2010-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/644556摘要：慢性肝損傷所引起的細胞外基質堆積過程，導致肝纖維化的發生。肝硬化是肝纖維化的末期，此時肝細胞被大量纖維組織圍繞形成肝內結節，肝臟結構變形繼而引發腹水、肝腦性病變以及靜脈曲張出血等危急生命的併發症。肝移植是目前治療肝硬化病人最有效的方法，但由於肝臟捐贈來源有限因而侷限了此治療法的發展，所以尋找有效替代方案是非常重要的。幹細胞因為具有自我更新以及分化的能力，被認為可供細胞治療之用。最近臨床研究證實，骨髓間葉幹細胞可以被應用在多種疾病的治療上。骨髓間葉幹細胞可以分化成屬於內胚層的肝細胞，曾被報導過有減緩肝纖維化的作用，不過，促進肝纖維化的結果也有人提出，因此對於骨髓間葉幹細胞之於肝纖維化的治療仍有爭議。此外，關於骨髓間葉幹細胞如何影響肝纖維化的分子機制，還有許多未知，所以需要更多研究進一步探討。本研究計畫擬利用二甲基亞硝胺誘導肝纖維化之動物模式，來評估從綠螢光小鼠分離出的骨髓間葉幹細胞，是否具有改善肝纖維化的效果。我們假設受傷的肝臟會提供利基來調整骨髓間葉幹細胞的適應性 (plasticity)，透過這些改變的功能表型，骨髓間葉幹細胞可發揮治療肝纖維化的作用。為了證實這個假設，本計劃擬利用微陣列實驗來分析移植入正常肝臟以及受傷肝臟的骨髓間葉幹細胞，兩組間的基因表現差異，接著將針對在肝損傷組中有變化的基因，以肝纖維化之細胞模式來探討該基因如何影響纖維化過程。透過本計劃的執行，將有助於澄清骨髓間葉幹細胞應用在治療慢性肝纖維化的可行性，並且對於骨髓間葉幹細胞的治療機轉有更好的了解。<br> Abstract: Liver fibrosis refers to the excessive accumulation of extracellular matrix followingchronic liver injuries. Cirrhosis, the end-stage of progressive fibrosis, is characterized byseptum formation and rings of scar that surround the nodules of hepatocytes. This results inmany life-threatening complications, including ascites, hepatic encephalopathy and varicealhemorrhage. Liver transplantation has been the most effective treatment for these patients.Since liver transplantation is critically limited by the shortage of available donor livers,searching for an effective alternative therapy is very important.Stem cells and their possible use in cell therapy have drawn much attention recently, dueto their potential for self-renewal and differentiation. Bone marrow-derived mesenchymalstem cells (BMSC) are currently investigated clinically as cellular therapy for a variety ofdiseases. Differentiation of BMSC toward endodermal lineages, including hepatocytes andtheir therapeutic effect on liver fibrosis has been described but remains controversial.Moreover, the underlying mechanisms of how BMSC repair damaged liver are poorlyunderstood.In this project, we will develop a green fluorescent protein/dimethylnitrosamine model toevaluate the usefulness of BMSC transplantation for liver fibrosis. We hypothesize thatinjured liver environment would create a niche for BMSC plasticity and theses phenotypicalchanges of BMSC are the possible mechanisms for decreasing liver fibrosis. To prove thishypothesis, microarray experiment will be performed to profile the changes of geneexpression in BMSC between normal and injured liver environment. Furthermore, genes withexpression that altered in relation to liver injury will be studied in in vito fibrogenesis model.In conclusion, carrying out this project will help to clarify the potential of BMSC in treatmentof chronic liver fibrosis and provide a better understanding of its therapeutic mechanisms.骨髓間葉幹細胞肝纖維化四氯化碳硫代乙醯胺mesenchymal stem cellliver fibrosiscarbon tetrachloridethioacetamide