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Smooth muscle cell differentiation： Mechanisms and models for vascular diseases

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Frontiers in biology 2017年第6期12卷 392-405页

作者： Yujie Deng Caixia Lin Huanjiao Jenny Zhou Wang Min Center for Translational Medicine The First Affiliated Hospital Sun Yat-Sen University Guangzhou 510080 China Department of Pathology and the vascular biology and therapeutics program Yale University Sehool of Medicine New Haven CT 06520USA

vascular smooth muscle cells (VSMCs) are mature cells that play critical roles in both normal and aberrant cardiovascular conditions. In response to various environmental cues, VSMCs can dedifferentiate from a contractile state to a highly proliferative synthetic state through the so-called ‘phenotypic switching’ process. Changes in VSMC phenotype contribute to numerous vascular-related diseases, including atherosclerosis, calcification, and restenosis following angioplasty. Adventitial VSMC progenitor cells also contribute to formation of the neointima. Herein, we review both, the roles of VSMC differentiation in vascular diseases, and the in vitro models used to investigate the molecular mechanisms involved in the regulation of VSMC differentiation and phenotype modulation. A comprehensive understanding of VSMC behavior in vascular diseases is essential to identify new therapeutic targets for the prevention and treatment of cardiovascular diseases.

关键词： vascular smooth muscle cells progenitor differentiation transcription factor cardiovascular disease

Metabolic regulation of T cell development by Sinl-mTORC2 is mediated by pyruvate kinase M2

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Journal of Molecular Cell biology 2019年第2期11卷 93-106页

作者： Xinxing Ouyang Yuheng Han Guojun Qu Man Li Ningbo Wu Hongzhi Liu Omotooke Arojo Hongxiang Sun Xiaobo Liu Dou Liu Lei Chen Qiang Zou Bing Su Shanghai Institute of Immunology Department of Immunology and Microbiology Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education Shanghai Jiao Tong University School of Medicine Shanghai 200025 China Department of Immunobiology and the vascular biology and therapeutics program Yale University School of Medicine 333 Cedar Street New Haven CT 06520 USA

Glucose metabolism plays a key role in thymocyte development. The mammalian target of rapamycin complex 2 (mT0RC2) is a critical regulator of cell growth and metabolism, but its role in early thymocyte development and metabolism has not been fully studied. We show here that genetic ablation of Sinl, an essential component of mTORC2, in T lineage cells results in severely impaired thymocyte development at the CD4^- CD8^- double negative (DN) stages but not at the CD4^+ CD8^+ double positive (DP) or later stages. Notably, Sinl-deficient DN thymocytes show markedly reduced proliferation and ***, we discover that the M2 isoform of pyruvate kinase (PKM2) is a novel and crucial Sinl effector in promoting DN thymocyte development and metabolism. At the molecular level, we show that Sinl-mTORC2 controls PKM2 expression through an AKT-dependent PPAR-y nuclear translocation. Together, our study unravels a novel mTORC2-PPAR-γ-PKM2 pathway in immune-metabolic regulation of early thymocyte development.

关键词： mT0RC2 Sinl thymocyte development PPAR-γ PKM2 metabolism

Spliceosomal repression:unleashing human cell totipotency

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Signal Transduction and Targeted Therapy 2024年第10期9卷 4162-4164页

作者： Felipe F.Lüttmann Kee-Pyo Kim Johnny Kim The Center for Cardiovascular Regeneration and Immunology at TRON-Translational Oncology at the University Medical Center of the Johannes Gutenberg-University Mainz gGmbH MainzGermany Department of Medical Life Sciences College of MedicineThe Catholic University of KoreaSeoulRepublic of Korea vascular biology and therapeutics program and Department of Comparative Medicine Yale University School of MedicineNew HavenCTUSA

In a recent publication in Cell,Li et *** that inhibiting the spliceosome in human pluripotent stem cells(hPSCs)can induce a stable totipotent state.1 This study signifies the importance of post-transcriptional regulation in controlling developmental potential and provides a powerful model system for studying the process of human pre-implantation development in vitro.

关键词： inhibiting implantation

Sin1/mTORC2 regulate B cell growth and metabolism by activating mTORC1 and Myc

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Cellular & Molecular Immunology 2019年第9期16卷 757-769页

作者： Man Li Adam S.Lazorchak Xinxing Ouyang Huihui Zhang Hongzhi Liu Omotooke A.Arojo Lichong Yan Jingsi Jin Yuheng Han Guojun Qu Yuhong Fu Xiaocao Xu Xiaobo Liu Wenqian Zhang Zhengfeng Yang Chuan Ruan Qijun Wang Dou Liu Chuanxin Huang Lu Lu Shibo Jiang Fubin Li Bing Su Shanghai Institute of Immunology Department of Immunology and MicrobiologyKey Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of EducationShanghai Jiao Tong University School of MedicineShanghai 200025China Department of Immunobiology and the vascular biology and therapeutics program Yale University School of Medicine333 Cedar StreetNew HavenConnecticut 06520USA Present address:EMD Serono Research&Development Institute Inc.45 Middlesex TpkeBillericaMA 01821–3936USA Hongqiao International Institute of Medicine Shanghai Tongren Hospital and Faculty of Basic MedicineShanghai Jiao Tong University School of MedicineShanghai 200025China Shanghai Public Health Clinical Center and School of Basic Medical Sciences Key Laboratory of Medical Molecular Virology of MOE/MOHFudan UniversityShanghaiChina

Proper control of B cell growth and metabolism is crucial for B-cell-mediated immunity,but the underlying molecular mechanisms remain incompletely *** this study,Sin1,a key component of mTOR complex 2(mTORC2),specifically regulates B cell growth and *** ablation of Sin1 in B cells reduces the cell size at either the transitional stage or upon antigen stimulation and severely impairs ***1 deficiency also severely impairs B-cell proliferation,antibody responses,and anti-viral *** the molecular level,Sin1 controls the expression and stability of the c-Myc protein and maintains the activity of mTORC1 through the Akt-dependent inactivation of GSK3 and TSC1/2,***,our study reveals a novel and specific role for Sin1 in coordinating the activation of mTORC2 and mTORC1 to control B cell growth and metabolism.

关键词： metabolism immunity stimulation

Hypoxia Enhances the Therapeutic Potential of Superparamagnetic Iron Oxide-labeled Adipose-derived Stem Cells for Myocardial Infarction

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2017年第4期37卷 516-522页

作者：王剑向波邓继先林宏宇 Darren H.Freed Rakesh C.Arora 田钢虹 Department of vascular Surgery Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430022China National Research Council of Canada Winnipeg R3B 1Y6Canada Department of Physiology Faculty of MedicineUniversity of ManitobaWinnipeg R3E 3P5Canada Department of Pharmacology and therapeutics Faculty of MedicineUniversity of ManitobaWinnipeg R3E OT6Canada Division of Cardiac Surgery University of Alberta Hospital Edmonton T6G 2B7Canada Cardiac Science program Institute of Cardiovascular ScienceSt.Boniface General Hospital Winnipeg R2H 2A6Canada

Adipose-derived stem cells（ASCs） induce therapeutic angiogenesis due to pro-angiogenic cytokines secretion. Superparamagnetic iron oxide（SPIO） nanoparticles are critical for magnetic resonance（MR） tracking of implanted cells. Hypoxia is a powerful stimulus for angiogenic activity of ASCs. In this study, we investigated whether therapeutic potency could be enhanced by implantation of hypoxia-preconditioned SPIO-labeled ASCs（SPIOASCs） into the infarcted myocardium. ASCs and SPIOASCs were cultured under 2% O_2（hypoxia） or 95% air（normoxia）. Cells were intramyocardially injected into the infarcted myocardium after 48-h culture. We found that hypoxia culture increased the m RNA expression of hypoxia-inducible factor-1 alpha（HIF-1α） and vascular endothelial growth factor（VEGF） in ASCs and SPIOASCs. The VEGF protein in the conditioned medium was significantly higher in hypoxic ASCs and SPIOASCs than in normoxic ASCs and SPIOASCs. The capillary density and left ventricular contractile function in the infarcted myocardium were significantly higher 4 weeks after implantation with hypoxic ASCs and SPIOASCs than with normoxic ASCs and SPIOASCs. Improvement in the capillary density and left ventricle function didn＇t differ between hypoxic ASCs-transplanted rats and hypoxic SPIOASCs-transplanted rats. Hypoxic culture enhanced the angiogenic efficiency of ASCs. It was concluded that implantation of hypoxic ASCs or SPIOASCs promotes therapeutic angiogenesis and cardiac function recovery in the infarcted myocardium. SPIO labeling does not impact the beneficial effect of hypoxic ASCs.

关键词： hypoxia adipose-derived stem cells superparamagnetic iron oxide myocardial infarction

Involvement of the TAGE-RAGE system in non-alcoholic steatohepatitis: Novel treatment strategies

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World Journal of Hepatology 2014年第12期6卷 880-893页

作者： Masayoshi Takeuchi Jun-ichi Takino Akiko Sakasai-Sakai Takanobu Takata Tadashi Ueda Mikihiro Tsutsumi Hideyuki Hyogo Sho-ichi Yamagishi Department of Advanced Medicine Medical Research Institute Kanazawa Medical University Uchinadamachi Ishikawa 920-0293 Japan Laboratory of Biochemistry Faculty of Pharmaceutical Sciences Hiroshima International University Kure Hiroshima 737-0112 Japan Department of Hepatology Kanazawa Medical University Uchinada-machi Ishikawa 920-0293 Japan Department of Gastroenterology and Metabolism Hiroshima University Hospital Hiroshima 734-8551 Japan Department of Pathophysiology and therapeutics of Diabetic vascular Complications Kurume University School of Medicine Kurume Fukuoka 830-0011 Japan

Non-alcoholic fatty liver disease(NAFLD)is a major cause of liver disease around the *** includes a spectrum of conditions from simple steatosis to non-alcoholic steatohepatitis(NASH)and can lead to fibrosis,cirrhosis,liver failure,and/or hepatocellular *** is also associated with other medical conditions such as obesity,diabetes mellitus(DM),metabolic syn-drome,hypertension,insulin resistance,hyperlipidemia,and cardiovascular disease(CVD).In diabetes,chronic hyperglycemia contributes to the development of both macro-and microvascular conditions through a variety of metabolic ***,it can cause a variety of metabolic and hemodynamic conditions,including upregulated advanced glycation end-products(AGEs)*** our previous study,the most abundant type of toxic AGEs(TAGE);i.e.,glyceraldehyde-derived AGEs,were found to make a significant contribution to the pathogenesis of DM-induced ***,accumulating evidence suggests that the binding of TAGE with their receptor(RAGE)induces oxidative damage,promotes inflammation,and causes changes in intracellular signaling and the expression levels of certain genes in various cell populations including hepatocytes and hepatic stellate *** of these effects could facilitate the pathogenesis of hypertension,cancer,diabetic vascular complications,CVD,dementia,and ***,inhibiting TAGE synthesis,preventing TAGE from binding to RAGE,and downregulating RAGE expression and/or the expression of associated effector molecules all have potential as therapeutic strategies against ***,we examine the contributions of RAGE and TAGE to various conditions and novel treatments that target them in order to prevent the development and/or progression of NASH.

关键词： Non-alcoholic fatty liver disease Non-alcoholic steatohepatitis Advanced glycation end-products Toxic advanced glycation end-products Receptor for advanced glycation end-products Toxic advanced glycation end-products-receptor for advanced glycation end-products system Diabetes mellitus Cardiovascular disease Dietary fructose Dietary advanced glycation end-products

Natural,synthetic and commercially-available biopolymers used to regenerate tendons and ligaments

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Bioactive Materials 2023年第1期19卷 179-197页

作者： Behzad Shiroud Heidari Rui Ruan Ebrahim Vahabli Peilin Chen Elena M.De-Juan-Pardo Minghao Zheng Barry Doyle vascular Engineering Laboratory Harry Perkins Institute of Medical ResearchQEII Medical Centre and the UWA Centre for Medical ResearchThe University of Western AustraliaNedlands6009Australia School of Engineering The University of Western AustraliaPerthAustralia Australian Research Council Centre for Personalised therapeutics Technologies Australia Division of Surgery(Orthopaedics) Medical SchoolThe University of Western AustraliaPerthAustralia T3mPLATE Harry Perkins Institute of Medical ResearchQEII Medical Centre and the UWA Centre for Medical ResearchThe University of Western AustraliaNedlands6009Australia Science and Engineering Faculty Queensland University of TechnologyBrisbaneQueenslandAustralia Perron Institute for Neurological and Translational Science Nedlands6009Australia BHF Centre for Cardiovascular Science The University of EdinburghUK

Tendon and ligament(TL)injuries affect millions of people *** play a significant role in TL tissue repair,whether the treatment relies on tissue engineering strategies or using artificial tendon *** biopolymer governs the mechanical properties,biocompatibility,degradation,and fabrication method of the TL *** natural,synthetic and hybrid biopolymers have been studied in TL regeneration,often combined with therapeutic agents and minerals to engineer novel scaffold ***,most of the advanced biopolymers have not advanced to clinical use ***,we aim to review recent biopolymers and discuss their features for TL tissue *** introducing the properties of the native tissue,we discuss different types of natural,synthetic and hybrid biopolymers used in TL tissue ***,we review biopolymers used in commercial absorbable and non-absorbable TL ***,we explain the challenges and future directions for the development of novel biopolymers in TL regenerative treatment.

关键词： Synthetic biopolymers Natural biopolymers Hybrid composites Tendon scaffolds Commercial grafts

Central nervous system and peripheral cell labeling by vascular endothelial cadherin-driven lineage tracing in adult mice

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Neural Regeneration Research 2020年第10期15卷 1856-1866页

作者： Alejandro Soto-Avellaneda Brad E.Morrison Biomolecular Ph.D.program Boise State UniversityBoiseIDUSA Department of Biological Sciences Boise State UniversityBoiseIDUSA

Understanding the contribution of endothelial cells to the progenitor pools of adult tissues has the potential to inform therapies for human *** address whether endothelial cells transdifferentiate into non-vascular cell types,we performed cell lineage tracing analysis using transgenic mice engineered to express a fluorescent marker following activation by tamoxifen in vascular endothelial cadherin promoter-expressing cells(VEcad-CreERT2;B6 Cg-Gt(ROSA)26Sortm9(CAG-tdTomato)Hze).Activation of target-cell labeling following 1.5 months of ad libitum feeding with tamoxifen-laden chow in 4–5 month-old mice resulted in the tracing of central nervous system and peripheral cells that include:cerebellar granule neurons,ependymal cells,skeletal myocytes,pancreatic beta cells,pancreatic acinar cells,tubular cells in the renal cortex,duodenal crypt cells,ileal crypt cells,and hair follicle stem *** Nestin expression has been reported in a subset of endothelial cells,Nes-CreERT2 mice were also utilized in these *** tracing of cells in adult Nes-CreERT2 mice revealed the labeling of canonical progeny cell types such as hippocampal and olfactory granule neurons as well as ependymal ***,Nestin tracing also labeled skeletal myocytes,ileal crypt cells,and sparsely marked cerebellar granule *** findings provide support for endothelial cells as active contributors to adult tissue progenitor *** information could be of particular significance for the intravenous delivery of therapeutics to downstream endothelial-derived cellular *** animal experiments were approved by the Boise State University Institute Animal Care and Use Committee(approval No.006-AC15-018)on October 31,2018.

关键词： endothelial lineage tracing progenitor cells transdifferentiation ve-cadherin

Left atrial enlargement and non-paroxysmal atrial fibrillation as risk factors for left atrial thrombus/spontaneous Echo contrast in patients with atrial fibrillation and low CHA2DS2-VASc score

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Journal of Geriatric Cardiology 2020年第3期17卷 155-159页

作者： Wei-Dong LIN Yu-Mei XUE Fang-Zhou LIU Xian-Hong FANG Xian-Zhang ZHAN Hong-Tao LIAO Gary Tse Shu-Lin WU Guangdong Cardiovascular Institute Guangdong General HospitalGuangzhouChina Department of Medicine and therapeutics Faculty of MedicineChinese University of Hong KongHong KongChina Li Ka Shing Institute of Health Sciences Faculty of MedicineChinese University of Hong KongHong KongChina

Objective To determine the risk factors for thromboembolism in lower risk patients with non-valvular atrial fibrillation(AF)and low CHA2DS2-VASc scores,which remain *** We retrospectively analyzed the baseline clinical characteristics,routine laboratory parameters,and echocardiographic measurements of 705 patients(71.1%male;mean age:52.10±9.64 years)with low CHA2DS2-VASc score(0 or 1;1 point for female sex)out of 1346 consecutive patients with non-valvular AF who underwent transesophageal echocardiography(TEE)at Guangdong Cardiovascular Institute between January 2013 and December *** Patients with left atrial thrombus(LAT)or spontaneous echo contrast(SEC)on TEE(24/705,4%)showed a higher incidence rate of vascular disease(54.2%vs.32.9%,P=0.045)and non-paroxysmal AF(79.2%vs.29.4%,P<0.001),larger left atrial diameter(43.08±4.59 vs.36.02±5.53 mm,P<0.001),and lower left ventricular ejection fraction(58.23±8.82%vs.64.15±7.14%,P<0.001)than those *** logistic regression analysis identified left atrial diameter[odds ratio(OR)=1.171,95%confidence interval(CI):1.084–1.265,P<0.001]and non-paroxysmal AF(OR=3.766,95%CI:1.282–11.061,P=0.016)as independent risk factors for LAT/*** ROC curve analysis,a left atrial dimeter cutoff of 37.5 mm yielded 95.0%sensitivity and 62.7%specificity(AUC:0.847,P<0.0001,95%CI:0.793–0.914).Conclusion In patients with non-valvular AF with low CHA2DS2-VASc score,the presence of LAT or SEC was associated with left atrial enlargement,which had moderate predictive value,and non-paroxysmal AF.

关键词： Atrial fibrillation Left atrial diameter Left atrial spontaneous echo contrast Left atrial thrombus