Vitamin A is required for reproduction and normal embryonic development. We have determined that all-trans-retinoic acid (atRA) can support development of the mammalian embryo to parturition in vitamin A-deficient (VAD) rats. At embryonic day (E) 0.5, VAD dams were fed purified diets containing either 12 g of atRA per g of diet (230 g per rat per day) or 250 g of atRA per g of diet (4.5 mg per rat per day) or were fed the purified diet supplemented with a source of retinol (100 units of retinyl palmitate per day). An additional group was fed both 250 g of atRA per g of diet in combination with retinyl palmitate. Embryonic survival to E12.5 was similar for all groups. However, embryonic development in the group fed 12 g of atRA per g of diet was grossly abnormal. The most notable defects were in the region of the hindbrain, which included a loss of posterior cranial nerves (IX, X, XI, and XII) and postotic pharyngeal arches as well as the presence of ectopic otic vesicles and a swollen anterior cardinal vein. All embryonic abnormalities at E12.5 were prevented by feeding pharmacological amounts of atRA (250 g͞g diet) or by supplementation with retinyl palmitate. Embryos from VAD dams receiving 12 g of atRA per g of diet were resorbed by E18.5, whereas those in the group fed 250 g of atRA per g of diet survived to parturition but died shortly thereafter. Equivalent results were obtained by using commercial grade atRA or atRA that had been purified to eliminate any potential contamination by neutral retinoids, such as retinol. Thus, 250 g of atRA per g of diet fed to VAD dams (Ϸ4.5 mg per rat per day) can prevent the death of embryos at midgestation and prevents the early embryonic abnormalities that arise when VAD dams are fed insufficient amounts of atRA.

Surface modification with PEG or albumin reduces phagocytic internalization of nano-particles but not micro-particles.

In recent years, stem cell-based models that reconstruct mouse and human embryogenesis have gained significant traction due to their near-physiological similarity to natural embryos. Embryo models can be generated in large numbers, provide accessibility to a variety of experimental tools such as genetic and chemical manipulation, and confer compatibility with automated readouts, which permits exciting experimental avenues for exploring the genetic and molecular principles of self-organization, development, and disease. However, the current embryo models recapitulate only snapshots within the continuum of embryonic development, allowing the progression of the embryonic tissues along a specific direction. Hence, to fully exploit the potential of stem cell-based embryo models, multiple important gaps in the developmental landscape need to be covered. These include recapitulating the lesser-explored interactions between embryonic and extraembryonic tissues such as the yolk sac, placenta, and the umbilical cord; spatial and temporal organization of tissues; and the anterior patterning of embryonic development. Here, it is detailed how combinations of stem cells and versatile bioengineering technologies can help in addressing these gaps and thereby extend the implications of embryo models in the fields of cell biology, development, and regenerative medicine.

Advances in the field of stem cell-based models have in recent years lead to the development of blastocyst-like structures termed blastoids. Blastoids can be used to study key events in mammalian pre-implantation development, as they mimic the blastocyst morphologically and transcriptionally, can progress to the post-implantation stage and can be generated in large numbers. Blastoids were originally developed using mouse pluripotent stem cells, and since several groups have successfully generated blastocyst models of the human system. Here we provide a comparison of the mouse and human protocols with the aim of deriving the core requirements for blastoid formation, discuss the models’ current ability to mimic blastocysts and give an outlook on potential future applications.