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研究生:陳雅惠
研究生(外文):Ya-Hui Chen
論文名稱:肝細胞在肝臟修復再生過程中之可塑性及治療潛能
論文名稱(外文):Plasticity of Hepatocytes in liver regeneration
指導教授:張美惠張美惠引用關係陳惠玲陳惠玲引用關係
指導教授(外文):Mei-Hwei ChangHui-Ling Chen
口試委員:余俊賢陳慧玲顏伶汝陳佑宗王弘毅楊偉勛
口試委員(外文):Chun-Hsien YuHuey-Ling ChenBetty Lin-Ju YenChen You-TzungHurng-Yi WangWei-Shiung Yang
口試日期:2014-06-25
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
語文別:中文
論文頁數:110
中文關鍵詞:肝細胞肝細胞移植卵圓幹細胞小肝細胞樣祖細胞肝臟再生細胞分化轉分化
外文關鍵詞:HepatocytesHepatocyte transplantationHepatic oval cellssmall hepatocyte-like progenitor cellsRegenerationCell differentiationTransdifferentiation
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肝細胞是一種具有高度可塑性的細胞。在大部份的肝傷害後,肝臟修復工作主要藉由成熟肝細胞增生來修補受損的區域。然而,在特殊肝損害的情況下,成熟肝細胞亦可轉變為兼具有幹細胞的特性,它們可能經由肝細胞去分化或是轉分化的過程參與肝臟修復,這些過程涉及複雜的信號轉導途徑,調控機制仍不清楚。
關於卵圓幹細胞(Hepatic oval cells, OCs)、小肝細胞樣祖細胞(Small hepatocyte-like progenitor cells, SHPCs)和肝細胞(Hepatocytes)在肝臟修復過程中所扮演的角色及細胞分化源由的關連性仍然備受爭議。SHPCs是一種肝祖細胞(Heaptic progenitor cells),同時具有胚胎肝母細胞(Hepatoblasts)、卵圓幹細胞和成熟肝細胞的表型特徵。為了探討成熟肝細胞和SHPCs細胞分化祖源的關連性,我們應用一個能夠產生50% DPPIV陽性肝細胞的DPPIV chimeric liver的動物實驗模式,大鼠在接受Retrorsine及部分肝切除(Hepatectomy, PH)處理之後,會誘發SHPCs集群的生成,利用DPPIV蛋白表現可以標定追蹤成熟肝細胞的位置以及偵測SHPCs是否具有 DPPIV 蛋白表現。結果在所有的分析樣品內,我們都沒有觀察到任何DPPIV陽性的SHPCs集群。此外,在連續組織切片中使用gamma-glutamyl-transpeptidase(GGT,胚胎肝母細胞的標誌)和glucose-6-phosphatase(G6Pase,成熟肝細胞的標誌)染色進行分析,顯示SHPCs集群是一個包含了不同分化階段肝細胞的異質群體(Heterogeneous population)。在後續連續切片中,使用免疫螢光雙染色分別標示卵圓幹細胞特定標誌(CK-19/OV-6, laminin, EpCAM)和肝細胞的特定標誌(HNF-4α, C/EBPα),也發現卵圓幹細胞的增生和SHPCs集群生成可能是有相關性。4,4’-Methylenedianiline(DAPM)是一種膽道毒素,會破壞膽管週圍細胞進而抑制卵圓幹細胞的活化。在暴露於Retrorsine的大鼠模式中,利用DAPM藥物重複處理全面性抑制卵圓幹細胞的活化,誘發SHPCs集群的生成,亦沒有發現SHPCs集群的產生。另外,將分離出來的DPPIV陽性卵圓幹細胞移植進入已暴露Retrorsine的DPPIV-deficient大鼠肝臟內再進行部分肝切除術後,可以發現有DPPIV陽性SHPCs集群的存在。這些結果強烈顯示,成熟肝細胞無法經由去分化產生SHPCs集群,SHPCs集群可能是由卵圓幹細胞分化而來。
為了探討肝細胞轉分化為膽管上皮細胞(Biliary epithelial cells, BECs)的潛力,在第二部份的研究中,我們使用DAPM和D-galactosamine(DAPM + D-gal)建立急性肝臟及膽道損傷(Acute hepatio-biliary injury)的大鼠實驗模式,進行DPPIV陽性肝細胞移植,利用DPPIV蛋白標記來追蹤移植細胞位置及移植細胞分化狀況。另外,應用DPPIV chimeric liver大鼠模式,分別給予DAPM+D-gal和DAPM+BDL傷害,誘發急性肝臟及膽道損傷和慢性膽道的損傷,探討DPPIV陽性肝細胞在不同肝臟受損情況下如何參與肝臟修復。結果顯示,成熟肝細胞可以逐步轉分化成為BECs。在急性肝臟及膽道損傷進行肝細胞移植的實驗,移植的DPPIV陽性肝細胞會滯留於肝門靜脈內,沿著肝門靜脈增生慢慢排列形成雙層板狀的結構。在雙層板結構內,移植的DPPIV陽性肝細胞會逐漸失去原本肝細胞的特性,慢慢出現膽道(Biliary)特有的基因表現,最後形成具有DPPIV蛋白表現的膽管(Bile duct)。在DPPIV chimeric liver誘發急性肝臟及膽道損傷和慢性膽道損傷的研究,我們觀察到位於肝門靜脈週圍能夠表現膽道特異基因(HNF-1β)的細胞也都具有DPPIV蛋白表現,這些細胞會延續連接到具有DPPIV蛋白表現的膽管。為了進一步確認移植肝細胞和膽管生成的關聯性,應用DPPIV chimer liver動物模式,在誘發急性或慢性膽道損傷之前,先給予動物Retrorsine處理,經由抑制肝細胞的增生阻礙DPPIV陽性BECs的生成,我們沒有發現DPPIV陽性BECs存在。這些結果顯示,在急性和慢性膽道損傷的環境中,成熟肝細胞可能會經由類似膽管板(Ductal plate)結構機制的方式轉化成為BEC進行膽道的再生修復。過程可能會受到Notch信息傳遞所調控。
綜合我們的研究,肝細胞具有很強的可塑性,在不同的肝損傷環境中,可以針對肝臟修復的需求,適時進行細胞轉變參與肝臟修復,有時也會與卵圓幹細胞互相配合來執行肝臟的修復工作。讓我們對於了解肝臟修復再生作用的機制可以更邁前一步。


Hepatocytes are cells with high plasticity. Mature hepatocyte proliferation is usually responsible for liver regeneration after most causes of injury. However, under the special contribution of liver damage, mature hepatocytes can function as facultative stem cells for each other and replenish the inhibited cellular compartment by a process of trans-differentiation, involving complex signaling pathways. Mechanism of its regulation is still unclear.
The potential lineage relationship between hepatic oval cells, small hepatocyte-like progenitor cells (SHPCs), and hepatocytes in liver regeneration is debated. SHPCs are a type of progenitor cells group and express phenotypic characteristics of fetal hepatoblasts, hepatic oval cells, and mature hepatocytes. To test whether mature hepatocytes can give rise to SHPCs, rats with dipeptidyl peptidase IV (DPPIV) chimeric livers, which harbored endogenous DPPIV-deficient hepatocytes and transplanted DPPIV-positive hepatocytes, were subjected to retrorsine treatment followed by partial hepatectomy (PH). DPPIV-positive hepatocytes comprised about half of the DPPIV chimeric liver mass. Tissues from DPPIV chimeric livers after retrorsine/PH treatment showed large numbers of SHPC clusters. None of the SHPC clusters were stained positive for DPPIV in any analyzed samples. Furthermore, serial sections stained for gamma-glutamyl-transpeptidase (GGT, a marker of fetal hepatoblasts) and glucose-6-phosphatase (G6Pase, a marker of mature hepatocytes) showed SHPCs are a heterogeneous population of cells at different stages of differentiation in hepatic progenitor cell and hepatocyte lineage. Using double immunofluorescence staining for markers specific for hepatic oval cells (CK-19/OV-6, Laminin, EpCAM) and hepatocytes (HNF-4α, C/EBPα) in serial sections, we find that a lineage relationship was present within a single oval cell proliferation and between oval cell proliferations and SHPC clusters. Extensive elimination of oval cell response by repeated administration of 4,4’-methylenedianiline (DAPM) to retrorsine-exposed rats impaired the emergence of SHPC clusters. DPPIV-positive hepatic oval cells are transplanted into the DPPIV-deficient rat subjected to retrorsine treatment and followed by partial hepatectomy. The DPPIV-positive SHPC clusters is observed. These findings highly suggest the hepatic oval cells but not mature hepatocytes as the origin of SHPC clusters in retrorsine-exposed rats.
However, we have recently used in vivo lineage tracing technique in rats and resolved the debate on the lineage relationship between mature SHPCs in retrorsine-exposed rats after PH. We have demonstrated that mature hepatocytes do not give rise to SHPCs. Taken together, these studies prompted us to hypothesize that being a terminal differentiated cell type, mature hepatocytes can not convert into BECs in the damaged livers. Therefore, whether hepatocytes can convert into biliary epithelial cells (BECs) during liver injury is much debated. To test this concept, we traced the fate of genetically labeled (DPPIV-positive) hepatocytes in hepatocyte transplantation model following acute hepato-biliary injury induced by DAPM and D-galactosamine (DAPM + D-gal) and in DPPIV-chimeric liver model subjected to acute (DAPM + D-gal) or chronic biliary injury caused by DAPM and bile duct ligation (DAPM + BDL). In both models before biliary injury, BECs are uniformly DPPIV-deficient and DPPIV-deficient hepatocytes are restricted to proliferate by retrorsine. We found that mature hepatocytes underwent a stepwise conversion into BECs. In the hepatocyte transplantation model, DPPIV-positive hepatocytes entrapped periportally proliferated and formed two-layered plates along portal veins. Within the two-layered plates, the hepatocytes gradually lost their identity, proceeded through an intermediate state, acquired a biliary phenotype, and subsequently formed bile ducts along the hilum-to-periphery axis. Additionally, in DPPIV-chimeric liver model, periportally located hepatocytes expressing HNF-1β were exclusively DPPIV-positive and were in continuity to DPPIV-positives bile ducts. Inhibition of hepatocyte proliferation by additional doses of retrorsine in DPPIV-chimeric livers prevented the appearance of DPPIV-positive BECs after biliary injury. Moreover, enriched DPPIV-positive BEC/hepatic oval cell transplantation produced DPPIV-positive BECs or bile ducts in unexpectedly low frequency and in mid-lobular regions. These results together suggest that mature hepatocytes but not contaminating BECs/hepatic oval cells are the sources of periportal DPPIV-positive BECs. These findings highly suggest that mature hepatocytes contribute to the biliary regeneration in the environment of acute and chronic biliary injury through a mechanism similar to fetal development of biliary duct without the need of exogenously genetic or epigenetic manipulation. The Notch signaling pawthay may regulate this response.
Finally, these results showed hepatocytes have a strong ability for regeneration during liver damage in various environment. Hepatocytes can self-replicate proliferation or transdifferentiation to repair the liver.


中文摘要 i
英文摘要 iv
博士論文容
第一章、緒論 1
第二章、研究方法與材料 10
2.1 實驗動物 10
2.2 利用Retrorsine加上D-galactosamie處理建立急性肝傷害的動物模式 10
2.3 肝細胞(Hepatocytes)的分離及移植 11
2.4 產生具有DPPIV嵌合型肝臟(DPPIV chimeric liver)的大鼠動物模式 11
2.5 產生誘導小肝細胞樣幹細胞(Small hepatocyte-like progenitor cells, SHPCs)增生之動物模式 12
2.6 利用外加4,4’-Methylenedianiline (DAPM)來破壞卵圓幹細胞(Hepatic oval cells, OCs)的生成 13
2.7 建立急性肝臟及膽道損傷(Acute hepatio-biliary injury)的動物模式 13
2.8 卵圓幹細胞(Hepatic oval cells, OCs)的分離和特徵 14
2.9 在具有DPPIV嵌合型肝臟(DPPIV chimeric liver)大鼠誘發急性肝臟及膽道損傷(Acute hepatio-biliary injury)和慢性膽道的損傷(Chronic biliary injury) 15
2.10 肝臟組織切片及Morphometric分析 15
2.11 組織化學染色法與免疫組織染色法 16
2.12 定量即時PCR(Real-time PCR)分析 17
2.13 實驗設計 17
2.14 統計分析 23
第三章、結果 24
第一節、小肝細胞樣幹細胞(Small hepatocyte-like progenitor cells, SHPCs)不是由成熟肝細胞去分化(Didifferentiation)而來,而是從卵圓幹細胞(Hepatic oval cells, OCs)分化成的 24
3.1.1移植肝細胞進入急性肝受損動物模式建立一個DPPIV chimeric liver大鼠的動物模式 24
3.1.2小肝細胞樣幹細胞(Small hepatocyte-like progenitor cells, SHPCs)不是源自於成熟肝細胞去分化(dedifferentiation) 25
3.1.3小肝細胞樣幹細胞(Small hepatocyte-like progenitor cells, SHPCs)可能是卵圓幹細胞(Hepatic oval cells, OCs)分化而來 27
第二節、探討在膽道損傷(Biliary injury)情況下,成熟肝細胞可以轉分化(Transdifferentiation)為膽道細胞進行膽道的再生修復(Biliary regeneration) 31
3.2.1在膽道損傷中,成熟肝細胞會藉由轉分化(Transdifferentiation)成為膽道細胞(Biliary cells)來進行膽道的再生修復(Biliary regeneration) 31
3.2.2利用卵圓幹細胞移植及再抑制肝細胞的實驗,確認成熟肝細胞在肝組織內可進行轉分化的能力 35
3.2.3成熟肝細胞可能會藉由Notch signaling pathway來調節轉分化(Transdifferentiation)的機制 37
第四章、討論 40
第一節、小肝細胞樣幹細胞(Small hepatocyte-like progenitor cells, SHPCs)不是由成熟肝細胞去分化(didifferentiation)而來,而是由卵圓幹細胞(Hepatic oval cells, OCs)分化而來 40
第二節、探討在膽道損傷(Biliary injury)中,成熟肝細胞可以轉分化(Transdifferentiation)進行膽道的再生修復(Biliary regeneration) 47
第五章、展望 54
論文英文簡述 56
參考文獻 63
圖表 71
圖一、第一部分實驗假說 71
圖二、實驗設計1 72
圖三、在Retrorsine/PH處理前(A,B)和處理後(C,D)的DPPIV chimeric liver組織學結構 73
圖四、成熟肝細胞不會生成小肝細胞樣幹細胞(SHPCs) 74
圖五、小肝細胞樣幹細胞(SHPCs)集群為肝祖細胞(Hepatic progenitor cells)和肝細胞譜系間處在不同分化階段的異質群體(Heterogeneous) 76
圖六、卵圓幹細胞(Hepatic oval cells, OCs)的增生現象與小肝細胞樣幹細胞(SHPCs)集群的關連性(1) 77
圖七、卵圓幹細胞(Hepatic oval cells, OCs)的增生現象與小肝細胞樣幹細胞(SHPCs)集群的關連性(2) 79
圖八、卵圓幹細胞(Hepatic oval cells, OCs)的增生現象與小肝細胞樣幹細胞(SHPCs)集群的關連性(3) 80
圖九、第一部分結論 82
圖十、第二部分實驗假說 83
圖十一、實驗設計2 84
圖十二、在Retrorsine + D-gal和Retrorsine + DAPM + D-gal急性肝臟或損傷膽管模式中,卵圓幹細胞活化及形成的膽道的組織動力學的變化 86
圖十三、在急性肝臟及膽道損傷(Acute hepatio-biliary injury)的環境下,移植DPPIV陽性肝細胞可以經由逐步轉分化成為膽管上皮細胞(Biliary epithelial cells, BECs)來進行肝修復作用 88
圖十四、在急性肝臟及膽道損傷的環境下,移植DPPIV陽性肝細胞會藉由類似膽管板(Ductal plate)結構機制來轉化成為膽管上皮細胞(BECs)(1週後) 90
圖十五、在急性肝臟及膽道損傷的環境下,移植DPPIV陽性肝細胞會藉由類似膽管板(Ductal plate)結構機制來轉化成為膽管上皮細胞(BECs)(2週後) 91
圖十六、在急性肝臟及膽道損傷的環境下,移植DPPIV陽性肝細胞會藉由類似膽管板(Ductal plate)結構機制來轉化成為膽管上皮細胞(BECs)(4週後) 93
圖十七、移植肝細胞會藉由類似膽管板(Ductal plate)結構機制來轉化成為膽管上皮細胞(BECs)之卡通圖示 95
圖十八、在DPPIV chimeric liver的大鼠來誘發急性肝臟及膽道損傷(Acute hepatio-biliary injury)(DAPM + D-gal)和慢性膽道的損傷(Chronic biliary injury)(DAPM + BDL)中,DPPIV陽性的肝細胞轉分化成為膽管上皮細胞(BECs) 96
圖十九、在肝細胞移植的動物模式中,觀察到的DPPIV陽性BECs是源自於成熟的肝細胞所轉變成的,而非來自於含有BECs/卵圓幹細胞的污染液的 98
圖二十、在DPPIV chimeric liver的動物模式中,觀察到的DPPIV陽性BECs是源自於成熟的肝細胞所轉變成的,而非來自於含有BECs/卵圓幹細胞的污染液的 100
圖二十一、成熟肝細胞經由類似胎兒發育過程的膽管板(Ductal plate)結構機制來轉分化成的膽管上皮細胞(BECs)可能是經由Notch signaling所調控的 102
圖二十二、實驗總結論 105
圖二十三、胚胎發育膽管生成之卡通圖和移植肝細胞在急性肝臟及膽道受損環境下會藉由類似膽管板(Ductal plate)結構機制來轉化成為膽管上皮細胞(BECs)之卡通圖示 106
附錄 110


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