Estrogen Controls embryonic stem cell proliferation via store‐operated calcium entry and the nuclear factor of activated T‐cells (NFAT)

Abstract

Embryonic stem cells (ESCs) can self-renew indefinitely and differentiate into all cell lineages. Calcium is a universal second messenger which regulates a number of cellular pathways. Previous studies showed that store-operated calcium channels (SOCCs) but not voltage-operated calcium channels are present in mouse ESCs (mESCs). In this study, store-operated calcium entry (SOCE) was found to exist in mESCs using confocal microscopy. SOCC blockers lanthanum, 2-aminoethoxydiphenyl borate (2-APB) and SKF-96365 reduced mESC proliferation in a concentration-dependent manner, suggesting that SOCE is important for ESC proliferation. Pluripotent markers, Sox-2, Klf-4, and Nanog, were down-regulated by 2-APB, suggesting that self-renewal property of mESCs relies on SOCE. 17β-estradiol (E2) enhanced mESC proliferation. This enhanced proliferation was associated with an increment of SOCE. Both stimulated proliferation and increased SOCE could be reversed by SOCC blockers suggesting that E2 mediates its stimulatory effect on proliferation via enhancing SOCE. Also, cyclosporin A and INCA-6, inhibitors of calcineurin [phosphatase that de-phosphorylates and activates nuclear factor of activated T-cells (NFAT)], reversed the proliferative effect of E2, indicating that NFAT is involved in E2-stimulated proliferation. Interestingly, E2 caused the nuclear translocation of NFATc4, and this could be reversed by 2-APB. These results suggested that NFATc4 is the downstream target of E2-induced SOCE. The present investigation provides the first line of evidence that SOCE and NFAT are crucial for ESCs to maintain their unique characteristics. In addition, the present investigation also provides novel information on the mechanisms of how E2, an important female sex hormone, affects ESC proliferation.

Novel Pancreatic Endocrine Maturation Pathways Identified by Genomic Profiling and Causal Reasoning

“…While the significance of this is unknown, cholesterol is, among other things, a precursor for steroid hormones such as estrogen and progesterone, and a recent report by Wong et al . links estrogen receptor signaling to embryonic stem cell proliferation and self-renewal [57]. Cholesterol is also known to play an important role in development, particularly through its role in the post-translational modification of the sonic hedgehog protein [58].…”

CBARA1 Plays a Role in Stemness and Proliferation of Human Embryonic Stem Cells

“…This hypothesis is in accordance with the findings of Nunez et al [35], who showed that salicylate-induced inhibition of mitochondrial Ca 2+ uptake leads to inhibition of store-operated Ca 2+ entry (SOCE) and impairs cell proliferation in Jurkat and human colon cancer cells. In this context, it is interesting to note that a recent study demonstrated that functional SOCE is present in mESCs and that prevention of SOCE attenuates mESC proliferation, arrests cells at the G0/G1 phase, and decreases the expression of pluripotent markers [36]. Conversely, stimulation of SOCE using 17β-estradiol increases mESC proliferation [36].…”

Role of Sex Hormone Levels and Psychological Stress in the Pathogenesis of Autoimmune Diseases

“…2-APB is a reliable blocker of store-operated Ca2+ entry but an inconsistent inhibitor of InsP3-induced Ca2+ release, suggesting that the self-renewal property of mESCs relies on SOCE. SOCC blockers can reverse both stimulated proliferation and increased SOCE, suggesting that E2 mediates its stimulatory effect on proliferation via enhancing SOCE [1]. …”

“…According to the Autoimmune Related Diseases Association (AARDA), it is estimated that 50 million Americans have an autoimmune disease based on the National Institute of Health (NIH) epidemiology studies as well as individual patient group data from members of the National Coalition of Autoimmune Patient Groups (NCAPG). There is an increase in the prevalence of autoimmune diseases in the older age group [1-2]. It has been observed that women are affected more than men.…”