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Please use this identifier to cite or link to this item: http://ntour.ntou.edu.tw:8080/ir/handle/987654321/17862

Title: 皮膚表皮幹細胞對修復糖尿病傷口能力之探討
To investigate the possibilities of utilizing epidermal stem cells for repairing diabetic wound
Authors: Wen-Yen Huang
黃文彥
Contributors: NTOU:Institute of Bioscience and Biotechnology
國立臺灣海洋大學:生物科技研究所
Keywords: 皮膚;表皮幹細胞;糖尿病;傷口
skin;epidermal stem cells;diabetes;wound
Date: 2010
Issue Date: 2011-07-04
Abstract: 皮膚傷口修復是經由一連串細胞與細胞和細胞與基質等的交互作用,並透過細胞訊息調控的一個複雜生物過程。一般正常人的傷口會經由這些修復步驟而癒合,但對於糖尿病的患者來說,因為體內的代謝失調,進而影響許多重要的生物機制沒辦法正確的執行,使得傷口一直處於無法癒合的狀態,增加感染的風險並導致慢性發炎及其他併發症,提高了病患的致死率。然而目前仍缺乏能有效率的改善糖尿病患傷口修復的方法,也使得病患必須留在醫院長期照護。近年來的多項研究證實幹細胞在傷口修復上扮演了重要角色,幹細胞功能的缺失可能是造成傷口無法正常修復的原因之一。在本研究中,我們嘗試以糖尿病的小鼠模式分析糖尿病傷口修復延滯的情形並探討皮膚幹細胞(包括表皮基底層幹細胞及毛囊幹細胞)對於改善糖尿病傷口修復的能力。我們初步發現在正常小鼠傷口修復的早期階段,傷口旁大量產生表現p63及角質素14的細胞,透過連續切片染色發現有些細胞並同時表現了角質素10,說明部份表現p63及角質素14的細胞是從去分化產生,我們並同時利用K5-CreER; Z/EG小鼠做為表皮幹細胞追蹤的動物模式,我們發現表現綠色螢光的細胞出現在於癒合傷口的表皮上層,說明皮膚幹細胞也參與了傷口的修復過程。進一步我們利用移植表皮基底層及毛囊幹細胞於裸鼠傷口的模式,進一步證實兩種幹細胞參與修復傷口癒合,而毛囊幹細胞除了促進傷口的癒合,在癒合處也可以產生新的毛囊。接下來,我們利用STZ誘導糖尿病小鼠,及db/db自發性第二型糖尿病鼠做為糖尿病傷口的動物模式,與正常老鼠比較下,此兩種糖尿病鼠的傷口修復都有延滯的現象,傷口旁表現p63的細胞與膠原蛋白(collagen)的生成顯著的降低。當我們移植表皮基底層幹細胞至db/db小鼠後發現,表皮基底層幹細胞移植可促進傷口癒合,並部份改善膠原蛋白的生成。我們希望本研究未來可以提供做為開發糖尿病患傷口治療的參考。
Wound healing is a complex biological process regulated by a series of interaction of cells, cell signals, and intracellular matrix that helps maintain the skin integrity. Diabetes impairs multiple aspects of the wound healing response and the delayed wound healing resulting in prolonged hospitalization for diabetic patients. However, effective therapies for diabetic wound are still lacking. Several lines of evidences suggest that stem cells play an important role in wound healing. Various impaired wound-healing states might be due to a deficiency in the function of stem cells. The current work sought to determine whether epidermal stem cells (basal stem/progenitor cells or bulge stem cells) can accelerate wound healing in diabetic mice model. We initially demonstrate that, in the early stage of acute wound healing, some distal lining K10-positive cells co-expressed p63 and Keratin 14 suggesting de-differentiation may occur in the wound healing process. We also discovered there was an expansion of p63-positive stem/progenitor cells in the basal layer neighboring to the wounded site. To further determine whether epidermal stem cells involve in wound healing process, we used K5-CreER; Z/EG mice as a model which allow us to label either basal stem/progenitor cells or bulge stem cells with EGFP before creating full-thickness wound. Based on using this lineage-tracing technique, we found EGFP-positive cells were localized in suprabasal layer of healed wound. The results confirm the involvement of epidermal stem cells. Next, we tried to investigate whether transplantation of basal stem/progenitor cells and/or bulge stem cells would promote wound healing in nude mice. We found, in combination with dermal fibroblast, both types of stem cell transplantation can heal the wound efficiently. Noticeably, when transplantation of bulge stem cells together with dermal fibroblast to wound site of nude mice, we found new hairs were generated from healed wound. To achieve the aim of determining whether epidermal stem cells can accelerate diabetic wound healing. We characterized wound healing process in two different diabetic mice models including streptozotocin-induced diabetic (type I diabetic) mice, and db/db (type II diabetic) mice. Delay in healing process was seen in two models. Although disorganized distal lining K10-positive cells that co-expressed p63 and K14 can be identified, however, the number of p63-positive cells was relatively low and collagen synthesis was largely reduced comparing to normal wound healing. To examine whether transplantation of basal stem/progenitor cells and/or bulge stem cells would promote wound healing in db/db diabetic mice, we showed that transplantation of basal stem/progenitor cells could partially promote wound closure and restore collagen synthesis. Hopefully the current study would lead to improvement of treatment for non-healed wound in diabetic patients.
URI: http://ethesys.lib.ntou.edu.tw/cdrfb3/record/#G0M97360036
http://ntour.ntou.edu.tw/ir/handle/987654321/17862
Appears in Collections:[生命科學暨生物科技學系] 博碩士論文

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