Technische Universität Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Center for Regenerative Therapies Dresden (CRTD), Fetscherstraße 105, 01307 Dresden, Germany.
Technische Universität Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Center for Regenerative Therapies Dresden (CRTD), Fetscherstraße 105, 01307 Dresden, Germany.
Stem Cell Reports. 2020 Mar 10;14(3):374-389. 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.
维持健康的光感受器-视网膜色素上皮（RPE）界面对于视力至关重要。在这个界面的中心，RPE 顶端膜的突起包裹着光感受器外节（POS），可能参与通过吞噬作用回收 POS。调节 POS 包绕及其与吞噬作用关系的分子仍有待破译。通过超微结构分析，我们揭示了 Mer 受体酪氨酸激酶（MERTK）配体 GAS6 和 PROS1，而不是 αVβ5 整联蛋白受体配体，触发了人胚胎干细胞（hESC）衍生的 RPE 对 POS 的包绕。此外，我们发现 POS 的包绕是 POS 碎片化和内化所必需的。一致地，MERTK 突变的 RPE 中 POS 的包绕、碎片化和内化被消除，而在视网膜色素变性（RP38）患者 RPE 中挽救 MERTK 的表达则逆转了这些缺陷。我们的结果表明，由于 MERTK 功能障碍导致的包绕丧失可能导致 RP38 患者的视力损害。
