研究方向
1.腸道干細(xì)胞相關(guān)研究：潰瘍性結(jié)腸炎中腸道干細(xì)胞的病變相關(guān)研究；研究病理微環(huán)境中的細(xì)胞因子或微生物代謝產(chǎn)物對腸道干細(xì)胞以及腸上皮屏障功能的影響；腸道干細(xì)胞衰老研究。
2.肝臟相關(guān)研究：肝臟干細(xì)胞／膽管細(xì)胞在肝纖維化中的病理改變及其對發(fā)病機(jī)制的影響；肝臟干細(xì)胞移植的臨床轉(zhuǎn)化研究。
3.腫瘤相關(guān)研究：二維腫瘤細(xì)胞系和三維腫瘤類器官技術(shù)體系的精準(zhǔn)醫(yī)學(xué)轉(zhuǎn)化研究；開發(fā)、優(yōu)化預(yù)測原發(fā)腫瘤轉(zhuǎn)移目的器官的策略；開發(fā)優(yōu)化評估原發(fā)腫瘤轉(zhuǎn)移風(fēng)險(xiǎn)的策略。
4.藥物吸收模型：胃、腸道氣液界面類器官模型在藥物吸收模型方面的轉(zhuǎn)化應(yīng)用。
科學(xué)貢獻(xiàn)
王霞博士主要從事成體干細(xì)胞和人體疾病的研究工作，并取得了突出的研究成果。她們成功利用P63 基因敲除小鼠為模型，揭示了胚胎發(fā)育過程中殘留在鱗狀上皮／柱狀上皮交界處的一小部分特異細(xì)胞是巴瑞特氏食道腸化生的細(xì)胞來源。該機(jī)制對深入了解食道腺癌的細(xì)胞起源和特異性針對癌癥前體的早期診斷及其預(yù)防起到了重要作用。此項(xiàng)研究成果發(fā)表在國際頂級(jí)期刊Cell上。此外，王霞博士創(chuàng)建了一個(gè)體外培養(yǎng)腸道成體干細(xì)胞以及氣液界面類器官的技術(shù)平臺(tái)，利用這一技術(shù)，從單個(gè)腸上皮干細(xì)胞培養(yǎng)出的干細(xì)胞系在體外能長期保持良好的自我更新狀態(tài)和穩(wěn)定的多向分化潛能，還可以在氣液界面培養(yǎng)體系中定向分化成為包含多種細(xì)胞類型的三維立體的腸道上皮組織，并首次成功建立了假膜性結(jié)腸炎的疾病模型。這項(xiàng)技術(shù)是干細(xì)胞研究領(lǐng)域的重大突破，為人類成體干細(xì)胞及其相關(guān)疾病的研究提供了重要的基礎(chǔ)研究平臺(tái)，并在干細(xì)胞的臨床應(yīng)用和新型藥物開發(fā)方面具有重大的應(yīng)用價(jià)值和發(fā)展前景。此項(xiàng)研究結(jié)果發(fā)表在國際頂級(jí)期刊Nature上。
此外，王霞博士領(lǐng)導(dǎo)的科研團(tuán)隊(duì)創(chuàng)建了高效穩(wěn)定的二維腫瘤細(xì)胞系和三維腫瘤類器官技術(shù)平臺(tái)（Zhao et al., Advanced Science, 2022）。該技術(shù)平臺(tái)體現(xiàn)了二維腫瘤細(xì)胞系和三維腫瘤類器官的雙重優(yōu)勢，不僅精準(zhǔn)地再現(xiàn)了原發(fā)性腫瘤的特征，更成功地捕捉到了腫瘤間和腫瘤內(nèi)藥物反應(yīng)及致瘤性的異質(zhì)性。該平臺(tái)可用于構(gòu)建腫瘤類器官庫，作為藥物篩選平臺(tái)，開展腫瘤類器官的臨床試驗(yàn)，能夠給腫瘤患者提供個(gè)性化的藥物敏感性預(yù)判，并可以促進(jìn)實(shí)現(xiàn)腫瘤個(gè)性化和精準(zhǔn)醫(yī)療。在此技術(shù)體系基礎(chǔ)上，王霞課題組及其合作團(tuán)隊(duì)成功從結(jié)直腸癌患者的原發(fā)腫瘤組織中建立了單個(gè)腫瘤細(xì)胞來源的腫瘤細(xì)胞系，鑒定了原發(fā)腫瘤組織中的轉(zhuǎn)移種子。全面系統(tǒng)地描繪了結(jié)直腸癌原發(fā)腫瘤組織中轉(zhuǎn)移種子的細(xì)胞、分子生物學(xué)特征，揭示了其轉(zhuǎn)移目的器官特異性的分子機(jī)制。同時(shí)，還鑒定了一組可用于預(yù)測和評估原發(fā)結(jié)直腸癌腫瘤轉(zhuǎn)移風(fēng)險(xiǎn)的標(biāo)志基因（Zhao et al., Journal of Experimental Medicine, 2024）。這項(xiàng)研究不僅為腫瘤轉(zhuǎn)移機(jī)制的研究開辟了新的領(lǐng)域，也為未來癌癥治療提供了新的策略和方向。
研究成果
1.2D腸道干細(xì)胞和3D氣液界面類器官培養(yǎng)體系
圖1：腸道干細(xì)胞氣液界面類器官技術(shù)體系示意圖（Wang et al., Nature, 2015）
2.二維腫瘤細(xì)胞系和三維腫瘤類器官技術(shù)平臺(tái)
圖2：二維腫瘤細(xì)胞系和三維腫瘤類器官技術(shù)平臺(tái)示意圖（Zhao et al., Advanced Science, 2022）
3.精準(zhǔn)醫(yī)療的新靶向——原發(fā)腫瘤中的轉(zhuǎn)移種子
圖3. 系統(tǒng)探究結(jié)直腸癌原發(fā)腫瘤中的轉(zhuǎn)移種子 (Zhao et al., JEM, 2024）
榮譽(yù)和獎(jiǎng)項(xiàng)
拜耳青年研究員獎(jiǎng)，清華大學(xué)，2018
拜耳青年研究員獎(jiǎng)，清華大學(xué)，2017
國家級(jí)人才項(xiàng)目青年人才，2016
哈佛華人生命科學(xué)年度杰出研究獎(jiǎng)，哈佛醫(yī)學(xué)院，2012
優(yōu)秀論文獎(jiǎng)，中科院分子發(fā)育生物學(xué)重點(diǎn)實(shí)驗(yàn)室， 2009
朱李月華優(yōu)秀博士生獎(jiǎng)，中國科學(xué)院遺傳與發(fā)育生物學(xué)研究所， 2009
優(yōu)秀畢業(yè)生，中國科學(xué)院遺傳與發(fā)育生物學(xué)研究所， 2009
中國科學(xué)院研究生獎(jiǎng)學(xué)金，中國科學(xué)院遺傳與發(fā)育生物學(xué)研究所，2005
代表性科研論文:
1. Yuanyuan Zhao#, Bing Zhang#, Yiming Ma#, Mengmeng Guo, Fuqiang Zhao, Jianan Chen, Bingzhi Wang, Hua Jin, Fulai Zhou, Jiawei Guan, Qian Zhao, Qian Liu*, Hongying Wang*, Fangqing Zhao*, Xia Wang*. Distinct molecular profiles drive multifaceted characteristics of colorectal cancer metastatic seeds. Journal of Experimental Medicine (2024 May 6;221(5):e20231359. doi: 10.1084/jem.20231359.)
2. Chuandong Liu#, Jie Li#, Hua Jin#, Qian Zhao#, Fangle Li, Zurui Huang, Boyuan Mei, Wenxuan Gong*, Xia Wang*, Dali Han*. Colonic stem cell from severe ulcerative colitis maintains environment-independent immune activation by altering chromatin accessibility and global m 6A loss. Life Medicine, 2023. 2 (4):1-14.
3. Yuanyuan Zhao#, Mengmeng Guo#, Fuqiang Zhao, Qian Liu and Xia Wang*. Colonic stem cells from normal tissues adjacent to tumor drive inflammation and fibrosis in colorectal cancer. Cell Communication and Signaling, 2023, 21:186.
4. Aging Biomarker Consortium, Hainan Bao#, Jiani Cao#, Mengting Chen#, Min Chen#, Wei Chen#, Xiao Chen#, Yanhao Chen#, Yu Chen#, Yutian Chen#, Zhiyang Chen#, Jagadish K. Chhetri#, Yingjie Ding#, Junlin Feng#, Jun Guo#, Mengmeng Guo#, Chuting He#, Yujuan Jia#, Haiping Jiang#, Ying Jing#, Dingfeng Li#, Jiaming Li#, Jingyi Li#, Qinhao Liang#, Rui Liang#, Feng Liu#, Xiaoqian Liu#, Zuojun Liu#, Oscar Junhong Luo#, Jianwei Lv#, Jingyi Ma#, Kehang Mao#, Jiawei Nie#, Xinhua Qiao#, Xinpei Sun#, Xiaoqiang Tang#, Jianfang Wang#, Qiaoran Wang#, Siyuan Wang#, Xuan Wang#, Yaning Wang#, Yuhan Wang#, Rimo Wu#, Kai Xia#, Fu-Hui Xiao#, Lingyan Xu#, Yingying Xu#, Haoteng Yan#, Liang Yang#, Ruici Yang#, Yuanxin Yang#, Yilin Ying#, Le Zhang#, Weiwei Zhang#, Wenwan Zhang#, Xing Zhang#, Zhuo Zhang#, Min Zhou#, Rui Zhou#, Qingchen Zhu#, Zhengmao Zhu#, Feng Cao*, Zhongwei Cao*, Piu Chan*, Chang Chen*, Guobing Chen*, Hou-Zao Chen*, Jun Chen*, Weimin Ci*, Bi-Sen Ding*, Qiurong Ding*, Feng Gao*, Jing-Dong J. Han*, Kai Huang*, Zhenyu Ju*, Qing-Peng Kong*, Ji Li*, Jian Li*, Xin Li*, Baohua Liu*, Feng Liu*, Lin Liu*, Qiang Liu*, Qiang Liu*, Xingguo Liu*, Yong Liu*, Xianghang Luo*, Shuai Ma*, Xinran Ma*, Zhiyong Mao*, Jing Nie*, Yaojin Peng*, Jing Qu*, Jie Ren*, Ruibao Ren*, Moshi Song*, Zhou Songyang*, Yi Eve Sun*, Yu Sun*, Mei Tian*, Shusen Wang*, Si Wang*, Xia Wang*, Xiaoning Wang*, Yan-Jiang Wang*, Yunfang Wang*, Catherine C. L. Wong*, Andy Peng Xiang*, Yichuan Xiao*, Zhengwei Xie*, Daichao Xu*, Jing Ye*, Rui Yue*, Cuntai Zhang*, Hongbo Zhang*, Liang Zhang*, Weiqi Zhang*, Yong Zhang*, Yun-Wu Zhang*, Zhuohua Zhang*, Tongbiao Zhao*, Yuzheng Zhao*, Dahai Zhu*, Weiguo Zou*, Gang Pei* & Guang-Hui Liu*. Biomarkers of aging. Science China Life Sciences. 2023. 66: 893-1066.
5. Yuanyuan Zhao#, Bing Zhang#, Yiming Ma, Fuqiang Zhao, Jianan Chen, Bingzhi Wang, Hua Jin, Fulai Zhou, Jiawei Guan, Qian Zhao, Hongying Wang, Qian Liu*, Fangqing Zhao*, Xia Wang*. Colorectal cancer patient-derived 2D and 3D models efficiently recapitulate inter- and intra-tumoral heterogeneity. Advanced Science. 2022 (DOI: 10.1002/advs.202201539)
6. Qian Zhao#, Jiawei Guan, Xia Wang*. Intestinal stem cells and intestinal organoids. Journal of Genetics and Genomics. 2020. 47(6):289-299. (Review)
7. Yamamoto Y*, Wang X*(*Co-first authors), Bertrand D, Kern F, Zhang T, Deluba M, Srivastava S, Khor CC, Hu YY, Wilson L, Blaszyk H, Rolshud D, Ming T,Liu JJ, Howitt B, Vincent M, Crum CP, Nagarajan N, Ho KY, McKeon F, and Xian W. Mutational spectrum of Barrett’s stem cells suggests paths to initiation of a precancerous lesion. Nature Communications. 2016. doi: 10.1038/ncomms10380.
8. Wang X*, Yamamoto Y*(*Co-first authors), Wilson LH, Zhang T, Howitt B, Ning G, Hong Y, Khor CC, Chevalier B, Bertrand D, Nagarajan N, Sylvester FA, Farrow MA, Lacy DB, Ho KY, Crum CP, McKeon F and Xian W. Cloning and variation of ground state intestinal stem cells. Nature. 2015. 522(7555):173-178.
9. Wang X*, Ouyang H*, Yamamoto Y*, (*Co-first authors), Kumar PA, Wei TS, Dagher R, Vincent M, Lu X, Bellizzi AM, Ho KY, Crum CP, Xian W, McKeon F. Residual embryonic cells as precursors of a Barrett's-like metaplasia. Cell. 2011. 145(7):1023-35. Featured Article in Cell. Highlighted in Nature Reviews Cancer. Faculty 1000 Biology: 10 (Exceptional).
10. Wang, X and Dai, J. Isoforms of OCT4 contribute to the confusing diversity in stem cell biology. Stem Cells. 2010. 28(5):885-93. (Invited Review)
11. Gao, Y., Wang, X. *(* Co-first authors), Han, J., Xiao, Z., Chen, B., Su, G., Dai, J. The novel OCT4 spliced variant OCT4B1 can generate three protein isoforms by alternative splicing into OCT4B. J Genet Genomics. 2010. 37(7):461-5
12. Zhang, J., Wang, X. *(* Co-first authors), Chen, B., Xiao, Z., Li, W., Lu, Y. and Dai, J. The human pluripotency gene NANOG/NANOGP8 is expressed in gastric cancer and associated with tumor development. Oncology Letters. 2010. 1(3):457-463.
13. Wang, X., Zhao, Y., Xiao, Z., Chen, B., Wei, Z., Wang, B., Zhang, J., Han, J., Gao, Y., Li, L., Zhao, H., Zhao, W., Lin, H. and Dai, J. Alternative translation of OCT4 by an internal ribosome entry site and its novel function in stress response. Stem Cells. 2009. 27(6):1265-75.
14. Zhang, J.*, Wang, X.* (* Co-first authors), Han, J., Chen, B., Wang, B., Suo, G. and Dai J. NANOGP8 is a retrogene expressed in cancers. FEBS Journal. 2006. 273(8): 1723-30.
