A Role for Proton Signaling in the Induction of Somatic Cells to Pluripotent Embryonic Stem Cells

Abstract

The mechanisms of embryonic stem (ES) cell establishment and egg cell fertilization have been studied without examining the interactions of these cell types, perhaps because of the lack of consideration for the similarities between ES cells and fertilized egg cells, especially the lack of calcium signaling. Here we unify the various concepts developed separately so fat in ES cells and fertilized eggs, although both types of cells have the same fate (i.e., to become somatic cells). We discuss the concept of water property changes in the cytoplasm that occur along with the cell cycle, which was initially introduced in the field of biophysics. With this aspect, the similarities and differences between ES cells and fertilized eggs are understandable, and the water property changes help explain why ES cells can have pluripotency, as fertilized eggs do, following a de novo stimulus such as acid treatment. Obokata et al. recently discovered a shortcut for generating pluripotent stem cells which they named “stimulus-triggered acquisition of pluripotency (STAP)” cells from somatic cells at the transient low-pH stimulation [1]. This report has had a significant impact on many developmental biologists and clinicians, because the low-pH treatment seemed an unexpectedly easy way to change somatic cells to pluripotent embryonic stem (ES) cells [2]. However, this method is not so surprising to biophysicists, because several types of cellular stress have been found to induce egg activation associated with a Ca2+ transient increase, such as the change in cytoplasmic pH caused by applying NH4Cl and/or CO2, or even mechanical pricking with a needle [3]. In 2002, Burdon et al. reported that the epiblast cells, which have pluripotency, were obtained from a prolonged culture of ES cells [4]. ES cells have an unusual cell cycle in which the G1 phase that operates in other types of cells is reduced [5]. Such features of ES cells are associated with the deregulated characteristics of the proliferation of tumor cells. Unlike these types of cells, a fertilized egg also starts its own cell cycle with Ca2+ oscillations [6]. This Ca2+ oscillation can be explained by a one- or two-calcium-pool model with the positive feedback of increased Ca2+ and inositol 1,4,5- trisphosphate (IP3) during the rising phase of each Ca2+ increase. It is thus reasonable to speculate that the cell cycle is the time keeper in Ca2+ oscillation in both cultured ES cells in vitro and circadian calcium rhythms in the somatic cells in the body, which were also found to be associated with a slow frequency of Ca2+ oscillation, with 1 cycle/day [7]. The property changes of water state in the cell are another critical issue. Mantre described that the state of water in the somatic cells in the body has ordered-structured bound water (like ice), whereas ES cells as well as cancer cells have free (normal) water in the G1 and G2 phases [8]. Only protons, not other ions, are able to move on the surface of bound water, whereas in free water all types of ions (including protons) can move by diffusion. In this review article, we describe the differences between somatic cells and ES cells regarding proton signaling, which regulates Ca2+ oscillation, and the change in water properties associated with cell cycle. Proton signaling plays a critical role in the nuclear reprogramming to the pluripotent stage.