A Human Retinal Pigment Epithelium-Based Screening Platform Reveals Inducers of Photoreceptor Outer Segments Phagocytosis

被引：6

作者：

Schreiter, Sven ^{[1
]}

Vafia, Katerina ^{[1
]}

Barsacchi, Rico ^{[2
]}

Tsang, Stephen H. ^{[4
]}

Bickle, Marc ^{[2
]}

Ader, Marius ^{[1
]}

Karl, Mike O. ^{[1
,3
]}

Tanaka, Elly M. ^{[5
]}

Almedawar, Seba ^{[1
]}

机构：

[1] Tech Univ Dresden, Ctr Mol & Cellular Bioengn CMCB, Ctr Regenerat Therapies Dresden CRTD, Fetscherstr 105, D-01307 Dresden, Germany

[2] Max Planck Inst Mol Cell Biol & Genet, Pfotenhauerstr 108, D-01307 Dresden, Germany

[3] German Ctr Neurodegenerat Dis DZNE Dresden, Tatzberg 41, D-01307 Dresden, Germany

[4] CUMC Edward S Harkness Eye Inst, 635 West 165th St, New York, NY 10032 USA

[5] Vienna Bioctr VBC, Res Inst Mol Pathol IMP, Campus Vienna Bioctr 1, A-1030 Vienna, Austria

来源：

STEM CELL REPORTS | 2020年 / 15卷 / 06期

关键词：

ALPHA-V-BETA-5; INTEGRIN; ZINC PYRITHIONE; CELLS; EXPRESSION; JUXTANODIN; MORPHOLOGY; MECHANISM; CHANNELS; MERTK;

D O I：

10.1016/j.stemcr.2020.10.013

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

Phagocytosis is a key function in various cells throughout the body. A deficiency in photoreceptor outer segment (POS) phagocytosis by the retinal pigment epithelium (RPE) causes vision loss in inherited retinal diseases and possibly age-related macular degeneration. To date, there are no effective therapies available aiming at recovering the lost phagocytosis function. Here, we developed a high-throughput screening assay based on RPE derived from human embryonic stem cells (hRPE) to reveal enhancers of POS phagocytosis. One of the hits, ramoplanin (RM), reproducibly enhanced POS phagocytosis and ensheathment in hRPE, and enhanced the expression of proteins known to regulate membrane dynamics and ensheathment in other cell systems. Additionally, RM rescued POS internalization defect in Mer receptor tyrosine kinase (MERTK) mutant hRPE, derived from retinitis pigmentosa patient induced pluripotent stem cells. Our platform, including a primary phenotypic screening phagocytosis assay together with orthogonal assays, establishes a basis for RPE-based therapy discovery aiming at a broad patient spectrum.

引用

页码：1347 / 1361

页数：15

共 38 条

[1] MERTK-Dependent Ensheathment of Photoreceptor Outer Segments by Human Pluripotent Stem Cell-Derived Retinal Pigment Epithelium [J].

Almedawar, Seba ;

Vafia, Katerina ;

Schreiter, Sven ;

Neumann, Katrin ;

Khattak, Shahryar ;

Kurth, Thomas ;

Ader, Marius ;

Karl, Mike O. ;

Tsang, Stephen H. ;

Tanaka, Elly M. .

STEM CELL REPORTS, 2020, 14 (03) :374-389

[2]

[Anonymous], 2016, DEVELOPMENT, DOI DOI 10.1074/JBC.M116.721340

[3] KNIME:: The Konstanz Information Miner [J].

Berthold, Michael R. ;

Cebron, Nicolas ;

Dill, Fabian ;

Gabriel, Thomas R. ;

Koetter, Tobias ;

Meinl, Thorsten ;

Ohl, Peter ;

Sieb, Christoph ;

Thiel, Kilian ;

Wiswedel, Bernd .

DATA ANALYSIS, MACHINE LEARNING AND APPLICATIONS, 2008, :319-326

[4] Ermin, a myelinating oligodendrocyte-specific protein that regulates cell morphology [J].

Brockschnieder, D ;

Sabanay, H ;

Riethmacher, D ;

Peles, E .

JOURNAL OF NEUROSCIENCE, 2006, 26 (03) :757-762

[5] High-throughput screening identifies compounds that protect RPE cells from physiological stressors present in AMD [J].

Cai, Hui ;

Gong, Jie ;

Abriola, Laura ;

Hoyer, Denton ;

Noggle, Scott ;

Paull, Daniel ;

Del Priore, Lucian V. ;

Fields, Mark A. .

EXPERIMENTAL EYE RESEARCH, 2019, 185

[6] Zinc pyrithione activates K+ channels and hyperpolarizes the membrane of rat pulmonary artery smooth muscle cells [J].

Eid, Basma G. ;

Gurney, Alison M. .

PLOS ONE, 2018, 13 (02)

[7] The mechanism of action of ramoplanin and enduracidin [J].

Fang, X ;

Tiyanont, K ;

Zhang, Y ;

Wanner, J ;

Boger, D ;

Walker, S .

MOLECULAR BIOSYSTEMS, 2006, 2 (01) :69-76

[8] Differential roles of CD36 and αvβ5 integrin in photoreceptor phagocytosis by the retinal pigment epithelium [J].

Finneman, SC ;

Silverstein, RL .

JOURNAL OF EXPERIMENTAL MEDICINE, 2001, 194 (09) :1289-1298

[9] The Clinically-tested S1P Receptor Agonists, FTY720 and BAF312, Demonstrate Subtype-Specific Bradycardia (S1P1) and Hypertension (S1P3) in Rat [J].

Fryer, Ryan M. ;

Muthukumarana, Akalushi ;

Harrison, Paul C. ;

Mazurek, Suzanne Nodop ;

Chen, Rong Rhonda ;

Harrington, Kyle E. ;

Dinallo, Roger M. ;

Horan, Joshua C. ;

Patnaude, Lori ;

Modis, Louise K. ;

Reinhart, Glenn A. .

PLOS ONE, 2012, 7 (12)

[10] Dysfunctional autophagy in RPE, a contributing factor in age-related macular degeneration [J].

Golestaneh, Nady ;

Chu, Yi ;

Xiao, Yang-Yu ;

Stoleru, Gianna L. ;

Theos, Alexander C. .

CELL DEATH & DISEASE, 2017, 8 :e2537-e2537

← 1 2 3 4 →