第二章肝細胞移植 Hepatocyte Transplantation

Size: px

Start display at page:

Download "第二章肝細胞移植 Hepatocyte Transplantation"

羊申
9 years ago
Views:

1 第二章肝細胞移植 Hepatocyte Transplantation 生技碩專研一黃國清

2 Anatomy 人體內最大器官 (1.5 公斤 )

outward from a central vein At each of the six

4 LIVER ANATOMY Liver lobules hexagonal structures consisting of hepatocytes Hepatocytes radiate outward from a central vein At each of the six corners of a lobule is a portal triad Liver sinusoids

5 LIVER ANATOMY

6 Functions Metabolic Synthesis Breakdown Other functions storage of vitamin A,D,B12,F Excretion of waste products from bloodstream into bile Vascular storage of blood

7 Synthesis Protein metabolism Synthesis of amino acids Carbohydrate metabolism Gluconeogenesis Glycogenolysis Glycogenesis Lipid metabolism Cholesterol synthesis Lipogenesis Production of coagulation factors I, II, V, VII, IX, X and XI, and protein C, protein S and antithrombin Main site of red blood cell production Produces insulin-like growth factor 1 (IGF-1), a polypeptide protein anabolic effects Production of trombopoetin

8 Breakdown Breaks down insulin and other hormones Breaks down hemoglobin Breaks down or modifies toxic substances (methylation) sometimes results in toxication Converts ammonia to urea

9 Other functions Produces albumin, the major osmolar component of blood serum Synthesizes angiotensinogen, the hormone responsible for raising blood pressure when activated by renin (enzyme released when the kidney senses low blood pressure)

11 細胞移植器官來源缺乏不需要所有的細胞同時工作以維護我們的生理需求這將可能使一名捐贈者可以分享給更多受贈者, 並且擴大有限的捐贈器官其實用的效率便利性完整的器官無法長期保存, 分離的細胞可以冷凍保存且在任何我們需要的時刻解凍安全的完整的器官移植仍然有潛在的外科手術風險細胞移植可以透過經皮注射的方式達到治療目的

12 Nat. Rev. Gastroenterol. Hepatol. 7, (2010)

13 Nat. Rev. Gastroenterol. Hepatol. 7, (2010)

14 Transplantation 2012;93:

15 Desmosome: a cell structure specialized for cell-to-cell adhesion J Intern Med 2012;272:

16 Current Opinion in Nephrology and Hypertension 2009, 18:

17 J Intern Med 2012;272:

18 Transplantation 2012;93:

19 J Intern Med 2012;272:

21 Transplantation 2012;93:

22 肝細胞移植的基礎研究成果

23 移植肝細胞的位置肝外位置不是生理上正常的肝細胞生長環境需要生長因子和大量的細胞外間質來重建移植的肝細胞其功能基因表現顯示當移植入宿主肝臟時其表現較好

24 Intraperitoneal transplantation of rat hepatocyte microbeads in rats with ALF. Jitraruch, Suttiruk; Dhawan, Anil; Hughes, Robin D.; Filippi, Celine; Soong, Daniel; Philippeos, Christina; Lehec, Sharon C.; Heaton, Nigel D.; Longhi, Maria S.; Mitry, Ragai R. (2014): Intraperitoneal transplantation of rat hepatocyte microbeads in rats with ALF. Figure_6.tif. PLOS ONE /journal.pone g006.

25 細胞如何移植進入到宿主肝臟

26 1. 細胞嵌入, 繁殖和細胞 - 細胞相互作用 (cell engraftment, proliferation, and cell-cell interaction) hepatocyte transplantation efficacy is limited because the transplanted cells become entrapped in portal spaces and are subsequently destroyed by the innate immune system remaining transplanted hepatocytes are poorly engrafted in the liver parenchyma Cell Medicine, Vol. 4, pp , 2012

27 經由肝動脈移植的細胞仍將由於受到較高的壓力而損害經由門靜脈移植的細胞佔據門靜脈分枝而引起短暫缺血性的再灌流傷害 (Ischemia reperfusion injury)

28 Ischemia reperfusion injury tissue damage caused when blood supply returns to the tissue after a period of ischemia or lack of oxygen restoration of circulation results in inflammation and oxidative damage through the induction of oxidative stress

29 Mechanisms Reperfusion of ischemic tissues is often associated with microvascular injury, particularly due to increased permeability of capillaries and arterioles These "activated" endothelial cells produce more reactive oxygen species

30 Figure 1 Multifaceted hepatic ischemia-reperfusion injury. Kupffer and endothelial cells produce cytokines and chemokines, recruiting neutrophils that further accentuate injury. EC: Endothelial cell; KC: Kupffer cell; ATP: Adenosine triphosphate; TNF: Tumor necrosis factor; IL: Interleukin; ICAM: Intercellular adhesion molecule; VCAM: Vascular adhesion molecule; PAF: Platelet activation factor; LTB4: Leukotriene B4; GMS-CSF: Granulocyte macrophage colony stimulating factor; INF: Interferon; ROS: Reactive oxygen species World J Gastroenterol December 28; 16(48):

31 僅僅只有 20% 移植的細胞透過內皮細胞的裂縫能夠嵌入到宿主肝板內

32 需要多少細胞去達到治療效果? 取決於肝臟疾病的特性和嚴重程度急性肝臟衰竭較多肝細胞代謝性肝臟疾病較少肝細胞通常一次的肝細胞移植只能移植約宿主肝臟質量 2~5% 的捐贈者細胞單次移植中小於 1% 的移植肝細胞是不足以達到治療的目標

33 提高移植效率增加細胞嵌入的比例刺激移植細胞本身的繁殖多次的移植

34 增加細胞嵌入的比例以 gadonium 使 Kupffer 細胞失去活性 rapamycin 或是加上 tacrolimus 干擾單核白血球和嗜中性白血球的浸潤血管擴張劑和 cyclophosphamide, doxorubicin 和 monocrotaline(mct) 化學藥劑引起內皮細胞的破壞改善細胞嵌入

35 刺激肝細胞的繁殖部分肝臟切除, 局部缺血,CCl4, 肝細胞生長因子同時刺激宿主和捐贈者細胞將在 1~2 次細胞循環 (cell cycle) 後停止繁殖需要選擇性抑制宿主細胞繁殖能力或是提升捐贈者細胞繁殖能力

36 宿主前置處理輻射 Inhibition of native hepatocytes promoted proliferation of transplanted hepatocytes (transplantation 2010;93: ) 甲狀腺素對於肝細胞而言, 甲狀腺素是一種強烈的繁殖刺激因子但是它也會促進細胞凋零的程序, 特別是先前帶有基因損害的細胞因此細胞移植後運用甲狀腺素提高了捐贈者細胞的繁殖競爭並且有助於大量的繁殖

39 多次的移植

40 細胞排斥機制和免疫抑制肝臟是一個免疫豁免 (immunoprivileged) 器官分離的肝細胞較容易受到攻擊並且引起強烈的異體免疫反應 (alloimmunity)

42 冷凍保存 Cryopreservation Needed Emergency treatment For repeated use of cell from the same donor Detrimental effect Viability and metabolic functions of hepatocytes May reduce engraftment in the liver Acceptable agents Dimethyl sufoxide (DMSO) Nat. Rev. Gastroenterol. Hepatol. 7, (2010)

43 代替細胞來源 Liver stem and/or progenitor cells Fetal liver cells Mature-liver-derived stem cells Bone-marrow-derived stem cells Embryonic stem cells Xenotransplantation Nat. Rev. Gastroenterol. Hepatol. 7, (2010)

44 Summarized possible mechanism for hepatic stem cell differentiation. Suzuki A et al. Development 2003;130:

47 臨床研究結果

48 Nat. Rev. Gastroenterol. Hepatol. 7, (2010)

49 Nat. Rev. Gastroenterol. Hepatol. 7, (2010)

50 Nat. Rev. Gastroenterol. Hepatol. 7, (2010)

51 Nat. Rev. Gastroenterol. Hepatol. 7, (2010)

52 謝謝聆聽歡迎討論

名称未設定

名称未設定 127 Insulin IR Glucose transport GLUT4 P P IRS PI3K P GLUT4 Akt/PKB GSK-3 P Inactive GSK-3 Active GS Active GS Inactive P Glycogen synthesis 128 129 IRS-1 PH PTB 1242 IRS-2 PH PTB NGDY NDQY 1338 IRS-3

第二章 肝細胞移植 Hepatocyte Transplantation

第二章肝細胞移植 Hepatocyte Transplantation