凝血酶調節素（TM）原先在血管內皮細胞所發現，是為人所熟知的抗凝血及抗纖維蛋白溶解(fibrinolysis)的因子。TM藉由與不同蛋白的交互作用而有抗凝血、抗纖維蛋白溶解、抗發炎的功能。TM的lectin-like區域本身也具有抗發炎反應的功能；TM的類上皮生長因子區域 (EGF-like domain)本身也有促進血管新生的功能。TM除了表現於血管內皮細胞之外，也表現於上皮的刺狀層 (spinous layer)，且在人及老鼠受傷後的新生表皮會大量表現。然而，TM表現於上皮細胞的功能並未被充分了解。本實驗利用會表現TM的細胞株HaCaT 細胞，以及穩定表現綠螢光蛋白(eGFP) 和TM的突變株(無lectin-like區域，TMGdL)的HaCaT研究TM在上皮細胞中的生物功能。在刮傷癒合分析(scratch wound healing assay)中，TMGdL表現的HaCaT細胞，其移動速度比綠螢光蛋白表現的HaCaT細胞還要慢（爬行12小時後，平均速度分別是2.0 與 7.0 um/hr）。仔細分析二者的爬行路徑發現，TMGdL表現的HaCaT細胞的路徑較不規則（不直接爬往受傷區域）。這種改變的路徑與我們之前在利用shRNA使TM表現量降低的HaCaT細胞中有相同的情形。而0.5 nM 到 1.5 nM的可溶性TM（soluble TM，稱為TMD123）則可以促進HaCaT細胞移行。利用shRNA使TM表現量降低的HaCaT細胞，其生長速率比對照組的HaCaT細胞還要慢；TMGdL表現的HaCaT細胞，其生長速率也比綠螢光蛋白表現的HaCaT細胞還要慢。此外，HaCaT細胞之間的黏著可被TM專一性的單株抗體以及ethylene glycol tetra acetic acid (EGTA)所阻斷（分別是36 %以及55 %）。TMGdL表現的HaCaT細胞其與細胞外基質（extracellular matrix）的黏著能力比綠螢光蛋白表現的HaCaT細胞還要低。另一方面，利用胰蛋白酶分離分析（trypsin detachment assay）也發現，TMGdL表現的HaCaT細胞比綠螢光蛋白表現的HaCaT細胞更易與基質分離。TM表現量下降的HaCaT細胞，在第一型膠原蛋白上延展的面積比控制組小。我們的結果顯示上皮細胞中的TM調節細胞與細胞間以及細胞與基質的黏著，上皮細胞的生長，以及上皮細胞的移動速度以及方向。另外，我們的結果也暗示可溶性的TMs可以促進傷口癒合時的表皮再生（reepithelialization），這些可溶性的TMs也許可以作為癒合傷口的天然藥物。

Thrombomodulin (TM) is a glycosylated type I transmembrane protein that is originally identified in vascular endothelium and is well-characterized as a natural anti-coagulant and anti-fibrinolytic factor. TM exerts its anti-coagulant, anti-fibrinolytic, and anti-inflammatory functions through interactions with diverse proteins. The lectin-like domain and epidermal growth factor (EGF) domains of TM alone also exert anti-inflammatory and angiogenic activities, respectively. TM was highly expressed in the spinous layer of epidermis, and it was shown that TM was strongly expressed by stratifying keratinocytes within the neoepidermis in both murine and human wounds. However, the functions of TM expressed in epithelial cells are not well-characterized. In this study, the biological functions of TM were studied in TM-abundant epithelium cell line HaCaT cells transfected with green fluorescent protein (eGFP) or lectin-like domain-deleted TM (TMGdL). HaCaT cells expressed TMGdL showed slower rate of migration than that of eGFP-expressed HaCaT cells in scratch wound healing assay (2.0 and 7.0 um/hr 12hr after scratch, respectively). Careful analysis of the migratory tracks of eGFP- or TMGdL-expressed HaCaT cells revealed that substantially less directed motion was observed in TMGdL- overexpressed cells, which was in line with our previous study that TM- knocked-down HaCaT cells displayed altered migratory tracks. Soluble TM, denoted as TMD123, promoted HaCaT cells migration at the concentrations of 1 and 1.5 nM. The proliferation rate of TM-knocked-down HaCaT cells was slower than that of control HaCaT cells; TMGdL-overexpressed HaCaT cells also displayed slower proliferation rate than eGFP-expressed HaCaT cells. Moreover, adhesion between HaCaT cells was blocked by TM-specific monoclonal antibody (up to 36 %) and ethylene glycol tetra acetic acid (EGTA) (up to 55 %); adhesion strength measured by trypsin detachment assay showed that TMGdL-overexpressed HaCaT cells were detached easier than eGFP- expressed HaCaT cells. Spreading area of TM-knocked-down HaCaT cells was smaller than that of control HaCaT cells on type I collagen-coating dish. Our results indicated that TM regulated cell-to-cell and cell-to-matrix adhesion, and rate as well as direction of migration in epithelial cells. Moreover, our data also suggested that soluble TMs would enhance re-epithelialization during wound healing, and they can be natural product(s) as drug candidates for skin injury.

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