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Mesenchymal stromal cells attenuate post-stroke infection by preventing caspase-1-dependent splenic marginal zone B cell death

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Signal Transduction and Targeted Therapy 2021年第3期6卷 590-592页

作者： Yinong Huang Jiancheng Wang Xiaofan Lai Yuan Qiu Jianye Cai Yuanchen Ma Yilin Liu Wei Qiu Zhengqi Lu andy peng xiang Department of Neurology The Third Affiliated HospitalSun Yat-Sen UniversityGuangzhouChina Center for Stem Cell Biology and Tissue Engineering Key Laboratory for Stem Cells and Tissue EngineeringMinistry of EducationSun Yat-Sen UniversityGuangzhouChina The Seventh Affiliated Hospital Sun Yat-sen UniversityShenzhenChina

Dear Editor,Spontaneous infection is one of the most common complications of acute ischemic stroke(AIS)and leads to increased morbidity and mortality in stroke ***,current interventions fail to improve clinical outcomes in these *** stroke-induced immunodeficiency is thought to contribute to the risk of infection,1 we hypothesized that mesenchymal stromal cell(MSC)therapy,which harnesses potent immunomodulatory capacities,could be a potential ***,we show that intravenously administered MSCs preferentially migrate to the marginal zone(MZ)of the spleen,preserve the injured MZ B cells and ameliorate post-stroke infection and mortality in the mouse middle cerebral artery occlusion(MCAO)model of AIS.

关键词： infection mortality spleen

Human iP SC-derived mesenchymal stem cells relieve high blood pressure in spontaneously hypertensive rats via splenic nerve activated choline acetyltransferase-positive cells

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Science China Life Sciences 2024年

作者： Zhen Zhang Weijun Huang Xiaoran Zhang Zhecun Wang Manting Xie Bingbing Xie Yiling Wang Xiaoyong Chen andy peng xiang Qiuling xiang Center for Stem Cell Biology and Tissue Engineering Key Laboratory for Stem Cells and Tissue Engineering Ministry of Education Sun Yat-sen University Department of Physiology Zhongshan School of Medicine Sun Yat-sen University Department of Vascular Surgery the First Affiliated Hospital Sun Yat-sen University

Despite substantial advancements in modern medicine, the management of hypertension remains a major challenge. Stem cell-based therapies have recently demonstrated remarkable efficacy in treating cardiovascular diseases, including hypertension. However, the antihypertensive mechanism of mesenchymal stem cells（MSCs） has not been extensively explored. This study aimed to investigate the role of injected MSCs in regulating blood pressure homeostasis. Our previous study demonstrated that human induced pluripotent stem cellderived mesenchymal stem cells（hiPSC-MSCs） are functional and homogeneous sources for MSC-based therapy. After the injection of hiPSCMSCs, a significant reduction in blood pressure and end target organ inflammation were observed in spontaneously hypertensive rats（SHRs）. Cell tracking assays demonstrated that the injected hiPSC-MSCs accumulated in the spleens of the SHRs. The injected hiPSC-MSCs accumulated adjacent to the splenic nerve, potentially contributing to the antihypertensive effects. Furthermore, the hiPSC-MSCs released abundant glutamate, which acts as a neuromodulator to activate the splenic sympathetic nerve. After inhibition of glutamate synthesis by siRNA, the ability of hiPSC-MSCs to activate sympathetic nerves was significantly diminished. In addition, the antihypertensive effects of hiPSC-MSCs were eliminated after splenic nerve denervation（SND）, underscoring the critical role of the splenic nerve. Moreover, activation of the splenic nerve resulted in increased release of norepinephrine（NE）, which increased the number of choline acetyltransferase-positive（ChAT+） cells in the spleen and peripheral blood. Consequently, the acetylcholine（ACh） produced by elevated ChAT+cells could act as a vasodilator, lowering blood pressure and mitigating inflammation in end target organs. In summary, our findings indicate that hiPSC-MSCs effectively lower blood pressure in hypertension by influencing the splenic nerves and regulating ChAT+cells. The co

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Mesenchymal stem cells for treatment of steroid-resistant acute rejection after liver transplantation

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Liver Research 2017年第2期1卷 140-145页

作者： Yingcai Zhang Shihui Li Guoying Wang Yanwen peng Qi Zhang Hua Li Jian Zhang Genshu Wang Shuhong Yi Xiaoyong Chen andy peng xiang Yang Yang Guihua Chen Department of Hepatic Surgery Liver Transplantation CenterThe Third Affiliated Hospital of Sun Yat-sen UniversityOrgan Transplantation InstituteSun Yat-sen UniversityOrgan Transplantation Research Center of Guangdong ProvinceGuangzhouChina Cell-Gene Therapy Translational Medicine Research Center The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina Center for Stem Cell Biology and Tissue Engineering Key Laboratory for Stem Cells and Tissue EngineeringMinistry of EducationSun Yat-sen UniversityGuangzhouChina

A patient with steroid-resistant acute rejection 50 days after ABO-compatible orthotopic liver transplantation(LT)received regular infusion of allogeneic mesenchymal stem cells(MSCs)after three sessions of steroid pulse therapy which failed to control the pathogenetic condition as shown by *** function improved gradually after intravenous injection of MSCs once weekly for 10 weeks(as confirmed by biopsy)and remained stable under administration of conventional immunosuppressive *** was no evidence of neoplasms 5 years after *** infusion appears to successfully reverse resistance to immunosuppressive agents and may be a useful treatment for post-liver transplant steroid-resistant rejection.

关键词： Mesenchymal stem cells(MSCs) Liver transplantation(LT) Steroid-resistant acute rejection Immunoregulation

Assessment of embryotoxicity of compounds in cosmetics by the embryonic stem cell test

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Assessment of embryotoxicity of compounds in cosmetics by th...

Human mesenchymal stromal cells enhance the immunomodulatory function of CD8＋CD28- regulatory T cells

第八届中国化妆品学术研讨会

作者： Bruce T.Lahn andy peng xiang Center for Stem Cell Biology and Tissue Engineering Sun Yat-sen University

The new EU legislations for cosmetics(Seventh Amendment) have laid down deadlines for the replacement of animal tests in *** policy stimulates the acceptance of in vitro approaches to test embryotoxic potentials of compounds in cosmetics *** embryonic stem cell test(EST) designed by The European Centre for the Validation of Alternative Methods(ECVAM) is currently the most promising in vitro assay to predict the embryotoxic potential of *** this study,six selected compounds (hydroquinone,eugenol,dibutyl phthalate,antimony(Ⅲ) oxide,neodymium(Ⅲ) nitrate hydrate,melamine) formerly involved in cosmetic products were selected to test their embryotoxic potentials by the EST. 5-Fluorouracil and penicillin G were separately set as positive and negative *** embryotoxic potential was determined by the prediction model(PM),which was calculated from three endpoints,the IC50 3T3,IC50 ES,and ***,eugenol,and antimony(Ⅲ) oxide indicated with strong embryotoxicity,while dibutyl phthalate,neodymium(Ⅲ) nitrate hydrate,and melamine exhibited a weak *** results may provide a valuable attempt to expand the application of EST to the cosmetics field.

关键词： Cosmetics embryotoxicity embryonic stem cell test

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Cellular & Molecular Immunology 2015年第6期12卷 708-718页

作者： Qiuli Liu Haiqing Zheng Xiaoyong Chen Yanwen peng Weijun Huang Xiaobo Li Gang Li Wenjie Xia Qiquan Sun an andy peng xiang Cell-gene Therapy Translational Medicine Research Center The Third Affiliated Hospital Zhongshan School of Medicine Sun Yat-sen University Guangzhou Guangdong China Center for Stem Cell Biology and Tissue Engineering The Key Laboratory for Stem Cells and Tissue Engineering Ministry of Education Sun Yat-sen University Guangzhou China Department of Rehabilitation Medicine The Third Affiliated Hospital Sun Yat-sen University Guangzhou China Institute of Blood Transfusion Guangzhou Blood Centre Guangzhou China Department of Renal Transplantation The Third Affiliated Hospital Sun Yat- sen University Guangzhou China Department of Biochemistry Zhongshan Medical School Sun Yat-sen University Guangzhou China These authors contributed enuallv tn this wnrk

One important aspect of mesenchymal stromal cells （MSCs）-mediated immunomodulation is the recruitment and induction of regulatory T （Treg） cells. However, we do not yet know whether MSCs have similar effects on the other subsets of Treg cells. Herein, we studied the effects of MSCs on CD8＋CD28- Treg cells and found that the MSCs could not only increase the proportion of CD8＋CD28- T cells, but also enhance CD8＋CD28-T cells＇ ability of hampering naive CD4＋ T-cell proliferation and activation, decreasing the production of IFN-γ by activated CD4＋ T cells and inducing the apoptosis of activated CD4＋ T cells. Mechanistically, the MSCs affected the functions of the CD8＋CD28- T cells partially through moderate upregulating the expression of IL-10 and FasL. The MSCs had no distinct effect on the shift from CD8＋CD28＋ T cells to CD8＋CD28- T cells, but did increase the proportion of CD8＋CD28- T cells by reducing their rate of apoptosis. In summary, this study shows that MSCs can enhance the regulatory function of CD8＋CD28- Treg cells, shedding new light on MSCs-mediated immune regulation.

关键词： antigens CD28 CD8-positive T cells mesenchymal stromal cells regulatory T cells

Mesenchymal stromal cells alleviate acute respiratory distress syndrome through the cholinergic anti-inflammatory pathway

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Signal Transduction and Targeted Therapy 2022年第10期7卷 3884-3897页

作者： Xiaoran Zhang Xuxia Wei Yiwen Deng Xiaofeng Yuan Jiahao Shi Weijun Huang Jing Huang Xiaoyong Chen Shuwei Zheng Jieying Chen Keyu Chen Ruiming Xu Hongmiao Wang Weiqiang Li Shiyue Li Huimin Yi andy peng xiang Department of Surgical Intensive Care The Third Affiliated HospitalSun Yat-Sen UniversityGuangzhouGuangdong 510630China Center for Stem Cell Biology and Tissue Engineering Key Laboratory for Stem Cells and Tissue EngineeringMinistry of EducationSun Yat-Sen UniversityGuangzhouGuangdong 510080China National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine Zhongshan School of MedicineSun Yat-Sen UniversityGuangzhouGuangdong 510080China Department of General Intensive Care Unit Lingnan HospitalThe Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdong 510530China Department of Anesthesiology The First Affiliated HospitalSun Yat-sen UniversityGuangzhouGuangdong 510080China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease the First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou Medical UniversityGuangzhouGuangdong 510120China

Mesenchymal stromal cells(MSCs)have been considered a promising alternative for treatment of acute respiratory distress syndrome(ARDS).However,there is significant heterogeneity in their therapeutic efficacy,largely owing to the incomplete understanding of the mechanisms underlying the therapeutic activities of ***,we hypothesize that the cholinergic antiinflammatory pathway(CAP),which is recognized as a neuroimmunological pathway,may be involved in the therapeutic mechanisms by which MSCs mitigate *** lipopolysaccharide(LPS)and bacterial lung inflammation models,we found that inflammatory cell infiltration and Evans blue leakage were reduced and that the expression levels of choline acetyltransferase(ChAT)and vesicular acetylcholine transporter(VAChT)in lung tissue were significantly increased 6 hours after MSC *** the vagus nerve was blocked orα7 nicotinic acetylcholine(ACh)receptor(α7nAChR)-knockout mice were used,the therapeutic effects of MSCs were significantly reduced,suggesting that the CAP may play an important role in the effects of MSCs in ARDS *** results further showed that MSC-derived prostaglandin E2(PGE2)likely promoted ACh synthesis and ***,based on the efficacy of nAChR andα7nAChR agonists,we found that lobeline,the nicotinic cholinergic receptor excitation stimulant,may attenuate pulmonary inflammation and alleviate respiratory symptoms of ARDS patients in a clinical study(ChiCTR2100047403).In summary,we reveal a previously unrecognized MSC-mediated mechanism of CAP activation as the means by which MSCs alleviate ARDS-like syndrome,providing insight into the clinical translation of MSCs or CAP-related strategies for the treatment of patients with ARDS.

关键词： distress cholinergic inflammation

A single-nucleus transcriptomic atlas of primate testicular aging reveals exhaustion of the spermatogonial stem cell reservoir and loss of Sertoli cell homeostasis

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Protein & Cell 2023年第12期14卷 888-907页

作者： Daoyuan Huang Yuesheng Zuo Chen Zhang Guoqiang Sun Ying Jing Jinghui Lei Shuai Ma Shuhui Sun Huifen Lu Yusheng Cai Weiqi Zhang Fei Gao andy peng xiang Juan Carlos Izpisua Belmonte Guang-Hui Liu Jing Qu Si Wang Advanced Innovation Center for Human Brain Protection National Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing100053China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Aging Translational Medicine Center International Center for Aging and CancerBeijing Municipal Geriatric Medical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of SciencesBeijing 100101China Institute for Stemcell and Regeneration CAsBeijing100101China China National Center for Bioinformation Beijing 100101China The Fifth People's Hospital of Chongqing Chongqing 400062China 11Sino-Danish College University of Chinese Academy of SciencesBeijing 101408China Sino-Danish Center for Education and Research Beijing 101408China Center for Stem Cell Biology and Tissue Engineering Key Laboratory for Stem Cells and Tissue EngineeringMinistry of EducationSun Yat-sen UniversityGuangzhou510000China Department of Biochemistry Zhongshan School of MedicineSun Yat-sen UniversityGuangzhou 510000China Altos Labs Inc.San DiegoCA 92121USA and Aging Biomarker Consortium China

The testis is pivotal for male reproduction,and its progressive functional decline in aging is associated with ***,the regulatory mechanism underlying primate testicular aging remains largely ***,we resolve the aging-related cellular and molecular alterations of primate testicular aging by establishing a single-nucleus transcriptomic ***-expression patterns along the spermatogenesis trajectory revealed molecular programs associated with attrition of spermatogonial stem cell reservoir,disturbed meiosis and impaired spermiogenesis along the sequential ***,Sertoli cell was identified as the cell type most susceptible to aging,given its deeply perturbed age-associated transcriptional ***,downregulation of the transcription factor Wilms'Tumor 1(WTi),essential for Sertoli cell homeostasis,was associated with accelerated cellular senescence,disrupted tight junctions,and a compromised cell identity signature,which altogether may help create a hostile microenvironment for ***,our study depicts in-depth transcriptomic traits of non-human primate(NHP)testicular aging at single-cell resolution,providing potential diagnostic biomarkers and targets for therapeutic interventions against testicular aging and age-related male reproductive diseases.

关键词： single-nucleus RNA sequencing primate testis aging WT1

A versatile tool for tracking the differentiation of human embryonic stem cells

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Frontiers in Biology 2010年第5期5卷 455-463页

作者： Weiqiang LI Jie QIN Xinyu LI Li ZHANG Chang LIU Fei CHEN Zifei WANG Lirong ZHANG Xiuming ZHANG Bruce TLAHN andy peng xiang Center for Stem Cell Biology and Tissue Engineering Sun Yat-Sen UniversityNo.74 Zhongshan Road 2Guangzhou 510080China The Key Laboratory for Stem Cells and Tissue Engineering Ministry of EducationGuangzhou 510080China Zhongshan Medical School Sun Yat-sen UniversityGuangzhou 510080China Department of Human Genetics and Howard Hughes Medical Institute University of ChicagoChicagoIllinois 60637USA Department of Pathophysiology Guangdong College of PharmacyGuangzhou 510006China Cell Therapy Center The Third Affiliated HospitalSun Yat-sen UniversityGuangzhou 510630China

The ability of human embryonic stem cells(hESCs)to undergo indeﬁnite self-renewal in vitro and to produce lineages derived from all three embryonic germ layers both in vitro and in vivo makes such cells extremely valuable in both clinical and research ***,the generation of specialized cell lineages from a mixture of differentiated hESCs remains technically difﬁ*** speciﬁc promoter-driven reporter genes are power-ful tools for tracking cell types of interest in differentiated cell ***,we describe the construction of modular lentivectors containing different tissue-speciﬁc promoters(Tα1 ofα-tubulin;aP2 of adipocyte Protein 2;and AFP of alpha fetoprotein)driving expression of humanized Renilla greenﬂuorescent protein(hrGFP).To this end,we used MultiSite gateway technology and employed the novel vectors to successfully monitor hESC *** present a versatile method permitting target cells to be *** system will facilitate research in developmental biology,transplantation,and in vivo stem cell tracking.

关键词： human embryonic stem cells lentivector transduction greenﬂuorescent protein

Establishment and characterization of two new human embryonic stem cell lines,SYSU-1 and SYSU-2

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Chinese Medical Journal 2007年第7期120卷 589-594页

作者： HUANG Guo LI Wei-qiang CHEN Rui CHEN Zhen-guang ZHANG Xiu-ming MAO Fu-xiang HUANG Shao-liang LI Shu-nong Bruce T Lahn andy peng xiang Centre for Stem Cell Biology and Tissue Engineering Sun Yat-sen University Guangzhou 510080 China Fourth People＇s Hospital of Shenzhen Shenzhen 518033 China Department of Thoracic Surgery First Affiliated Hospital Sun Yat-sen University Guangzhou 510080 China

Background Human embryonic stem cells can propagate indefinitely in vitro and are able to differentiate into derivatives of all three embryonic germ layers. The excitement surrounding human embryonic stem cells lies largely in their potential to produce specialized cells that can be used for transplant therapies. However, further investigation requires additional cell lines with varying genetic background. Therefore, efforts to derive and establish more human embryonic stern cell lines are highly warranted. Methods Surplus embryos （blastocysts） from donors were used to isolate the inner cell mass by immunosurgery. All cells were cultured continuously on irradiated murine embryonic fibroblasts feed layer and likely human embryonic stem cell colonies were subsequently characterized by cell surface marker staining, karyotyping and teratoma formation. Results Two human embryonic stern cell lines （SYSU-1 and SYSU-2） were established from surplus embryos. The two lines express several pluripotency markers including alkaline phosphatase, SSEA- 4, Tra-1-60, Oct-4, Nanog and Rex-1. They remain in undifferentiated state with normal karyotype after prolonged passages and can form embryoid bodies in vitro and teratoma in vivo. Conclusion Two new human embryonic stem cell lines have been established from surplus embryos. They can be used to understand selfrenewal and differentiating mechanisms and provide more choices for regenerative medicine.

关键词： embryonic stem cells blastocysts inner cell mass cell differentiation