臺灣博碩士論文加值系統

眾所周知，眼角膜上皮幹細胞 (Stem cells) 所在的位置介於解剖學上角膜與結膜之間，也就是所謂的輪部 (Limbus)。在過去，藉由自體或異體的輪部移植再加上羊膜 (Amniotic membrane) 移植，我們已經可以成功地治療因化學藥物灼傷、熱灼傷、眼類天疱瘡 (Ocular cicatricial pemphigoid)、或史蒂芬氏強生症候群 (Stevens-Johnson syndrome) 導致眼角膜輪部幹細胞缺損 (Limbal stem cell deficiency, LSCD) 的病患。有報告指出當進行體外輪部上皮細胞培養時，羊膜本身是一個相當理想的幹細胞壁龕 (Niche)。最近的研究顯示培養於羊膜上的輪部上皮細胞可以成功地重建由於輪部幹細胞缺損而破壞的眼表層組織。然而，此一培養模式維持角膜上皮細胞存活能力的分子機制至今仍未十分明瞭。
當輪部上皮細胞於羊膜上培養時會牽涉到包括入侵、移行、以及增殖等一系列複雜的過程。Matrix metalloproteinases (MMPs)，特別是角膜上皮細胞生成用以分解細胞外基質的蛋白水解酶MMP-2及 MMP-9，已經被證實在角膜及水晶體上皮細胞移行的過程中扮演主要的調節角色。因此，在第一個部分我們要探討於此一細胞培養模式中MMP-9的表現及其重要角色。由zymography的結果得知無論是否與羊膜一起培養，MMP-9蛋白質表現量呈現一時間依存性的增加。然而，具活性的MMP-9只在羊膜組中表現並於培養第二週起漸增。經校正後平均MMP-9蛋白質表現以輪部上皮細胞培養於完整羊膜組者最高，分別為培養於去上皮羊膜組及無羊膜組的2.76 +/- 0.69倍及 4.25 +/- 0.30倍。由RT-PCR的結果也證實在完整羊膜組中MMP-9 mRNA的表現亦較其他兩組為高。根據免疫組織化學染色結果顯示MMP-9蛋白表現主要集中在輪部上皮細胞。當進一步以MMPs的抑制劑GM6001以及專一性的MMP-9抗體處理培養於完整羊膜上的輪部上皮細胞一星期後，我們發現細胞的生長受到抑制，同時MMP-9的活性也明顯降低。相反的，以MMP-9的抗體處理無羊膜的輪部上皮細胞時卻不會影響其生長。這部分的結果顯示當輪部上皮細胞培養在完整羊膜上時，MMP-9的表現不但隨時間增加，也與細胞的生長密切相關。這同時也暗示了細胞與其間質之交互作用在此一培養模式的重要性。
許多文獻指出細胞內的訊息傳遞路徑諸如MAPK及PI3-K/Akt等的活化對於細胞的移行、分化以及增殖等生理功能的調節相當重要。因此，接下來我們想瞭解在此一培養模式中究竟有那些細胞內的訊息傳遞路徑參與調控MMP-9的表現。由原位 (in situ) zymography的結果發現當輪部上皮細胞培養在完整羊膜上時，MMP-9的表現在細胞移行的前端相對較多。以上皮生長因子接受體 (EGFR) 的抑制劑AG1478、β4 integrin的抗體、PKC的抑制劑Ro318220和GÖ6976、PI3-K的抑制劑LY294002和Wortmannin、MEK1/2的抑制劑U0126,及JNK的抑制劑SP600125處理培養於完整羊膜上的輪部上皮細胞一星期後，我們可以明顯發現細胞的生長受到抑制；但是加入p38 MAPK的抑制劑SB202190時細胞的生長不受影響。然而，zymography的結果卻顯示MMP-9的活性會被LY294002及Wortmannin抑制，但不會受U0126和SB202190的影響。RT-PCR也印證了相同的結果。文獻指出PI3-K/Akt可以藉由其下游轉錄因子NF-kappaB的核轉位作用調控許多基因的表現，因此我們進一步探討PI3-K/Akt/NF-kappaB的訊息傳遞路徑是否調控MMP-9的表現。免疫螢光染色法證實LY294002同時抑制了Akt的磷酸化以及NF-kappaB的核轉位。此外，NF-kappaB的抑制劑Helenalin也會抑制輪部上皮細胞的生長；而由zymography、RT-PCR及免疫螢光染色的結果亦顯示出MMP-9的表現也會受到Helenalin抑制。綜合以上結果可知當輪部上皮細胞培養在完整羊膜上時，雖然PI3-K以及MAPKs均可影響細胞的生長，但是只有PI3-K/Akt/NF-kappaB的訊息傳遞路徑參與調控MMP-9的表現。
最近的研究指出當輪部上皮細胞培養在完整羊膜上時，其特殊的輪部上皮細胞性質得以保存。且不同的培養基質會引導上皮細胞走向不同的分化型態。然而，在此一培養模式中，究竟是那些因子產生釋放出來？又負責執行那些功能？這是我們接下來亟欲探討的主題。藉由Annexin V-FITC 螢光染色法，我們發現培養於完整羊膜上的輪部上皮細胞其細胞凋亡 (Apoptosis) 的數目顯然比沒有培養在羊膜上的少很多。為了找出可能的 ”抗細胞凋亡因子”，我們進行cDNA微矩陣分析。由結果得知當細胞培養於完整羊膜上時，interleukin-1 receptor antagonist (IL-1RA) 的表現明顯增加。這一點可從RT-PCR、real-time quantitative PCR (Q-PCR)以及ELISA均得到一致的結果加以印證。除此之外，當在無羊膜的輪部上皮細胞外加入重組的IL-1RA 蛋白時，可以觀察到細胞凋亡的數目明顯減少。如果我們把外源性IL-1 RA的中和抗體加入培養在完整羊膜上的輪部上皮細胞時，則會誘發細胞凋亡的現象。這些結果顯示完整的羊膜可以防止培養於其上的輪部上皮細胞進行細胞凋亡，而IL-1RA在輪部上皮細胞和完整羊膜接觸且產生交互作用的過程中可能扮演著”抗細胞凋亡”的媒介角色之一。
綜合以上結果，我們發現當輪部上皮細胞與羊膜一起培養時，MMP-9蛋白質表現量呈現一時間依存性的增加，其表現會受到PI3-K訊息傳遞路徑的調控，我們推測MMP-9的表現可能在輪部上皮細胞的生長中扮演樞紐的角色。同時，我們也進一步證實輪部上皮細胞在羊膜上生長時，可能受到integrin和上皮生長因子(epidermal growth factor，EGF) 的調控。因此，本研究將有助於瞭解在羊膜上培養輪部上皮細胞的模式中，關於MMP-9表現及其分子調控之機制。此外，IL-1RA “抗細胞凋亡”的新角色在未來也可以應用在組織工程上，治療各種眼表層的疾病。

Stem cells (SCs) of the corneal epithelium have been found to be located exclusively at the limbus—that is, the anatomical junction between the cornea and the conjunctiva. Together with limbal auto- or allo-graft, amniotic membrane (AM) transplantation successfully reconstructs the ocular surface in patients with limbal stem cell deficiency (LSCD) secondary to chemical or thermal burns, ocular cicatricial pemphigoid and Stevens-Johnson syndrome. It has been proposed that AM itself may serve as an ideal “niche” to support the ex vivo expanded limbal epithelial cells (LECs). Recent studies have also shown that ex vivo expanded LECs cultivated on AM are capable of restoring the corneal surface with LSCD. However, the molecular mechanisms underlying maintenance of survival ability in this culture model are not fully understood.
Outgrowth of LECs on AM involves serial and complex processes, including invasion, migration, and proliferation. Matrix metalloproteinases (MMPs), especially MMP-2 and MMP-9, the primary matrix-degrading enzymes produced by the corneal epithelium, have been shown to play a key role in regulating cell migration of the corneal and lens epithelia. In the first part of the present study, we investigated the expression and pivotal role of MMP-9 in this culture model by zymographic, RT-PCR, and immunohistochemical analyses. The expression of MMP-9 in cultures with or without AM all increased in a time-dependent manner. However, the active form of MMP-9 emerged only in cultures on AM from the second week. The averaged corrected ratio of MMP-9 expression in cultures on intact AM (preserving amniotic epithelial cells; iAM) versus those on denuded AM (removing amniotic epithelial cells; deAM) or plastic dishes was 2.76 +/- 0.69- or 4.25 +/- 0.30-fold, respectively. MMP-9 transcripts were up-regulated in cultures on iAM compared with those of the other two culture conditions. Immunohistochemical staining demonstrated that the MMP-9 protein was located on the LECs. Up-regulation of MMP-9 associated with limbal outgrowth was significantly attenuated by both MMPs inhibitor GM6001 and MMP-9 antibody, consistent with the inhibition of MMP-9 activity. In contrast, the sizes of limbal outgrowth were not different between the control and MMP-9 antibody-treated plastic dishes. These results demonstrated that MMP-9 not only was up-regulated, it was also involved in the outgrowth of LECs. It also suggests that cell-cell matrix interaction is involved in the expansion of LECs on iAM.
Several lines of evidence have indicated that activation of intracellular signaling pathways such as mitogen-activated protein kinases (MAPKs) and phosphatidylinostiol 3-kinase (PI3-K)/Akt cascades are critical to regulate several cellular functions, including migration, differentiation, and proliferation. Therefore, in the second part of the study, we looked into the signaling pathways mediating outgrowth of LECs and MMP-9 expression in this model. By using in situ zymography, we found that MMP-9 was preferentially expressed at leading edge of limbal epithelial outgrowth. AG1478 (EGFR inhibitor) at 1 µM, β4 integrin antibody at 8µg/ml, Ro318220 at 10 µM and GÖ6976 at 1 µM (PKC inhibitors), LY294002 as well as Wortmannin (PI3-K inhibitors) at 30 µM, Helenalin (NF-kappaB inhibitor) at 10 µM, U0126 (MEK1/2 inhibitor) at 10 µM and SP600125 (c-Jun N-terminal kinase (JNK) inhibitor) at 10 µM significantly suppressed the expansion of LECs on iAM as compared to that of control group, whereas the outgrowth was not inhibited by 30 µM of SB202190 (p38 MAPK inhibitor). However, gelatin zymography demonstrated that enzymatic activity of MMP-9 was attenuated by LY294002, Wortmannin and Helenalin, but not affected by U0126 and SB202190, which was confirmed by the results of RT-PCR. Furthermore, LY294002 also down-regulated phosphorylated-Akt expression and NF-kappaB nuclear translocation of LECs grown on iAM as evidenced by immunofluorescent study. Taken together, these results indicate that although both PI3-K and MAPK pathways are involved in limbal outgrowth; however, only PI3-K/Akt/NF-kappaB signaling regulates MMP-9 expression in ex vivo expansion of LECs on iAM.
Recent studies indicate that iAM preserves the limbal epithelial phenotype and distinct epithelial morphologies are noted among various culture matrices. However, the factors responsible for the maintenance of cell survival during the interaction between LECs and iAM were not well understood. Therefore, the third part of the present study focused on identifying the roles of these candidate factor(s). Using Annexin V-FITC staining, we found that human LECs expanded on intact human AM demonstrated lesser apoptotic cells as compared with those on plastic dishes. To identify the anti-apoptotic factors, we performed cDNA microarray analysis and showed that interleukin-1 receptor antagonist (IL-1RA) was over-expressed in cultures on iAM, which was confirmed by RT-PCR, real-time quantitative PCR (Q-PCR) and ELISA. In addition, we also noted that the phenomenon of apoptosis detected in cultures on plastic dishes could be reversed by adding recombinant IL-1RA protein into the media, whereas apoptosis of LECs cultivated on iAM could be induced by addition of exogenous IL-1 RA neutralizing antibody. These results demonstrated that intact human AM may prevent cultured human LECs from undergoing apoptosis. IL-1RA might be one of candidate mediators to exert as an anti-apoptotic molecule during the interaction between human LECs and intact human AM.
In summary, we found that MMP-9 expression was up-regulated in a time-dependent manner during ex vivo expansion of human limbal explants on iAM, which might play a key element during outgrowth of LECs. We next elucidated, at least in part, that PI3-K, but not p42/p44 MAPK regulated MMP-9 expression in this model. We also established significant roles of integrin- and EGF-related signals in this culture system. Finally, by using cDNA microarray analysis, we identified a naturally occurring cytokine, IL-1RA, as an anti-apoptotic molecule during the interaction between LECs and iAM, thus disclosing a new therapeutic target for tissue engineering in the treatment of ocular surface disorders.

Table of Contents
Page
Table of Contents (目錄)......................................vi
Abbreviations (縮寫表).......................................vii
Abstract in Chinese (中文摘要).................................x
Abstract in English (英文摘要)................................xv
CHAPTER 1 INTRODUCTION.....................................1
SECTION 1. Background and Significance.......................2
SECTION 2. Specific Aims....................................23
SECTION 3. Figures and Tables...............................24
CHAPTER 2 MATERIALS AND METHODS...........................35
CHAPTER 3 RESULTS.........................................48
SECTION 1. Role of Matrix Metalloproteinase-9 in Ex Vivo
Expansion of Human Limbal Epithelial Cells
Cultured on Human Amniotic Membrane..............49
SECTION 2. Signaling Pathways Involved in Ex Vivo Expansion
of Human Limbal Epithelial Cells Cultured on
Human Amniotic Membrane..........................75
SECTION 3. Interleukin-1 Receptor Antagonist Prevents
Apoptosis in Ex Vivo Expansion of Human Limbal
Epithelial Cells Cultivated on Human Amniotic
Membrane........................................127
CHAPTER 4 CONCLUSION AND PERSPECTIVES....................158
REFERENCES..................................................164
PUBLICATIONS................................................188

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