中文信息

肺再生修复与纤维化

课题组长

姓名：

席莹助理教授研究员博士生导师, PhD, 助理教授

职务：

所在院所：

生命科学与技术学院

荣誉称号：

教育经历：

1999/09—2003/07，南京大学，学士
2004/09—2010/03，中科院上海生物化学与细胞生物学研究所，博士

博士后及工作经历：

2010/12—2016/07，美国加州大学旧金山分校(UCSF)，医学院，博士后
2016/07—2019/08，美国基因泰克公司(Genentech)，免疫系，高级研究员
2019/09—至今，上海科技大学，生命科学与技术学院，助理教授（TENURE-TRACK）

课题组简介

研究方向：

肺干细胞，组织再生，呼吸系统疾病

研究内容：

多种急慢性呼吸系统疾病发生严重的弥漫性肺泡损伤，急性损伤如流感病毒和新型冠状病毒感染，慢性损伤如肺纤维化等。目前这些疾病都缺乏有效的治疗手段。我们课题组聚焦肺泡上皮的损伤修复过程，利用小鼠肺损伤模型、谱系特异性基因敲除小鼠和类器官培养系统，结合单细胞测序和生物信息学分析等手段，深入研究肺上皮干细胞的命运决定，旨在重建受损的肺泡上皮屏障，恢复气体交换功能，以期为肺纤维化及其他急慢性肺上皮损伤导致的疾病提供新的治疗靶点和治疗手段。

课题组网站：

研究成果展示

1）鉴定新型肺干细胞

利用单细胞测序、干细胞移植、谱系示踪和小鼠肺损伤模型，鉴定了一种新型干/祖细胞——谱系阴性的上皮干/祖细胞（lineage-negative epithelial stem/ progenitors，LNEP），位于远端气道，具有肺泡和气管的分化潜能，并揭示了决定LNEP 分化命运和肺泡上皮损伤修复的关键调控机制——缺氧/Notch 和Wnt 信号的平衡（Nature 2015, Nature Cell Biology 2017)。我们发现肺严重损伤后的缺氧环境激活Notch信号，促使LNEP 增殖、分化产生基底样细胞，导致肺泡上皮的异常修复。这种异常修复的机制也存在于多种肺疾病组织中，包括肺纤维化、流感感染及急性呼吸窘迫综合症。目前我们聚焦肺泡上皮的异常修复机制，探索促进肺泡再生的调控手段，并研究其对纤维化及其他肺损伤疾病治疗的意义。

图1，肺泡修复再生的调控机制

2）开发促进肺泡再生、治疗肺纤维化的新方法

我们利用RNA编辑系统CRISPR/CasRx敲低β-Catenin降解复合物中的骨架蛋白Axin，激活Wnt/β-Catenin信号通路。编辑元件由AAV6载体，通过气管插管的方式特异性地递送到肺上皮细胞，激活肺上皮细胞中的Wnt/β-Catenin信号通路，而不影响其他细胞类型。结果表明，上皮细胞中特异的Wnt/β-Catenin信号通路激活不仅促进了肺泡再生，还能在预防性和治疗性模型中抑制博莱霉素诱导的小鼠肺纤维化（Molecular Therapy, 2024) (图2）。该研究第一次证明了促进肺泡干细胞增殖可以有效治疗肺纤维化，为肺纤维化疾病提供了一种新的潜在治疗手段。

图2，CasRx介导的Wnt信号激活促进肺泡再生并抑制肺纤维化

图3，实验室常用研究手段

代表性论文（*第一作者，#通讯作者）

1. Xi Y(席莹)*; Tiffany Horng^#; .A case of too much sugar: Lung DCs flummoxed by flu.IMMUNITY. 13 Feb 2024.
2. Ma, Hsiao-Yen*; Vander Heiden, Jason A.; Uttarwar, Salil; Xi, Ying; N'Diaye, Elsa-Noah; LaCanna, Ryan; Caplazi, Patrick; Gierke, Sarah; Moffat, John; Wolters, Paul J.; Ding, Ning^#; .Inhibition of MRTF activation as a clinically achievable anti-fibrotic mechanism for Pirfenidone.EUR RESPIR J. 30 Dec 2022. 61(4).
3. Xi, Ying*; LaCanna, Ryan; Ma, Hsiao-Yen; N'Diaye, Elsa-Noah; Gierke, Sarah; Caplazi, Patrick; Sagolla, Meredith; Huang, Zhiyu; Lucio, Laura; Arlantico, Alexander; Jeet, Surinder; Brightbill, Hans; Emson, Claire; Wong, Aaron; Morshead, Katrina B.; DePianto, Daryle J.; Roose-Girma, Merone; Yu, Charles; Tam, Lucinda; Jia, Guiquan; Ramalingam, Thirumalai R.; Marsters, Scot; Ashkenazi, Avi; Kim, Si Hyun; Kelly, Ryan; Wu, Shuang; Wolters, Paul J.; Feldstein, Ariel E.; Heiden, Jason A. Vander; Ding, Ning^#; .A WISP1 antibody inhibits MRTF signaling to prevent the progression of established liver fibrosis.CELL METABOLISM. 2022. 34(9):1377-+.
4. Zhang, Dan*; Liu, Yutong; Zhu, Yezhang; Zhang, Qian; Guan, Hongxing; Liu, Shengduo; Chen, Shasha; Mei, Chen; Chen, Chen; Liao, Zhiyong; Xi, Ying; Ouyang, Songying; Feng, Xin-Hua; Liang, Tingbo^#; Shen, Li^#; Xu, Pinglong^#; .A non-canonical cGAS-STING-PERK pathway facilitates the translational program critical for senescence and organ fibrosis.NATURE CELL BIOLOGY. May 2022.
5. Lu, Tiantian*; Cao, Yiyuan; Zhao, Peng; Shen, Shengxi; Xi, Ying^#; .Organoid: a powerful tool to study lung regeneration and disease.CELL REGENERATION. 26 Apr 2021.
6. Xi, Ying*; Kim, Thomas; Brumwell, Alexis N.; Driver, Ian H.; Wei, Ying; Tan, Victor; Jackson, Julia R.; Xu, Jianming; Lee, Dong-Kee; Gotts, Jeffrey E.; Matthay, Michael A.; Shannon, John M.; Chapman, Harold A.^#; Vaughan, Andrew E.; .Local lung hypoxia determines epithelial fate decisions during alveolar regeneration.NATURE CELL BIOLOGY. 2017. 19(8):904-14.
7. Kanegai, Cindy M.^#*; Xi, Ying; Donne, Matthew L.; Gotts, Jeffrey E.; Driver, Ian H.; Amidzic, Gorica; Lechner, Andrew J.; Jones, Kirk D.; Vaughan, Andrew E.; Chapman, Harold A.; Rock, Jason R.; .Persistent Pathology in Influenza-Infected Mouse Lungs.AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY. 2016. 55(4):613-615.
8. Vaughan, Andrew E.^#*; Brumwell, Alexis N.; Xi, Ying; Gotts, Jeffrey E.; Brownfield, Doug G.; Treutlein, Barbara; Tan, Kevin; Tan, Victor; Liu, Feng Chun; Looney, Mark R.; Matthay, Michael A.; Rock, Jason R.; Chapman, Harold A.^#; .Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury.NATURE. 2015. 517(7536):621-5.
9. Xu, Pinglong^#*; Bailey-Bucktrout, Samantha; Xi, Ying; Xu, Daqi; Du, Dan; Zhang, Qian; Xiang, Weiwen; Liu, Jianming; Melton, Andrew; Sheppard, Dean; Chapman, Harold A.; Bluestone, Jeffrey A.; Derynck, Rik^#; .Innate Antiviral Host Defense Attenuates TGF-beta Function through IRF3-Mediated Suppression of Smad Signaling.MOLECULAR CELL. 2014. 56(6):723-737.
10. Xi, Ying*; Tan, Kevin; Brumwell, Alexis N.; Chen, Steven C.; Kim, Yong-Hyun; Kim, Thomas J.; Wei, Ying; Chapman, Harold A.^#; .Inhibition of Epithelial-to-Mesenchymal Transition and Pulmonary Fibrosis by Methacycline.AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY. 2014. 50(1):51-60.
11. Xi, Y.*; Wei, Y.^#*; Sennino, B.; Ulsamer, A.; Kwan, I.; Brumwell, A. N.; Tan, K.; Aghi, M. K.; McDonald, D. M.; Jablons, D. M.; Chapman, H. A.^#; .Identification of pY654-beta-catenin as a critical co-factor in hypoxia-inducible factor-1 alpha signaling and tumor responses to hypoxia.ONCOGENE. 2013. 32(42):5048-5057.
12. Ulsamer, Arnau*; Wei, Ying; Kim, Kevin K.; Tan, Kevin; Wheeler, Sarah; Xi, Ying; Thies, R. Scott; Chapman, Harold A.^#; .Axin Pathway Activity Regulates in Vivo pY654-beta-catenin Accumulation and Pulmonary Fibrosis.JOURNAL OF BIOLOGICAL CHEMISTRY. 2012. 287(7):5164-5172.
13. Chen, Ting*; Li, Meng*; Ding, Yu; Zhang, Le-shuai; Xi, Ying; Pan, Wei-jun; Tao, Dong-lei; Wang, Ji-yong; Li, Lin^#; .Identification of Zinc-finger BED Domain-containing 3 (Zbed3) as a Novel Axin-interacting Protein That Activates Wnt/beta-Catenin Signaling.JOURNAL OF BIOLOGICAL CHEMISTRY. 2009. 284(11):6683-6689.
14. Ding, Yu*; Xi, Ying*; Chen, Ting; Wang, Ji-yong; Tao, Dong-lei; Wu, Zhi-li; Li, Yi-ping; Li, Chen; Zeng, Rong; Li, Lin^#; .Caprin-2 enhances canonical Wnt signaling through regulating LRP5/6 phosphorylation.JOURNAL OF CELL BIOLOGY. 2008. 182(5):865-872.
15. Gan, Xiao-qing*; Wang, Ji-yong*; Xi, Ying; Wu, Zhi-li; Li, Yi-ping; Li, Lin^#; .Nuclear Dvl, c-Jun, beta-catenin, and TCF form a complex leading to stabilization of beta-catenin-TCF interaction.JOURNAL OF CELL BIOLOGY. 2008. 180(6):187-11.