TY - JOUR
T1 - Cellular crosstalk regulates the aqueous humor outflow pathway and provides new targets for glaucoma therapies
AU - Thomson, Benjamin R.
AU - Liu, Pan
AU - Onay, Tuncer
AU - Du, Jing
AU - Tompson, Stuart W.
AU - Misener, Sol
AU - Purohit, Raj R.
AU - Young, Terri L.
AU - Jin, Jing
AU - Quaggin, Susan E.
N1 - Funding Information:
We are grateful to Phoebe Leeaw, Dilip Deb, and Brianna Jenkins for technical and animal husbandry assistance and to Angelo Tanna and Mark Johnson for many useful discussions. Ryan Embry and Matthew Schipma provided invaluable advice and assistance with bioinformatic analysis. This study was funded by NIH R01 HL124120, R01 EY025799 (to S.E.Q.), and NIH R01EY014685 (to T.L.Y.) as well as the Research to Prevent Blindness Lew R. Wasserman Award (to T.L.Y.). We are grateful to Michael Ryczko of Mannin Research and Yves Durocher and his team at the National Research Council Canada for recombinant protein production. Human eye tissue was provided by Eversight. Svep1-floxed mice were generated with the assistance of Northwestern University Transgenic and Targeted Mutagenesis Laboratory, which is partially supported by NCI CCSG P30 CA60553 to the Robert H. Lurie Comprehensive Cancer Center at Northwestern University. Imaging was performed at the Center for Advanced Microscopy of the Feinberg School of Medicine, also supported by NCI CCSG P30 CA060553. Single-cell RNA sequencing was performed at the NuSeq Core of the Center for Genetic Medicine, supported by NIH grant 1S10OD025120 awarded to the Department of Biochemistry and Molecular Genetics and Dr. Xinkun Wang. We also acknowledge support from the George M. O’Brien kidney core grant P30 DK114857, the University of Wisconsin vision research core grant P30 EY016665 and an unrestricted grant from Research to Prevent Blindness, Inc. to the UW-Madison Department of Ophthalmology and Visual Sciences.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - Primary congenital glaucoma (PCG) is a severe disease characterized by developmental defects in the trabecular meshwork (TM) and Schlemm’s canal (SC), comprising the conventional aqueous humor outflow pathway of the eye. Recently, heterozygous loss of function variants in TEK and ANGPT1 or compound variants in TEK/SVEP1 were identified in children with PCG. Moreover, common variants in ANGPT1and SVEP1 have been identified as risk alleles for primary open angle glaucoma (POAG) in GWAS studies. Here, we show tissue-specific deletion of Angpt1 or Svep1 from the TM causes PCG in mice with severe defects in the adjacent SC. Single-cell transcriptomic analysis of normal and glaucomatous Angpt1 deficient eyes allowed us to identify distinct TM and SC cell populations and discover additional TM-SC signaling pathways. Furthermore, confirming the importance of angiopoietin signaling in SC, delivery of a recombinant ANGPT1-mimetic promotes developmental SC expansion in healthy and Angpt1 deficient eyes, blunts intraocular pressure (IOP) elevation and RGC loss in a mouse model of PCG and lowers IOP in healthy adult mice. Our data highlight the central role of ANGPT1-TEK signaling and TM-SC crosstalk in IOP homeostasis and provide new candidates for SC-targeted glaucoma therapy.
AB - Primary congenital glaucoma (PCG) is a severe disease characterized by developmental defects in the trabecular meshwork (TM) and Schlemm’s canal (SC), comprising the conventional aqueous humor outflow pathway of the eye. Recently, heterozygous loss of function variants in TEK and ANGPT1 or compound variants in TEK/SVEP1 were identified in children with PCG. Moreover, common variants in ANGPT1and SVEP1 have been identified as risk alleles for primary open angle glaucoma (POAG) in GWAS studies. Here, we show tissue-specific deletion of Angpt1 or Svep1 from the TM causes PCG in mice with severe defects in the adjacent SC. Single-cell transcriptomic analysis of normal and glaucomatous Angpt1 deficient eyes allowed us to identify distinct TM and SC cell populations and discover additional TM-SC signaling pathways. Furthermore, confirming the importance of angiopoietin signaling in SC, delivery of a recombinant ANGPT1-mimetic promotes developmental SC expansion in healthy and Angpt1 deficient eyes, blunts intraocular pressure (IOP) elevation and RGC loss in a mouse model of PCG and lowers IOP in healthy adult mice. Our data highlight the central role of ANGPT1-TEK signaling and TM-SC crosstalk in IOP homeostasis and provide new candidates for SC-targeted glaucoma therapy.
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U2 - 10.1038/s41467-021-26346-0
DO - 10.1038/s41467-021-26346-0
M3 - Article
C2 - 34663817
AN - SCOPUS:85117608039
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 6072
ER -