fibroblasts in an in vivo mouse model and in cultured primary human dermal fibroblasts. Furthermore, hBD-3 promoted angiogenesis by enhancing the dermal fibroblast production of angiogenic factors, such as VEGF, PDGF, and FGF [ 10 ]. In this study, we demonstrate that the secretion of another angiogenic factor ANG by fibroblasts was increased not only by hBD-hBD-1, hBD-2, hBD-3, and hBD-4.…”

“…In addition to antimicrobial properties, hBDs exhibit diverse bioactivities and regulate cell proliferation and migration, skin barrier function, wound healing, and angiogenesis [ 7 ]. It has been reported that hBDs also induce the production of various cytokines, growth factors, and angiogenic factors and induce autophagy in epidermal keratinocytes [ 9 , 10 , 19 , 23 , 24 ]. Angiogenesis plays a critical role in many biological processes, such as development, tissue remodeling, reproduction, wound healing, and carcinogenesis.…”

“…In cutaneous wound healing, which occurs in healthy subjects, hBD-2 and hBD-3 are especially expressed by keratinocytes at wound sites [ 8 ]. hBD-3 was recently reported to promote wound healing by modulating inflammatory responses, angiogenesis, and cell proliferation and migration in dermal fibroblasts [ 10 ]. Angiogenesis, which is the formation of new blood vessels, is orchestrated by angiogenic factors and is an important process in development, as well as wound healing [ 11 ].…”

“…Angiogenesis, which is the formation of new blood vessels, is orchestrated by angiogenic factors and is an important process in development, as well as wound healing [ 11 ]. A recent study showed that hBD-3 induced the production of angiogenic factors, including vascular endothelial growth factor (VEGF), platelet-derived growth factors (PDGF), and fibroblast growth factor (FGF), by dermal fibroblasts [ 10 ]. Angiogenin (ANG), a member of the RNase family that was initially discovered to be a tumor angiogenesis factor, is one of the most potent angiogenic factors and promotes the growth, survival, migration, and invasion of endothelial cells [ 12 ].…”