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Somatic Role for the Oct4 Pluripotency Gene Described
Review of “Activation of the pluripotency factor OCT4 in smooth muscle cells is atheroprotective” from Nature Medicine by Stuart P. Atkinson
Alongside Nanog, Oct4 (or Pou5f1 to friends) represents the quintessential pluripotency gene  and is highly expressed in pluripotent stem cells (PSCs). There exists some evidence of a somatic role for Oct4 expression in differentiated cells, although this remains controversial due to a number of confounding elements.
The laboratory of Gary K Owens (University of Virginia, USA) has been studying the de-differentiation of smooth muscle cells (SMCs) after vascular injury or during the development of atherosclerosis [2-4]. In their new study, they report an important somatic role for the Oct4 pluripotency gene as a critical regulator of SMC function. Furthermore, in this Nature Medicine report, they show that Oct4 loss leads to an increase in atherosclerotic lesion size and a decrease in plaque stability, together suggesting that Oct4 has an atheroprotective role .
To boost the development of atherosclerosis, the authors employed a mouse strain that spontaneously develops atherosclerotic lesions on a standard chow diet combined with a high-fat diet. This induced the expression of the pluripotent iso¬form of OCT4 (OCT4A) in SMCs within atherosclerotic arteries. However, the SMC-specific knock-out of Oct4 led to worsened plaque pathogenesis due to a reduction in SMC-derived cells within lesions. This also led to an increase in lesion size and a decrease in plaque stability due to an increase in the necrotic core area and intraplaque hemorrhage.
So how is Oct4 affecting SMCs? The study demonstrated that the loss of Oct4 impaired did not impair SMC proliferation or apoptosis. Instead, Oct4 loss inhibited SMC migration in in vitro in response to pro-atherogenic oxidized phospholipids and in ex vivo aortic explants, due, in part, to the loss of migration-associated gene expression.
The last part of the study assessed the mechanisms behind the re-activation of Oct4 expression in SMCs. Their findings suggested that HIF-1alpha and KLF4-dependent DNA demethylation of the OCT4 promoter in response to hypoxic and inflammatory stress stimuli caused the repression of Oct4 in cultured SMCs. The authors also confirmed this finding in mouse atherosclerotic lesions employing a technique which enables the detection of histone/DNA modifications at gene loci in single cells within fixed histological sections (ISH-PLA ).
While this represents the first direct evidence of a somatic role for the Oct4 pluripotency gene, the authors want to go a step further, and understand whether the disease-mediated upregulation of OCT4 expression exists in other cell types. Furthermore, they aim to use this information to create therapeutic strategies which can promote plaque stabilization and even reverse disease pathology.
- Scholer HR, Ruppert S, Suzuki N, et al. New type of POU domain in germ line-specific protein Oct-4. Nature 1990;344:435-439.
- Owens GK, Kumar MS, and Wamhoff BR Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev 2004;84:767-801.
- Alexander MR and Owens GK Epigenetic control of smooth muscle cell differentiation and phenotypic switching in vascular development and disease. Annual review of physiology 2012;74:13-40.
- Libby P Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol 2012;32:2045-2051.
- Cherepanova OA, Gomez D, Shankman LS, et al. Activation of the pluripotency factor OCT4 in smooth muscle cells is atheroprotective. Nat Med 2016;22:657-665.
- Gomez D, Shankman LS, Nguyen AT, et al. Detection of histone modifications at specific gene loci in single cells in histological sections. Nat Methods 2013;10:171-177.