臺灣博碩士論文加值系統

角膜為眼球表面上皮細胞構成之無血管透明組織，角膜上皮細胞則由位於角膜及鞏膜接合處之輪部上皮層（limbal epithelium）內的幹細胞分化而來。因灼傷、感染或其他因素導致角膜輪部組織缺損（total limbal deficiency）的患者，透過於人體羊膜上增殖培養之角膜輪部上皮組織的移植，已可成功重建患者缺損的眼表組織並恢復視力。此種體外增殖的培養模式已建構出組織工程角膜之雛形，而富含幹細胞的輪部上皮組織，更是該組織工程眼角膜成功之關鍵。然而迄今有關角膜輪部上皮幹細胞的特性與鑑別、以及對於羊膜上增殖培養之輪部上皮細胞的屬性與特徵的了解，仍十分有限。本研究以兔子作為角膜幹細胞研究模型，來鑑定兔子輪部上皮組織，與羊膜上增生輪部上皮細胞的細胞生理特徵。在對p63、Ki-67、keratin 3、keratin 14、connexin 43、integrin 6/4與3/1等角膜上皮細胞分化標誌進行免疫染色鑑定後發現，在羊膜上自兔子角膜輪部上皮組織中增殖的底層（basal layer）上皮細胞，仍保有與輪部上皮底層細胞相似的特徵，而生長在羊膜上的上皮細胞具有更高的細胞活性，且該增生細胞組織中亦應富含輪部上皮幹細胞的存在，因此確認羊膜具有保存與增生輪部上皮幹細胞的能力。（相關結果已發表於2003年Invest. Ophthalmol. Visual Sci.期刊第44卷第4698-4704頁）。由即時定量RT-PCR分析不同眼表組織中TAp63與Np63蛋白的表現，以及利用antisense oligonucleotides阻擋活體培養輪部上皮細胞TAp63與Np63的表現，發現在輪部上皮細胞中，TAp63與Np63蛋白可能扮演不同的角色，其中TAp63與維持輪部上皮細胞保有分化潛力但為進入最終分化路徑有關，而Np63則與維持輪部上皮幹細胞的細胞分裂能力，或是促使輪部上皮幹細胞進入最終分化路徑有關（相關結果將發表於2005年Invest. Ophthalmol. Visual Sci.期刊）。比較TAp63與Np63蛋白在兔子角膜的表現與該處上皮組織分化程度，發現兔子角膜在不同輪部區域的上皮組織，呈現出在p63表現量越低的區域其K3的表現量越高的現象，而將不同p63表現量的輪部組織置於羊膜上培養，亦發現與在羊膜上上皮細胞的生長能力亦有密切關連，顯示在活體角膜上皮組織中p63蛋白表現，仍與該處上皮組織進行最終分化與否具有密切關連。因此，p63蛋白即便無法作為角膜輪部上皮幹細胞的專一性細胞標誌，但由其影響上皮細胞分裂與分化之能力，仍可證實其在角膜輪部上皮幹細胞的生長分化，以及維持角膜組織之恆定性方面，扮演重要之角色。

Severe damage to the limbal epithelium due to chemical/thermal burns, virus infection and other pathological events may lead to loss of the limbal epithelial stem cells. Limbal epithelial stem cell deficiency lead to chronic inflammation and vascular invasion of the cornea eventually and cause functional blindness. The autologous and allogenic transplantation of limbal epithelial cells expanded on human amniotic membrane have been introduced to improve the outcome of ocular surface reconstruction in limbal deficient eyes. However, the identification of limbal stem cells and the incorporation of sufficient number of these cells in the bio-engineered corneal tissue remain to be explored. In this study, we employ the cell biological and molecular biological means to identify the characteristics of rabbit limbal epithelial stem cells in normal limbus and in epithelial sheet outgrown from limbal explant cultured on amniotic membrane. The immunofluorescent staining and confocal microscopy were used to examine the expressions of p63, Ki-67, keratins 3 and 14, connexin 43, and integrin 6/4 and  subunits in corneal and limbal tissues, and in limbal explant and its epithelial outgrowth cultured for two weeks on amniotic membrane. Preliminary results showed that the epithelial cell sheet outgrown from limbal explant on amniotic membrane exhibits a phenotype similar to that of the limbus. These results suggested that amniotic membrane is a substrate capable of supporting the propagation and preservation of p63-positive limbal epithelial cells (published in Invest. Ophthalmol. Visual Sci. 2003;44:4698-4704). The real-time Q-RT-PCR was employed to quantify the relative abundance of TAp63 and Np63 transcripts in limbal, peripheral corneal and central corneal epithelia. Antisense oligonucleotides were designed to specifically suppress the expression of TAp63 or Np63 in limbal keratinocytes and their effects on cell proliferation and differentiation were examined. The expressions of TAp63 and Np63 transcripts appeared to be site specific; TAp63 was expressed at the highest level in limbus, decreased in peripheral cornea and was undetectable in the central cornea. Np63 was also expressed at the highest level in limbus, decreased in peripheral cornea and was undetectable in the central cornea. Suppression of TAp63 expression inhibited limbal keratinocyte proliferation but promote differentiation. Suppression of Np63 expression also inhibited cell proliferation but had no obvious effect on cell differentiation. These suggested that TAp63 and Np63 affect the proliferation of limbal keratinocytes by a different mechanism (published in Invest. Ophthalmol. Visual Sci. 2005). We also compared the p63 expression pattern and differentiation levels in different rabbit limbal quadrates. We found that the superior limbal quadrate exhibited the highest level of p63 expression and was characterized by lowest differentiation level. In contrast, the inferior limbal quadrate exhibited very low or undetectable levels of p63 expression and was characterized with terminal differentiation. The ex vivo AM-based epithelial explant culture also showed that the explant from superior limbus has the greatest epithelial outgrowth activity than the cells from other limbal quadrates. Taken together, our results suggested that p63 is not a specific marker of corneal epithelial stem cells. However, different p63 isoforms still play specific roles in maintaining stem cell functions and the entrance to terminal differentiation lineage of corneal epithelial keratinocytes.

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