课题组成员：
教授: 李炜
博士后：何昕，欧尚坤，王守碧，张敏杰
实验师：宗荣荣
实验助理：何卉，郭子涵
研究生：郭俞利，刘小东，刘彦博，吴涵，林斯婕，庄净斌，Mohammad Alzogool，何协舟，吴益明，宋淑琳，张圣鹏，蔡敏清，赵健凯，林丽宏，张玲瑜，杨明轩
Tel: 0592-2183761
E-mail: wei1018@xmu.edu.cn
主要研究领域：
角膜上皮干细胞研究方向
角膜上皮干细胞（Corneal epithelial stem cell），亦即角膜缘干细胞，位于角膜缘上皮基底部，它们是角膜上皮的唯一细胞来源。一定数量的角膜上皮干细胞对维持角膜上皮的动态稳定和角膜组织的透明性发挥极其重要的作用。严重眼表面疾病如眼瘢痕性类天疱疮、Stevens-Johnson综合征、眼部酸碱化学伤及热烧伤、严重干眼症等常导致角膜上皮干细胞部分或全部缺失，眼表组织广泛破坏，发生持续性角膜上皮缺损、慢性炎症、角膜上皮结膜化和新生血管侵入，引起角膜透明度下降，造成患者严重视力障碍甚至失明。
严重角膜上皮干细胞缺乏患者的治疗往往非常困难，角膜上皮干细胞移植是此类患者重建眼表面的必要手段，也是此类患者复明的关键。为了获得足够量的角膜上皮干细胞进行移植，往往需要对供体细胞进行体外扩增。近年来，不同的研究小组发展了不同的方法用于体外扩增角膜缘干细胞，但至今仍然没有形成一个标准化的稳定的体外培养扩增方法。本研究小组在国家重大科学研究计划（973）项目、国家自然科学基金以及福建省自然科学基金等项目资助下，对角膜上皮干细胞增殖与分化的调控机制进行了深入研究，在此基础上优化角膜上皮干细胞的体外扩增方法，以期提高角膜上皮干细胞移植的成功率。我们建立了大鼠角膜上皮干细胞缺乏动物模型，旨在阐明以干细胞缺乏为特征的严重眼表疾病的发病机理。我们还应用体外与体内模型探讨微环境对角膜上皮干细胞的调控作用，以期从改善微环境角度治疗部分干细胞缺乏，并在体外模拟干细胞微环境，增强体外干细胞扩增效果。
羊膜相关的组织工程研究方向
羊膜 (Amniotic membrane) 是包在胚体外的第一层胎膜，来源于羊膜腔顶部的细胞滋养层，其组织结构可分为上皮层，基底膜层，以及基质层。羊膜因为其特殊的生物学特性和很弱的免疫原性，近10余年来在眼科及其它组织工程领域得到广泛应用。在眼科，羊膜组织主要用于眼表与角膜疾病的治疗。大量的临床应用研究发现羊膜具有抗炎症、抗疤痕形成、抗新生血管，以及促进眼表面上皮损伤愈合作用。本课题组具有长时间的羊膜研究背景，在既往的研究中，从细胞生物学和分子生物学层面系统研究了羊膜组织应用于治疗眼表面疾病的作用机理，在很大程度上加深了我们对羊膜这一特殊人体组织在眼科领域及组织工程领域应用机理的认识。现在，我们的研究在国家自然科学基金和福建省自然科学基金资助下，致力于推动羊膜在不同医学学科的应用，探索羊膜新的适应症范围，并积极开发与羊膜相关的组织工程产品。
眼表鳞状上皮化生研究方向
鳞状上皮化生（Squamous metaplasia）是一种由分泌型非角化复层上皮转变为非分泌型角化鳞状上皮的病理过程，是机体对慢性刺激、慢性炎症、病毒感染以及维生素A缺乏等的一种适应性反应，常发生在上皮组织，包括角结膜、气管和支气管、肾盂、胆囊及宫颈等组织的粘膜上皮。病理学上认为鳞状化生是一种癌前病变。鳞状上皮化生见于多种严重眼表面疾病，如酸碱化学烧伤、热烧伤、先天性无虹膜、Sjögren’s 综合征、Stevens-Johnson 综合征、眼瘢痕性类天疱疮等，严重危及视力甚至致盲。鳞状上皮化生与角膜缘干细胞缺乏一起被认为是眼表面衰竭的两种主要类型。目前，除维生素A缺乏引起者之外，还没有针对其它原因引起的眼表鳞状上皮化生的有效治疗方法。
本研究小组建立了角膜、结膜鳞状上皮化生的体外组织培养模型，在国家自然科学基金项目资助下，对鳞状上皮化生的分子机制进行深入研究，重点探讨Notch，Wnt，P38 MAPK，TGF-beta等信号通路在鳞状上皮化生中的作用，并发展出了多种针对眼表面鳞状上皮化生的治疗方法。
代表性论文：
1.Mao Y, Ou S, Zhu C, Lin S, Liu X, Liang M, Yu J, Wu Y, He H, Zong R, Lin Z, Liu Z, Li W. Downregulation of p38 MAPK signaling pathway ameliorates tissue engineered corneal epithelium. Tissue Eng Part A. 2022 Sep 6.
2.Yu JW, Wu YM, Dai QX, Wu H, Pan JT, Guo YL, Yan K, Zhu HM , Mao Y , Lin SJ, Li W, Liu G , Chu CC.In vivo assembly drug delivery strategy based on ultra-small nanoparticles: Toward high drug permeation and accumulation for CNV treatment. Chemical Engineering Journal.2022 Jul 8；450（1）
3.Zhao Z, Liang M, He H,Wang X, Zhu C, Li L, Liu B, Zong R, Jin Q, Wu H, Li W, Lin Z. Ovalbumin-Induced Allergic Inflammation Diminishes Cross-Linked Collagen Structures in an Experimental Rabbit Model of Corneal Cross-Linking.Front Med (Lausanne). 2022 May 26;9:762730.
4.Li S, Tang L, Zhou J, Anchouche S, Li D, Yang Y, Liu Z, Wu J, Hu J, Zhou Y, Yin J, Liu Z, Li W. Sleep deprivation induces corneal epithelial progenitor cell over-expansion through disruption of redox homeostasis in the tear film. Stem Cell Reports. 2022 May 10;17(5):1105-1119.
5.Yu Z, Hao R, Du J, Wu X, Chen X, Zhang Y, Li W, Gu Z, Yang H.A human cornea-on-a-chip for the study of epithelial wound healing by extracellular vesicles.iScience. 2022 Apr 4;25(5):104200.
6.He X, Wang S, Sun H, He H, Shi Y, Wu Y, Wu H, Liu Z, Zhuang J, Li W. Lacrimal Gland Microenvironment Changes After Obstruction of Lacrimal Gland Ducts. Invest Ophthalmol Vis Sci. 2022 Mar 2;63(3):14.
7.Wang S, He X, Li Q, Zhang Y, Hu J, Zong R, Zhuang J, Quantock AJ, Gao Y, Li W, Liu Z. Obstructive Sleep Apnea Affects Lacrimal Gland Function. Invest Ophthalmol Vis Sci. 2022 Mar 2;63(3):3.
8.Guo Y, Zhang H, Zhao Z, Luo X , Zhang M, Bu J, Liang M, Wu H , Yu J, He H, Zong R, Chen Y, Liu Z, Li W. Hyperglycemia Induces Meibomian Gland Dysfunction. Invest Ophthalmol Vis Sci. 2022 Jan 3;63(1):30.
9.Bu J, Zhang M, Wu Y, Jiang N, Guo Y, He X, He H, Jeyalatha MV, Reinach PS, Liu Z, Li W. High-Fat Diet Induces Inflammation of Meibomian Gland. Invest Ophthalmol Vis Sci. 2021 Aug 2;62(10):13.
10.Liu Z, Xiu Y, Qiu F, Zhu Z, Zong R, Zhou X, An J, Wang Q, Reinach PS, Li W, Chen W, Liu Z. Canonical Wnt signaling drives myopia development and can be pharmacologically modulated. Invest Ophthalmol Vis Sci. 2021 Jul 1;62(9):21.
11.Cheng X, He D, Liao C, Lin S, Tang L, Wang YL, Hu J, Li W, Liu Z, Wu Y, Liao Y. IL-1/IL-1R signaling induced by all-trans-retinal contributes to complement alternative pathway activation in retinal pigment epithelium. J Cell Physiol. 2021 May;236(5):3660-3674.
12.Li D, Dai Q, Chen H, Lin H , Lu Z, Zheng H ,Peng Lv , Li W , Liu G ,Chu C.Metal-organic nanostructure based on TixOy/Ruthenium reaction Units: For CT/MR Imaging-Guided X-ray induced dynamic therapy. Chem Eng J.2021 Mar;417:129262.
13.Yu J, Chu C, Wu Y, Liu G, Li W.The phototherapy toward corneal neovascularization elimination:An efficient, selective and safe strategy. Chinese Chem Lett.2020 Nov;32(1):99-101.
14.Lin X, Wu Y, Tang L, Ouyang W, Yang Y, Liu Z, Wu J, Zheng X, Huang C, Zhou Y, Zhang X, Chen Y, Li W, Hu J, Liu Z. Comparison of treatment effect and tolerance of the topical application of mizoribine and cyclosporine a in a mouse dry eye model. Transl Vis Sci Technol. 2020 Dec 15;9(13):22.
15.He X, Zhao Z, Wang S, Kang J, Zhang M, Bu J, Cai X, Jia C, Li Y, Li K, Reinach PS, Quantock AJ, Liu Z, Li W. High-fat diet-induced functional and pathologic changes in lacrimal gland. Am J Pathol. 2020 Dec; 190(12): 2387-2402.
16.He J, Ou S, Ren J, Sun H, He X, Zhao Z, Wu H, Qu Y, Liu T, Jeyalatha V, Zhang L, Li Q, Reinach PS, Quantock AJ, Hao J, Liu Z, Li W. Tissue engineered corneal epithelium derived from clinical-grade human embryonic stem cells. Ocul Surf. 2020 Oct;18(4):672-680.
17.Chu C,* Yu J, Ren E, Ou S, Zhang Y, Wu Y, Wu H, Zhang Y, Zhu J, Dai Q, Wang X, Zhao Q, Li W,* Liu Z, Chen X, Liu G*. Multimodal Photoacoustic Imaging-Guided Regression of Corneal Neovascularization: A Non-Invasive and Safe Strategy. Adv. Sci. 2020 May 29;7(14):2000346.
18.Wu Y, Wu J, Bu J, Tang L, Yang Y, Ouyang W, Lin X, Liu Z, Huang C, Quantock AJ, Ma X, Li W, Zhou Y, Liu Z. High-fat diet induces dry eye-like ocular surface damages in murine. Ocul Surf. 2020 Apr;18(2):267-276.
19.Bu J, Yu J, Wu Y, Cai X, Li K, Tang L, Jiang N, Jeyalatha MV, Zhang M, Sun H, He H, Quantock AJ, Chen Y, Liu Z, Li W. Hyperlipidemia Affects Tight Junctions and Pump Function in the Corneal Endothelium. Am J Pathol. 2020 Mar;190(3):563-576.
20.Han Y, Jiang N, Su T, Yang QC, Yan CC, Ye L, Yuan Q, Zhu PW, Li W, Liu ZG, Shao Y. Netrin-1 promotes epithelium repair in corneal injury. Int J Ophthalmol. 2020 Feb 18;13(2):206-212.
21.Bu J, Wu Y, Cai X, Jiang N, Jeyalatha MV, Yu J, He X, He H, Guo Y, Zhang M, Quantock AJ, Liu Z, Li W. Hyperlipidemia induces meibomian gland dysfunction. Ocul Surf. 2019 Jun 12. 17(4):777-786.
22.Li Y, Jin R, Li L, Yoon HJ, Choi JH, Park JH, Liu Z, Li W, Li Z, Yoon KC. Expression and Role of Nucleotide-Binding Oligomerization Domain 2 (NOD2) in the Ocular Surface of Murine Dry Eye. Invest Ophthalmol Vis Sci. 2019 Jun 3;60(7):2641-2649.
23.Che X, Wu H, Jia C, Sun H, Ou S, Wang J, Jeyalatha MV, He X, Yu J, Zuo C, Liu Z, Li W. A Novel Tissue-Engineered Corneal Stromal Equivalent Based on Amniotic Membrane and Keratocytes. Invest Ophthalmol Vis Sci. 2019 Feb 1;60(2):517-527.
24.Chu C, Ren E, Zhang Y, Yu J, Lin H, Pang X, Zhang Y, Liu H, Qin Z, Cheng Y, Wang X, Li W, Kong X, Chen X, Liu G. Zinc(II)-Dipicolylamine Coordination Nanotheranostics: Toward Synergistic Nanomedicine by Combined Photo/Gene Therapy. Angew Chem Int Ed Engl. 2019 Jan 2;58(1):269-272.
25.Tang L, Wang X, Wu J, Li SM, Zhang Z, Wu S, Su T, Lin Z, Chen X, Liao X, Bai T, Qiu Y, Reinach PS, Li W, Chen Y, Liu Z. Sleep Deprivation Induces Dry Eye Through Inhibition of PPARα Expression in Corneal Epithelium. Invest Ophthalmol Vis Sci. 2018 Nov 1;59(13):5494-5508.
26.Yang Y, Huang C, Lin X, Wu Y, Ouyang W, Tang L, Ye S, Wang Y, Li W, Zhang X, Liu Z. 0.005% Preservative-Free Latanoprost Induces Dry Eye-Like Ocular Surface Damage via Promotion of Inflammation in Mice. Invest Ophthalmol Vis Sci. 2018 Jul 2;59(8):3375-3384.
27.Jie J, Yang J, He H, Zheng J, Wang W, Zhang L, Li Z, Chen J, Vimalin Jeyalatha M, Dong N, Wu H, Liu Z, Li W. Tissue remodeling after ocular surface reconstruction with denuded amniotic membrane. Sci Rep. 2018 Apr 23;8(1):6400.
28.Li S, Ning K, Zhou J, Guo Y, Zhang H, Zhu Y, Zhang L, Jia C, Chen Y, Sol Reinach P, Liu Z, Li W. Sleep deprivation disrupts the lacrimal system and induces dry eye disease. Exp Mol Med. 2018 Mar 2;50(3):e451. doi: 10.1038/emm.2017.285.
29.Zhang X, Lin X, Liu Z, Wu Y, Yang Y, Ouyang W, Li W, Liu Z. Topical Application of Mizoribine Suppresses CD4+ T-cell-Mediated Pathogenesis in Murine Dry Eye. Invest Ophthalmol Vis Sci. 2017 Dec 1;58(14):6056-6064.
30.Wu Y, Bu J, Yang Y, Lin X, Cai X, Huang C, Zheng X, Ouyang W, Li W, Zhang X, Liu Z. Therapeutic Effect of MK2 Inhibitor on Experimental Murine Dry Eye. Invest Ophthalmol Vis Sci. 2017 Sep 1;58(11):4898-4907.
31.Jeyalatha MV, Qu Y, Liu Z, Ou S, He X, Bu J, Li S, Reinach PS, Liu Z, Li W. Function of meibomian gland: Contribution of proteins. Exp Eye Res. 2017 Oct;163:29-36.
32.Li S, Zhou J, Zhang L, Li J, Yu J, Ning K, Qu Y, He H, Chen Y, Reinach PS, Liu CY, Liu Z, Li W. Ectodysplasin A regulates epithelial barrier function through sonic hedgehog signalling pathway. J Cell Mol Med. 2018 Jan;22(1):230-240.
33.Chen J, Li Z, Zhang L, Ou S, Wang Y, He X, Zou D, Jia C, Hu Q, Yang S, Li X, Li J, Wang J, Sun H, Chen Y, Zhu YT, Tseng SCG, Liu Z, Li W. Descemet's Membrane Supports Corneal Endothelial Cell Regeneration in Rabbits. Sci Rep. 2017 Aug 1;7(1):6983.
34.Zhang X, M VJ, Qu Y, He X, Ou S, Bu J, Jia C, Wang J, Wu H, Liu Z, Li W. Dry Eye Management: Targeting the Ocular Surface Microenvironment. Int J Mol Sci. 2017 Jun 29;18(7).
35.Li S, Zhou J, Bu J, Ning K, Zhang L, Li J, Guo Y, He X, He H, Cai X, Chen Y, Reinach PS, Liu Z, Li W. Ectodysplasin A protein promotes corneal epithelial cell proliferation. J Biol Chem. 2017 Aug 11;292(32):13391-13401.
36.Wu H, Lin Z, Yang F, Fang X, Dong N, Luo S, Shang X, Li W, Liu Z. Meibomian Gland Dysfunction Correlates to the Tear Film Instability and Ocular Discomfort in Patients with Pterygium. Sci Rep. 2017 Mar 24;7:45115.
