Heparin-Binding Epidermal Growth Factor–Like Growth Factor as a Critical Mediator of Tissue Repair and Regeneration

Abstract

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the EGF family. It contains an EGF-like domain as well as a heparin-binding domain that allows for interactions with heparin and cell-surface heparan sulfate. Soluble mature HB-EGF, a ligand of human epidermal growth factor receptors 1 and 4, is cleaved from the membrane-associated pro-HB-EGF by matrix metalloproteinase or a disintegrin and metalloproteinase in a process called ectodomain shedding. Signaling through human epidermal growth factor receptors 1 and 4 results in a variety of effects, including cellular proliferation, migration, adhesion, and differentiation. HB-EGF levels increase in response to different forms of injuries as well as stimuli, such as lysophosphatidic acid, retinoic acid, and 17β-estradiol. Because it is widely expressed in many organs, HB-EGF plays a critical role in tissue repair and regeneration throughout the body. It promotes cutaneous wound healing, hepatocyte proliferation after partial hepatectomy, intestinal anastomosis strength, alveolar regeneration after pneumonectomy, neurogenesis after ischemic injury, bladder wall thickening in response to urinary tract obstruction, and protection against ischemia/reperfusion injury to many cell types. Additionally, innovative strategies to deliver HB-EGF to sites of organ injury or to increase the endogenous levels of shed HB-EGF have been attempted with promising results. Harnessing the reparatory properties of HB-EGF in the clinical setting, therefore, may produce therapies that augment the treatment of various organ injuries.