Biomaterial Database

IKKβ Inhibition Attenuates Epithelial Mesenchymal Transition of Human Stem Cell-Derived Retinal Pigment Epithelium. 2023

Srinivasa R Sripathi, and Ming-Wen Hu, and Ravi Chakra Turaga, and Rebekah Mikeasky, and Ganesh Satyanarayana, and Jie Cheng, and Yukan Duan, and Julien Maruotti, and Karl J Wahlin, and Cynthia A Berlinicke, and Jiang Qian, and Noriko Esumi, and Donald J Zack

Department of Ophthalmology, Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

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.

UI	MeSH Term	Description	Entries
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D013234	Stem Cells	Relatively undifferentiated cells that retain the ability to divide and proliferate throughout postnatal life to provide progenitor cells that can differentiate into specialized cells.	Colony-Forming Units,Mother Cells,Progenitor Cells,Colony-Forming Unit,Cell, Mother,Cell, Progenitor,Cell, Stem,Cells, Mother,Cells, Progenitor,Cells, Stem,Colony Forming Unit,Colony Forming Units,Mother Cell,Progenitor Cell,Stem Cell
D014409	Tumor Necrosis Factor-alpha	Serum glycoprotein produced by activated MACROPHAGES and other mammalian MONONUCLEAR LEUKOCYTES. It has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. Also known as TNF-alpha, it is only 30% homologous to TNF-beta (LYMPHOTOXIN), but they share TNF RECEPTORS.	Cachectin,TNF-alpha,Tumor Necrosis Factor Ligand Superfamily Member 2,Cachectin-Tumor Necrosis Factor,TNF Superfamily, Member 2,TNFalpha,Tumor Necrosis Factor,Cachectin Tumor Necrosis Factor,Tumor Necrosis Factor alpha
D016212	Transforming Growth Factor beta	A factor synthesized in a wide variety of tissues. It acts synergistically with TGF-alpha in inducing phenotypic transformation and can also act as a negative autocrine growth factor. TGF-beta has a potential role in embryonal development, cellular differentiation, hormone secretion, and immune function. TGF-beta is found mostly as homodimer forms of separate gene products TGF-beta1, TGF-beta2 or TGF-beta3. Heterodimers composed of TGF-beta1 and 2 (TGF-beta1.2) or of TGF-beta2 and 3 (TGF-beta2.3) have been isolated. The TGF-beta proteins are synthesized as precursor proteins.	Bone-Derived Transforming Growth Factor,Platelet Transforming Growth Factor,TGF-beta,Milk Growth Factor,TGFbeta,Bone Derived Transforming Growth Factor,Factor, Milk Growth,Growth Factor, Milk
D017346	Protein Serine-Threonine Kinases	A group of enzymes that catalyzes the phosphorylation of serine or threonine residues in proteins, with ATP or other nucleotides as phosphate donors.	Protein-Serine-Threonine Kinases,Serine-Threonine Protein Kinase,Serine-Threonine Protein Kinases,Protein-Serine Kinase,Protein-Serine-Threonine Kinase,Protein-Threonine Kinase,Serine Kinase,Serine-Threonine Kinase,Serine-Threonine Kinases,Threonine Kinase,Kinase, Protein-Serine,Kinase, Protein-Serine-Threonine,Kinase, Protein-Threonine,Kinase, Serine-Threonine,Kinases, Protein Serine-Threonine,Kinases, Protein-Serine-Threonine,Kinases, Serine-Threonine,Protein Kinase, Serine-Threonine,Protein Kinases, Serine-Threonine,Protein Serine Kinase,Protein Serine Threonine Kinase,Protein Serine Threonine Kinases,Protein Threonine Kinase,Serine Threonine Kinase,Serine Threonine Kinases,Serine Threonine Protein Kinase,Serine Threonine Protein Kinases
D051550	I-kappa B Kinase	A protein serine-threonine kinase that catalyzes the PHOSPHORYLATION of I KAPPA B PROTEINS. This enzyme also activates the transcription factor NF-KAPPA B and is composed of alpha and beta catalytic subunits, which are protein kinases and gamma, a regulatory subunit.	CHUK Kinase,Conserved Helix-Loop-Helix Ubiquitous Kinase,I Kappa B alpha-Associated Protein Kinase,I kappa B Kinase,IKBKB,IKK 1 Kinase,IKK 2 Kinase,IKK alpha,IKK beta,IKK epsilon,IKK gamma,IKKepsilon,IkappaB Kinase,IkappaB Kinase alpha,IkappaB Kinase beta,IkappaB Kinase epsilon,IkappaB Kinase gamma,IkappaBalpha Kinase,NF-kappaB Essential Modifier,NK-kappa B-Activating Kinase NAK,B Kinase, I-kappa,Conserved Helix Loop Helix Ubiquitous Kinase,Essential Modifier, NF-kappaB,I Kappa B alpha Associated Protein Kinase,Kinase alpha, IkappaB,Kinase beta, IkappaB,Kinase epsilon, IkappaB,Kinase, I-kappa B,Kinase, IkappaB,NF kappaB Essential Modifier,NK kappa B Activating Kinase NAK
D055213	Retinal Pigment Epithelium	The single layer of pigment-containing epithelial cells in the RETINA, situated closely to the tips (outer segments) of the RETINAL PHOTORECEPTOR CELLS. These epithelial cells are macroglia that perform essential functions for the photoreceptor cells, such as in nutrient transport, phagocytosis of the shed photoreceptor membranes, and ensuring retinal attachment.	Epithelium, Retinal Pigment,Pigment Epithelium, Retinal
D058750	Epithelial-Mesenchymal Transition	Phenotypic changes of EPITHELIAL CELLS to MESENCHYME type, which increase cell mobility critical in many developmental processes such as NEURAL TUBE development. NEOPLASM METASTASIS and DISEASE PROGRESSION may also induce this transition.	Epithelial-Mesenchymal Transformation,Epithelial Mesenchymal Transformation,Epithelial Mesenchymal Transition,Transformation, Epithelial-Mesenchymal,Transition, Epithelial-Mesenchymal
D018630	Vitreoretinopathy, Proliferative	Vitreoretinal membrane shrinkage or contraction secondary to the proliferation of primarily retinal pigment epithelial cells and glial cells, particularly fibrous astrocytes, followed by membrane formation. The formation of fibrillar collagen and cellular proliferation appear to be the basis for the contractile properties of the epiretinal and vitreous membranes.	Proliferative Vitreoretinopathy,Vitreoretinopathy Neovascular Inflammatory,Inflammatories, Vitreoretinopathy Neovascular,Inflammatory, Vitreoretinopathy Neovascular,Neovascular Inflammatories, Vitreoretinopathy,Neovascular Inflammatory, Vitreoretinopathy,Proliferative Vitreoretinopathies,Vitreoretinopathies, Proliferative,Vitreoretinopathy Neovascular Inflammatories