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

Abstract

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.

Suboptimal in vitro culture conditions: an epigenetic origin of long‐term health effects

“…Moreover, some of the changes that the authors described in cloned mice were also present in a control group derived from normal zygotes exposed to the same IVC system, as the reconstructed embryos. Supporting our results, other research groups have also been reporting the incidence of increased body weights in adult mice generated from in vitro cultured embryos (Sjoblom et al, 2005). Moreover, it has also been reported that disturbance of the preimplantation embryo development may generate hypertensive offspring (Kwong et al, 2000).…”

Porcine Granulocyte-Macrophage Colony-Stimulating Factor Improves the <i>in vitro</i> Development of Cloned Porcine Embryos

“…Therefore, treatment with GM-CSF may improve the efficiency of transgenic pig production and also the establishment of SCNT-derived embryonic stem cells. Similarly, treatment with GM-CSF improves not only blastocyst formation in vitro but also posttransfer embryonic survival in murine [40] and bovine [28] embryos. Treatment with pGM-CSF during IVC affected not only ICM cells but also TE cells and the expression of Cdx-2 mRNA in cloned blastocysts.…”

Seminal fluid and reproduction: much more than previously thought

“…In addition embryos derived from these matings display perturbations in blastocyst formation which can be partially rescued using in vitro culture [13]. A definitive study by Sjoblom et al has demonstrated that addition of GM-CSF into culture media can alleviate some of the detrimental effects of embryo culture on pregnancy outcomes, such as altered placental morphogenesis [47]. The addition of many these embryotrophic growth factors to in vitro embryo culture media is now being more closely investigated for their use in human assisted reproduction to allow closer mimicry of the in vivo environment.…”