Stem Cell Reports
Volume 14, Issue 3, 10 March 2020, Pages 374-389
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Article
MERTK-Dependent Ensheathment of Photoreceptor Outer Segments by Human Pluripotent Stem Cell-Derived Retinal Pigment Epithelium

https://doi.org/10.1016/j.stemcr.2020.02.004Get rights and content
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Highlights

  • 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

Summary

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.

Keywords

retinal pigment epithelium
photoreceptor outer segments
human embryonic stem cells
human pluripotent stem cells
phagocytosis
ensheathment
MERTK
GAS6
MFGE8
PROS1

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