Crosstalk between Signaling Pathways and Energy Metabolism in Pluripotency

Abstract

The sequential change from totipotency to multipotency occurs during early mammalian embryo development. However, due to the lack of cellular models to recapitulate the distinct potency of stem cells at each stage, their molecular and cellular characteristics remain ambiguous. The establishment of isogenic naïve and primed pluripotent stem cells to represent the pluripotency in the inner cell mass of the pre-implantation blastocyst and in the epiblast from the post-implantation embryo allows the understanding of the distinctive characteristics of two different states of pluripotent stem cells. This review discusses the prominent disparities between naïve and primed pluripotency, including signaling pathways, metabolism, and epigenetic status, ultimately facilitating a comprehensive understanding of their significance during early mammalian embryonic development.

Keywords: Cellular metabolism; Early embryo development; Naï Pluripotent stem cells; Primed pluripotent stem cells; Signaling pathways; ve pluripotent stem cells.

Fig. 1

Graphical illustration of main signaling pathways in naïve (A) and primed (B) pluripotent stem cells (PSCs). (A) (i) BMP4 mediates active phosphorylation of Smad1/5/8 to form protein complex with Smad4 to induce Dusp9, encoding Mkp4 (a dual phosphatase for MAPK) to inactivate Erk1/2. (ii) LIF binds to gp130/LIFR and activates JAK/STAT3 pathway to induce naïve pluripotency. Upon LIF mediated LIFR phosphorylation recruits Zap70 and Shp2 serving as both negative feedback of JAK/STAT3 signaling and a signaling transducer to Ras/Raf toward Erk1/2 activation. PKC and SRC serve as upstream kinase transducing signals toward Erk1/2. (iii) Wnt binding to LRP and Fz receptor inhibits β-catenin destruction complex (i.e., Gsk3β/Axin1/APC) and stabilizes β-catenin for Tcf3 inhibition. Plasma membrane localization of β-catenin/Oct4 in a complex with E-cadherin is found in naïve PSCs. CHIR99021 as a Gsk3β inhibitor; PD0325901 as a Mek1 inhibitor. (B) (i) Fgf2 binding to Fgf2 receptor recruits Shp2 to the plasma membrane, to serve a binding site for Grb2. Sos activation by Grb2 binding activates Ras and the downstream signaling which leads to lineage specification. PKC and SRC serve as upstream kinase transducing signals toward Erk1/2. Activin binding to Activin Receptor (ActR) induces Smad2/3 phosphorylation. Gray-colored proteins refer to inhibited proteins.

Fig. 2

Graphical illustration of main metabolism pathways in naïve (A) and primed (B) pluripotent stem cells (PSCs). (A) Bivalent metabolism with active glycolysis and OxPHOS contributes to ATP production. Excess glucose is converted and stored as glycogen by activation of Gys1 upon Gsk3β inhibition. Subsequent inhibition of AMPK by glycogen activates de novo fatty acid synthesis in naïve PSCs. (B) The attenuated mitochondrial metabolism in primed pluripotency is highlighted. Primed PSCs predominantly utilize glycolysis to generate ATP. The activation of AMPK due to depletion of glycogen inhibits overall fatty acid synthesis. However, certain fatty acids (e.g., MUFAs), are recognized for their crucial function in sustaining primed human PSCs. Decreased fatty acid oxidation by epigenetic suppression of CPT1 is a typical feature of primed PSCs. Gray-colored proteins refer to inhibited proteins. The unique mitochondrial structure distinguishing naïve from primed PSCs is also underlined.