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Lianchun Wang
Associate Professor of Biochemistry and Molecular Biology; Georgia Cancer Coalition Scholar


Heparan sulfate proteoglycan in angiogenesis, stem cell, hemostasis and leukocyte trafficking/inflammation.

E-mail: lwang@ccrc.uga.edu
Telephone: 706-542-6445
Fax: 706-542-4412

Short Biography
Research Interests
Publications

Short Biography:
Dr. Wang has extensive training and working experience in angiogenesis, inflammation, stem cell, cancer and blood coagulation. He received his Bachelors of Medicine (Experimental Medicine) and Masters of Science degrees from Hunan Medical University (Now Xiangya Medical School of Central South University), China. In 1999, he obtained his medical degree from Heidelberg University, Germany. After receiving his MD degree, Dr. Wang became a postdoctoral researcher in Jeffrey Esko's group in the Department of Cellular and Molecular Medicine, University of California San Diego. Dr. Wang was appointed Assistant Professor at the University of Georgia in August 2006 and was promoted to associate professor in 2012. Full publications: 56

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Research Interests:

Angiogenesis. One of the major research goals in our lab is to understand the functions and the underlying cellular and molecular mechanism of heparan sulfate (HS) proteoglycans in angiogenesis, the process to form new blood vessels. By generating and examining serial gene knockout mice, our studies uncovered that the axon guidance Slit3-Robo4 signaling is a novel proangiogenic pathway [Zhang B., et al (2009). Blood 114(19): 4300-9.] and endothelial HS facilitates the Slit3-Robo4 signaling to promote vascular development [Wang L, et al (2005). Nat Immunol. 6(9): 902-10; Zhang B, et al. (2014). J Clin Invest. 124(1): 209-21; Qiu H, et al (2015). Methods Mol Biol. 1229: 549-55.]. The latter studies provided the first evidence that endothelial HS essentially modulates vascular development and also revealed a novel link of HS deficiency via disruption of Slit3-Robo4 signaling to human disease, the “congenital diaphragm hernia”. Our studies also uncovered that endothelial HS is essentially required for tumor angiogenesis by enhancing VEGF signaling [Fuster MM, et al. (2007). J Cell Biol. 177: 539-49.] and suggested that endothelial HS may modulate additional angiogenic signaling, such as IGF-1 and hypoxia, to facilitate angiogenesis too [Qiu H. et al. (2013). Mol Cell Proteomics 12(8): 2160-73.]. In ongoing studies we are proceeding to determine how the Slit3-Robo4 signaling is finely tuned and to elucidate the major HS-modulating signaling pathways in physiological and pathological angiogenesis. We are also exploring targeting HS for treatment of related human diseases.

Stem cell biology. Embryonic stem cells are special cell types that are distinguished by their characteristics of self-renewal and pluripotency. Self-renewal allows embryonic stem cells to proliferate indefinitely in their undifferentiated state, whereas pluripotency implies their capacity to differentiate into the three germ layers and ultimately into all cell types of the adult body. Both traits are tightly regulated by numerous cell signaling pathways. Our recent studies discovered that HS is dispensable for mouse embryonic stem self-renewal, but is essentially required for the cells to commit to differentiation and to differentiate into mesoderm cell lineage [Kraushaar DC et al. (2010). J Biol Chem. 285(8): 5907-16; Kraushaar DC et al (2012). J Biol Chem. 287(27): 22691-700; Kraushaar DC and Wang L (2013). Biol Chem. 394(6): 741-51], highlighting key regulatory roles of HS in stem cell function. Our ongoing studies are advancing to investigate the functions and the regulatory mechanisms of HS on tissue-specific stem cells with major interests in bone marrow and tumor microenvironment.

Hemostasis (Blood coagulation). Our previous studies examined the interaction of the anticoagulant drug – heparin – with heparin-binding protein histidine-rich glycoprotein and with anti-heparin antibodies in heparin-induced thrombocytopenia patients. Our recent studies uncovered that the axon guidance molecule Slit3 strongly binds heparin, and its C-terminal fragment potentially neutralizes heparin`s anticoagulant activity, remerging a potential to develop the C-terminal fragment as a heparin blocker for clinical application [Condac E. et al. (2012). Glycobiology 22(9): 1183-92]. Recently we have started to examine the interaction of heparin/HS with protein ligands at the single molecule level [Guo CL, et al. (2012). Chem Commun.(Camb). 48(100): 12222-4]. Particularly, we examined this interaction on the endothelial cell surface under physiological conditions and discovered that endothelial HS contains at least three types of antithrombin-binding sites [Guo CL. et al. (2015). Phys Chem Chem Phys. 17(20): 13301-6]. Currently we are proceeding to test the long-prevailing hypothesis that endothelial HS is a key natural anticoagulant molecule in hemostasis using cell-based in vitro studies and in in vivo mouse models, and to explore development of HS analogs to improve current antithrombotic therapeutics.

Leukocyte trafficking and inflammation. Our previous studies elucidated that inhibition of both P- and L-selectin function represents the major molecular mechanism underlying the potent anti-inflammatory effect of heparin and determined the structure-function relationship of heparin`s anti-inflammatory role [Wang L, et al. (2002). J Clin Invest. 110:127-36.], and also uncovered that endothelial HS functions to facilitate neutrophil trafficking in inflammation via multiple molecular mechanisms including interaction with L-selectin expressed by neutrophils, immobilizing chemokine on the endothelial luminal cell surface and mediating abluminal-to-luminal chemokine transcytosis [Wang L. et al. (2005). Nat Immunol. 6(9): 902-10. NEWS and VIEWS in Nat Immunol. (2005). 6(9): 861-2; Zhang SY, et al. (2012). J Biol Chem. 287(8): 5542-53]. Currently, we are investigating the HS structure required to mediate leukocyte trafficking in vivo and are developing HS analogs for treatment of inflammatory diseases.

Publications since 2002:

Guo CL, Fan X, Qiu H, Xiao WY, Wang LC, Xu BQ (2015). High-resolution probing heparan sulfate-antithrombin interaction on single endothelial cell surface: Single-molecule AFM studies. Phys Chem Chem Phys. 17(20): 13301-6.

Qiu, H, Xia WY, Yue JW, Wang LC (2015). Heparan sulfate modulates Slit3-induced endothelial cell migration. Methods Mol Biol. 1229: 549-55.

Chuang YJ, Zhen ZP, Zhang F, Liu F, Mishra JP, Tang W, Chen HM, Huang XL, Wang LC, Chen XY, Xie J, Pan ZW (2014). Novel photostimulable near-infrared persistent luminescent nanprobes for ultrasensitive and longitudinal deep-tissue bioimaging. Theranostics 4(11): 1112-22.

Zhang B, Xiao WY, Qiu H, Zhang FM, Moniz HA Condac E, Gutierrez-Sanchez G, Heiss C, Clugston RD, Azadi P, Greer JJ, Bergmann C, Moremen KW, Li D, Linhardt RJ, Esko JD, Wang LC (2014). Heparan sulfate deficiency disrupts developmental angiogenesis and causes congenital diaphragmatic hernia. J Clin Invest. 124(1): 209-221.

Zhen ZP, Tang W, Chuang YJ, Todd T, Zhang WZ, Lin X, Niu G, Liu G, Wang LC, Pan ZW, Chen XY, Xie J (2014). Tumor vasculature targeted photodynamic therapy for enhanced delivery of nanoparticles. ACS Nano 8(6): 6004-13.

Zhang FM, Moniz HA, Moremen KW, Wang LC, Linhardt RJ (2014). Analysis of the impact of GFP tagging on protein-heparin interaction by surface plasmon resonance. Glycoconjugate J. 31(4): 299-307.

Zhang FM, Moniz HA, Walcott B, Moremen KW, Linhardt RJ, Wang LC (2013). Characterization of the interaction between Robo1 and heparin and other glycosaminoglycans. Biochimie 95(12): 2345-53.

Chen HM, Zhen ZP, Tang W, Todd T, Chuang JY, Tang W, Wang LC, Pan Z, and Xie J (2013). Label-free mesoporous silica nanparticles for fluorescence imaging and drug delivery. Theranostics 3(9): 650-7.

Qiu H, Jiang JL, Liu M, Huang X, Ding SJ, Wang LC (2013). Quantitative phosphoproteomics analysis reveals broad regulatory role of heparan sulfate on endothelial signaling. Mol Cell Proteomics 12(8): 2160-73.

Kraushaar DC, Wang LC (2013). Heparan sulfate: a key regulator of embryonic stem cell fate. Biol Chem. 394(6): 741-51.

Guo CL, Wang B, Wang LC, Xu BQ (2012). Structural basis of single molecular heparin-FX06 interaction revealed by SPM measurements and molecular simulations. Chem Commun. 48(100): 12222-4.

Condac E, Strachan H, Gutierrez-Sanchez G, Brainard BM, Giese C, Heiss C, Johnson D, Azadi P, Bergmann C, Orlando R, Esmon C, Harenberg J, Moremen K, Wang LC (2012). C-terminal of Slit3 binds heparin and neutralizes heparin`s anticoagulant activity. Glycobiology 22(9): 1183-92.

Kraushaar DC, Rai S, Condac E, Nairn A, Zhang SY, Yamaguchi Y, Moremen K, Dalton S, Wang LC (2012). Heparan sulfate facilitates FGF and BMP signaling to drive mesoderm differentiation of mouse embryonic stem cells. J Biol Chem. 287(27): 22691-700.

Zhang S, Condac E, Qiu H, Jiang J, Gutierrez-Sanchez G, Bergmann C, Handel T, Wang LC (2012). Heparin-induced leukocytosis requires 6-O-sulfation and is caused by blockade of Selectin- and CXCL12-mediated leukocyte trafficking in mice. J Biol Chem. 287: 5542-53.

Zhou B, Honor LB, He H, Ma Q, Oh JH, Butterfield C, Lin RZ, Melero-Martin JM, Dolmatova E, Duffy HS, Gise AV, Zhou P, Hu YW, Wang G, Zhang B, Wang LC, Hall JL, Moses MA, McGowan FX, Pu WT (2011). Adult mouse epicardium modulates myocardial injury by secreting paracrine factors. J Clin Invest. 121(5): 1894-904.

Fuster MM, Wang LC (2010). Endothelial heparan sulfate in angiogenesis. Prog Mol Biol Transl Sci. 93C: 179-212.

Kumar A, Hou Xu, Lee C, Li Y, Maminsishkis A, Tang Z, Zhang F, Langer H, Arjunan P, Dong L, Wu Z, Zhu LY, Wang LC, Wang M, Colosi P, Chavakis T, Li X (2010). PDGF-DD targeting arrests pathological angiogenesis by modulating GSK3β phosphorylation. J Biol Chem. 285(20): 15500-10.

Wijelath E, Namekata M, Murray J, Furuyashiki M, Zhang S, Coan D, Wakao M, Harris RB, Suda Y, Wang LC, Sobel M (2010). Multiple mechanisms for exogenous heparin modulation of vascular endothelial growth factor activity. J Cell Biochem. 111(2): 461-8.

Pomin VH, Sharp J, S, Li XY, Wang LC, Prestegard JH (2010). Characterization of Glycosaminoglycans by 15N-NMR Spectroscopy and in vivo isoltopic labeling. Anal Chem. 82(10): 4078-88.

Kraushaar DC, Yamaguchi Y and Wang LC (2010). Heparan sulfate is required for embryonic stem cells to exit from self-renewal. J Biol Chem. 285(8): 5907-16.

Stanford KI, Wang LC, Castagnola J, Song D, Bishop JR, Brown JR, Lawrence R, Bai X, Habuchi H, Tanaka M, Cardoso WV, Kimata K and Esko JD (2010). Heparan sulfate 2-O-sulfotransferase is required for triglyceride-rich lipoprotein clearance. J Biol Chem. 285(1): 286-94.

Zhang B, Dietrich UM, Geng JG, Bicknell R, Esko JD, and Wang LC (2009). Repulsive axon guidance molecule Slit3 is a novel angiogenic factor. Blood 114(19): 4300-9.

Lawrence R, Olson Sk, Steele RE, Wang LC, Warrior R, Cummings RD and Esko JD (2008). Evolutionary differences in glycosaminoglycan fine structure detected by quantitative glycan reductive isotope labeling. J Biol Chem. 283(48): 33674-84.

Schuksz M, Fuster M, Brown JR, Crawford BE, Ditto DP, Lawrence R, Glass CA, Wang LC, Elson-Schwab L, Tor Y, Esko JD (2008). Surfen, a small molecule antagonist of heparan sulfate. Proc Natl Acad Sci USA 105(35): 13075-80.

Cai CL, Martin JC, Sun YF, Cui L, Wang LC, Yang L, Liang XQ, Stallcup WB, Denton CP, McCulloch A, Chen J, Evans SM (2008). A myocardial lineage derives from Tbx18 epicardial cells. Nature 354(7200): 104-8. (*, co-first author).

Borsig L*, Wang LC*, Cavalcante MC, Cardilo-Reis L, Ferreira PL, Mourao PA, Esko JD, Pavao MS (2007). Selectin-blocking activity of a fucosylated chondroitin sulfate glycosaminoglycan from sea-cucumber: Effect on tumor metastasis and neutrophil recruitment. J Biol Chem. 282(20): 14984-91.(*, co-first author).

Fuster MM, Wang LC, Catagnola J, Sikora L, Reddi K, Lee PH, Radel KA, Schuksz M, Bishop JR, Gallo RL, Sriramaro P, Esko JD (2007). Genetic alteration of endothelial heparan sulfate selectively inhibits tumor angiogenesis. J Cell Biol. 177: 539-549.

Macarthur JM, Bishop JR, Stanford KI, Wang LC, Bensadoun A, Witztum JL, Esko JD (2007). Liver heparan sulfate proteoglycans mediate clearance of triglyceride-rich lipoproteins independently of LDL receptor family members. J Clin Invest. 117(1): 153-164.

Wang LC, Fuster MM, Sriramarao P, Esko JD (2005). Endothelial deficiency of heparan sulfate impairs L-selectin and chemokine mediated neutrophil trafficking during inflammatory responses. Nat Immunol. 6: 902-910.

Rele SM, Cui W, Wang LC, Hou S, Barr-Zarse G, Tatton D, Gnanou Y, Esko JD and Chaikof EL (2005). Dendrimer-like PEO glycopolymers exhibit anti-inflammatory properties. J Am Chem Soc. 127: 10132-10133.

Tang N, Wang LC, Esko JD, Giordano FJ, Huang Y, Gerber H, Ferrara N, Johnson RS (2004). Loss of HIF-1α in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis. Cancer Cell 6: 485-495.

Bobardt MD, Salmon P, W Wang LC, Esko JD, Gabuzda D, Fiala M, Trono D, Van der Schueren B, David G, Gallay PA (2004). Contribution of proteoglycans to human immunodeficiency virus type 1 brain invasion. J Virol. 78: 6567-6584.

Fuster MM, Brown JR, Wang LC, and Esko JD (2003). A disaccharide precursor of sialyl Lewis X inhibits the metastatic potential of tumor cells. Cancer Res. 63: 2775-2781.

Wang LC, Brown JR, Varki A. and Esko JD (2002). Heparin’s anti-inflammatory effects require glucosamine 6-O-sulfation and are mediated by blockade of L- and P-selectins. J Clin Invest. 110: 127-136.

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Publications: Author's Last Name: Wang

Journal Articles
Book Chapters are listed at the bottom of this page.

Book Chapters

L. Wang. 2009. Glycans in inflammation and angiogenesis. In: Glycans in Diseases and Terapeutics Research Signpost, In press.

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