Granulocyte-Macrophage Colony-Stimulating Factor Alleviates Adverse Consequences of Embryo Culture on Fetal Growth Trajectory and Placental Morphogenesis

Growth factors secreted by the female reproductive tract promote development of the preimplantation embryo and potentially act as epigenetic determinants of postimplantation developmental competence and pregnancy outcome. In a comprehensive embryo transfer study in mice, we examined the late gestational and postnatal effects of embryo exposure to the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF), identified as a key physiological regulator of cell number and viability in mouse and human blastocysts. Embryo development in culture in the absence of GM-CSF restricted fetal growth, accelerated postnatal growth, and increased adult body mass and adiposity in offspring compared with in vivo-grown embryos, especially in males. Addition of GM-CSF to embryo culture medium increased the proportion of transferred embryos that generated viable progeny and alleviated the effects of in vitro culture on fetal and postnatal growth trajectory but did not prevent programming of adult obesity. Placental morphogenesis was modified by embryo culture, which inhibited development of labyrinthine exchange tissue and adversely altered some structural correlates of placental transfer function. GM-CSF reversed the effect of culture on labyrinthine growth and increased the surface area of placental trophoblast available for nutrient exchange. These findings indicate that the detrimental influence of embryo culture on fetal viability and growth may be largely mediated through altered placental morphogenesis and can be alleviated by GM-CSF. This demonstrates that embryonic exposure to GM-CSF is essential for normal placental development and fetal growth.