实验室主要研究方向

人胚胎干细胞和人诱导多能干细胞是多能干细胞的两种主要来源，它们能分化为人体各种细胞类型。人多能干细胞结合定向分化技术在发育相关基础研究、细胞替代治疗、细胞疾病模型构建及药物筛选等方面具有广泛而重要的应用前景。我们实验室具有成熟的神经定向分化系统，可以将人多能干细胞靶向分化为神经上皮、区域性神经前体细胞、多种功能性神经元和胶质细胞。

1.人神经发育机制

聚焦人脑发育过程中，神经系统的原基，神经系统的区域特征和功能神经元及胶质细胞是如何逐步构建起来的，并最终形成人脑。我们建立了完善的神经定向分化平台，其可以在培养皿中模拟整个神经系统发育过程，包括神经外胚层的生成、区域化及神经或胶质再生。

2.神经系统疾病模型构建与应用

人多能干细胞的一个重要应用是可以在体外模拟疾病的产生，从而用于细胞模型的构建及药物筛选。我们实验室运用多能干细胞来构建神经胶质母细胞瘤（GBM）模型，以模拟GBM的产生过程，以及模拟特定神经遗传性疾病（如脊髓性肌萎缩症：SMA），来研究其发病机制及治疗方法。

3.细胞替代治疗

神经退行性疾病，如帕金森、癫痫症和阿尔兹海默症等是神经系统的重症疾病。针对这些疾病的治疗主要集中在护理与康复，疗效并不显著。基于细胞的替代治疗，重塑病损的神经环路是彻底缓解这些疾病的终极途径。人多能干细胞能定向分化为各类神经前体细胞(NPC)。在小鼠模型中，NPC移植被证实可以校正帕金森、癫痫症和阿尔兹海默症等疾病表型。因此，基于NPC的细胞替代治疗，正成为彻底缓解与治愈这些疾病的重要途径。

美高梅本科生院副院长;

美高梅特聘教授、博导;

国家重大科学研究计划（2012年）和国家重点研发计划（2018年）首席科学家；

上海市神经再生高校重点实验室负责人;

上海市优秀学术带头人;

入选上海市“浦江人才”计划、“曙光”计划、教育部“新世纪优秀人才”支持计划。

2020年杰青资助

1.Xiangjie Xu, Yanhua Du, Lin Ma, Shuwei Zhang, Lei Shi, Zhenyu Chen, Zhongshu Zhou, Yi Hui, Yang Liu, Yujiang Fang, Beibei Fan, Zhongliang Liu, Nan Li, Shanshan Zhou, Cizhong Jiang, Ling Liu and Xiaoqing Zhang*. Mapping germ-layer specification preventing genes in hPSCs via genome-scale CRISPR screening. iScience 2021.24, 101926.

2.Lei Shi, Wenjing Li, Yang Liu, Zhenyu Chen, Yi Hui, Pengcheng Hao, Xiangjie Xu, Shuwei Zhang, Hexi Feng, Bowen Zhang, Shanshan Zhou, Nan Li, Lei Xiao, Ling Liu, Lin Ma, Xiaoqing Zhang*. Generation of hypoimmunogenic human pluripotent stem cells via expression of membrane-bound and secreted β2m-HLA-G fusion proteins. Stem Cells. 2020 Nov;38(11):1423-1437.

3.Yiran Wang, Chongchong Xu, Lin Ma, Yongchao Mou, Bowen Zhang, Shanshan Zhou, Yue Tian, Jessica Trinh, Xiaoqing Zhang*, Xue-Jun Li*. Drug screening with human SMN2 reporter identifies SMN protein stabilizers to correct SMA pathology. Life Science Alliance. 2019. vol 2 ,no 2 ,e201800268 (*Co-Correspondence)

4.Lin Ma, Yiran Wang, Yi Hui, Yanhua Du, Zhenyu Chen, Hexi Feng, Shuwei Zhang, Nan Li, Jianren Song, Yujiang Fang, Xiangjie Xu, Lei Shi, Bowen Zhang, Jiayi Cheng, Shanshan Zhou, Ling Liu* and Xiaoqing Zhang*. Wnt / Notch pathway is essential for the maintenance and expansion of human medial ganglionic eminence progenitors. Stem Cell Reports, 2019.14; 12 (5):934-949.

5.Ling Liu, Zhenyu Chen, Xin Zhang, Shun Li, Yi Hui, Hexi Feng, Guohua Jin, Xiaohui Zhou and Xiaoqing Zhang*. Protection of ZIKV infection-induced neuropathy by abrogation of acute antiviral response in human neural progenitors. Cell Death and Differentiation. 2019 Apr 5. doi: 10.1038/ s41418-019-0324-7.

6.Zhenyu Chen# ; Xudong Ren# ; Xiangjie Xu# ; Xiaojie Zhang; Yi Hui; Zhongliang Liu; Ling Liu* ; Xiaoqing Zhang* . Genetic Engineering of HumanEmbryonic Stem Cells for Precise Cell Fate Tracing during Human Lineage Development, Stem Cell Reports, 2018.11.13, 11: 1~15. (*Co-Correspondence)

7.Fang Y, Liu Z, Chen Z, Xu Z, Xiao M, Yu Y, Zhang Y, Zhang X-B, Du Y, Jiang C, Zhao Y, Wang Y, Fan B, Terheyden-Keighley D, Liu Y, Shi L, Hui Y, Zhang X, Zhang B, Feng H, Ma L, Zhang Q, Jin G, Yang Y, Xiang B*, Liu L* and Zhang X-Q*. Smad5 acts as an intracellular pH messenger and maintains bioenergetic homoeostasis. Cell Research 2017, 27(9):1083-1099.

8.Du Y, Liu Z, Cao X, Chen X, Chen Z, Zhang X, Zhang X*, Jiang C*. Nucleosome eviction along with H3K9ac deposition enhances Sox2 binding during human neuroectodermal commitment. Cell Death Differ 2017, 24(6):1121-1131.

9.Li G, Jiapaer Z, Weng R, Hui Y, Jia W, Xi J, Wang G, Zhu S, Liu L, Zhang X*, Kang J*. Dysregulation of the SIRT1/OCT6 Axis Contributes to Environmental Stress-induced Neural Induction Defects. Stem Cell Reports 2017, 8(5):1270-1286.

10.Chi L, Fan B, Zhang K, Du Y, Liu Z, Fang Y, Chen Z, Ren X, Xu X, Jiang C, Li S, Ma L, Gao L*, Liu L*, Zhang X*. (2016) Targeted differentiation of regional ventral neuroprogenitors and related neuronal subtypes from human pluripotent stem cells. Stem Cell Reports. 7(5)：941-954.

11.Liu Z, Hui Y, Shi L, Chen Z, Xu X, Chi L, Fan B, Fang Y, Liu Y, Ma L, Wang Y, Xiao L, Zhang Q, Jin G*, Liu L*, Zhang X*. （2016）Efficient CRISPR/Cas9-mediated versatile, predictable, and donor-free gene knockout in human pluripotent stem cells. Stem Cell Reports. 7(3):496-507.

12.Chi L, Fan B, Feng D, Chen Z, Liu Z, Hui Y, Xu X, Ma L, Fang Y, Zhang Q, Jin G, Liu L*, Guan F* and Zhang X*. (2017) The dorsoventral patterning of human forebrain follows an activation/transformation model. Cerebral Cortex. 27 (5): 2941-2954.

13.Liu L, Liu X, Ren X, Tian Y, Chen Z, Xu X, Du Y, Jiang C, Fang Y, Liu Z, Fan B, Zhang, Q, Jin G, Yang X and Zhang X*. (2016) Smad2 and Smad3 have differential sensitivity in relaying TGFbeta signaling and inversely regulate em’n’n’narly lineage specification. Scientific Reports. 6:21602.

14.Liu Z, Chi L, Fang Y, Liu L* and Zhang X*（2013）. Specific expression pattern of a novel Otx2 splicing variant during neural differentiation. Gene. 523(1):33-8.

15.Zhang X-Q, Huang TC, Chen J, Pankratz TM, Xi J-J, Li J, Yang Y, LaVaute MT, Li X-J, Ayala M, Bondarenko IG, Du Z-W, Jin Y, Golos GT and Zhang S-C. (2010) Pax6 is a human neuroectoderm cell fate determinant. Cell Stem Cell. 7(1): 90-100.

16.Zhang X-Q, Zhang S-C. (2010): Differentiation of neural precursors and dopaminergic neurons from human embryonic stem cells. Methods Mol Biol. 584: 355-66.

17.Li X-J*, Zhang X-Q*, Johnson MA, Wang Z-B, Lavaute T, Zhang S-C. (2009) Coordination of sonic hedgehog and Wnt signaling determines ventral and dorsal telencephalic neuron types from human embryonic stem cells. Development. 136(23): 4055-63. (*, equal contribution. Highlighted by the journal)

18.Zhang X-Q*, Zhang G*, Zhang H*, Karin M, Bai H, Cai D-S. (2008): Hypothalamic IKKbeta/NF-kappa B and ER stress link overnutrition to energy imbalance and obesity. Cell. 135(1): 61-73. (*, equal contribution. Highlighted by the journal)

19.Zhang X-Q, Wang F-F, Chen X-Q, Chen Y-J, Ma L. (2008): Post-endocytic fates of delta-opioid receptor are regulated by GRK2-mediated receptor phosphorylation and distinct beta-arrestin isoforms. J Neurochem. 106(2): 781-92.

20.Zhang X-Q, Wang F-F, Chen X-Q, Li J-L, Xiang B, Li B-M, Zhang Y-Q, Ma L. (2005): Beta-arrestin1 and beta-arrestin2 are differentially required for phosphorylation-dependent and independent internalization of delta-opioid receptors. J Neurochem. 95(1): 169-78.