Tuesday, May 6, 2025
5/6/2025
Stem cell-based 3D model of human yolk sac for experimental interrogations - Proposal Abstract The yolk sac is an extra-embryonic organ that is vital for early embryo development, serving as the nutrient supply center during the first trimester. It absorbs nutrients and synthesizes lipoproteins, which are transported to the embryo through the vasculature and blood cells that are also produced by the yolk sac. Accordingly, severe damage to the yolk sac by environmental insults, such as maternal infection, disease, and chemical agent, leads to death or maldevelopment of the embryo. An example is maternal diabetes, in which high levels of glucose impair the yolk sac to cause embryo abnormalities. Nonetheless, our knowledge of environmental factors that are harmful to the yolk sac remains highly limited. More investigations on the yolk sac are crucial to preserve healthy pregnancy. Since actual human yolk sac tissue is generally inaccessible, many studies are conducted using animals, namely rodents, which have provided mechanistic insights into the yolk sac formation. However, distinct differences exist between the yolk sac of rodents and human, which necessitates the establishment of human yolk sac models that are amenable to experimental interrogations. The objective of the proposed project is to create an in vitro yolk sac model, or yolk sac organoid, using human pluripotent stem cells, with the long-term goal of utilizing it to study the impact of environmental and genetic factors. We have recently developed a culture protocol, which allows aggregates of human pluripotent stem cells to form large cysts surrounded by blood vessel-like structures. These cysts robustly express various transcripts that are enriched in the human yolk sac. We hypothesize that these stem cell-derived cysts represent the morphological and functional properties of the human yolk sac, and can serve as yolk sac organoids to be utilized for further investigations. In Aim 1, we will characterize the stem cell-derived cyst at the cellular and molecular levels to reveal which cell types of the human yolk sac are recapitulated. In Aim 2, we will evaluate whether the yolk sac-like cyst can serve as an effective in vitro model to study the nutrient absorption function of the human yolk sac. In Aim 3, we will test the roles of key regulator genes in the yolk sac-like cyst formation to assess similarities between the rodent and human yolk sacs at the genetic level. The proposal is significant because it aims to establish an experimentally tractable model of the human yolk sac. As the yolk sac is a vital organ to support embryo development, understanding of its susceptibility to environmental and genetic disturbances is crucial to ensure a healthy pregnancy. An in vitro model made of human pluripotent stem cells should be of great value to facilitate investigations on the human yolk sac. The proposal is innovative because the creation of an organoid that represents the human yolk sac at the morphological and functional level is highly unique, and the idea of applying the yolk sac organoid to discover reproductively harmful factors is novel.
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