Activation of the pluripotency factor OCT4 in smooth muscle cells is atheroprotective

• Published in: Nature medicine Vol. 22; no. 6; pp. 657 - 665
• Main Authors: Cherepanova, Olga A, Gomez, Delphine, Shankman, Laura S, Swiatlowska, Pamela, Williams, Jason, Sarmento, Olga F, Alencar, Gabriel F, Hess, Daniel L, Bevard, Melissa H, Greene, Elizabeth S, Murgai, Meera, Turner, Stephen D, Geng, Yong-Jian, Bekiranov, Stefan, Connelly, Jessica J, Tomilin, Alexey, Owens, Gary K
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2016; Nature Publishing Group
• Subjects: 13; 13/51; 38/32; 38/43; 38/70; 38/77; 38/90; 631/80; 64/60; 692/699/75/593/2100; Animals; Aorta - metabolism; Apolipoproteins E - genetics; Atherosclerosis; Atherosclerosis - genetics; Biomedicine; Blotting, Western; Cancer Research; Care and treatment; Cell Lineage; Cell Movement - genetics; Cell Survival; Cellular biology; Chromatin Immunoprecipitation; Coronary Artery Disease - metabolism; Diet, Western; Embryonic stem cells; Genetic aspects; Health aspects; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Infectious Diseases; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors - metabolism; Lesions; Male; Metabolic Diseases; Mice; Mice, Knockout; Middle Aged; Molecular Medicine; Muscle cells; Mutagenesis, Site-Directed; Myocytes, Smooth Muscle - cytology; Myocytes, Smooth Muscle - metabolism; Neurosciences; Octamer Transcription Factor-3 - genetics; Octamer Transcription Factor-3 - metabolism; Physiological aspects; Plaque, Atherosclerotic - genetics; Protein expression; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Smooth muscle; Stem cells; Transcription factors; United States
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.4109

The pluripotency factor OCT4 is expressed in smooth muscle cells of atherosclerotic lesions in both mice and humans, and has atheroprotective effects in mice. Although somatic cell activation of the embryonic stem cell (ESC) pluripotency factor OCT4 has been reported, this previous work has been controversial and has not demonstrated a functional role for OCT4 in somatic cells. Here we demonstrate that smooth muscle cell (SMC)-specific conditional knockout of Oct4 in Apoe −/− mice resulted in increased lesion size and changes in lesion composition that are consistent with decreased plaque stability, including a thinner fibrous cap, increased necrotic core area, and increased intraplaque hemorrhage. Results of SMC-lineage-tracing studies showed that these effects were probably the result of marked reductions in SMC numbers within lesions and SMC investment within the fibrous cap, which may result from impaired SMC migration. The reactivation of Oct4 within SMCs was associated with hydroxymethylation of the Oct4 promoter and was hypoxia inducible factor-1α (HIF-1α, encoded by HIF1A ) and Krüppel-like factor-4 (KLF4)-dependent. These results provide the first direct evidence that OCT4 has a functional role in somatic cells, and they highlight the potential role of OCT4 in normal and diseased somatic cells.