Primary Cilium-Mediated Retinal Pigment Epithelium Maturation Is Disrupted in Ciliopathy Patient Cells

Helen Louise May-Simera, Qin Wan, Balendu Shekhar Jha, Juliet Hartford, Vladimir Khristov, Roba Dejene, Justin Chang, Sarita Patnaik, Quanlong Lu, Poulomi Banerjee, Jason Silver, Christine Insinna-Kettenhofen, Dishita Patel, Mostafa Lotfi, May Malicdan, Nathan Hotaling, Arvydas Maminishkis, Rupa Sridharan, Brian Brooks, Kiyoharu MiyagishimaMeral Gunay-Aygun, Rajarshi Pal, Christopher Westlake, Sheldon Miller, Ruchi Sharma, Kapil Bharti

Research output: Contribution to journalArticlepeer-review

Abstract

Primary cilia are sensory organelles that protrude from the cell membrane. Defects in the primary cilium cause ciliopathy disorders, with retinal degeneration as a prominent phenotype. Here, we demonstrate that the retinal pigment epithelium (RPE), essential for photoreceptor development and function, requires a functional primary cilium for complete maturation and that RPE maturation defects in ciliopathies precede photoreceptor degeneration. Pharmacologically enhanced ciliogenesis in wild-type induced pluripotent stem cells (iPSC)-RPE leads to fully mature and functional cells. In contrast, ciliopathy patient-derived iPSC-RPE and iPSC-RPE with a knockdown of ciliary-trafficking protein remain immature, with defective apical processes, reduced functionality, and reduced adult-specific gene expression. Proteins of the primary cilium regulate RPE maturation by simultaneously suppressing canonical WNT and activating PKCδ pathways. A similar cilium-dependent maturation pathway exists in lung epithelium. Our results provide insights into ciliopathy-induced retinal degeneration, demonstrate a developmental role for primary cilia in epithelial maturation, and provide a method to mature iPSC epithelial cells for clinical applications. May-Simera et al. show that primary cilia regulate the maturation and polarization of human iPSC-RPE, mouse RPE, and human iPSC-lung epithelium through canonical WNT suppression and PKCδ activation. RPE cells derived from ciliopathy patients exhibit defective structure and function. These results provide insights into ciliopathy-induced retinal degeneration.

Original languageEnglish (US)
Pages (from-to)189-205
Number of pages17
JournalCell Reports
Volume22
Issue number1
DOIs
StatePublished - Jan 2 2018
Externally publishedYes

Keywords

  • CEP290
  • RPE
  • WNT signaling
  • apical-basal polarity
  • cell maturation
  • cilia
  • ciliopathy
  • iPS cells
  • primary cilium
  • retinal pigment epithelium

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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