摘要:細胞移植可以取代器官移植成為器官衰竭病人的第一治療選擇。不管在動物實驗或臨床上肝細胞移植已被證明可用來治療多種不同的肝臟疾病。在過去我们的研究結果已發展出適合肝細胞移植的抗排斥藥物(Wu YM, et al. Hepatology 2006)1-2 及移植肝細胞可大範圍取代宿主肝臟的宿主前置治療模式(Wu YM, et al. Hepatology 2008)3.然而肝細胞移植的發展仍需克服肝細胞來源短缺以及異體排斥的問題.幹細胞移植是近年來被應用在許多疾病上並且具有其治療的可行性。因此,幹細胞移植有可能成為協助治療肝臟疾病新的選擇。臍帶血(Umbilical cord blood) 是新生兒出生時在胎盤和臍帶內所存留的血液。臍帶血內富含造血幹細胞(Hematopoietic stem cells) 與間葉幹細胞(Mesenchymal stemcells)。源自於臍帶血的幹細胞被廣泛地應用於癌症治療以及免疫系統恢復等,因此也大大提升了臍帶血的臨床重要性。然而臍帶血血清仍被視為生物廢棄物。臍帶血血清的收集技術簡易,對於長期保存更不是問題。目前少數的文獻顯示臍帶血血清能有效地治療乾眼症的病人。肝病乃為台灣人之國病,然而國內器官捐贈風氣不盛,使得罹患急性肝衰竭的病人在等待的過程中死亡。急性肝衰竭(Acute liver failure) 是肝臟細胞(Hepatocyte) 在短時間內大量壞死(Necrosis)。藥物中毒、病毒性肝炎、酗酒等都能造成肝臟急性衰竭。治療急性肝衰竭的有效方法為肝臟移植。然而急性肝衰竭的病程發展快速以及肝臟移植(liver transplantation) 受限於宿主器官來源不足,因此發展一個有效的治療策略乃為重要。在我們最新的研究發現人類臍帶血血清可以提高大鼠急性肝衰竭的存活率並且降低肝臟內GOT 和GPT 表現。同時我們從體外分離出肝細胞與人類臍帶血血清共同培養後,發現人類臍帶血血清促進肝細胞的增生能力。因此,如果臍帶血血清中的細胞激素或是生長因子能夠延緩肝衰竭的發展以及促進肝細胞的再生,藉此度過危險期,則臍帶血可以成為一個嶄新的治療策略。另外我們也企圖去尋找究竟在人類臍帶血血清中存在著哪些具有治療潛力的生物分子並進一步探討其分子機制。在這個計劃裡,第一年我們將運用cytokine protein array 分析人類臍帶血血清內的生物分子並且尋找有效的治療分子。第二年,我們將探討人類臍帶血血清對hepaticKupffer cells 發炎(inflammatory) 機制影響。第三年,我們將利用D-galactosamineyl 誘導大鼠急性肝衰竭動物模式藉此探討人類臍帶血血清的治療有效性。我們預期可以從此計畫執行中獲得人類臍帶血血清的治療價值並且發展一個臨床上可行的治療方式以延緩個體存活率,另一方面我們積極尋找人類臍帶血血清其治療分子機制。
Abstract: Cell transplantation can replace the whole organ transplantation as the first therapeuticchoice for patient with organ failure. Whether in animal experiments or clinical liver, thehepatocyte transplantation has been evidenced can be used to treat a wide variety of liverdisease. We demonstrated previously the suitable immunosuppression protocol forhepatocytes transplantation (Wu YM, et al. Hepatology 2006, IF:11.56) 1-2 and extensive liverrepopulation by transplanted hepatocytes after suitable preconditioning treatment of recipients(Wu YM, et al. Hepatology 2008, IF:11.56)3. However the development of hepatocytetransplantation still needs to overcome the shortage of sources of hepatocyte and allograftrejection. Stem cell transplantation has been shown to have the therapeutic potential in severaldifferent kinds of diseases. Moreover, the autograft of stem cell can overcome the problems oforgan shortage and allograft rejection. So stem cell transplantation has the potential to be thenew therapeutic strategy for liver diseases.Umbilical cord blood is blood that remains in the placenta and in the attached umbilicalcord after children. Cord blood is obtained from the umbilical cord at the time of children,after the cord has been detached from newborn. Umbilical cord blood contains stem cells,including hematopoietic and mesenchymal stem cell. Umbilical cord blood is well-recognizedto be useful for treating hematopoietic and genetic disorders. Removing the umbilical cordblood is not harmful to the baby and the blood would normally be thrown away as medicalwaste. Umbilical cord plasma is normally discarded, they are easily isolated and storage.Umbilical cord plasma enriches the many growth factors that are required for cell growth, cellsurvival, and tissue regeneration.The liver disease is popular in Taiwan. Many patients of liver failure are died during ofthe waiting. Acute liver failure is a liver cell necrosis in a short time. Drug intoxicity, viralhepatitis, alcohol abuse can cause acute liver failure. It is therapeutic way with livertransplantation in acute liver failure. However, the liver transplantation is limited into organof donor insufficient. It is important for development the therapeutic strategy of acute liverfailure. We are hypothesis that umbilical cord plasma able to prolonged survival and increasethe hepatocyte regeneration.Our recent result shows the human umbilical cord plasma can prolongation the ratsurvival of acute liver failure and decrease the level of GOT, GPT. We will coculture theprimary hepatocytes with human umbilical cord plasma. This result shows the humanumbilical cord plasma can promote the proliferation of hepatocytes. Therefore, if the humanumbilical cord plasma enrich of cytokine and growth factor can prolongation survival andpromote the proliferation of hepatocytes. It is good strategy for clinical therapy of acute liverfailure. Further we are attempting to find out the therapeutic factor to investigate themolecular mechanism.It this project, we will find out the effective factors of umbilical cord blood plasma bycytokine protein array. Secondary, we will focus on the study of immunomodulation effectbetween human umbilical cord plasma and activates of Kupffer cell. Simultaneously, we willexplore the therapeutic efficiency of human umbilical cord plasma in acute liver failure. Wewill try to develop a novel strategy for clinical therapy of acute liver failure by humanumbilical cord plasma. On the other hand, we made a great effort among exploring themolecular pathway of human umbilical cord therapy.