2. Academic Validation
  3. IKKβ Inhibition Attenuates Epithelial Mesenchymal Transition of Human Stem Cell-Derived Retinal Pigment Epithelium

IKKβ Inhibition Attenuates Epithelial Mesenchymal Transition of Human Stem Cell-Derived Retinal Pigment Epithelium

  • Cells. 2023 Apr 13;12(8):1155. doi: 10.3390/cells12081155.
Srinivasa R Sripathi 1 2,  Ming-Wen Hu 1,  Ravi Chakra Turaga 3 4,  Rebekah Mikeasky 1,  Ganesh Satyanarayana 4 5,  Jie Cheng 1,  Yukan Duan 1,  Julien Maruotti 6,  Karl J Wahlin 7,  Cynthia A Berlinicke 1,  Jiang Qian 1,  Noriko Esumi 1,  Donald J Zack 1 8 9 10 11
Affiliations

Affiliations

  • 1 Department of Ophthalmology, Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 2 Henderson Ocular Stem Cell Laboratory, Retina Foundation of the Southwest, Dallas, TX 75231, USA.
  • 3 Caris Life Sciences, 350 W Washington St., Tempe, AZ 85281, USA.
  • 4 Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
  • 5 Emory Eye Center, Department of Ophthalmology, Emory University, Atlanta, GA 30322, USA.
  • 6 Research and Development, Phenocell, 06130 Grasse, France.
  • 7 Shiley Eye Institute, University of California, San Diego, CA 92093, USA.
  • 8 Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 9 Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 10 Department of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 11 Institute for NanoBioTechnology, Johns Hopkins University, Whiting School of Engineering, Baltimore, MD 21218, USA.
PMID: 37190063 DOI: 10.3390/cells12081155
Abstract

Epithelial-mesenchymal transition (EMT), which is well known for its role in embryonic development, malignant transformation, and tumor progression, has also been implicated in a variety of retinal diseases, including proliferative vitreoretinopathy (PVR), age-related macular degeneration (AMD), and diabetic retinopathy. EMT of the retinal pigment epithelium (RPE), although important in the pathogenesis of these retinal conditions, is not well understood at the molecular level. We and Others have shown that a variety of molecules, including the co-treatment of human stem cell-derived RPE monolayer cultures with transforming growth factor beta (TGF-β) and the inflammatory cytokine tumor necrosis factor alpha (TNF-α), can induce RPE-EMT; however, small molecule inhibitors of RPE-EMT have been less well studied. Here, we demonstrate that BAY651942, a small molecule inhibitor of nuclear factor kapa-B kinase subunit beta (IKKβ) that selectively targets NF-κB signaling, can modulate TGF-β/TNF-α-induced RPE-EMT. Next, we performed RNA-seq studies on BAY651942 treated hRPE monolayers to dissect altered biological pathways and signaling events. Further, we validated the effect of IKKβ inhibition on RPE-EMT-associated factors using a second IKKβ inhibitor, BMS345541, with RPE monolayers derived from an independent stem cell line. Our data highlights the fact that pharmacological inhibition of RPE-EMT restores RPE identity and may provide a promising approach for treating retinal diseases that involve RPE dedifferentiation and EMT.

Keywords

PVR and AMD; TGF–β/–α; differentiation; epithelial-mesenchymal transition; kinase inhibitors; retinal pigment epithelium; stem cells; transcriptomics.

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