Dissecting the Role of Sox2 in Stemness Regulation and Regenerative Medicine

Review Article

J Stem Cell Res Transplant. 2017; 4(1): 1026.

Dissecting the Role of Sox2 in Stemness Regulation and Regenerative Medicine

Chanoumidou K1,2, Hadjimichael C¹, Vogiatzoglou A1,3 and Kretsovali A1*

¹Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology – Hellas (FORTH), 70013 Heraklion, Crete, Greece

²Department of Molecular Biology and Genetics, Democritus University of Thrace, Dragana, Alexandroupolis, 68100 Evros, Greece

³Department of Biology, University of Crete, 71409 Heraklion, Crete, Greece

*Corresponding author: Androniki Kretsovali, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology – Hellas (FORTH), 70013 Heraklion, Crete, Greece

Received: October 18, 2016; Accepted: January 20, 2017; Published: January 23, 2017


The necessity of Sox2 for successful establishment of pluripotent state and maintenance of adult stem cells highlights its role in stemness regulation during development. Interestingly, Sox2 is implicated in both self-renewal maintenance and differentiation decisions. Its role in pluripotent cells is well documented whereas recent studies underline Sox2 importance in neural and mesenchymal stem cells function. Reprogramming experiments have revealed the potential of Sox2 for imposing changes in cell fate. In particular, Sox2 is essential for induced pluripotent cells generation and somatic cells conversion into another type. Sox2 pro-neural role has been utilized for the somatic cells and mesenchymal stem cells transition to induced neural stem cells as well as for their trans-differentiation to induced Neurons. This conversion ability, in combination with its role as pro-sensory factor, nominates Sox2 a key player in transplantation therapies. In this review, we discuss the multiple roles of Sox2 in the regulation of pluripotent, neural and mesenchymal stem cells pointing to their applications for tissue regeneration.

Keywords: Sox2; Pluripotency; Stem cells; Differentiation; Regenerative medicine


ESC: Embryonic Stem Cells; NSC: Neural Stem Cells; MSC: Mesenchymal Stem Cells; iPSC: induced Pluripotent Stem Cells; NPC: Neural Progenitor Cells; iNSC: Induced Neural Stem Cells; iN: induced Neurons; CNS: Central Nervous System; SVZ: Subventricular Zone; DG: Dentate Gyrus; ENS: Enteric Nervous System


Sex determining region Y-box 2 (Sox2) belongs to the SOX family that consists of transcription factors with a single High Mobility Group (HMG) box DNA– binding domain [1]. To date, twenty Sox genes have been discovered in mammals that are further divided into subgroups from A to H, based on the homology degree in the HMG domain [2]. Sox2 is the most representative and well-studied member of SoxB1 group, which also includes Sox1 and Sox3 [1].

Functionally, Sox2 is crucial for successful embryonic development whereas its abnormal activity has been connected to cancer development [3]. Sox2 is involved in cancer physiology through several mechanisms that vary depending on the cancer type. Particularly, Sox2 overexpression influences cell proliferation, invasion, apoptosis and metastasis via regulating oncogenic pathways, including Wnt/β-catenin, PI3K/mTOR, JAK/STAT3 and EGFR signaling [3]. Many studies investigate its function in embryonic and adult stem cells highlighting its role as both stemness factor, as well as lineage specifier. Mediators of Sox2 regulatory network include many transcription factors, microRNAs as well as epigenetic and signaling pathways regulators [4]. In this review, we discuss the aforementioned biological roles of Sox2, with particular emphasis in embryonic, neural and mesenchymal stem cells regulation.

The Multifunctional Role of Sox2 in Stemness Regulation

Sox2 function in Embryonic Stem Cells

Sox2 expression is detected in the Inner Cell Mass (ICM) and extra embryonic ectoderm of pre-implantation blastocysts [5]. Its deletion in the zygote, results in early embryonic lethality due to failure of epiblast formation with no impact on trophectoderm development [5]. Owing to Sox2 deficient mice lethality [5], analysis of hypomorphic mice mutants were necessary for the investigation of Sox2 functional role during embryonic development. Using the aforementioned mutants with decreased expression of Sox2, Que and colleagues illustrated that Sox2 plays important role in endoderm development. Specifically, Sox2 is involved in the differentiation and morphogenesis of esophagus, trachea and lung, while its reduction leads to the abnormal development of lung and esophageal atresia as well as tracheal-esophageal fistula defects [6]. Additionally, Sox2 is involved in the development of ectoderm that will be discussed later on. Interestingly, heterozygous Sox2 mice are phenotypically normal, although the pituitary size, hormone production and testicular size are reduced [7]. Hence, Sox2 seems to be a central regulator for early Pluripotent Stem Cells (PSC) formation and embryonic development.

In accordance with the data in pre-implantation embryos, Sox2 is highly expressed in Embryonic Stem Cells (ESC), where together with the proteins Oct4 and Nanog constitute the core transcriptional network responsible for stemness maintenance. Strikingly, a synergistic function of Sox2 and Oct4 for the activation of Oct-Sox enhancers/promoters has been identified, leading to the regulation of various transcription factors [5]. In particular, they activate the expression of pluripotent genes (Nanog, Sox2, Oct4 etc), while suppressing the expression of key genes essential for the in vitro differentiation and in vivo developmental processes (Pax6, Gbx2) [8,9]. Although Sox2 has a pivotal role in gene expression regulation, it is striking to find that Oct-Sox enhancers are still activated in Sox2/- ESC. This suggests that Oct-Sox complexes could be also formed by a direct interaction between Oct4 and other Sox family members [10]. Interestingly, forced expression of Oct4 partially rescues the phenotype of Sox2 loss of function [11], proving that Sox2 is critical for the maintenance of stem cell identity mainly through securing Oct4 expression levels. To conclude, Sox2-Oct4 interaction and their (auto)-regulatory activity is of paramount importance for ESC selfrenewal and pluripotency maintenance [10,12].

Except for its function as a stemness factor in PSC, Sox2 also orchestrates the cell fate decision. Sox2 expression levels need to be strictly optimized in ESC, whilst either higher or lower levels disrupt ESC self-renewal and promote their differentiation [11,13]. More specifically, reduction of Sox2 expression drives cells towards trophectoderm, whereas conflicting are the results considering the effects of Sox2 overexpression. Kopp and colleagues observed that in mouse ESC (mESC) forced expression of Sox2 more than four folds caused massive cell death, while small increases of its expression level lead to exit from pluripotency and differentiation towards all neuroectoderm, mesoderm and trophectoderm [13]. On the contrary, another study reported that overexpression of Sox2 does not impair mESC self-renewal but biases lineage choice in favor of neuroectoderm only under serum-free culture conditions (Figure 1) [14].