Heparin-binding EGF-like growth factor accelerates keratinocyte migration and skin wound healing

Abstract

Members of the epidermal growth factor (EGF) family are the most important growth factors involved in epithelialization during cutaneous wound healing. Heparin-binding EGF-like growth factor (HB-EGF), a member of the EGF family, is thought to play an important role in skin wound healing. To investigate the in vivo function of HB-EGF in skin wound healing, we generated keratinocyte-specific HB-EGF-deficient mice using Cre/loxP technology in combination with the keratin 5 promoter. Studies of wound healing revealed that wound closure was markedly impaired in keratinocyte-specific HB-EGF-deficient mice. HB-EGF mRNA was upregulated at the migrating epidermal edge, although cell growth was not altered. Of the members of the EGF family, HB-EGF mRNA expression was induced the most rapidly and dramatically as a result of scraping in vitro. Combined, these findings clearly demonstrate, for the first time, that HB-EGF is the predominant growth factor involved in epithelialization in skin wound healing in vivo and that it functions by accelerating keratinocyte migration, rather than proliferation.

HB‐EGF decelerates cell proliferation synergistically with TGFα in perinatal distal lung development

“…Indeed, several lines of evidence point to a fundamental role for HB-EGF in cell proliferation and tumorigenesis (Miyamoto et al, 2006). However, no hypoplastic abnormalities have been found in HB-EGF null mice to date; rather, HB-EGF null mice exhibit hyperplastic abnormalities Jackson et al, 2003;Yamazaki et al, 2003;Iwamoto and Mekada, 2006) as well as defects in cell migration (Mine et al, 2005;Shirakata et al, 2005). These findings suggest that HB-EGF may not function as a growth factor in developmental and physiological processes.…”

“…Importantly, analyses of HB-EGF null mice have shown that HB-EGF is a crucial factor for proper heart development and function Jackson et al, 2003;Yamazaki et al, 2003;Iwamoto and Mekada, 2006), eyelid development (Mine et al, 2005), skin wounding healing (Shirakata et al, 2005), and skin hyperplasia . Notably, HB-EGF has been suggested to be involved in proper lung development, as HB-EGF null newborns exhibit saccular wall thickening, a decrease in the number of sacculi, and the immature differentiation of type II epithelial cells .…”

Heparin‐binding epidermal growth factor‐like growth factor as a novel targeting molecule for cancer therapy

“…(21) HB-EGF gene expression has been demonstrated in a variety of tissues, predominantly the lung, heart, brain and skeletal muscle. (22) HB-EGF participates in a variety of physiological and pathological processes, (11) including wound healing, (23) eyelid formation, (24) blastocyst implantation, (25) retinoic acid-induced epidermal hyperplasia (26) and atherosclerosis. (27) Recently, HB-EGF knockout mice have been established.…”

“…(52) In eyelid formation in the mouse embryo and skin wound healing, HB-EGF plays a role in cell motility, but not in cell proliferation. (23,24) In MDCK cells, expression of sHB-EGF, but not non-cleavable proHB-EGF, increases cell migration, decreases cell-matrix and cell-cell interactions and promotes the development of long unbranched tubular structures, suggesting that proHB-EGF, and sHB-EGF give rise to distinct effects on cell-cell and cell-extracellular matrix interactions. (53) It has been shown that HB-EGF binds to N-arginine dibasic convertase, a metalloendopeptidase of the M16 family, and that N-arginine dibasic convertase is expressed on the cell surface of MDA-MB451 cells, where it modulates HB-EGF-induced cell migration.…”

Isolation of all CD44 transcripts in human epidermis and regulation of their expression by various agents

“…The variable v3 domain of CD44 protein harbors attachment site for heparan sulfate GAG [32], whereas dermatan/chondroitin sulfate GAG decorate invariable N-terminal domain [3]. Attachment of GAGs was demonstrated to enhance the presentation of growth factors, including heparinbinding growth factor [33], and this mechanism is important during certain physiological and disease processes including control of dermatoporosis (chronologic skin aging) [34][35][36], wound healing [37], keratinocyte migration [37] and tumor development and metastasis [38,39]. Despite its relatively low level of transcription, CD44v2-3,9-10 was up-regulated by PMA, in the presence of high calcium, by FCS, EGF and H 2 O 2 .…”