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Blockade of CD300A enhances the ability of human NK cells to lyse hematologic malignancies

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Cancer Biology & Medicine 2024年第4期21卷 331-346页

作者： Shuangcheng Li Tianci Wang Xinghui Xiao Xiaodong Zheng Haoyu Sun Rui Sun Hongdi Ma Zhigang Tian Xiaohu Zheng Hefei National Research Center for Physical Sciences at Microscale The CAS Key Laboratory of Innate Immunity and Chronic DiseaseSchool of Basic Medical SciencesCenter for Advanced Interdisciplinary Science and Biomedicine of IHMDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230027China Institute of Immunology University of Science and Technology of ChinaHefei 230027China Hefei TG ImmunoPharma Corporation Limited Hefei 230601China Research Unit of NK Cell Study Chinese Academy of Medical SciencesBeijing 100864China key laboratory of Quantitative Synthetic Biology Shenzhen Institute of Synthetic BiologyShenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China

Objective: The human cluster of differentiation(CD)300A, a type-I transmembrane protein with immunoreceptor tyrosine-based inhibitory motifs, was investigated as a potential immune checkpoint for human natural killer(NK) cells targeting hematologic malignancies(HMs).Methods: We implemented a stimulation system involving the CD300A ligand, phosphatidylserine(PS), exposed to the outer surface of malignant cells. Additionally, we utilized CD300A overexpression, a CD300A blocking system, and a xenotransplantation model to evaluate the impact of CD300A on NK cell efficacy against HMs in in vitro and in vivo settings. Furthermore, we explored the association between CD300A and HM progression in patients.Results: Our findings indicated that PS hampers the function of NK cells. Increased CD300A expression inhibited HM lysis by NK cells. CD300A overexpression shortened the survival of HM-xenografted mice by impairing transplanted NK cells. Blocking PS–CD300A signals with antibodies significantly amplified the expression of lysis function-related proteins and effector cytokines in NK cells, thereby augmenting the ability to lyse HMs. Clinically, heightened CD300A expression correlated with shorter survival and an “exhausted” phenotype of intratumoral NK cells in patients with HMs or solid tumors.Conclusions: These results propose CD300A as a potential target for invigorating NK cell-based treatments against HMs.

关键词： NK cell CD300A phosphatidylserine immune checkpoint hematologic malignancy

Structural determinants specific for retromer protein sorting nexin 5 in regulating subcellular retrograde membrane trafficking

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The Journal of Biomedical Research 2023年第6期37卷 492-506页

作者： Qing Chen Meiheng Sun Xu Han Hongfei Xu Yongjian Liu jiangsu key laboratory of xenotransplantation and Department of Medical GeneticsNanjing Medical UniversityNanjingJiangsu 211166China Department of Neuroscience University of Pittsburgh Kenneth P.Dietrich School of Arts and SciencesPittsburghPA 15260USA

The endosomal trafficking of signaling membrane proteins, such as receptors, transporters and channels, is mediated by the retromer-mediated sorting machinery, composed of a cargo-selective vacuolar protein sorting trimer and a membrane-deforming subunit of sorting nexin proteins. Recent studies have shown that the isoforms, sorting nexin 5 (SNX5) and SNX6, have played distinctive regulatory roles in retrograde membrane trafficking. However, the molecular insight determined functional differences within the proteins remains unclear. We reported that SNX5 and SNX6 had distinct binding affinity to the cargo protein vesicular monoamine transporter 2 (VMAT2). SNX5, but not SNX6, specifically interacted with VMAT2 through the Phox domain, which contains an alpha-helix binding motif. Using chimeric mutagenesis, we identified that several key residues within this domain were unique in SNX5, but not SNX6, and played an auxiliary role in its binding to VMAT2. Importantly, we generated a set of mutant SNX6, in which the corresponding key residues were mutated to those in SNX5. In addition to the gain in binding affinity to VMAT2, their overexpression functionally rescued the altered retrograde trafficking of VMAT2 induced by siRNA-mediated depletion of SNX5. These data strongly suggest that SNX5 and SNX6 have different functions in retrograde membrane trafficking, which is determined by the different structural elements within the Phox domain of two proteins. Our work provides a new information on the role of SNX5 and SNX6 in the molecular regulation of retrograde membrane trafficking and vesicular membrane targeting in monoamine neurotransmission and neurological diseases.

关键词： vesicular monoamine transporter 2 SNX5 SNX6 retromer retrograde trafficking

Generation of B Cell-Deficient Pigs by Highly Efficient CRISPR/Cas9-Mediated Gene Targeting

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Journal of Genetics and Genomics 2015年第8期42卷 437-444页

作者： Fengjiao Chen Ying Wang Yilin Yuan Wei Zhang Zijian Ren Yong Jin Xiaorui Liu Qiang Xiong Qin Chen Manling Zhang Xiaokang Li Lihua Zhao Ze Li Zhaoqiang Wu Yanfei Zhang Feifei Hu Juan Huang Rongfeng Li Yifan Dai State key laboratory of Reproductive Medicine and jiangsu key laboratory of xenotransplantation Nanjing Medical University

Generating B cell-deficient mutant is the first step to produce human antibody repertoires in large animal models. In this study, we applied the clustered regularly interspaced short palindromic repeat （CRISPR）/CRISPR-associated （Cas） system to target the JH region of the pig IgM heavy chain gene which is crucial for B cell development and differentiation. Transfection of IgM-targeting Cas9 plasmid in primary porcine fetal fibroblasts （PFFs） enabled inducing gene knock out （KO） in up to 53.3% of colonies analyzed, a quarter of which harbored biallelic modification, which was much higher than that of the traditional homologous recombination （HR）. With the aid of somatic cell nuclear transfer （SCNT） technology, three piglets with the biallelic lgM heavy chain gene mutation were produced. The piglets showed no antibody-producing B cells which indicated that the biallelic mutation of the lgM heavy chain gene effectively knocked out the function of the IgM and resulted in a B cell-deficient phenotype. Our study suggests that the CRISPR/Cas9 system combined with SCNT technology is an efficient genome-editing approach in pigs.

关键词： CRISPR/Cas9 system lgM heavy chain Pig genome editing B cell-deficiency Somatic cell nuclear transfer

Unbalanced omega-6/omega-3 ratio in red meat products in China

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The Journal of Biomedical Research 2013年第5期27卷 366-371页

作者： Ming Yu Qianqian Gao Yan Wang Wei Zhang Lin Li Ying Wang Yifan Dai State key laboratory of Reproductive Medicine Jiangsu Key Laboratory of Xenotransplantation Nanjing Medical University

Dietary meats play a crucial role in human health. The objective of this survey was to determine the fatty acid content and omega-6/omega-3 polyunsaturated fatty acids （n-6/n-3 PUFA） ratio of fresh red meat （beef and pork） from four cities （Shanghai, Nanjing, Yinchuan and Hohhot） in China. The results showed that the n-6/n-3 PUFA ratio from all the samples ranged from 6 to 23. The total n-6 PUFA concentrations ranged from 290.54 mg/100 g in beef from Nanjing to 1601.48 mg/100 g in pork from Hohhot, whereas the total concentrations of n-3 PUFA ranged from 46.34 mg/100 g in beef from Nanjing to 96.03 mg/100 g in pork from Nanjing. The results indicated that the n-6/n-3 ratio in the red meat from all four regions is unbalanced and is much higher than that （〈 5：1） rec- ommended by the WHO/FAO. The total amount of n-3 PUFA was far lower than the required daily dose. There- fore, potential solutions to increase the n-3 PUFA content in meat products or to provide alternative source of n-3 PUFA should be explored.

关键词： lipid polyunsaturated fatty acid red meat

Protective effects on acute hypoxic-ischemic brain damage in mfat-1 transgenic mice by alleviating neuroinflammation

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The Journal of Biomedical Research 2021年第6期35卷 474-490页

作者： Xue Geng Meng Wang Yunjun Leng Lin Li Haiyuan Yang Yifan Dai Ying Wang jiangsu key laboratory of xenotransplantation Nanjing Medical UniversityNanjingJiangsu 211166China key laboratory of Targeted Intervention of Cardiovascular Disease Collaborative Innovation Center for Cardiovascular Disease Translational MedicineNanjing Medical UniversityNanjingJiangsu 211166China.

Acute hypoxic-ischemic brain damage(HIBD)mainly occurs in adults as a result of perioperative cardiac arrest and asphyxia.The benefits of n-3 polyunsaturated fatty acids(n-3 PUFAs)in maintaining brain growth and development are well documented.However,possible protective targets and underlying mechanisms of mfat-1 mice on HIBD require further investigation.The mfat-1 transgenic mice exhibited protective effects on HIBD,as indicated by reduced infarct range and improved neurobehavioral defects.RNA-seq analysis showed that multiple pathways and targets were involved in this process,with the anti-inflammatory pathway as the most significant.This study has shown for the first time that mfat-1 has protective effects on HIBD in mice.Activation of a G protein-coupled receptor 120(GPR120)-related anti-inflammatory pathway may be associated with perioperative and postoperative complications,thus innovating clinical intervention strategy may potentially benefit patients with HIBD.

关键词： hypoxic-ischemic brain damage mfat-1 transgenic mice n-3 PUFAs RNA-seq neuroinflammation GPR120 receptor

Antigenicity of tissues and organs from GGTA1/CMAH/β4GalNT2 triple gene knockout pigs

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The Journal of Biomedical Research 2019年第4期33卷 235-243页

作者： Ronggen Wang Miaomiao Ruan Runjie Zhang Lei Chen Xiaoxue Li Bin Fang Chu Li Xueyang Ren Jiying Liu Qiang Xiong Lining Zhang Yong Jin Lin Li Rongfeng Li Ying Wang Haiyuan Yang Yifan Dai jiangsu key laboratory of xenotransplantation key laboratory of Targeted Intervention of Cardiovascular Disease Collaborative Innovation Center for Cardiovascular Disease Translational Medicine State key laboratory of Reproductive Medicine Nanjing Medical UniversityNanjingJiangsu 211166China Shenzhen xenotransplantation Medical Engineering Research and Development Center Institute of Translational MedicineShenzhen Second People rs HospitalFirst Affiliated Hospital of Shenzhen UniversityShenzhenGuangdong 518035China.

Clinical xenotransplantations have been hampered by human preformed antibody-mediated damage of the xenografts.To overcome biological incompatibility between pigs and humans,one strategy is to remove the major antigens[Gal,Neu5 Gc,and Sd(a)]present on pig cells and tissues.Triple gene(GGTAI,CMAH,and β4 GalNT2)knockout(TKO)pigs were produced in our laboratory by CRISPR-Cas9 targeting.To investigate the antigenicity reduction in the TKO pigs,the expression levels of these three xenoantigens in the cornea,heart,liver,spleen,lung,kidney,and pancreas tissues were examined.The level of human IgG/IgM binding to those tissues was also investigated,with wildtype pig tissues as control.The results showed that aGal,Neu5 Gc,and Sd(a)were markedly positive in all the examined tissues in wildtype pigs but barely detected in TKO pigs.Compared to wildtype pigs,the liver,spleen,and pancreas of TKO pigs showed comparable levels of human IgG and IgM binding,whereas corneas,heart,lung,and kidney of TKO pigs exhibited significantly reduced human IgG and IgM binding.These results indicate that the antigenicity of TKO pig is significantly reduced and the remaining xenoantigens on porcine tissues can be eliminated via a gene targeting approach.

关键词： pig xenotransplantation GGTA1 CMAH β4GaINT2 antigenicity

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基于纳米离子储层的双网络胃穿孔封堵水凝胶

Science China Materials 2022年第3期65卷 827-835页

作者：袁月辉吴昊任雪洋王建武刘瑞清胡本慧顾宁 School of Biomedical Engineering and Informatics Nanjing Medical UniversityNanjing 211166China State key laboratory of Bioelectronics Jiangsu Key Laboratory for Biomaterials and DevicesSchool of Biological Science and Medical EngineeringSoutheast UniversityNanjing 210009China School of Materials Science and Engineering Nanyang Technological UniversitySingapore 639798Singapore jiangsu key laboratory of xenotransplantation Nanjing Medical UniversityNanjing 211166China

近年来,对于可注射水凝胶用于内部组织损伤修复的研究取得了一定进展,但将此类水凝胶用于胃穿孔治疗时,依然面临强酸性胃液及胃壁的剧烈形变带来的严峻问题.鉴于此,我们提出了一种基于纳米离子储库(INR)的双网络水凝胶策略,该水凝胶具... 详细信息

近年来,对于可注射水凝胶用于内部组织损伤修复的研究取得了一定进展,但将此类水凝胶用于胃穿孔治疗时,依然面临强酸性胃液及胃壁的剧烈形变带来的严峻问题.鉴于此,我们提出了一种基于纳米离子储库(INR)的双网络水凝胶策略,该水凝胶具有优异的黏附和机械性能,可以简便地涂覆于穿孔部位,在封堵穿孔的同时促进组织修复.结果显示,在蓝光条件下,聚丙烯酰胺(PAM)可以于5 s内在胃组织上交联形成第一重网络,并通过机械互锁增强黏附性能;此外,纳米羟基磷灰石作为纳米离子储库可在酸性环境下释放Ca^(2+),与海藻酸钠(SA)形成第二重网络,抑制水凝胶在胃液中的溶胀.同时,通过在体系中引入碳二亚胺/N-羟基琥珀酰亚胺(EDC/NHS),可以促进水凝胶-组织界面上酯酰胺共价键的形成,从而进一步增强黏附力.因此我们认为,这种通过纳米离子储库策略获得的双网络水凝胶有望用于解决胃穿孔乃至其他类似的生物医学问题.

关键词：穿孔部位酸性胃液组织界面胃穿孔纳米离子组织修复胃组织黏附性能

Inhibitory role of peroxiredoxin 2 in LRRK2 kinase activity induced cellular pathogenesis

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The Journal of Biomedical Research 2020年第2期34卷 103-113页

作者： Kang Yan Wenfeng Zhang Xu Han Fei Chang Yongjian Liu jiangsu key laboratory of xenotransplantation School of Basic Medical ScienceNanjing Medical UniversityNanjingJiangsu 211166China Department of Pharmacology&Chemical Biology University of Pittsburgh School of MedicinePittsburghPA 15216USA

Parkinson’s disease(PD) is a major neurodegenerative disease. One of the known genetic contributors to PD pathogenesis is leucine-rich repeat kinase 2(LRRK2) whose mutations with elevated kinase activity could lead to both familial and sporadic PD. However, how the pathogenic kinase activity of LRRK2 is regulated remains largely unclear. Here we report that peroxiredoxin 2(Prx2) was identified as a novel interacting protein to LRRK2 with preferential expression in dopaminergic neurons over other Prx proteins. We also confirmed that Prx2 interacted with LRRK2 through its COR domain and its overexpression significantly decreased the kinase activity of mutant LRRK2. Functionally, overexpressed Prx2 rescued the transfected cells from LRRK2 mutant induced apoptotic processes. Importantly, overexpressed Prx2 reversed the altered subcellular distribution of cationindependent mannose 6-phosphate receptor(CI-M6 PR) induced by PD-mutant LRRK2. Our results suggest that,by interacting with LRRK2, Prx2 may play an inhibitory role in the LRRK2 mediated cellular toxicity in PD by inhibiting its kinase activity.

关键词： peroxiredoxin 2 LRRK2 Parkinson's disease

Factors in?uencing the somatic cell nuclear transfer ef?ciency in pigs

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Frontiers of Agricultural Science and Engineering 2019年第1期6卷 73-80页

作者： Yong JIN Manling ZHANG Xinrong JU Shuang LIANG Qiang XIONG Lihua ZHAO Xiaowei NIE Daorong HOU Qiang LIU Junzheng WANG Chenyu WANG Xiaokang LI Lining ZHANG Xiaorui LIU Ying WANG Haiyuan YANG Yifan DAI Rongfeng LI jiangsu key laboratory of xenotransplantation/key laboratory of Targeted Intervention of Cardiovascular Disease/Collaborative Innovation Center for Cardiovascular Disease Translational Medicine Nanjing Medical University

Using a data set from our laboratory, we assessed the effects of several factors on pig cloning ef?ciency. The results demonstrated that cells at high con?uence( > 90%) used as donor cell resulted in higher pregnancy rate, delivery rate and overall cloning ef?ciency(number of live offspring born per reconstructed embryo transferred to recipients) compared with the cells at 60% to79% con?uence and 80% to 89% con?uence. Cells with four, ?ve and six passages compromised the pregnancy and delivery rates compared with ?rst passage cells. The number of blastocysts transferred by somatic cell nuclear transfer(SCNT) did not signi?cantly affect the cloning ef?ciency, but transfer of blastocyst derived from in vitro culture 5 d after SCNT achieved a signi?cantly higher pregnancy rate compared with one to two cell SCNT embryos from overnight culture. The highest pregnancy rate, delivery rate and the largest litter size were obtained when Bama Miniature pig ?broblasts were used as donor cells and Landrace/Yorkshire hybrid gilts were used as recipients. Recipients treated with chemicals for estrus synchronization had higher pregnancy rates compared with untreated recipients. Our data might be helpful for improving SCNT ef?ciency in pigs.

关键词： blastocyst donor cell estrus synchronization pregnancy rate pig cloning somatic cell nuclear transfer