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標題: | 利用化學藥物配方轉化人類纖維母細胞成為類寡突細胞以及用於改善脫髓鞘現象 Generation of oligodendrocyte-like cells from human fibroblasts and improvement of demyelination by chemical cocktails |
作者: | 吳志昊 Chi-Hou Ng |
指導教授: | 呂仁 Jean Lu |
共同指導教授: | 黃筱鈞 Hsiao-Chun Huang |
關鍵字: | 寡突膠質細胞,寡突膠質前驅細胞,多發性硬化症,誘導式類寡突膠質細胞,雙環己酮草酰二腙藥物誘導,脫髓鞘,髓鞘化, oligodendrocytes,oligodendrocyte progenitor cells,multiple sclerosis,induced oligodendrocyte-like cells,cuprizone-induced model,demyelination,remyelination, |
出版年 : | 2022 |
學位: | 博士 |
摘要: | 寡突膠質細胞,神經膠質細胞的一種,其僅存在或出現於中央神經系統,在傳遞神經信號和保護有髓神經這兩部分發揮著重要且關鍵的作用。寡突膠質細胞的主要功能或作為是供應養分給神經細胞,以及提供物理上的隔離 (髓鞘),除了能保護神經,還能促進神經中的訊號傳遞。寡突膠質細胞若出現功能性障礙或寡突膠質細胞的缺失都會導致各種不同的脫髓鞘病變的發生。多發性硬化症是眾多的脫髓鞘病變當中最常見的病變之一。 多發性硬化症是由於免疫系統出現障礙或自體免疫相關的基因發生突變而使其攻擊自體的髓鞘鹼性蛋白所引起的病變。雖然在病變初期使用抗發炎藥物確實能有效地減緩或改善多發性硬化症的病況,然而在病變的後期該成效並不佳,而且無法逆轉由於免疫系統攻擊自體髓鞘鹼性蛋白所導致的脫髓鞘病症。因此,以寡突膠質細胞或寡突前驅細胞來進行細胞治療,利用功能正常的寡突膠質細胞或寡突前驅細胞去直接取代原來細胞的功用或是用以產生具正常進行髓鞘化功能的寡突膠質細胞,並以此改善髓鞘包覆的問題來減緩或治療脫髓鞘病變病情的想法為次世代多發性硬化症的治療提供了希望。 為了有效的治療脫髓鞘疾病,開發新的治療方法來促進髓鞘的再生是必要的。 在這項研究中,我們建立了一種新的方法來取得類寡突膠質細胞,我們成功在3天內將人類成體纖維母細胞轉化成為誘導式類寡突膠質細胞。在經過Valproic Acid處理後,再利用SU9516、Y27632 以及Forskolin 三種藥物的共同作用下,成功取得誘導式類寡突膠質細胞,而且這種細胞表現出與寡突膠質細胞相似的形態和分子特徵。另外,為了追求與發展體內的藥物治療方案,我們利用了Cuprizone誘導的小鼠脫髓鞘動物模型。利用立體定位儀將小分子化學藥物雞尾酒直接注射到脫髓鞘小鼠大腦的胼胝體中。經過兩周的恢復,通過光學和電子顯微鏡的觀察,了解到這種小分子化學物的組合能夠成功改善小鼠的脫髓鞘情況,促進了小鼠的髓鞘再生。這些結果為再生醫學對開發或探索脫髓鞘疾病的方法提供了基礎。 Oligodendrocytes (OLG) are central nervous system (CNS) residing glial cells that have a critical position in transmitting neural signals and protecting myelinated nerves. It supports neurons with nutrients and provides a physical barrier between individual neurons. The dysfunction or reduction of OLGs results in many distinct demyelinating disorders. Multiple sclerosis (MS) is among the most commonly occurring demyelinating diseases and can be caused by mutations in autoimmune or immune system genes that target myelin basic protein (MBP) and associated OLGs. The anti-inflammatory drugs have been shown to improve early symptoms of multiple sclerosis. However, anti-inflammatory drugs are ineffective in the later stages and are unable to reverse the demyelination symptoms. Therefore, cell therapy utilizing oligodendrocyte progenitor cells (OPCs), thereby regenerating OLG and restoring myelin, offers hope for the next generation of MS treatment. In order to treat demyelinating diseases, it is necessary to develop a method of treatment that facilitates remyelination. In this study, we have explored a method that converts human fibroblasts into induced oligodendrocyte lineage cells (iOLCs) within 3 days in vitro. After exposure to treatment with valproic acid (VPA) followed by small molecules SU9516, Y27632, and Forskolin (FSK), the induced cells exhibited morphological and molecular characteristics similar to OLGs. In pursuit of the development of an in vivo cell-free remyelination chemotherapy approach, we used a mouse demyelination model induced by cuprizone. An injection of small molecule drugs (Y27632, SU9516, and FSK) was administered directly into the corpus callosum (CC) of the demyelinated mouse brain. Based on light and electron microscopy, the combination of these small molecules was able to rescue the demyelinating phenotype within two weeks. These results provide a basis for regenerative medicine to explore the development of therapies for demyelinating diseases. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/84917 |
DOI: | 10.6342/NTU202202714 |
全文授權: | 同意授權(限校園內公開) |
電子全文公開日期: | 2027-08-24 |
顯示於系所單位: | 基因體與系統生物學學位學程 |
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