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The William Harvey Research Institute - Barts and The London

Professor Qingzhong Xiao, MD, PhD

Qingzhong

Professor of Stem Cell and Cardiovascular Disease

Centre: Clinical Pharmacology

Email: q.xiao@qmul.ac.uk
Telephone: +44(0) 20 7882 6584

Profile

ORCID iD: https://orcid.org/0000-0001-9101-0498 

I obtained my Bachelor degree in medicine from Chongqing University of Medical Sciences, China, in 1994. Subsequently, he worked as Teaching Assistant at the Department of Laboratory Medicine, Guangzhou Medical College, and promoted to Lecturer in Clinical Microbiology and Immunology in 1999. In the meantime, I obtained my Master Degree in Medical Immunology and Doctoral Degree (PhD) in Pathology and Pathophysiology in 1999 and 2003, respectively, at Sun Yat-Sen Medical College, Sun Yat-Sen University, Guangzhou, China. I joined Professor Qingbo Xu’s group at St Georges’ (2003-2006) and King’s College London (2006-2009), University of London, UK, working as a postdoctoral research fellow and research associate, where I established novel approaches to successfully induce embryonic stem cell differentiate toward vascular endothelial cells and smooth muscle cells and investigated the therapeutic effects of stem cell-derived vascular cells in the cardiovascular diseases, such as damaged/injured vessels.

In 2010, as the recipient of British Heart Foundation (BHF) Intermediate Basic Science Research Fellowship I joined William Harvey Research Institute (WHRI) to expand and fulfil my research ambition in stem cell biology, genetics and cardiovascular diseases. Since then, supported by the BHF fellowship and project grants, I have set-up my independent research laboratory (Stem Cell and Cardiovascular Disease) at WHRI. I was promoted to Senior Lecturer and Reader in Stem Cell and Cardiovascular Disease in 2013 and 2016, respectively, and became Professor (Chair) of Stem Cell and Cardiovascular Disease in 2018.   

My long-term research aim is to uncover the critical signal pathways that govern vascular development, identify the key molecules that control cardiovascular disease progression, and further develop them into a more effective therapeutic for cardiovascular disease.

Research

Current Group Members:

Dr Wei Wu (PDRA, 2018~), Dr Weiwei An (PDRA, 2015~), Miss Eithne Margaret Maguire (PhD student, 2016~), Mr Shiping He (PhD student, 2015~), Mr Stuart William Alfred Pearce (PhD Student, 2015~), Mr Tayyab A. Afzal (Part-time PhD Student, 2013~), Miss Mei Yang (PhD Associate, 2018~), Mr Ian Jay (Laboratory Manager).

Previous PDRAs/PhD Students/Visitors:

Dr Iliana Fauzi (PDRA, 2016~2018), Dr Le Anh Luong (PDRA, 2013~2017), Dr Guanmei Wen (PDRA, 2012~2015), Dr Feng Yang (PhD student; Awarded: 2017), Dr Xiaotian Yu (PhD student; Awarded: 2015), Dr Hanqing Zhao (PhD student; Awarded: 2015), Dr Qishan Chen (Joint PhD student; Awarded: 2015), Dr Yuan Huang (Joint PhD student; Awarded: 2014), Dr Anna E. Pepe (PhD student, Awarded: 1999), Dr Gang Wang (PhD student; Awarded: 2011), Dr Zhenling Luo (PhD student; Awarded: 2011), Dr Jiangyong Chen (Academic Visitor, 2016~2017), Dr Dan Chen (Academic Visitor, 2015~2016), Dr Cheng Zhang (Academic Visitor, 2014~2015), Dr Luyang Lin (Academic Visitor, 2012~2013).

Summary 

Unravelling novel molecular mechanisms underlying vascular cell differentiation from stem/progenitor cells

One of our main research interests is specifically focussed on the study of identifying novel targets/molecules and/or signalling pathways, such as microRNAs, transcription factors, and other molecules, which are crucial for vascular endothelial cell (EC) and smooth muscle cell (SMC) differentiation from murine/human pluripotent stem cells (ESCs: embryonic stem cells; iPSCs: induced pluripotent stem cells) as well as adult stem/progenitor cells including blood vessel wall stem cells. By establishing a simple but very efficient vascular cell differentiation model(s), we are the first to report that matrix protein Collagen-IV, Nox4, Nrf3, Pla2g7, HDAC3, HDAC7, Cbx3, hnRNPA1, hnRNPA2B1, microRNA-34a, and miR-22 play a regulatory role in vascular cell differentiation from ESCs or adult stem/progenitor cells. We will continue exploring the underlying signal pathways of vascular cell differentiation from murine/human iPSCs, and its implications in vascular diseases. Our findings provide useful mechanistic insights into stem cell differentiation toward vascular endothelial cells and smooth muscle cells, and could significantly enhance the knowledge of stem cell biology and vascular biology, such as stem cell differentiation and self-renewal, vasculogenesis, angiogenesis, and vascular repair.

Stem/progenitor cells (SPCs) and cardiovascular diseases (CVD) 

Atherosclerosis is the underlying cause of CVDs. Growing evidence indicates that SPCs play a crucial role in the development of atherosclerosis and heart disease. Using various mouse models and human tissue samples, we are studying the contribution of SPCs to the pathogenesis of atherosclerosis, uncovering the novel mechanisms of SPC differentiation into endothelial and smooth muscle cells, and investigating a potential use of stem cell therapy for vascular disease.

Identifying and exploring the potential novel therapeutic targets for cardiovascular diseases

CVD is still the number one killer. Accumulating evidence indicates that different proteases such as matrix metalloproteinases (MMPs) and neutrophil elastase (NE) play an important and distinct role in the development of atherosclerotic lesions and atheromatous plaque rupture. However, its functional role and underlying molecular mechanism remain to be explored. Our group have become very focused on the investigating the underlying molecular mechanisms of SPC migration into atherosclerotic lesion and its relevance in the development of vascular diseases. We have recently demonstrated for the first time that MMP8 plays a causal role in atherosclerosis and neointima SMC hyperplasia, and that MMP8 possesses a divergent and regulatory role in SPC migration into atherosclerotic lesions, angiogenesis, and macrophage differentiation/polarisation. Moreover, by using various animal models of cardiovascular diseases, we are exploring if the identified genes/molecules (e.g. miR-34a, miR-22, Nrf3, and hnRNPA1) from our abovementioned stem cell differentiation studies represent a novel therapeutic target for cardiovascular diseases. 

Cellular reprogramming and cardiovascular regeneration

Cellular reprogramming of somatic cells into pluripotent stem cells or other somatic cells has opened the new avenues of biomedical research and regenerative medicine. Endothelium dysfunction or damage is a hallmark of the onset of vascular diseases, and cell therapy strategies that aim to rapidly repair and restore vascular function are being increasingly explored as viable therapeutic avenues. Development of fast and robust new methodologies that produce well-characterised, homogenous, clinical-grade cells suitable for tissue repair/re-modelling would have great utility. One of our most recent research projects will be studying if the identified vascular cell differentiation genes from our stem cell studies could directly reprogram other somatic cells into functional vascular ECs and SMCs, and their therapeutic potential in vascular diseases.

Functional involvements of Non-coding RNAs in stem cell fate decision and vascular diseases

Recently, growing evidence has suggested that non-coding RNAs including microRNAs and long non-coding RNAs play crucial roles in embryonic development and various diseases. Thus, we are also interested in the significance of these molecules in stem cell pluripotency and vascular cell specifications, and their application in the prevention of vascular diseases.

Figures: 

Translating newly identified vascular development genes into therapeutics for treating vascular disease

During stem cell differentiation, instinct signal pathways composed of multiple genes are activated and by extinct stimuli/signalling pathways such as endoplasmic reticulum (ER) stress, reactive oxygen species (ROS) and/or auto-secreted growth factors (TGFβ1 and VEGF), respectively. After activation/up-regulation, they trigger/initiate vascular endothelial or smooth muscle cell differentiation. Stem cell-derived endothelial cells are the ideal cellular source for cardiovascular regeneration and engineered vascular grafts. Newly identified SMC differentiation regulators (e.g. miR-22, miR-34a, hnRNPA1, Cbx3) are the potential therapeutic targets for cardiovascular diseases (e.g. angioplasty-induced restenosis and atherosclerosis).

 

Proteinases (e.g, MMP8 and NE) and Vascular Disease

We are the first to confirm a causal effect for matrix metalloproteinase-8 (MMP8) in atherosclerosis. MMP8 controls atherosclerosis through 1) converting Angiotensin I (Ang I) to Ang II, which in turn regulates VCAM-1 in endothelium and increases recruitment of leukocytes into vascular wall, leading to vascular inflammation and atherosclerosis progression (Circ Res. 2009); 2) up-regulating CD31 in endothelial cells and augmenting atherosclerotic angiogenesis (Cardiovasc Res. 2013); 3) increasing bone marrow-derived stem/progenitor cell mobilisation into atherosclerotic plaque by cleaving ADAM10 and E-cadherin (Circ Res. 2013); 4) promoting angioplasty-induced restenosis by controlling smooth muscle cell behaviours (Arterioscler Thromb Vasc Biol., 2014); and 5) modulating macrophage differentiation & polarisation (J Biol Chem. 2015). Recently, we have demonstrated that another proteinase, Neutrophil Elastase (NE), also promotes atherosclerosis (J Am Heart Assoc. 2018), and we are currently investigating the underlying cellular & molecular mechanisms of atherosclerosis controlled by NE.    

Key Publications

For a full list of publications click here

 

  • Yang F, Chen Q, He S, Yang M, Maguire EM, An W, Afzal TA, Luong LA, Zhang L, Xiao Q. miR-22 Is a Novel Mediator of Vascular Smooth Muscle Cell Phenotypic Modulation and Neointima Formation. Circulation. 2018 Apr 24;137(17):1824-1841. doi: 10.1161/CIRCULATIONAHA.117.027799.
  • Wen G, An W, Chen J, Maguire EM, Chen Q, Yang F, Pearce SWA, Kyriakides M, Zhang L, Ye S, Nourshargh S, Xiao Q. Genetic and Pharmacologic Inhibition of the Neutrophil Elastase Inhibits Experimental Atherosclerosis. J Am Heart Assoc. 2018 Feb 8;7(4). pii: e008187. doi: 10.1161/JAHA.117.008187.
  • Zhang C, Chen D, Maguire EM, He S, Chen J, An W, Yang M, Afzal TA, Luong LA, Zhang L, Lei H, Wu Q, Xiao Q. Cbx3 inhibits vascular smooth muscle cell proliferation, migration, and neointima formation. Cardiovasc Res. 2018 Mar 1;114(3):443-455. doi: 10.1093/cvr/cvx236.
  • Zhang L, Chen Q, An W, Yang F, Maguire EM, Chen D, Zhang C, Wen G, Yang M, Dai B, Luong LA, Zhu J, Xu Q, Xiao Q. Novel Pathological Role of hnRNPA1 (Heterogeneous Nuclear Ribonucleoprotein A1) in Vascular Smooth Muscle Cell Function and Neointima Hyperplasia. Arterioscler Thromb Vasc Biol. 2017 Nov;37(11):2182-2194. doi: 10.1161/ATVBAHA.117.310020.
  • Wen G, Zhang C, Chen Q, Luong le A, Mustafa A, Ye S, Xiao Q. A Novel Role of Matrix Metalloproteinase-8 in Macrophage Differentiation and Polarization. J Biol Chem. 2015 Jul 31;290(31):19158-72.
  • Zhao H, Wen G, Huang Y, Yu X, Chen Q, Afzal TA, Luong le A, Zhu J, Ye S, Zhang L, Xiao Q. MicroRNA-22 regulates smooth muscle cell differentiation from stem cells by targeting methyl CpG-binding protein 2. Arterioscler Thromb Vasc Biol. 2015 Apr;35(4):918-29.
  • Yu X, Zhang L, Wen G, Zhao H, Luong LA, Chen Q, Huang Y, Zhu J, Ye S, Xu Q, Wang W, Xiao Q. Upregulated sirtuin 1 by miRNA-34a is required for smooth muscle cell differentiation from pluripotent stem cells. Cell Death Differ. 2015 Jul;22(7):1170-80.
  • Xiao Q, Zhang F, Grassia G, Hu Y, Zhang Z, Xing Q, Yin X, Maddaluno M, Drung B, Schmidt B, Maffia P, Ialenti A, Mayr M, Xu Q, Ye S. Matrix metalloproteinase-8 promotes vascular smooth muscle cell proliferation and neointima formation. Arterioscler Thromb Vasc Biol. 2014 Jan;34(1):90-8.
  • Luo Z, Wen G, Wang G, Pu X, Ye S, Xu Q, Wang W, Xiao Q. MicroRNA-200C and -150 play an important role in endothelial cell differentiation and vasculogenesis by targeting transcription repressor ZEB1. Stem Cells. 2013 Sep;31(9):1749-62.
  • Fang C, Wen G, Zhang L, Lin L, Moore A, Wu S, Ye S, Xiao Q. An important role of matrix metalloproteinase-8 in angiogenesis in vitro and in vivo. Cardiovasc Res. 2013 Jul 1;99(1):146-55.
  • Pu X*, Xiao Q*, Kiechl S, Chan K, Ng FL, Gor S, Poston RN, Fang C, Patel A, Senver EC, Shaw-Hawkins S, Willeit J, Liu C, Zhu J, Tucker AT, Xu Q, Caulfield MJ, Ye S. ADAMTS7 cleavage and vascular smooth muscle cell migration is affected by a coronary-artery-disease-associated variant. Am J Hum Genet. 2013 Mar 7;92(3):366-74. (*Joint first author)
  • Huang Y, Lin L, Yu X, Wen G, Pu X, Zhao H, Fang C, Zhu J, Ye S, Zhang L, Xiao Q. Functional involvements of heterogeneous nuclear ribonucleoprotein A1 in smooth muscle differentiation from stem cells in vitro and in vivo. Stem Cells. 2013 May;31(5):906-17.
  • Xiao Q, Zhang F, Lin L, Fang C, Wen G, Tsai TN, Pu X, Sims D, Zhang Z, Yin X, Thomaszewski B, Schmidt B, Mayr M, Suzuki K, Xu Q, Ye S. A Functional Role of Matrix Metalloproteinase-8 in Stem/Progenitor Cell Migration and Their Recruitment into Atherosclerotic Lesions. Circulation Research. 2013 Jan 4;112(1):35-47.
  • Xiao Q*, Pepe AE, Wang, G, Luo Z, Zhang L, Zeng L, Zhang Z, Hu Y, Ye S and Xu Q*. Nrf3-Pla2g7 Interaction Plays an Essential Role in Smooth Muscle Differentiation From Stem Cells. Arterioscler Thromb Vasc Biol. 2012; Mar;32(3):730-44 (*Joint correspondence author)
  • Xiao Q*, Wang G, Yin X, Luo Z, Margariti A, Zeng L, Mayr M, Ye S, Xu Q*. Chromobox protein homolog 3 is essential for stem cell differentiation to smooth muscles in vitro and in embryonic arteriogenesis. Arterioscler Thromb Vasc Biol. 2011 Aug;31(8):1842-52. (*Joint correspondence author)
  • Zhang L, Jin M, Margariti A, Wang G, Luo Z, Zampetaki A, Zeng L, Ye S, Zhu J, Xiao Q*(Correspondence author). Sp1-dependent activation of HDAC7 is required for platelet-derived growth factor-BB-induced smooth muscle cell differentiation from stem cells. J Biol Chem. 2010 Dec 3;285(49):38463-72.
  • Pepe AE, Xiao Q*(Correspondence and senior author), Kobayashi A, Hu Y, Xu Q. Crucial role of nrf3 in smooth muscle cell differentiation from stem cells. Circulation Research. 2010 Mar 19;106(5):870-9.
  • Margariti A*, Xiao Q* (*joint first authors), Zampetaki A, Zhang Z, Li H, Hu Y, Zeng L, Xu Q. Histone deacetylase 7 splicing modulates the SRF-myocardin complex during embryonic stem cell differentiation. J Cell Science 122:460-70; 2009.
  • Zeng L*, Xiao Q* (*joint first authors), Margariti A, Zhang Z, Patel S, Hu Y, Xu Q. HDAC3 is crucial in Shear- and VEGF-induced Stem Cells Differentiation toward Endothelial Cells. J. Cell Biology 174:1059-69; 2006.
  • Xiao Q, Zhang Z, Zeng L, Hu Y, Xu Q. Sca-1+ Progenitors Derived from Embryonic Stem Cells Differentiate into Endothelial Cells: Implications for Stem Cell-based Therapy in the Injured Artery. Arterioscler Thromb Vasc Biol 26:2244-51; 2006.

Sponsors

British Heart Foundation

Collaborators

Internal: Prof Shu Ye; Prof Wen Wang; Prof Sussan Nourshargh
 
External: Prof Qingbo Xu (Kings College); Prof Manuel Mayr (Kings College); Dr Lingfang Zeng (Kings College); Prof Jianhua Zhu (Zhejiang University, China); Dr Li Zhang (Zhejiang University, China); Prof  Guoan Luo (Tsinghua University, China).