人類胎盤絨毛膜蛻膜間葉細胞對於高糖受損內皮細胞與後肢缺血模式之血管新生的療效探討

Abstract

糖尿病（Diabetes Mellitus, DM）是全球十大死亡原因之一。根據台灣衛生福利部國民健康署的統計，台灣約有200萬名DM患者，2016年有9,960名患者死於DM。2016年人口增加了4.5％。根據統計，15-25％的糖尿病患者在其一生中患有糖尿病足潰瘍（Diabetic Foot Ulcer, DFU）。 DFU被認為是發病過程中最主要的問題，也是DM患者住院的主要原因。迄今為止，由於糖尿病導致正常的血管新生受損，大量DM患者需要截肢，造成嚴重的併發症。在過往的研究中，間葉細胞（Mesenchymal stromal cells, MSCs）已被廣泛研究為再生醫學的理想細胞來源，能透過旁泌作用(paracrine effect)，促進血管新生。越來越多的證據表明，MSCs移植可以加速傷口閉合，改善臨床症狀，避免截肢。在我們的研究中，我們成功地從人類胎盤蛻膜中分離出一種間葉細胞，命名為胎盤絨毛膜蛻膜間葉細胞(placenta choriodecidual-derived mesenchymal stromal cells, pcMSCs)。.透過使用由pcMSCs和人類臍靜脈內皮細胞（human umbilical vein endothelial cells, HUVEC）組成的共同培養系統(transwell system)，我們發現pcMSCs改善了HUVEC在血管形成(tube formation)的能力，增加VEGFR2和VEGF的表現。此外，給予pcMSCs可以延緩後肢壞死，降低缺血性小鼠模型肢體截肢率。因此，我們推論，pcMSCs能夠促進血管生成能力，並且在DFU動物模式中擁有治療效果。 pcMSCs提供了可獲得的細胞來源以及有效的治療。

Diabetes mellitus (DM) is one of top the 10 causes of death worldwide. According to the statistics of the Health Promotion Administration, Ministry of Health and Welfare, Taiwan, there are about 2 million DM patients in Taiwan, and 9,960 patients died from DM in 2016. The population increased 4.5% in year 2016 compared to the number in 2015. In generally, 15-25% of diabetic patients are suffered from diabetic foot ulcer (DFU) during their life-time. DFU is considered to be the major issue of morbidity and the leading cause of hospitalization for DM patients. To date, a significant number of DM patients required amputations due to a complex result of impaired angiogenesis. Therefore, DFU is not only a patient problem but also a major health care concern throughout the world. In recent studies, mesenchymal stem cells (MSCs) have been reported to be an ideal cell source for regenerative therapy with no ethical issues, played an important role in DFU. Growing evidence has demonstrated that MSCs transplantation could accelerate wound closure, ameliorate clinical parameters, and avoid amputation. In our studies, we have successfully isolated a type of MSCs from human placenta decidal membranes, named pcMSCs. By using a co-culture system consisting of pcMSCs and human umbilical vein endothelial cells (HUVECs), we found that pcMSCs improved the ability of tube formation in HUVEC and upregulated VEGF and VEGFR2 expression. Furthermore, the administration of pcMSCs could retard the necrosis of hind limb and reduce the rate of limb amputation in ischemic murine model. Thus, our study showed the potential therapeutic effects of cell therapy in DFU animal model and the pro-angiogenesis ability of pcMSCs. The application of pcMSCs provided an effective treatment and an accessible cell source for the application in cell-based therapies.