Abstract
It is becoming increasingly clear that cells are remarkably sensitive to the biophysical cues of their microenvironment and that these cues play a significant role in influencing their behaviors. In this study, we investigated whether the early pre-implantation embryo is sensitive to mechanical cues, i.e. the elasticity of the culture environment. To test this, we have developed a new embryo culture system where the mechanical properties of the embryonic environment can be precisely defined. The contemporary standard environment for embryo culture is the polystyrene petri dish (PD), which has a stiffness (1 GPa) that is six orders of magnitude greater than the uterine epithelium (1 kPa). To approximate more closely the mechanical aspects of the in vivo uterine environment we used polydimethyl-siloxane (PDMS) or fabricated 3D type I collagen gels (1 kPa stiffness, Col-1k group). Mouse embryo development on alternate substrates was compared to that seen on the petri dish; percent development, hatching frequency, and cell number were observed. Our results indicated that embryos are sensitive to the mechanical environment on which they are cultured. Embryos cultured on Col-1k showed a significantly greater frequency of development to 2-cell (68±15% vs. 59±18%), blastocyst (64±9.1% vs. 50±18%) and hatching blastocyst stages (54±25% vs. 21±16%) and an increase in the number of trophectodermal cell (TE,65±13 vs. 49±12 cells) compared to control embryos cultured in PD (mean±S.D.; p<.01). Embryos cultured on Col-1k and PD were transferred to recipient females and observed on embryonic day 12.5. Both groups had the same number of fetuses, however the placentas of the Col-1k fetuses were larger than controls, suggesting a continued effect of the preimplantation environment. In summary, characteristics of the preimplantation microenvironment affect pre- and post-implantation growth.
Highlights
Every living structure, from cells to tissues and up to the level of the entire organism has the capability to sense and respond to physical forces; this property is defined as mechanotransduction
In the series of experiments, zygotes were cultured on a soft collagen, which had a stiffness of 1 k Pa (Col-1k), similar to the one present in the fallopian tubes, or on two-dimensional collagen coated dishes, with a stiffness of 1 G Pa (Col-1G), which is similar to the stiffness of the petri dish (PD)
We conducted experiments to more closely replicate the mechanical environment that embryos encounter in vivo during their journey from the fallopian tube to the uterus
Summary
From cells to tissues and up to the level of the entire organism has the capability to sense and respond to physical forces; this property is defined as mechanotransduction. Stem cells sense the stiffness of the environment and initiate alternate differentiation patterns [1,2,3]. While multiple groups are studying the molecular mechanisms mediating the mechanotransduction effects, relatively few studies have evaluated the role of mechanotransduction during early embryo development [4]. This is important, as events occurring during this sensitive period of development can have long-lasting health effects, as proposed by the Developmental Origins of Health and Disease (DOHaD) Hypothesis [5,6]. A number of works have demonstrated that embryonic blastomeres, fallopian tube and uterine epithelium are all soft, on the order of 100–
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