Trophoblast Stem Cells: Another stem cell type isolated from the early embryo
While embryonic stem cells are widely studied, a lesser known, but still significant, population of stem cells also resides within the early developing embryo: trophoblast stem cells (TSCs).
In brief, in most mammals the trophoblast is the part of the early embryo that later significantly contributes to the placenta of the fetus. The embryo and mother work together to create the placenta; while the trophoblast of the embryo becomes the chorion part of the placenta, the maternal uterine cells and surrounding blood vessels form the maternal placental components (Gilbert, 2003).
The placenta is the organ in mammals that connects the uterine wall to the developing fetus, bringing the two blood systems close together. The placenta allows the fetus to safely receive essential gases, such as oxygen, and nutrients from the mother. At the same time, it also lets the fetus expel waste through the mother’s kidneys. Additionally, the placenta releases essential pregnancy-related hormones and growth factors that, for example, let the uterus hold the fetus. Lastly, the placenta secretes immune response regulators to give the fetus immune protection against the mother (so that the fetus is not rejected by the mother’s immune system, as a tissue graft or organ transplant would be) (Rossant and Cross, 2001; Gilbert, 2003). Overall, the placenta plays a key role in early development; even small abnormalities in the placenta can lead to death of the fetus (Rossant and Cross, 2001).
While TSCs give rise to the placenta, these stem cells establish their identity long before the placenta develops; their fate is determined during the early embryo. Soon after the egg and sperm join during fertilization, the resultant zygote (fertilized egg cell) starts undergoing cell division. The resulting cells continue to undergo synchronous cell division. When the embryo is at the 16-cell stage (called a morula), it is a solid sphere of cells and already the precursors of the trophoblast cells are defined; the external, relatively larger cells mostly become the trophoblast cells. By the 64-cell stage, these cells’ fates are set; while the trophoblast will become the placenta, the other cells in the embryo can become the fetus. In mammalian development, this is the first differentiation event (Rossant and Cross, 2001; Gilbert, 2003).
A few cell divisions later, the trophoblast contributes to significant cellular rearrangements in the embryo which make it enter the blastocyst stage (see Figure 1). The blastocyst, which contains approximately 150 cells, is made up of three main parts: the blastocoel (an internal, fluid-filled cavity), the inner cell mass (ICM), and the trophoblast. When the embryo was a morula, the surrounding trophoblast precursors caused fluid to be secreted into the morula (utilizing sodium pumps in the trophoblast cell membranes); this secretion created the blastocoel cavity. The ICM is a cluster of cells inside the blastocyst that will later become the adult organism; human embryonic stem cells can be derived from the ICM, as was previously discussed. Lastly, the trophoblast is a monolayer of cells, specifically polarized epithelial cells, which surround the blastocoel and ICM, similar to their future role of surrounding the fetus as its placenta (Rossant and Cross, 2001; Gilbert, 2003).
A great deal of cell signaling occurs right before implantation of the late blastocyst into the uterine wall in order to ready the trophoblast for the next developmental stage, gastrulation. Prior to implantation, the ICM and neighboring trophoblast cells secrete proteins that make the trophoblast become highly proliferative and take on different, distinct trophoblast characteristics. Upon uterine implantation, which occurs around day 7 or 8 in human development, the trophoblast differentiates into a variety of extraembryonic (outside of the embryo proper) structures to assist with implantation and placenta development. To firmly implant the embryo, trophoblast cells ingress into the uterus wall.
During gastrulation, the blastula undergoes distinct cellular reorganizations to reach the next developmental stage, which is called a gastrula. (The hallmark of gastrulation is the creation of three distinct tissue, or germ, layers, in the embryo which will make up all the tissues of the future adult organism; these layers are the ectoderm, the mesoderm, and the endoderm [see Figure 2].)
While the internal components of the developing gastrula undergo significant rearrangements, during gastrulation the extraembryonic portions are also rapidly changing, anchoring the embryo on the uterine wall and establishing an exchange of nutrients and gases with the mother. At this time, the TSCs give rise to cytotrophoblast stem cells, which are precursors of all trophoblast cells. The cytotrophoblast makes up the inner single cell layer of the trophoblast, surrounding the gastrula and anchoring the chorion to the maternal endometrium. Some cytotrophoblasts will later become stem cells in the chorionic villi, which provides more surface area on the chorion to maximize contact to the maternal blood supply (Rossant and Cross, 2001; Gilbert, 2003).
