Lu Chen, MD, PhD

Affiliations

Professor, Center for Eye Disease and Development, Vision Science Graduate Program, and School of Optometry & Vision Science, University of California at Berkeley

Adjunct faculty, The Proctor Foundation for Research in Ophthalmology, University of California San Francisco

Research Areas

Lymph and Blood Vascular Biology, Ocular Vascular Diseases, Inflammation, Transplantation Immunity, Glaucoma

Our research focuses on molecular and cellular mechanisms of ocular inflammation and immunity, particularly those involved in lymphatic and blood vessel development and regulation. Unlike blood vessels which have been studied extensively in the past, lymphatic research represents an explosive field of new discovery in recent years. The cornea offers an ideal site for vascular studies due to its accessible location, transparent nature, and vessel-free and -inducible features. Once induced, corneal lymphatics enhance high volume delivery of antigens and immune cells, and accelerate transplant rejection. Our primary long-term goal is to elucidate the fundamental mechanisms underlying lymphatic formation and to discover novel therapeutic targets to treat lymphatic-related diseases inside and outside of the eye.

Research on corneal lymphatics has broad clinical implications. For example, we have discovered that Schlemm's canal, a critical structure for aqueous humor drainage, possesses lymphatic features. We have also reported the presence and function of typical lymphatics in the optic nerve and ocular fluid clearance. Further investigation on these novel phenomena promise for divulging new mechanisms and therapeutic strategies for glaucoma and other major eye diseases. Moreover, the lymphatic network penetrates most tissues in the body, and its dysfunctions have been found in a diverse array of disorders, which include but are not limited to cancer metastasis, diabetes, obesity, lymphedema, central nervous system disorders, and inflammatory, infectious and immune diseases.

Selected Publications

Wang X, Lou N, Eberhardt A, Yang Y, Kusk P, Xu Q, Förstera B, Peng S, Shi M, Ladrón-de-Guevara A, Delle, Sigurdsson B, Xavier ALR, Ertürk A, Libby RT, Chen L*, Thrane AS, Nedergaard M*. An ocular glymphatic clearance system removes amyloid-β from the rodent eye. *Corresponding authors. Science Translational Medicine. 2020; 12(536):eaaw3210.

Shi M, Zhang L, Ye EA, Want A, Li G, Chen L. Aqueous humor induces lymphatic regression on the ocular surface. Ocul Surf. 2020; S1542-0124(20)30032-X.

Yang Y, Li G, Chen L. High resolution three-dimensional imaging of the ocular surface and intact eyeball using tissue clearing and light-sheet microscopy. Ocul Surf. In press.

Mu C, Shi M, Liu P, Chen L, Marriot G. Daylight-mediated, passive, and sustained release of the glaucoma drug timolol from a contact lens. ACS Cent Sci. 2018; 4(12):1677-1687.

Zhang LW, Li GY, Shi M, Liu HH, Ge SK, Ou Y, Flanagan J, Chen L. Establishment and characterization of an acute model of ocular hypertension by laser-induced occlusion of episcleral veins. Invest Ophthalmol Vis Sci. 2017; 58:3879-3886.

Liu HH, Zhang L, Shi M, Chen L, Flanagan JG. Comparison of laser and circumlimbal suture induced elevation of intraocular pressure in albino CD-1 mice. PLoS One. 2017; 12(11):e0189094.

Wang D, Wu F, Yuan H, Wang A, Kang GJ, Truong T, Chen L, McCallion AS, Gong X, Li S. Sox10+ cells contribute to vascular development in multiple organs. Arterioscler Thromb Vasc Biol. 2017; 37:1727-1731.

Sessa R, Chen L. Lymphangiogenesis – a new player in herpes simplex virus 1 triggered T cell response. Immunol. Cell Biol. 2017; 95(1):5-6. Invited Commentary Article by the Editor.

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. 2017; 58:79-86.

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; 26:262-5.

Kang GY, Ecoiffier E, 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.

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.

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.

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.

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.

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.

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.

Bianchi R, Fischer 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.

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.

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.

Truong T, Huang E, Yuen D, Chen L. Corneal lymphatic valve formation in relation to lymphangiogenesis. Invest Ophthalmol Vis Sci. 2014; 55:1876-1883.

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.

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 at Swiss Federal Institute of Technology by Proulx ST and Detmar M. "Watching Lymphatic Vessels Grow by Making Them Flow". Cell Research 2011 (1-2). doi: 10.1038/cr.2011.191.]

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 at Stanford Cardiovascular Institute. "Lymphangiogenesis: A Potential New Therapy for Lymphedema?" Circulation. 2012; 125:853-855. doi: 10.1161/CIRCULATIONAHA.111.083477.]

Ecoiffier T, Sadovnikova A, Yuen D, Chen L. Conjunctival lymphatic response to corneal inflammation. J. Ophthalmol. J. Ophthalmol. 2012;2012:953187.]

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 at Korea Advanced Institute of Science and Technology. "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.