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標題: | 間葉幹細胞上類鐸受體2配體增強間葉幹細胞於氣喘模式小鼠之療效 Toll-Like Receptor 2 Ligation Enhances Therapeutic Effects of Mesenchymal Stem Cells on Murine Model of Asthmatic Inflammation |
作者: | Hui-Chieh Yu 俞惠潔 |
指導教授: | 江伯倫(Bor-Luen Chiang) |
關鍵字: | 間葉幹細胞,異質性,類鐸受體2,一氧化氮,調節性T細胞, Mesenchymal stem cell,Heterogeneity,Toll-like receptor 2,Nitric oxide,Regulatory T cell, |
出版年 : | 2018 |
學位: | 博士 |
摘要: | 現行的治療方法無法達成治癒氣喘的目標,因此發展新的氣喘療法仍是當務之急。僅管間葉幹細胞近來已因其免疫抑制特性的優勢而有潛力成為新興氣喘療法,其潛在的異質性將削弱其治療效益。在這篇論文中,我們進行了一個利用類鐸受體2之配體刺激間葉幹細胞以增強其氣喘療效的實驗計畫。根據實驗結果,在尾靜脈注射投予間葉幹細胞前,用一個類鐸受體2之配體(Pam3CSK4)刺激間葉幹細胞,可增強其對已誘發氣喘的小鼠的療效。為確效此刺激方法,我們進一步分析其作用機轉,並證實在間葉幹細胞中,Pam3CSK4 可透過轉錄因子 NF-κB 的途徑,刺激細胞激素 IL-6 的產生,進而活化轉錄因子 STAT3。轉錄因子 STAT3 磷酸化而活化後,隨即刺激激發型一氧化氮合成酶(iNOS)的表現量,進而合成更多與間葉幹細胞免疫調控能力相關的關鍵因子一氧化氮(NO)。經 Pam3CSK4 刺激的間葉幹細胞最後便藉由誘發更多調控型 CD4+CD25+Foxp3+ T 細胞而達到其免疫抑制能力增強的效果。本篇研究所提出的間葉幹細胞改良方法,除在細胞和小鼠氣喘模式上均可得到較為穩定的治療成效外,我們更進一步藉由研究其免疫調控機轉而達到確效的目的。藉由對間葉幹細胞的改良,未來可望能減少利用間葉幹細胞治療所產生的副作用,以利長期治療的規劃。 Under current therapeutic strategies, the cure to asthma remains elusive; thus- novel approaches for treating asthma are desperately needed. Despite that mesenchymal stem cells (MSCs) have recently been established as potential candidates by virtue of their immunomodulatory properties, the underlying heterogeneity of MSCs diminishes their therapeutic efficacy. Here we evaluated a toll-like receptor (TLR) 2 ligation protocol of MSCs to augment their therapeutic benefits on asthma. We surmise that more effective MSCs were activated with a TLR2 ligand, Pam3CSK4, at low concentration (1 μg/mL) for a longer period (96 h) induction prior to intravenous administration for ameliorating asthma in mice in a post-treatment manner. We further validated this regimen by demonstrating that Pam3CSK4 activated STAT3 in BM-MSCs through IL-6, which was likely stimulated with NF-κB signaling. Nitric oxide (NO), the key suppressive molecule of Pam3CSK4-primed BM-MSCs, was later highly increased through upregulation of iNOS, which was in the downstream of STAT3 phosphorylation. The intensified suppressive functions of BM-MSCs were then executed by inducing CD4+CD25+Foxp3+ regulatory T cells in a post-treatment manner. The consistent therapeutic outcomes and the valid suppressive mechanisms in the study might shed light on eliminating the proinflammation-prone uncertainties of MSCs, and enhancing the future feasibility of obtaining long-term effects with this regimen. |
URI: | http://tdr.lib.ntu.edu.tw/handle/123456789/1250 |
DOI: | 10.6342/NTU201800752 |
全文授權: | 同意授權(全球公開) |
顯示於系所單位: | 臨床醫學研究所 |
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