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

Abstract

There are controversial claims that the embryonic stem cell (ESC) pluripotency factor OCT4 is activated in somatic cells, but there is no evidence it plays a functional role in these cells. Herein we demonstrate that smooth muscle cell (SMC)-specific conditional knockout of Oct4 within Apoe−/− mice resulted in increased lesion size and changes consistent with decreased plaque stability including a thinner fibrous cap, increased necrotic core, and increased intra-plaque hemorrhage. Results of SMC-lineage tracing studies showed that these changes were likely due to marked reductions in SMC number within lesions including impaired SMC migration and investment within the fibrous cap. Re-activation of Oct4 within SMCs was associated with hydroxymethylation of the Oct4 promoter and was HIF1α- and KLF4-dependent. Results provide the first direct evidence that OCT4 plays a functional role in somatic cells and highlight the importance of further investigation of possible OCT4 functions in normal and diseased somatic cells.

Radiosensitive Smooth Muscle Cells Populate Neointimal Lesions Through a Platelet Derived Growth Factor Receptor Beta Dependent Mechanism

“…Interestingly, recent studies by our lab 6,7 and others 8,9 have begun to demonstrate that SMCs are capable of many more functions than those just related to contraction, dilation, and ECM deposition. The role of SMCs in alternative pathways is thought to be mediated through a process known as SMC phenotypic switching.…”

“…Unlike it's cardiac muscle and skeletal muscle cousins, SMCs, although fully differentiated, are not terminally differentiated and in response to vascular injury 12,13 or disease [6][7][8] retain the capability to undergo phenotypic switching; a process characterized by coordinate and profound down regulation of SMC marker genes and upregulation of ECM synthesis, pluripotency genes, and migratory genes such as KLF4 6,14,15 and OCT4 7 . Although multiple SMC genes 10 have been described and used to identify SMCs in vivo, including smooth muscle alpha actin (ACTA2) 16 , smooth muscle myosin heavy chain (MYH11) 17 , h1-calponin 18 , and smooth muscle 22-alpha (TAGLN) 19 , phenotypic switching of SMCs is a process which is defined by down regulation (or loss) of these genes, making identification of phenotypically modulated SMCs in vivo exceedingly difficult using traditional methods which rely on gene or protein expression.…”

“…The wild type mouse aortic SMCs were isolated as previously described 7 . All experiments were performed between passages 11-15.…”

“…Interestingly, a former graduate student in the lab found that, although SMCs lose expression of SMC marker genes in response to phenotypic switching and undergo drastic epigenetic changes, they actually retain H3K4me2 on SMC gene promoter loci expression do NOT acquire this mark on the Myh11 promoter in vivo 6,7,33 . The drawback to this technique, however, is that it is semi-quantitative; that is, it labels around 70% of the SMCs in our SMC lineage tracing mouse.…”

"Smooth muscle cell-specific deletion of Col15a1 unexpectedly leads to impaired development of advanced atherosclerotic lesions"

“…ACTA2) can be expressed by myeloid-derived cells and endothelial cells and SMC can express marker genes of macrophages (e.g. CD68 and LGALS3) [14][15][16][17][18][19][20] . Therefore major unanswered questions remained in the field as to whether SMC are the primary source of collagens in vivo and if SMC produced collagens in turn impact plaque development.…”