Blastocyst-Derived Stem Cell Populations under Stress: Impact of Nutrition and Metabolism on Stem Cell Potency Loss and Miscarriage
Data from in vitro and in vivo models suggest that malnutrition and stress trigger adaptive responses, leading to small for gestational age (SGA) blastocysts with fewer cell numbers. These stress responses are initially adaptive, but become maladaptive with increasing stress exposures. The common stress responses of the blastocyst-derived stem cells, pluripotent embryonic and multipotent placental trophoblast stem cells (ESCs and TSCs), are decreased growth and potency, and increased, imbalanced and irreversible differentiation. SGA embryos may fail to produce sufficient antiluteolytic placental hormone to maintain corpus luteum progesterone secretion that provides nutrition at the implantation site. Myriad stress inputs for the stem cells in the embryo can occur in vitro during in vitro fertilization/assisted reproductive technology (IVF/ART) or in vivo. Paradoxically, stresses that diminish stem cell growth lead to a higher level of differentiation simultaneously which further decreases ESC or TSC numbers in an attempt to functionally compensate for fewer cells. In addition, prolonged or strong stress can cause irreversible differentiation. Resultant stem cell depletion is proposed as a cause of miscarriage via a “quiet” death of an ostensibly adaptive response of stem cells instead of a reactive, violent loss of stem cells or their differentiated progenies.
KeywordsMetabolism Embryonic stem cells Trophoblast stem cells Stress Transcription factors Potency Differentiation Proliferation
We acknowledge funding from the Office of the Vice President for Research at Wayne State University, NIH (1R03HD061431) and the Kam Moghissi Endowed chair (EEP) and support for GCP and DR from NIH (P30 ES020957).
Compliance with Ethical Standards
This research was supported by grants to DAR from NIH (1R03HD061431) and from the Office of the Vice President for Research at Wayne State University.
Conflicts of Interest
The authors declare no potential conflicts of interest.
- 8.McLaren A S, M.L. Embryogenesis in mammals. New York: Elsevier; 1976.Google Scholar
- 22.Knobil, E., & Neill, J. D.( 2006). Knobil and Neill's physiology of reproduction. Amsterdam; Boston: Elsevier, 2 v. (xxix, 3230 p.).Google Scholar
- 31.Li, Q., Gomez-Lopez, N., Drewlo, S. et al. (2015). Development and validation of a Rex1-RFP potency activity reporter assay that quantifies stress-forced potency loss in mouse embryonic stem cells. Stem cells and development.Google Scholar
- 41.Li, Q., Yang, Y., Louden, E., et al. (2016). High throughput screens for embryonic stem cells; stress-forced potency-stemness loss enables toxicological assays. In A. Faqi (Ed.), Methods in toxicology and pharmacology. Springer.Google Scholar
- 55.McEwen, E., Kedersha, N., Song, B., et al. (2005). Heme-regulated inhibitor kinase-mediated phosphorylation of eukaryotic translation initiation factor 2 inhibits translation, induces stress granule formation, and mediates survival upon arsenite exposure. The Journal of Biological Chemistry, 280, 16925–16933.CrossRefPubMedGoogle Scholar
- 56.Chakraborty, D., Cui, W., Rosario, G. X., et al (2016) HIF-KDM3A-MMP12 regulatory circuit circuit ensures trophoblast plasticity and placental adaptations to hypoxia. Proceedings of the National Academy, 113(46):E7212–E7221.Google Scholar
- 76.Wale, P. L., & Gardner, D. K. (2013) Oxygen affects the ability of mouse blastocysts to regulate ammonium. Biol Reprod.Google Scholar
- 87.Bolnick, A., Abdulhasan, M., Kilburn, B., et al. (2016) Commonly used fertility drugs, a diet supplement, and stress force AMPK-dependent block of stemness and development in cultured mammalian embryos. Journal of assisted reproduction and genetics. Google Scholar
- 89.Wallace, J. M., Aitken, R. P., Milne, J. S., et al. (2004) Nutritionally-mediated placental growth restriction in the growing adolescent: Consequences for the fetus. Biology of Reproduction. Google Scholar
- 93.Wallace JM, Luther JS, Milne JS et al. (2006) Nutritional modulation of adolescent pregnancy outcome -- a review. Placenta. 27 Suppl A:S61–S68.Google Scholar
- 96.Li, Q., Louden, E., Dai, J., et al. (2017). Stress forces first lineage differentiation of mouse ESCs, validation of a high throughput screen for toxicant stress. Submitted: Development.Google Scholar