MERTK-Dependent Ensheathment of Photoreceptor Outer Segments by Human Pluripotent Stem Cell-Derived Retinal Pigment Epithelium

• Published in: Stem cell reports Vol. 14; no. 3; pp. 374 - 389
• Main Authors: Almedawar, Seba, Vafia, Katerina, Schreiter, Sven, Neumann, Katrin, Khattak, Shahryar, Kurth, Thomas, Ader, Marius, Karl, Mike O., Tsang, Stephen H., Tanaka, Elly M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.03.2020; Elsevier
• Subjects: c-Mer Tyrosine Kinase - genetics; c-Mer Tyrosine Kinase - metabolism; Cell Line; ensheathment; GAS6; human embryonic stem cells; Human Embryonic Stem Cells - metabolism; Human Embryonic Stem Cells - ultrastructure; human pluripotent stem cells; Humans; Ligands; MERTK; MFGE8; Mutation - genetics; Phagocytosis; photoreceptor outer segments; Pluripotent Stem Cells - metabolism; PROS1; Receptors, Vitronectin - metabolism; Retinal Photoreceptor Cell Outer Segment - enzymology; Retinal Photoreceptor Cell Outer Segment - ultrastructure; retinal pigment epithelium; Retinal Pigment Epithelium - metabolism; Retinal Pigment Epithelium - ultrastructure; phagocytosis; PROS1; retinal pigment epithelium; photoreceptor outer segments; human pluripotent stem cells; ensheathment; MERTK; GAS6; MFGE8; human embryonic stem cells
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2020.02.004

Maintenance of a healthy photoreceptor-retinal pigment epithelium (RPE) interface is essential for vision. At the center of this interface, apical membrane protrusions stemming from the RPE ensheath photoreceptor outer segments (POS), and are possibly involved in the recycling of POS through phagocytosis. The molecules that regulate POS ensheathment and its relationship to phagocytosis remain to be deciphered. By means of ultrastructural analysis, we revealed that Mer receptor tyrosine kinase (MERTK) ligands, GAS6 and PROS1, rather than αVβ5 integrin receptor ligands, triggered POS ensheathment by human embryonic stem cell (hESC)-derived RPE. Furthermore, we found that ensheathment is required for POS fragmentation before internalization. Consistently, POS ensheathment, fragmentation, and internalization were abolished in MERTK mutant RPE, and rescue of MERTK expression in retinitis pigmentosa (RP38) patient RPE counteracted these defects. Our results suggest that loss of ensheathment due to MERTK dysfunction might contribute to vision impairment in RP38 patients. [Display omitted] •POS are ensheathed in vitro by human embryonic stem cell-derived RPE•POS ensheathment is upregulated by MERTK ligands: GAS6 and PROS1•αVβ5 integrin receptor ligands do not stimulate POS ensheathment•MERTK is essential for POS ensheathment and fragmentation before internalization Using ultrastructural scanning electron microscopy (SEM)-based analysis, Almedawar et al. show that MERTK ligands, GAS6 and PROS1, upregulate photoreceptor outer segments (POS) ensheathment in human embryonic stem cell-derived retinal pigment epithelial cells. The authors also demonstrate that MERTK is essential for POS ensheathment and fragmentation before internalization, and suggest that ensheathment defects contribute to the pathology of retinitis pigmentosa type 38.