Abstract
摘要:細胞移植有許多優點,並且可能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以用來治療多種不同的肝臟疾病,包含代謝性肝臟疾病、急性肝臟衰竭和慢性肝臟硬化。從我們過去的研究顯示通常每一次我們只能移植 1~2%的肝細胞,且約只有 20%的移植肝細胞能嵌入受贈者肝臟內。如此有限的嵌入移植肝細胞(佔整個肝臟體積的 0.2~0.4% )並不能達到我們治療肝臟疾病代謝缺失的目的。而如何增加移植肝細胞的數目及擴展移植細胞的來源進而改善肝細胞移植的治療效果是肝細胞移植成為臨床上肝臟疾病新的治療方式前需克服的兩大問題。在筆者過去五年的研究結果顯示,肝細胞和幹細胞一樣有很強大的分裂增殖能力,並且在經過受贈者的前置治療後能夠廣泛的取代宿主的肝細胞,將來我們可能只需要移植少量的捐贈者肝細胞(少於受贈者肝臟體積的 1%),經過適當的刺激後,他們能夠在受贈者肝臟內不斷複製,並達到我們治療的需求(大於 30%的受贈者肝臟被捐贈者肝細胞所取代)。在我們所研究出來的宿主非侵入性前置治療下不僅可增加移植肝細胞嵌入宿主肝臟,並且可誘導嵌入的移植肝細胞不斷複製,進而大範圍取代宿主肝細胞。(1-4) 近兩年來我們使用第九凝血因子惕除小鼠為研究模式(血友病 B的動物模式),發現在我們發展出來的捐贈者前置治療下可以很有效的增加肝細胞移植對此類肝臟基因缺陷疾病的治療效果。(5)我們先前研究顯示肝細胞移植會誘發免疫反應並且活化肝臟巨噬細胞吞噬能力將移植細胞清除。因此調控肝細胞移植後的肝臟的免疫微環境將有助於保護移植的細胞被吞噬進而可增進治療效果。間葉幹細胞是一群可做為細胞移植時的細胞來源並且其自身所擁有的免疫調控能力預計將有助於調節肝細胞移植時的免疫反應。初步結果發現間葉幹細胞能夠干擾肝臟巨噬細胞活化,因此我們將更進一步研究是否間葉幹細胞的免疫調節能力能更進一步增進肝細胞移植效果。我們期盼此一策略將有助於未來臨床上細胞移植的應用。
Abstract: Cell transplantation has many advantages and has the potential to replace the whole organ transplantation as the first therapeutic choice for patients with organ failure. Recently, hepatocyte transplantation has been demonstrated as an effective therapeutic strategy for different kinds of liver disease in animals and clinical trials, including metabolic liver disease, acute liver failure, and chronic liver cirrhosis. In our previous studies, we showed that just only 1~2% hepatocytes can be transplanted into recipients each time, and just only 20% of transplanted cells have the opportunity to engraft into the recipient’s liver finally。We can’t reach the therapeutic purpose to correct the metabolic deficiency of liver diseases by such limited engrafted transplanted hepatocytes (0.2~0.4% of the whole liver mass). How to improve the therapeutic efficiency of hepatocyte transplantation by the increasing percentage of donor cells engraftment and expand the source of donor cells are two big issues to overcome before clinical application of this new therapeutic strategy. According to our studies in the past five years, hepatocyts have strong proliferative capacity, and can repopulate extensively in the recipient’s liver by the replacement of the recipient’s hepatocytes after suitable preconditioning treatment of recipient. In our preconditioning protocol, we can transplant limited donor hepatocytes (less than 1% of the whole liver volume) and reach eventually the therapeutic target (more than 30% of donor cells repopulation in the recipient’s liver) by continuing proliferation of the engrafted donor cells in the recipient’s liver. We not only increased the percentage of donor cells engraftment but also stimulated the proliferation of engrafted donor cells under our noninvasive preconditioning treatment for the recipients. Both effects contributed to the improvement of therapeutic efficiency of hepatocyte transplantation.[1-4] We also demonstrated the donor preconditiong (genetic modified donor cells) can improve the therapeutic efficiency of hepatocyte transplantation for genetic liver disease in our factor IX knock-out mice (animal model for hemophilia B).[5] So, both the preconditioning treatment for donor and recipients have the advantages to improve the therapeutic efficiency of cell transplantation for liver diseases from our previous studies.[1-5] Our previous studies also disclosed that hepatocytes transplantation will induce the local immune response and activate the Kupffer cells activity which will clean the transplanted cells. So the immunoregulation of liver microenvironment after hepatocytes transplantation has the potential to enhance the therapeutic efficiency by preserving the transplanted cells. Mesenchymal stem cells (MSCs) have been demonstrated not only as an alternative donor cells source but also having the capacity of immunoregulation in our preliminary studies. We found the MSCs can perturb the activity of Kupffer cells in vitro. So, we tried to identify whether the immunoregulation effect of MSCs can enhance the therapeutic efficiency of hepatocytes transplantation in genetic liver disease in this project. We expect that the result of this project will help us to establish the new therapeutic strategy of cell therapy for clinical application in the future.
Keyword(s)
肝細胞移植
間葉系幹細胞
巨噬細胞
hepatocyte transplantation
Kupffer cell
Mesenchymal stem cell