I spent a good part of the last decade studying Wnt signaling, a cascade of proteins acting in a sequential manner in our cells that instruct cells on what to do and how to behave. Wnt signaling and a few other protein cascades like it are conserved across species and are one of the earliest group of proteins that make sure embryos develop normally and have the right beginnings to make a complete organism. Pioneering work by many developmental biologists on various animal model systems brought to light the importance of these players in shaping the embryo. Mouse embryos are the closest mammalian versions that scientists have used to extrapolate and understand the development of human embryos. Embryonic stem cells, the first cells that arise from the fusion of sperm with egg, are capable of giving rise to many different type of cells of our body given the right environment and proteins to nudge them into a specific fate. Mouse embryonic stem cells have been used precisely for this purpose to test the roles of various proteins that help in directing the cells to choose one fate over another. Being able to study embryonic cell behavior in a petri dish allows us to understand what really goes on in living organisms. The authors of a new paper published in Science this week build an embryo in the lab using a few cells from the mouse embryo and a supporting gel matrix. They use these embryos to reconstruct the sequence of events and shine a focus light on players directing these events, that occur a few days into the embryo’s journey to becoming a complete organism.
A freshly fertilized egg travels from the site of fertilization to the uterus to be implanted. During this time, it divides and gives rise to two types of cells – the embryonic stem cells (ES) that will give rise to all cells of the body and the trophoblast stem cells (TS) that will form the placenta and yolk sac. The proper and complete development of an organism from an embryo requires an exchange of information between the ES and the TS cells. In the study, the authors mix a few ES and TS cells and provide a gel matrix or extracellular matrix (ECM) to allow the development of the lab embryo referred to as ETS embryo. The gel matrix is sort of a replacement to the uterus where the embryo would get implanted if it were in a live organism, and it also provides a mix of nourishing proteins to the developing embryo. Upon mixing, the ES and TS cells rearranged themselves into distinct compartments as they would in a live embryo 22% of the time the authors attempted the experiment (see Fig.1 bottom panel).
Fig.1 Comparison of the lab-constructed ETS embryos with natural embryos
One of the first events of interaction between the ES and TS cells is the formation of a common and continuous hollow space or cavity between the two cell compartments and occurs approximately 6days post implantation. The chance of the cavities merging was greatly increased when ES cells were present in the mix as embryos made exclusively of TS cells initiated no cavity formation. They also show that the ES cells provide a crucial protein signal that induces TS cells to form the cavity. Next they observed whether the ETS embryo was capable of forming mesodermal cells that would go on to give rise to many tissues of the body including muscle, bone, linings of blood vessels, kidneys and other organs. The ETS embryos not only expressed proteins that would be expressed by the mesodermal cells in a normal embryo, but the chance that they would express these proteins increased greatly if TS cells were present in the ETS embryo thus reinforcing the importance of exchange of crucial early signals between ES and TS cells. From previous studies, they knew that one obvious candidate for the signal that could be provided by the TS cells is Wnt, the bread and butter of my graduate studies! In the study, the authors show that Wnt protein is indeed required for the ES cells of the ETS embryo to express mesoderm specific proteins setting the stage for the development of all those tissues that these mesodermal cells would give rise to later in development. The next major event in embryo development would be the generation of primordial germ cells (PGCs), the precursor cells that would ultimately become sperms or eggs. The 15 ETS embryos they observed were able to form cells that expressed the same proteins expressed by PGCs and this was again dependent on the cells receiving two important signals, Wnt and BMP.
The authors show that they are able to recapitulate some of the major early events of the developing embryo and identify important early precursor cells in their lab-constructed ETS embryo. Even though the ETS embryos lack the structure that provides the signals to ensure directionality to the developing embryo, about 70% of them were still able to express mesodermal proteins in the appropriate compartment. Although by no means perfect, the authors make a case that their ETS embryos would allow scientists to dig deeper into these early protein signals, uncover whether they come from ES cells or the TS cells and expose the intricate cross talk between these two cell types that basically govern how we ultimately develop. While the nerd in me was excited to read this paper that recaptures early embryonic development using a mix of stem cells and an artificial matrix, I also realized it won’t be too long before someone attempts to do this with human ES cells. Human ES cells are more complex to deal with and their optimal conditions of growth are different from those of mouse ES cells, but the seeds of possibility have been sown!
- Assembly of embryonic and extraembryonic stemcells to mimic embryogenesis invitro –embryos_in_dish