Interplay of Oct4 with Sox2 and Sox17: a molecular switch from stem cell pluripotency to specifying a cardiac fate

Brief Report: Oct4 and Canonical Wnt Signaling Regulate the Cardiac Lineage Factor Mesp1 Through a Tcf/Lef-Oct4 Composite Element

“…Choice for germ layers is directly related to Oct4 levels: 50%–150% of endogenous Oct4 maintains pluripotency, a drop in Oct4 level leads to the differentiation toward trophectoderm, and a twofold Oct4 level leads to mesoderm and endoderm [12]. Particularly, ectopic Oct4 triggers the expression of early mesoderm and cardiac genes [13–15]. Compared to its well‐characterized role in regulating pluripotency, how Oct4 contributes to lineage commitment and cell differentiation is unclear.…”

Transforming the Promise of Pluripotent Stem Cell-Derived Cardiomyocytes to a Therapy: Challenges and Solutions for Clinical Trials

“…Limiting or even eliminating spontaneous background differentiation, and maintaining consistent levels of octamer-binding transcription factor 4 (Oct4) expression, is of critical importance for successful induction of mesoderm. 35 Because of the importance of input cell status, media and substrates that enhance the stability of feeder free pluripotent cultures 36 will likely enhance differentiation outcomes. In addition, suitable "smart surfaces" for pluripotent expansion that skew differentiation toward the mesendoderm lineage might be tailored where required.…”

Human embryonic stem cells (hESCs) for heart regeneration

“…A more complete cardiac differentiation (defi ned by the expression of structural contractile proteins like β -myosin heavy chain) can fi nally be obtained by using another set of factors, such as those described in the commonly used Keller's protocol (vascular endothelial growth factor and Wnt antagonists in serum-free media) (Kattman et al , 2011). Although several small molecules have been reported to induce cardiac differentiation of pluripotent stem cells (reviewed in Liu et al , 2012) (and high-throughput screening predicts that others are yet to be identifi ed), those modulating the Wnt pathway are of special interest (Minami et al , 2012) because Wnt factors have a biphasic effect: they enhance cardiogenesis during the early pre-gastrulation phase whereas they inhibit it at a later stage, thereby rationalizing the use of Wnt antagonists during the fi nal steps of the progenitor cell cardiac differentiation whereas the earlier exposure of cells to BMPs may actually increase Wnt production (Stefanovic et al , 2009). The transition between the activating and repressing effects of Wnt factors on cardiogenesis occurs within a very narrow time frame (Mignone et al , 2010), which highlights that the exposure of ESC to cardio-instructive agents needs to be tightly developmental stage-specifi c (Kattman et al , 2011).…”

“…cardiomyocytes (as assessed by specifi c phenotypic markers, upregulation of cardiopoiesis-associated small non-coding RNAs and an epigenetic signature indicative of the activation of cardiac promoters), endothelial and smooth muscle cells (Blin et al , 2010). Simultaneously, pluripotency genes are downregulated, with the exception of Oct-4 which persists for a longer period of time because Oct-4 is also a marker of BMP-2-induced cardiopoiesis (Stefanovic et al , 2009). This highlights the ambivalent role of pluripotency-associated transcription factors which, on the one hand, maintain pluripotency through their respective cross-inhibition but, on the other hand, also act as initiators of a given differentiation path (mesoderm in the case of Oct-4, endoderm in the case of Nanog, neuro-ectoderm in the case of Sox-2).…”