Thrombomodulin Regulates Keratinocyte Differentiation and Promotes Wound Healing

Abstract

The membrane glycoprotein thrombomodulin (TM) has been implicated in keratinocyte differentiation and wound healing, but its specific function remains undetermined. The epidermis-specific TM knockout mice were generated to investigate the function of TM in these biological processes. Primary cultured keratinocytes obtained from TM(lox/lox); K5-Cre mice, in which TM expression was abrogated, underwent abnormal differentiation in response to calcium induction. Poor epidermal differentiation, as evidenced by downregulation of the terminal differentiation markers loricrin and filaggrin, was observed in TM(lox/lox); K5-Cre mice. Silencing TM expression in human epithelial cells impaired calcium-induced extracellular signal-regulated kinase pathway activation and subsequent keratinocyte differentiation. Compared with wild-type mice, the cell spreading area and wound closure rate were lower in keratinocytes from TM(lox/lox); K5-Cre mice. In addition, the lower density of neovascularization and smaller area of hyperproliferative epithelium contributed to slower wound healing in TM(lox/lox); K5-Cre mice than in wild-type mice. Local administration of recombinant TM (rTM) accelerated healing rates in the TM-null skin. These data suggest that TM has a critical role in skin differentiation and wound healing. Furthermore, rTM may hold therapeutic potential for the treatment of nonhealing chronic wounds.

Thrombomodulin regulates monocye differentiation via PKCδ and ERK1/2 pathway in vitro and in atherosclerotic artery

“…In addition, local administration of recombinant TM (rTM) improved healing rates in the skin of TM-null mice. Hence they suggested that TM plays a critical role in skin differentiation and wound healing36. Previous studies also focused on the ability of TM to mediate anti-inflammatory effects via its lectin-like domain.…”

Thrombomodulin Promotes Diabetic Wound Healing by Regulating Toll-Like Receptor 4 Expression

“…Our previous report suggested that sTM fragments released from keratinocytes promote cutaneous wound healing (Cheng et al, 2011). To evaluate more thoroughly the effects of TM on high-glucose-impaired wound healing, we used human rTMD23, which promotes wound healing in a manner similar to that of rTMD123 (Cheng et al, 2013), to treat high-glucose-maintained HaCaT cells. Using a scratch wound healing assay, we found that treatment with rTMD23 (20 and 200 ng ml − 1 ) significantly enhanced wound recovery at 72 hours after treatment (Figure 3a and b).…”

“…The protein structure of TM contains five functional domains from amino-to carboxyl-terminal, including the following: an NH 2 -terminal lectin-like region (TM domain (TMD)-1), an EGF-like domain consisting of six EGF-like repeats (TMD2), an O-glycosylation site-rich domain (TMD3), a transmembrane domain (TMD4), and a cytoplasmic tail (TMD5). Our studies have demonstrated that soluble TM (sTM) is released by the rhomboid serine protease, and recombinant TM domains 1, 2, plus 3, and 2 plus 3 (rTMD123 and rTMD23, respectively) may hold therapeutic potential to promote cutaneous wound healing (Cheng et al, 2013). In addition, circulating heterogeneous sTM fragments in the plasma are elevated in cardiovascular disease, inflammatory endothelial injuries, and diabetes (Ohlin et al, 2005).…”

Thrombomodulin promotes focal adhesion kinase activation and contributes to angiogenesis by binding to fibronectin

“…TM is expressed in various cell types and exerts multiple biological functions via its different domains [8]. TM plays important roles in regulating blood coagulation, inflammation, and skin wound healing [8, 10]. Our earlier study showed that TM mediates cell-cell adhesion through its lectin-like domain [11].…”