|AFFILIATIONS||Professor, Vision Science Graduate Group, University of California at Berkeley
Professor, Center for Eye Disease & Development, Program in Vision Science, and School of Optometry, University of California at Berkeley
Adjunct Research Associate, Proctor Foundation for Research in Ophthalmology, University of California at San Francisco
Adjunct Scientist, Schepens Eye Research Institute, Mass Eye & Ear Infirmary, Harvard Medical School
|RESEARCH||Lymph and Blood Vascular Biology, Corneal Inflammation, Transplantation Immunity, and Glaucoma
Our research focuses on mechanisms and regulation of lymphangiogenesis and angiogenesis and implications in ocular diseases and disorders, such as inflammation, graft rejection, and glaucoma. A broad spectrum of model systems, techniques and methods are used in our research to investigate the dynamic processes of the vascular events, in vivo, in vitro and in real time.
Unlike blood vessels which have been studied extensively in the past, lymphatic research signifies an explosive field of new discovery in recent years. The cornea provides an ideal tissue for vascular research due to its accessible location, transparent nature, and vascular-free (under normal condition) but -inducible (after a pathological insult) features. Once induced by an inflammatory, infectious, immunogenic, traumatic, or chemical insult, corneal lymphatics enhance high volume delivery of antigens and immune cells, and mediate transplant rejection. Our long-term goal is to elucidate the underlying mechanisms governing lymphangiogenesis and angiogenesis and to identify novel targets for therapeutic intervention.
Research on corneal lymphatics bears broader implications beyond the treatment of corneal diseases alone. For example, we have recently discovered that the Schlemm’s canal, a critical structure of the aqueous humor outflow pathway, expresses Prox-1, a master control gene for lymphatic development. Further investigation may lead to new avenues for treating glaucoma, a major blinding disease worldwide. Moreover, the lymphatic network penetrates most tissues in the body, and its dysfunction has been found in a wide array of disorders which include but are not limited to cancer metastasis, major organ transplant rejection, inflammatory and immune diseases, obesity, hypertension, AIDS and lymphedema. It is hopeful that beyond its contributions to eye diseases, our research will offer new therapeutic strategies for lymphatic disorders in general. The combination of preclinical models and human cell culture systems should provide the most translational information for patient conditions.
Sessa R, Yuen D, Wan S, Roster M, Padmanaban P, Ge S, Smith A, Fletcher R, Baudhuin-Kessel A, Yamaguchi TP, Lang RA, Chen L. Monocyte-derived Wnt5a regulates inflammatory lymphangiogenesis. Cell Research. 2016; 26:262-265.
Kang GY, Ecoiffier T, Truong T, Yuen D, Li G, Lee N, Zhang L, Chen L. Intravital imaging reveals dynamics of lymphangiogenesis and valvulogenesis. Scientific Reports. 2016; 6:19459. DOI:10.1038/srep19459
Kang GY, Truong T, Huang E, Su V, Ge S, Chen L. Integrin alpha 9 blockade suppresses lymphatic valve formation and promotes transplant survival. Invest Ophthalmol Vis Sci. 2016; 57(14):5935–5939.
Zhang L, Li G, Sessa R, Kang GJ, Shi M, Ge S, Gong AJ, Wen Y, Chintharlapalli S, Chen L. Angiopoietin-2 blockade promotes survival of corneal transplants. Invest Ophthalmol Vis Sci. In press.
Sessa R, Chen L. Lymphangiogenesis – a new player in herpes simplex virus 1 triggered T cell response. Immunol. Cell Biol. In press.
Invited Commentary Article by the Editor.
Altiok E, Ecoiffier T, Sessa R, Yuen D, Grimaldo S, Tran C, Li D, Rosner M, Lee N, Uede T, Chen L. Integrin alpha-9 mediates lymphatic valve formation in corneal lymphangiogenesis. Invest Ophthalmol Vis Sci. 2015; 56:6313-6319.
Grimaldo S, Yuen D, Theis J, Ng M, Ecoiffier T, Chen L. MicroRNA-184 regulates corneal lymphangiogenesis. Invest Ophthalmol Vis Sci. 2015; 56:7209-7213.
Heindl LM, Kaser-Eichberger A, Schlereth SL, Bock F, Regenfuss B, Reitsamer HA, McMenamin P, Lutty GA, Maruyama K, Chen L, Dana R, Kerjaschki D, Alitalo K, De Stefano ME, Junghans BM, Schroedl F, Cursiefen C. Sufficient Evidence for Lymphatics in the Developing and Adult Human Choroid? Invest Ophthalmol Vis Sci. 2015; 56:6709-6710.
Bjanchi R, Fisher E, Yuen D, Ernst E, Chen L, Otto VI, Detmar M. Mutation of threonin 34 in mouse podoplanin-Fc reduces CLEC-2 binding and toxicity in vivo while retaining anti-lymphangiogenic activity. J Biol Chem. 2014; 289:21016-21027.
Truong T, Huang E, Yuen D, Chen L. Corneal lymphatic valve formation in relation to lymphangiogenesis. Invest Ophthalmol Vis Sci. 2014; 55:1876-1883.
Yuen D, Grimaldo S, Sessa R, Ecoiffier T, Truong T, Huang E, Bernas M, Daley S, Witte M, Chen L. Role of angiopoietin-2 in corneal lymphangiogenesis. Invest Ophthalmol Vis Sci. 2014; 55:3320-3327.
Truong TN, Li H, Hong YK, Chen L. Novel characterization and live imaging of Schlemm’s canal expressing Prox-1. PLoS One. 2014; 9:e98245.
Falk Schroedl, Alexandra Kaser-Eichberger, Simona Schlereth, Felix Bock, Birgit Regenfuss, Herbert Reitsamer, Gerard Lutty, Kazuichi Maruyama, Lu Chen, Elke Luetjen-Drecoll, Reza Dana, Dontscho Kerjaschki, Kari Alitalo, Maria Egle De Stafano, Barbara Junghans, Ludwig Heindl, Claus Cursiefen. Consensus statement on the immunohistochemical detection of ocular lymphatic vessels. Invest Ophthalmol Vis Sci. 2014; 55:6640-6642.
Iolyeva M, Aebischer D, Proulx,ST, Willrodt AH, Ecoiffier T, Häner S, Bouchaud G, Krieg C, Onder L, Ludewig B, Santambrogio L, Boyman O, Chen L, Finke D, Halin C. Interleukin-7 is produced by afferent lymphatic vessels and supports lymphatic drainage. Blood, 2013; 122:2271-2281.
Choi I, Lee YS, Chung HK, Choi D, Ecoiffier T, Lee HN, Kim KE, Lee S, Park EK, Maeng YS, Kim NY, Ladner RD, Petasis NA, Koh CJ, Chen L, Lens HJ, Hong YK. Interleukin-8 can reduce post-surgical lymphedema formation by promoting lymphatic vessel regeneration. Angiogenesis. 2013; 16:29-44.
Schulz MMP, Reisen F, Zgraggen S, Fischer S, Yuen D, Kang GJ, Chen L, Schneider G, Detmar M. Phenotype-based high-content chemical library screening identifies novel inhibitors of in vivo lymphangiogenesis. Proc. Natl. Acad. Sci. USA.2012; 109:E2665-74.
Choi I, Lee S, Chung HK, Lee YS, Kim KE, Choi D, Park EK, Yang D, Ecoiffier T, Monahan J, Chen W, Aguilar B, Lee HN, Yoo J, Koh CJ, Chen L, Wong AK, Hong YK. 9-cis retinoic acid promotes lymphangiogenesis and enhances lymphatic vessel regeneration: therapeutic implications of 9-cis retinoic acid for secondary lymphedema. Circulation. 2012; 125:872-882.
Article published with Editorial Comment by Cooke JP. “Lymphangiogenesis: A Potential New Therapy for Lymphedema?”.
Ecoiffier T, Sadovnikova A, Yuen D, Chen L. Conjunctival lymphatic response to corneal inflammation. J. Ophthalmol. 2012;2012:953187.
Yuen D, Wu X, Kwan AC, LeDue J, Zhang H, Ecoiffier T, Pytowski B, Chen L. Live imaging of newly formed lymphatic vessels in the cornea. Cell Research. 2011; 21:1745–1749.
Article published with Research Highlight by Proulx ST and Detmar M. “Watching Lymphatic Vessels Grow by Making Them Flow”.
Truong T, Altiok EI, Yuen D, Ecoiffier T, Chen L. Novel characterization of lymphatic valve formation during corneal inflammation. PLoS One. 2011; 6 (7): e21918.
Yuen D, Leu R, Sadovnikova A, Chen L. Increased lymphangiogenesis and hemangiogenesis in infant cornea. Lym. Res. Biol. 2011; 9:109-114.
Zhang H, Grimaldo S, Yuen D, Chen L. Combined blockade of VEGFR-3 and VLA-1 markedly promotes high-risk transplant survival. Invest. Ophthalmol. Vis. Sci. 2011; 52:6529-6535.
Grimaldo S, Yuen D, Ecoiffier T, Chen L. Very Late Antigen-1 mediates corneal lymphangiogenesis. Invest. Ophthalmol. Vis. Sci. 2011; 52:4808-4812.
Yuen D, Pytowski B, Chen L. Combined blockade of VEGFR-2 and VEGFR-3 inhibits inflammatory lymphangiogenesis in early and middle stages. Invest. Ophthalmol. Vis. Sci. 2011; 52:2593-2597.
Zhang H, Hu X, Tse J, Tilahun F, Qiu M, Chen L. Spontaneous lymphatic vessel formation and regression in the cornea. Invest. Ophthalmol. Vis. Sci. 2011; 52:334-338.
Chen L, Hann B, Wu L. Experimental models to study lymphatic and blood vascular metastasis, in “From local invasion to metastatic cancer”. Stanley P.L. Leong (Editor), Humana Press. 2011.
Cueni LN, Chen L, Zhang H, Marino D, Huggenberger R, Alitalo A, Bianchi R, Detmar M. Podoplanin-Fc reduces lymphatic vessel formation in vitro and in vivo and causes disseminated intravascular coagulation when transgenically expressed in the skin. Blood. 2010, 116:4376-4384.
Article published with Comment by Kim H and Koh GY. “Podoplanin-Fc burns out platelets.” Blood. 2010; 116:4043-4044.
Grimaldo S, Garcia M, Zhang H, Chen L. Specific role of lymphatic marker podoplanin in retinal pigment epithelial cells. Lymphology. 2010; 43:128-134.
Zhang H, Tse J, Hu X, Witte M, Bernas M, Kang J, Tilahun F, Hong YK, Qiu M, Chen L. Novel discovery of LYVE-1 expression in the hyaloid vascular system. Invest. Ophthalmol. Vis. Sci. 2010; 51:6157-6161.
Ecoiffier T, Yuen D, Chen L. Differential distribution of blood and lymphatic vessels in the cornea. Invest. Ophthalmol. Vis. Sci. 2010; 51:2436-2440.
Dietrich T, Bock F, Yuen D, Hos D, Bachmann B, Zahn G, Wiegand S, Chen L, Cursiefen C. Cutting edge: Lymphatic vessels, not blood vessels, primarily mediate immune rejections after transplantation. J. Immunol. 2010; 184:535-539.
Chen L. Ocular Lymphatics: State-of-the-Art Review. Lymphology. 2009; 42:66-76. Invited review.
Chung ES, Chauhan S, Jin Y, Zhang Q, Nakao S, Chen L, Dana R. Contribution of macrophages to angiogenesis induced by VEGFR-3 specific ligands. Am. J. Pathol. 2009; 175:1984-1992.
Chen L, Huq S, Gardner H, de Fougerolles AR, Barabino S, Dana MR. Very late antigen (VLA)-1 blockade leads to marked survival of corneal allografts. Arch. Ophthalmol. 2007; 125:783-788.
Jin Y, Shen L, Chong EM, Hamrah P, Zhang Q, Chen L, Dana MR. The chemokine receptor CCR7 mediates corneal antigen-presenting cell trafficking. Molecular Vision 2007; 13:626-634.
Chen L, Hamrah P, Cursiefen C, Zhang Q, Pytowski B, Streilein JW, Dana MR. Vascular endothelial growth factor receptor-3 mediates induction of corneal alloimmunity. Ocul. Immunol. Inflamm. 2007; 15:275-278.
Cursiefen C, Chen L, Hamrah P, Pytowski B, Persaud K, Wu Y, Jackson D, Streilein JW, Dana MR. High constitutive expression of VEGFR-3 by corneal epithelium maintains corneal avascularity by serving as decoy receptor. Proc. Natl. Acad. Sci. USA. 2006; 103:11405-11410.
Chen L, Cursiefen C, Barabino S, Zhang Q, Streilein JW, Dana MR. Novel expression and characterization of lymphatic vessel endothelial hyaluronate receptor 1 (LYVE-1) by conjunctival cells. Invest. Ophthalmol. Vis. Sci. 2005; 46:4536-4540.
Barabino S, Shen L, Chen L, Rolando M, Dana R. The controlled environment chamber: a new model for dry eyes. Invest. Ophthalmol. Vis. Sci. 2005; 46:2766-2771.
Cursiefen C, Ikeda S, Smith RS, Jackson D, Mo JS, Chen L, Pytowski B, Dana MR, Streilein JW. Spontaneous corneal hem- and lymphangiogenesis with destrin-mutation depend on VEGFR3-signaling. Am. J. Pathol. 2005; 166:1367-1377.
Chen L, Hamrah P, Cursiefen C, Zhang Q, Pytowski B, Streilein JW, Dana MR. Vascular endothelial growth factor receptor-3 (VEGFR-3) mediates dendritic cell migration to lymph nodes and induction of immunity to corneal transplants. Nat. Med. 2004; 10:813-815.
Cursiefen C, Chen L, Borges LP, Jackson D, Cao J, Radziejewski C, D’Amore PA, Dana MR, Wiegand SJ, Streilein JW. VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J. Clin. Invest. 2004; 113:1040-1050.
Hamrah P, Chen L, Cursiefen C, Zhang Q, Joyce NC, Dana MR. Expression of vascular endothelial growth factor receptor-3 (VEGFR-3) on monocytic bone marrow-derived cells in the conjunctiva. Exp. Eye. Res. 2004; 79:553-561.
Cursiefen C, Cao J, Chen L, Liu Y, Maruyama K, Jackson D, Kruse FE, Wiegand SJ, Dana MR, Streilein JW. Inhibition of hemangiogenesis and lymphangiogenesis after normal-risk corneal transplantation by neutralizing VEGF promotes graft survival. Invest. Ophthalmol. Vis. Sci. 2004; 45:2666-2673.
Hamrah P, Chen L, Zhang Q, Dana MR. Novel expression of vascular endothelial growth factor receptor (VEGFR)-3 and VEGF-C on corneal dendritic cells. Am. J. Pathol. 2003; 163:57-68.
Cursiefen C, Chen L, Dana MR, Streilein JW. Corneal lymphangiogenesis: evidence, mechanisms, and implications for corneal transplant immunology. Cornea. 2003; 22:273-281.
Mower GD, Chen L. Laminar distribution of NMDA receptor subunit (NR1, NR2A, NR2B) expression during the critical period in visual cortex. Brain Res. Mol. Brain Res. 2003; 119:19-27.
Chen L, Yang C, Mower GD. Developmental changes in the expression of GABA-A receptor subunits (α1, α2, α3) during postnatal development of the visual cortex. Brain Res. Mol. Brain Res. 2001; 88:135-43.
Chen L, Cooper NGF, Mower GD. Subunit compositional changes of NMDA receptors during postnatal development of the visual cortex. Brain Res. Mol. Brain Res. 2000; 78:196-200.