Events

Speaker: Dr Daniel Rappolee Assoc Prof, Departments of Ob/Gyn and Repro Sci/Physiology, Wayne State University School of Medicine

Abstract: Stresses that divert energy from normal development, activate stress enzymes AMPK and SAPK which decrease anabolism, proliferation and stemness, and increase differentiation. Protein kinase inhibitor screens repeatedly show that these two enzymes, and a few others, control the cell biological and developmental homeostatic response of oocytes, totipotent two-cell embryos, blastocysts, and pluripotent ESCs and multipotent placental trophoblast stem cells (TSCs) of the blastocyst. Surprisingly most diet supplements and some major drugs such as aspirin and Metformin also activate AMPK and this leads to similar effects in cultured embryos and stem cells. High throughput screens in ESCs using stemness gene promoters and first differentiated lineage promoters to drive fluorescent reporters also show complementing stemness decrease and first lineage differentiation increase under stress or AMPK agonists. Interestingly hyperosmotic and hypoxic stress force a pseudo-differentiated state despite FGF4 (the growth factor needed for TSC stemness in the blastocyst) that is reversible for twice as long as normal development caused by removing FGF4. This extended reversibility presumably would enable a longer period of production of essential first lineage products (like the mouse analog of hCG) to sustain pregnancy if results in culture repeat in vivo. Reversibility would allow sufficient first lineage function and then stemness and proliferation could return if stress subsided. However pathogenesis should be mediated by 1) irreversibility of TSC differentiation following 2) diminished proliferation and 3) forced differentiation to compensate for fewer-than-normal cells. These three events can occur at levels of stress that do not cause high levels of apoptosis. Thus, part of the strategy of TSCs during the stress response is to prolong a pseudo-differentiated state, but upon irreversibility depletes stemness and would likely lead to miscarriage.