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Clinical Therapy Using iPSCs:Hopes and Challenges

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Genomics, Proteomics & Bioinformatics 2013年第5期11卷 294-298页

作者： Xiao Lu Tongbiao Zhao State Key Laboratory of Reproductive Biology Institute of ZoologyChinese Academy of Sciences

Induced pluripotent stem cells （iPSCs） are generated by ectopic expression of defined transcription factors in somatic cells. They can undergo unlimited self-renewal and maintain the embryonic stem cells （ESCs）-like ability to differentiate into all three germ layers, iPSCs can poten- tially provide unlimited autologous cells for therapy and therefore hold great promise for regener- ative medicine. Here we reviewed the recent advances in iPSC studies on disease modeling and clinical treatment as well as challenges correlated with clinical development of iPSCs, like tumori- genicity, immunogcnicity and genomic instability.

关键词： iPSC Regenerative medicineDisease modeling Immunogenicity Tumorigenicity

Cellular metabolism and homeostasis in pluripotency regulation

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Protein & Cell 2020年第9期11卷 630-640页

作者： Kun Liu Jiani Cao Xingxing Shi Liang Wang Tongbiao Zhao State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China

Pluripotent stem cells(PSCs)can immortally self-renew in culture with a high proliferation rate,and they possess unique metabolic characteristics that facilitate pluripotency regulation.Here,we review recent progress in understanding the mechanisms that link cellular metabolism and homeostasis to pluripotency regulation,with particular emphasis on pathways involving amino acid metabolism,lipid metabolism,the ubiquitin-proteasome system and autophagy.Metabolism of amino acids and lipids is tightly coupled to epigenetic modification,organelle remodeling and cell signaling pathways for pluripotency regulation.PSCs harness enhanced proteasome and autophagy activity to meet the material and energy requirements for cellular homeostasis.These regulatory events reflect a fine balance between the intrinsic cellular requirements and the extrinsic environment.A more complete understanding of this balance will pave new ways to manipulate PSC fate.

关键词： autophagy amino acid metabolism lipid metabolism pluripotent stem cell(PSC) ubiquitinproteasome system(UPS)

PIM2 regulates stemness through phosphorylation of 4E-BP1

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Science Bulletin 2017年第10期62卷 679-685页

作者： Hongyan Sun Jiani Cao Lin zhao Shaohua Zhu Shenghui Chen Yaqiong Li Bin zhao Tongbiao Zhao astate Key Laboratory of Stem Cell and Reproductive Biology Institute of Zoology Chinese Academy of Sciences Beijing 100101 China Graduate University of Chinese Academy of Sciences Beijing 100049 China Chinese Medicine Hospital in Linyi City Linyi 276600 China Life Sciences Institute Zhejiang University Hangzhou 310058 China

Embryonic stem cells(ESCs) can undergo unlimited self-renewal and maintain pluripotency to differentiate into any cell type of the three germ layers. Extensive studies have shown ESC identity is regulated by transcription factors, epigenetic regulators and multiple signal transduction pathways. However, the kinase regulation of pluripotency is not well understood. Here we show that the serine/threonine kinase PIM2, which is highly expressed in ESCs but not in somatic cells, functions as a crucial stemness regulator in ESCs. Knockout of Pim2 inhibits the self-renewal and differentiation capability of ESCs. Mechanistic studies identified that PIM2 can directly phosphorylate 4E-BP1, leading to release of e IF4E which facilitates the translation of pluripotent genes in ESCs. Our study highlights a novel kinase cascade pathway for ESC identity maintenance.

关键词：胚胎干细胞磷酸化蛋白丝氨酸/苏氨酸激酶 ESCs 信号转导通路自我更新遗传调控 eIF4E

Chimeric antigen receptor T (CAR-T) cells expanded with IL-7/IL-15 mediate superior antitumor effects

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Protein & Cell 2019年第10期10卷 764-769页

作者： Jianxia Zhou Liyuan Jin Fuping Wang Yuan Zhang Bing Liu Tongbiao Zhao State Key Laboratory of Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Graduate University of Chinese Academy of Sciences Beijing 100049China State Key Laboratory of Proteomics Translational Medicine Center of Stem Cells307-lvy Translational Medicine CenterLaboratory of OncologyAffiliated HospitalAcademy of Military Medical SciencesBeijing 100071China College of Life Sciences Hebei UniversityBaoding 071002China

Dear Editor,Genetic engineering of T cells to express chimeric antigen receptors(CARs)is an efficient approach for clinical therapy of hematological malignancies(Kuwana et al.,1987;Eshhar et al.,1993;Barrett et al.,2014).The CARs endow T cells with the ability to recognize specific antigens and bind them in an MHC-independent mariner,thereby overcoming some of the mechanisms that mediate tumor immune escape.In addition,by providing co-stimulatory signals,CARs endow T cells with enhanced cytotoxicity and persistence compared with primary T cells.A typical CAR comprises a single-chain variable frag me nt(scFv)derived from a monoclonal an tibody(mAb)for an tige n recog nition and signaling domains for co?activation(Eshhar et al.,1993;Sadelain et al.,2013).

关键词： al. Barrett clinical

The genomic stability of induced pluripotent stem cells

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Protein & Cell 2012年第4期3卷 271-277页

作者： zhao Chen Tongbiao Zhao Yang Xu Division of Biological Sciences University of CaliforniaSan DiegoLa JollaCA 92093-0322USA

With their capability to undergo unlimited self-renewal and to differentiate into all cell types in the body,in-duced pluripotent stem cells(iPSCs),reprogrammed from somatic cells of human patients with defined fac-tors,hold promise for regenerative medicine because they can provide a renewable source of autologous cells for cell therapy without the concern for immune rejection.In addition,iPSCs provide a unique opportu-nity to model human diseases with complex genetic traits,and a panel of human diseases have been suc-cessfully modeled in vitro by patient-specific iPSCs.Despite these progresses,recent studies have raised the concern for genetic and epigenetic abnormalities of iPSCs that could contribute to the immunogenicity of some cells differentiated from iPSCs.The oncogenic potential of iPSCs is further underscored by the find-ings that the critical tumor suppressor p53,known as the guardian of the genome,suppresses induced pluripotency.Therefore,the clinic application of iPSCs will require the optimization of the reprogramming technology to minimize the genetic and epigenetic ab-normalities associated with induced pluripotency.

关键词： induced pluripotent stem cells reprogram-ming genetic and epigenetic abnormalities

Treatment of multiple sclerosis by transplantation of neural stem cells derived from induced pluripotent stem cells

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Science China(Life Sciences) 2016年第9期59卷 950-957页

作者： Chao Zhang Jiani Cao Xiaoyan Li Haoyu Xu Weixu Wang Libin Wang Xiaoyang zhao Wei Li Jianwei Jiao Baoyang Hu Qi Zhou Tongbiao Zhao State Key Laboratory of Stem Cell and Reproductive Biology Institute of Zoology Chinese Academy of Sciences Beijing 100101 China Graduate University of Chinese Academy of Sciences Beijing 100049 China

Multiple sclerosis(MS) is an autoimmune disease of the central nervous system(CNS), with focal T lymphocytic infiltration and damage of myelin and axons. The underlying mechanism of pathogenesis remains unclear and there are currently no effective treatments. The development of neural stem cell(NSC) transplantation provides a promising strategy to treat neurodegenerative disease. However, the limited availability of NSCs prevents their application in neural disease therapy. In this study, we generated NSCs from induced pluripotent stem cells(iPSCs) and transplanted these cells into mice with experimental autoimmune encephalomyelitis(EAE), a model of MS. The results showed that transplantation of iPSC-derived NSCs dramatically reduced T cell infiltration and ameliorated white matter damage in the treated EAE mice. Correspondingly, the disease symptom score was greatly decreased, and motor ability was dramatically rescued in the iPSC-NSC-treated EAE mice, indicating the effectiveness of using iPSC-NSCs to treat MS. Our study provides pre-clinical evidence to support the feasibility of treating MS by transplantation of iPSC-derived NSCs.

关键词：神经干细胞多发性硬化移植治疗自身免疫性疾病中枢神经系统神经退行性疾病 NSCs 细胞浸润

Oxidative phosphorylation safeguards pluripotency via UDP-N-acetylglucosamine

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Protein & Cell 2023年第5期14卷 376-381页

作者： Jiani Cao Meng Li Kun Liu Xingxing Shi Ning Sui Yuchen Yao Xiaojing Wang Shiyu Li Yuchang Tian Shaojing Tan Qian zhao Liang Wang Xiahua Chai Lin Zhang Chong Liu Xing Li Zhijie Chang Dong Li Tongbiao Zhao State Key Laboratory of Stem Cell and Reproductive Biology Institute for Stem Cell and RegenerationInstitute of ZoologyChinese Academy of SciencesBeijing 100101China State Key Laboratory of Membrane Biology School of MedicineCenter for Synthetic and Systems BiologyTsinghua UniversityBeijing 100084China Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101China National Laboratory of Biomacromolecules CAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China Qufu Normal University Qufu 273165China University of Chinese Academy of Sciences Beijing 100049China

Dear Editor,Embryonic stem cells(ESCs)have been assumed to possess immature mitochondria and to favor anaerobic glycolysis over oxidative phosphorylation(OXPHOS)for energy production.This proposition is largely based on the findings that ESCs possess globular mitochondria with blurred cristae,and the facts that ESCs have higher glycolysis activity and lower mitochondrial respiration capacity than somatic cells(Kondoh et al.,2007;Folmes et al.,2011,2012;Zhang et al.,2012;Xu et al.,2013;Ito and Suda,2014;Gu et al.,2016).However,recent studies have shown that mitochondrial autophagy and mitochondrial dynamics are pivotal for ESC self-renewal and pluripotency(Todd et al.,2010;Liu et al.,2016,2020;Wang et al.,2019;Zhong et al.,2019).These studies have raised a fundamental question:what is the contribution and functional mechanism of mitochondrial respiration in pluripotency regulation?

关键词： Kondo phosphorylation raised

Cells derived from iPSC can be immunogenic -- Yes or No？

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Protein & Cell 2014年第1期5卷 1-3页

作者： Jiani Cao Xiaoyan Li Xiao Lu Chao Zhang Honghao Yu Tongbiao Zhao State Key Laboratory of Reproductive Biology Institute of Zoology Chinese Academy of Sciences Beijing 100101 China

The induced pluripotent stem cells （iPSCs）, derived by ectopic expression of reprogramming factors in somatic cells, can potentially provide unlimited autologous cells for regenerative medicine. In theory, the autologous cells derived from patient iPSCs should be immune tolerant by the host without any immune rejections. However, our recent studies have found that even syn- geneic iPSC-derived cells can be immunogenic in syn- geneic hosts by using a teratoma transplantation model （Nature 474：212-215, 2011）. Recently two research groups differentiated the iPSCs into different germ lay- ers or cells, transplanted those cells to the syngeneic hosts, and evaluated the immunogenicity of those cells. Both of the two studies support our conclusions that some certain but not all tissues derived from iPSCs can be immunogenic, although they claimed either ＂negli- gible＂ or ＂lack of＂ immunogenicity in iPSC derivatives （Nature 494：100-104, 2013; Cell Stem Cell 12：407-412, 2013）. To test the immunogenicity of clinically valuable cells differentiated from human iPSCs are emergenUy required for translation of iPSC technology to clinics.

关键词： Animals Cell Cycle Proteins/metabolism Cell Transplantation/methods* Cell Transplantation/methods* Graft Rejection/immunology Induced Pluripotent Stem Cells/immunology* Induced Pluripotent Stem Cells/transplantation* Membrane Proteins/metabolism Mice, Knockout Mice, Knockout Teratoma/immunology* Teratoma/metabolism

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“克隆猴”的前世今生

科学通报 2018年第18期63卷 1758-1763页

作者：王亮赵同标中国科学院动物研究所干细胞与生殖生物学国家重点实验室中国科学院大学存济医学院

进化和生理上最接近于人类的灵长类动物——猕猴(Macaca mulatta)被复制出来了,你相信吗?科幻电影中克隆人的脚步似乎离我们越来越近了.2018年1月24日,国际顶级生物学期刊Cell以封面文章的形式报道了一项振奋人心的重大成果:中国科学院... 详细信息

进化和生理上最接近于人类的灵长类动物——猕猴(Macaca mulatta)被复制出来了,你相信吗?科幻电影中克隆人的脚步似乎离我们越来越近了.2018年1月24日,国际顶级生物学期刊Cell以封面文章的形式报道了一项振奋人心的重大成果:中国科学院神经科学研究所孙强研究组[1]采用体细胞核移植技术(somatic cell nuclear transfer,SCNT)成功克隆出两只食蟹猴"中中"和"华华"."中中"、"华华"的诞生远非仅为克隆动物家族多添一位成员那么简

关键词： cloned monkey Kdm4d reprogramming somatic cell nuclear transfer(SCNT) totipotency