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Development of Bilaminar Embryo 11-6-09 1. Introduction a. The fetus is upside down, head down in the uterus and amniotic cavity since it fits best this way b. The legs have more room to move around in the upper portion of the amniotic cavity. c. Due to the positioning of the uterus, women in the final stages of pregnancy have to pee a lot because of pressure of the uterus on the urinary bladder d. The umbilical cord attaches at the naval(umbilicus) of the fetus and extends with it’s vessels over into the placenta which is imbedded in the wall of the uterus. e. The great majority of the time implantation of the developing embryo occurs on the posterior wall i. Anteriorly placed placenta makes it difficult to do a C-section delivery f. Occasionally (as is the case with the example shown in class), the growing fetus, specifically the placenta rests on the lower spine compression the vena cava return from the lower limbs i. Causing pain, swelling, etc 2. The placenta a. The umbilical cord and it’s blood vessels lead into the extraembryonic tissues consisting of the placenta, chorionic sac, and smooth chorion b. The placenta itself is the exchange organ between the mother and fetus i. Oxygen, nutrients, and wastes of the fetus all pass through the maternal and fetal blood through the placenta c. The umblicial cord can be seen going into the fetal aspect of the placenta and dividing out into branches that will ramify on the fetal surface and divide into smaller and smaller branches that will vascularize the fetal tissues themselves d. The fluid contained within the intact amniochorionic membrane is amniotic fluid. e. Looking at the maternal aspects of the placenta it appears quite rough, bulge like known as cotyledons i. Cotlyedons are filled with placenta villi and blood ii. Looking at the maternal aspects we also see some maternal tissue (endometrium) with fetal tissue deep to it iii. After the placenta is delivered (3rd stage), the placenta must be checked to see if it complete and that there are no missing parts 1. This is important because the embryo fetus needs the placenta to survive but not the other way around 2. Thus, if placental tissue is retained in the uterus it can continue to go through metabolism and grow while not following normal cellular controls and become a malignancy iv. If we break open one of the cotelydons we can see running within it small vessels leading out into a very spongy area (finger like area) which are the villi f. Placenta also creates hormones that affect mother’s body g. Placenta has also been used in cosmetics 3. Fertilization a. The ovary is the gonad that produces oocyte follicles during development 1 b. One of the developing follicles will be chosen to complete development and ovulate releasing secondary oocyte, cells, and other tissues which will be released into the peritoneal cavity and hopefully be picked up by the uterine tube i. Ovulation is usually the 11th day of a 28 day uterine cycle c. If spermatozoan are present, fertilization may take place d. Unfortunately however, the thing that helps determine when menstrual or uterine changes occur is not related to the first portion of the ovarian cycle, but rather the second portion of the ovarian cycle i. Or whether or not there is a degeneration and loss of function of the corpus luteum ii. The constant time within the ovarian cycle is that time period from ovulation to the loss of function of the corpus luteum, which is 14 days e. Preovulatory phase may be longer or shorter than 14 days i. If the womans ovarian cycles are regular than you can figure out the approximate time ovulation should occur. ii. However, if she is not regular, it is impossible to accurately determine when ovulation is taking place iii. The day of or the day immediate following ovulation are considered a woman’s fertile period f. Ovulated mass is released from ovary and is picked up by the uterine tube. This happens because the end of the uterine tube caps the site of ovulation on the ovary so that the egg can be picked up i. There is a chance that the ovum and associated eggs will fall into the peritoneal cavity, however this typically does not happen (if fertilization happens any place but the uterus it is considered an ectopic pregnancy 2 g. Remnants of follicle the remain in the ovary transform into the corpus luteum (yellow body) i. This produces progesterone which is important because it causes the lining of the uterus to change from proliferation to one that is secreting. ii. The secreting form of the uterus will be receptive to the possible little one that will be entering into the uterine cavity h. Zona Pellucida i. i. Layer of noncellular material around oocyte ii. Formed from contributions from the oocyte and follicular cells; iii. Thus the zona pellucida is present is present within the ovary (since follicular cells add to the zona peludica) as well as part of the ovulated mass. iv. Functions 1. It serves as the binding site for spermatozoa (contains binding sites on its surface) 2. Limits the number of spermatozoan that will try to fertilize oocyte 3. Holds together the small mass of early cells that results just after fertilization (thus preventing them from wandering away 4. Also prevents fertilized cells from making contact with maternal tissue The forming of the Conceptus i. Conceptus relates to the products of fertilization 1. Includes the embryo proper and all extraembryonic tissues (such as the placenta) 2. Everything that results from fertilization has the same genome (that which results from fertilization) ii. Follicular cells (corona radiata) probably make the ovulated mass a little larger and make it rough on its surface so the uterine tube can handle the mass more easily because it has been shown if you put the oocyte and zona without the corona radiate it will just sit and spin within the uterine tube instead of being transported further down the tube 1. These extra cells make it a larger mass, easier to handle for the uterine tube, and further the corona radiate (which originally are follicular cells) are probably releasing compounds that attract the spermatozoa if they are close enough iii. Thus the first spermatozoa must disperse the corona radiate so that later sperm can break through the zona pellucid 3 1. The head of the spermatozoa (the acrosome) contains enzymes 2. One of these enzymes released from the acrosomal vesicle is hyaluronidase which will help break down the matrix and cell adhesions between the cells of the corona radiate 3. Subsequent sperm make contact with the zona and bind to it a. These sperm’s acrosomal reaction will release enzymes will forge a path through the acellular zona pellucida iv. The plasmalemma (cell membrane) of the oocyte is against the zona pellucida 1. In fact, right before ovulation the oocyte has microvilli that go into the zona pellucida so that when spermatozoa digest their way through the zit they can make contact with the plasmelemma of the oocyte 2. The membranes of the spermatozoa and that of the occyte fuse, break open, and the contents of sperm go into the cytoplasm of the oocyte a. The nucleus, the mitochondria, and the flagella go into the oocyte b. The nucleus survives, will the mitochondria and flagella degenerate v. Cortical Granule and zona reaction 1. As a result of the spermatozoa penetration of the occyte, granules are released that were on the edge of the occyte out in the cortex of the occyte 2. The contents of these granules get into the previtiline space (cortical granule reaction) 3. The contents of the granules are released and cause a chemical change in the zona pellucida 4. In addition to the above reaction, the plasmalemma of the oocyte retracts from the zona and makes a true previtiline space a. When the plasmalemma retracts it prevents additional spermatozoa that were piercing the zona pellucida to make contact with the occyte (which has not retracted) as the sperm flagella is no longer effective b. This prevents the oocyte from being fertilized by more than one sperm for about 20 min or so 4 5. The chemical change to the zona pellucida takes ~20-30 minutes (zona reaction) a. The chemical change prevents the acrosomal enzymes from being able to penetrate the zona pellucida, thus preventing polyspermy i. If polyspermy does occur, often times the pregnancy will spontaneously abort either early or later 4. The Developing embryo a. As mentioned before, tissue remaining with the ovary becomes the corpus luteum producing progesterone which causes the lining of the uterus to change from the proliferative phase (stimulated by estrogen) to the secretory phase (receptive phase) b. Fertilization completes meiosis (specifically the second meiotic division) c. Now the male pronucleus is within the oocyte cytoplasm. When the female and male pronuclei merge the normal genetic component is created d. Replication and mitosis then begins to occur. e. Genetic variation happens because of maternal and paternal genomes have altered or triggered the metabolic processes within the cell to begin mitosis f. The beginning cell divisions take place as the conceptus is moving down the uterine tube still surrounded by the zona pellucida (which functionally holds the developing embryo together)—the radiate has now disappeared g. Within the developing embryo the first polar body given off by meiosis 2 and the first mitotic division results in two equal cells i. These 2 cells divide, then 4 cells, then 8 cells, etc ii. As we have mitotic division, the cells are getting smaller iii. Early mitotic divisions are just separating the initial cytoplasm but as they do they are producing more nuclei iv. Thus more cells are produced but each will temporarily be smaller 5 1. Part of that is through the process of keeping cells all contained within the zona pellucida not letting them abide fluid and swell up 2. But there are probably also cell-cell reactions that are helping to produce the reaction known as compaction a. Cells getting smaller and having more contact with each other h. What will happen as we get more cells is that some cells find themselves on the inside of the ball of cells and others will gravitate towards the outside i. Through cell to cell interactions, cells figure out who is on the inside and outside j. If I am a cell on the outside and I am destined to be a certain type of tissue and if I am on the inside destined to be a different type of tissue triggered by the positional relationship i. To illustrate this point, if we were to take cells at this stage and artificially them and let them come back together again, the cells that were on the side would not necessarily be on the inside again or visa versa, they rearrange themselves based on cell-cell interactions ii. However, somewhere along the way based on cell position a decision needs to be made what cells will be supporting cells and what will become a new individual k. ~4-5 days after fertilization the zona pellucida will break down i. The result of the enzymes produced by the sperm and other reactions with maternal tissue during the progress down the uterine tube will slowly cause this to occur ii. This allows the small compact ball of cells that may or may not have a cavity in it to “hatch out” of the zona pellucida causing the cells to become uncovered and the cells to enlarge, making the whole conceptus larger l. The small cavity within the cavity gets larger and larger and lineation between the cells on the inside and outside can be seen better m. So as we complete meiosis we throw off 2 polar bodies depending if the first polar body divides, mitosis begins, up to ~ the 32 cell stage the mitotic divisions are 6 synchronous..However after this stage it becomes asynchronous growing at different rates i. The 32 cell ball of cells (morula) are probably fighting it out to see who is on the inside and outside ii. As soon as the zona pellucida breaks down the conceptus can swell up and the blastocystic cavity becomes more obvious. And the morula transforms into the blastocyst (meaning having a cavity within it. 5. The parts of the Blastocysts and early stages of implantation a. The inner cell mast inside the blastocysts can also be referred to as the embryoblast (as these cells will give rise to the new person i. The inner cell mast can be divided into two parts 1. Epiblast (which later breaks down into three parts) a. Ectoderm b. Mesoderm c. Endoderm 2. Hypoblast a. Gives rise to the extraembryonic mesoderm b. Outer cell mast is known as the trophoblast (blastoform—which means to feed or support) i. The trophoblast ultimately differentiates into cells that will make up cytotrophoblast (the portion of the trophoblast that retains discrete cellularity) 1. Cytotrophblasts are a reserve cell population (a proliferating cell population) ii. The other differentiating portion of the trophoblast is the synctiotrophoblast which is part of the outer cell mass with a multinucleated cytoplasmic mass with many nuclei and organelles functioning as one big cell 1. Thus the synctiotrophoblast is the differentiated tissue of the trophoblast 2. When we said earlier that the placenta is made of trophoblastic tissue is making hormones etc it is actually the synctiotrophoblast that is producing these substances a. It is the more mature, differentiated, specialized tissue 3. As said earlier the cytotrophblasts are the reserve undifferentiated cells a. Perhaps cytotrophoblastic cells as they proliferate can merge and break down their cell membranes and let their cell 7 membranes and cytoplasms become a common pool as their individual plasmallema fuse contributing to the extensive plasmalemma of the synctiotrophoblast 4. The synctiotrophoblast then furter differentiates to become productive tissues iii. All trophoblastic structures can be lumped together and called the chorion 6. General outline of development a. The embryo proper transitions into the fetus and into a neonate i. The embryo typically refers to the developing individual in the first 8 weeks ii. At the end of 8 weeks, all of the organ systems within the body have at least started to develop b. The fetal period is from 8 weeks to 38 weeks i. Further growth and differentiation occurs during this time ii. At the time of labor the little one is a fetus, not an embryo c. The syntiotrophoblast, the connective tissues outside the embryo, and the cytotrophoblast (all outer cell mass structures) will be called the chorion 7. Embryo Implantation a. The endometrium is the mucosal lining of the uterus and will have epithelium on the surface and epithelium glands going into the underling stroma and many blood vessels b. It is the endometrium that undergoes changes of the uterine cycle driven by the ovarian cycle c. The myometrium is the muscular layer of the uterus. The endometrium lines this layer. However the major bulk of the uterus is the myometrium d. Implantation is the process by which the conceptus attaches to and grows into the endometrium e. Because the embryo grows into the endometrium breaking through the epithelial tissue is an invasive process 8 i. The conceptus invades the maternal tissues, with permission granted by maternal tissues 1. The conceptus sends out chemical signals and the endometrium responds so it is permissive invasion ii. The conceptus ends up being totally embedded in the endometrium in the interstitial space of the endometrium 1. Hence we as humans are said to have an interstitial implantation , meaning the conceptus has grown into and occupies extra and intracellular space of the endometrium iii. In other animals the conceptus stays in the uterine cavity and may have an appositional relationship with the endometrium of that species iv. With interstitial implantation and the way we have maternal blood going into fetal tissues we as humans have the most intimate relationship between the mother and developing child 1. Basically, humans posses the least barrier between maternal and fetal blood of any species f. The Disiduum i. Altered endometrial stroma. Happens as a result of implantation. 9 1. Chemicals released by conceptus will cause changes within the stromal cells (CT cells) of the endometrium. 2. The cells begin to accumulate glycogen, they swell up and become larger ii. The reaction that relates to the implantation process is called the disidual reaction 1. This resulting cells of this reaction are altered stromal cells which will provide a nutrient source as they break down or are broken down by the conceptus very early on. iii. The altered environment of the now disidua also alters the lymphocytes that live in the interstitial spaces (intercellular lymphocytes) that live in the disidual spaces and down regulates the ability of T-lymphocytes to recognize foreign material 1. Thus as a result of the implantation and reaction of the endometrium the conceptus is provided transient nutrient source but more importantly and immunological sequestered area to develop in 2. The lymphocytes that are in the disidua cannot recognize non-self as readily iv. The disdua can be broken down into 3 major areas 1. The disidua basalis which is between the conceptus and the myometrium a. As we will see, the conceptus is in the cavity of the uterus, invades into the endometrium from the epithelial surface, there is still connective tissue of the endometrium between the conceptus and the myometrium (which obviously is more basal to the implantation site (the dicidual basalis) b. Because the conceptus has grown all the way into the endometrium, as the conceptus enlarges, it bulges out the endometrium around it 2. For a period of time the altered endometrium forms a capsule over the expanding conceptus between the conceptus and the uterine cavity called the decidua capsularis 3. The everything else that is not directly related to the implantation site either basal or capsular to it is the dicidua paratalis (which mean wall) a. Thus the paratalis is all of the altered endometrium not directly related to the implantation site which is basalis and capsularis v. The conceptus is expanded out into the uterine cavity so the endometrium undergoes changes triggered by the implantation (chemicals released by the conceptus) 1. The disidual reaction takes places first at the implantation site and then spreads so that all endometrium is involved. 2. The word decidua means “shedding off” 3. Thus the dicidua (the altered endometrium) is lost at the time of parturion with the extraembryonic membranes (expulsion of the placenta after birth) and then the normal endometrium is established 8. The Forming of the Placenta a. 5-6 days old by the time the conceptus is in the uterine cavity b. By this time the zona pellucida has disappeared 10 c. The conceptus has differentiated into a trophoblast and embryoblast i. So the cells of that early conceptus have already established through mutual agreement if you will who is going to be the supporting cells and who is going to be the new individual d. With no zona pellucida present, the trophoblastic cells can make contact with the endometrial (maternal) tissue e. As it does this there are signals moving back and forth through the fluid within the uterine cavity between the conceptus and endometrium, developing a hand shake relationship i. As said before it is not just an invasion, it is a permissive invasion f. The trophoblast comes in contact with endometrial tissues and it is usually going to be in the area of the trophoblast that overlies the embryoblast i. For some reason these cells are “stickier” g. At the embryonic pole of the conceptus, the trophoblastic cells have slightly different properties then at the abembryonic pole i. Hence it is a little bit easier to stick to the maternal tissue at the embryonic pole h. Contact between the trophoblast and endometrial tissues triggers trophoblastic proliferation and the proliferated cells merge together to form the synctiotrophoblast i. Cells of trophoblastic origin that retain their discrete cellular identity remain as cytotrophoblast. i. If the cytotrophblastic cells are in the area where synctiotrophoblast is being formed, the cyto- cells will undergo mitotic division and many of the daughter cells will be added to the synctiotrophoblast ii. Some of the daughter cells will remain behind as reserve population cells to undergo further mitosis j. Within the synctiotrophoblast the nuclei will undergo mitosis i. The syn- cells through enzymatic activity, etc, begin to break through the epithelium of the endometrium invading into the underlying stroma (CT) 1. Permissive invasion 2. If the endometrium does not respond, the conceptus can send out all the signals and develop the best synctiotroblast possible but not be able to implant thus causing infertility called endometrium nonreceptiveness 3. As the syn- invades the endometrium, the rest of the conceptus follows along 4. As more trophoblast makes contact with more maternal tissues, more syntiotrophblast is formed k. “Lacuna means little leg” 11 i. If you think back to cartilage and bone, lacunae contain the cells within the matrix ii. In terms of development, lacunae are membrane bound spaces within the synctiotrophoblast 1. As stated before the syn- is a multinucleated cytoplasmic mass 2. Within the cytoplasmic mass are all the organelles needed for protein, steroid, etc, production (in general metabolism) 3. The syn- can develop membrane bound spaces within the general cytoplasm 4. Now these membrane bound spaces, since they are in maternal tissues, will not be filled with air but instead filled with fluid because maternal fluids are permeating through the conceptus 5. The lacunae will join together and become known as the innervillus space (space within the more mature placenta in between the villus projections) a. This innervillus space will contain maternal blood 6. Within the villi, we will have fetal blood vessels obtaining fetal blood. 7. So we see these areas within the synctiotrophoblast which are the developing lacunae a. Because ultimately these places will be filled with maternal blood 8. Syn- and conceptus tissue is invading in, the syn- is absorbing break down products from stromal cells that have undergone disidual reactions receiving or absorbing products from the glands that were rich 12 l. in glycogen and other nucleopolysaccharide material that can diffuse though synctiotrophoblast thus nourishing it and moving on into deep structures 9. But as the synctiotrophoblast and conceptus migrates further in, it comes in contact with maternal endometrial blood vessels and the synengulfs these, breaking into the maternal blood vessels 10. The syn- literally caps around the outside the luminal aspect of the blood vessel so it physically breaks down the vessel wall and forms a capping mechanism over the ends so there is no blood leakage 11. Now it is possible for the maternal blood to leak into the lucunar spaces 12. As lacunar spaces join together and syntiotrophblast taps into larger and larger vessels, it will get into more of the arterial aspect of the maternal vessels and larger venous aspects of disidual vessels and now will develop a circulation 13. Maternal blood released into lacunar spaces (developing innervillus spaces) coming out of the endometrial arterioles (ultimately arteries), circulating through the space technically outside the mothers circulation and then draining into maternal veins. 14. Thus the conceptus during this implantation process has opened up a shunt in maternal circulation. As the syn- continues to develop and the conceptus invades further and further in will ultimately have syn- form all the way around the conceptus. i. Remember the syn- is the differentiated tissue ii. Part of its differentiation is that it does not elaborate many surface antigens so even though the endometrium is a preferred sequested area immunologically, also the conceptus itself is practicing stealth technology by not elaborating a lot of surface antigens that would flag down the immune system saying “I am not self” 1. Thus these two things work together iii. The syn- is invading in and as it continues to enlarge we continue to have cellular proliferation in the cyto- and in the areas of the cyto- we begin to get some proliferation and begin to get accumulations of cells that will begin to penetrate into the syn-, kind of like going in between the lacunar spaces iv. We are developing some finger like projections and these are called primary villi v. Thus the primary villus will have syn- around the outside and a cyto-core, eventually getting cyto deeper into synvi. We have developed syn- all the way around around the conceptus and tapped into blood vessels all the way around the conceptus vii. Cyto- is growing out into the overlying syn- all the way around ultimately some tissue known as extraembryonic mesoderm will grow into the vill 13 1. The extraeembryonic mesoderm is developed from the hypoblast a. We have villus formation going into the innervillus space areas that now in addition to the syn- and cyto- have extraembyonic mesoderm which is a form of CT b. Anytime you here the word mesoderm think CT amoung other things c. This CT is outside the embryo proper thus being called extraembryonic mesoderm d. The syn, cyto, and invadining extraembryonic mesoderm is known as a secondary villus viii. Time proceeds, the cyto- has grown through the syn and even makes it to the outside where it comes in contact with the disidua (altered mesoderm) 1. Thus making a cyto- shall around the outside 2. However, even though the cyto- cells have surface antigens on them, the lymphocytes in the area cannot detect foreign material because of disidual reaction dicussed earlier 3. The extraembryonic mesoderm that had grown into those villi and formed on the inner aspect of the trophoblast is differentiating and gives rise to blood vessels 4. So now in this developing trophoblastic cell supporing tissue we have BVs forming 5. The BVs here in what will ultimately become placenta will ultimately connect with BV developing in the embryo proper and the early developing umbilical cord 14 ix. Now has been established fetal primitive fetal placental circulation 1. Maternal blood is coming into what was the lacunae and now is the innervillus space circulating through that. 2. Fetal blood is going to be moving through the fetal BVs within the villi 3. Materials will diffuse across this so called barrier or be carried across by facilitated diffusion or active transport 4. Notice that we have BVs, syn, all the way around the conceptus m. Review i. Trophoblastic cells have different properties ( more sticky) than other cells ii. When they come in contact with maternal tissue the cells proliferate to from syn15 iii. Syn- knows to invade with permission iv. Invades through the epithelium through basal lamina into underlying stroma endometrium that is going to begin to trigger disidual changes within that area v. Lacunae are within the syn- and contain maternal blood vi. Only tissue of conceptus that maternal blood will come in contact with is synvii. Syn- develops ALL the way around the BV 1. As we look at this, you can envision that if this happens to tap into a rather large artery early on, the syn- does not have much strength and hemmorage out which is a reason for early spontaneous abortion called implantation bleeding viii. We are developing innervillus space and inbetween villi are the maternal blood containing spaces ix. The villi themselves will consist of syn- on their outer surface, cyto on the inside, and also extraembyronic mesoderm which will make umblicius BVs x. Primary villus is syn and cyto xi. Secondary is syn, cyto, and extraembyronic mesoderm xii. Tertiary is syn, cyto, extraembyonic mesoderm and BV xiii. Notice cyto has gone to the outside moving around but disidual reaction has been completed so it does not trigger an immune response, the cytoproliferation could add to the syn- on the outer aspect xiv. Up until mid pregnancy, material must diffuse through syntio, cyto, extraembryonic mesoderm, and fetal capillary endothelial cells xv. But during the second half of pregnancy, much of the cyto has been used up or degenerated and the fetal BVs marginate ( move to outside of villus) so that the only layers that material must pass through would be syn, its basal lamina, the basal lamina of fetal BVs and the endothelium of fetal BV. 1. Thus it is not a very strong membrane (barrier) xvi. Also, we can see those villi that we looked at can be branching to increase surface area xvii. All the good nutrients make it through the placental membrane from maternal blood to fetal blood xviii. Waste products go the other direction to be eliminated by kidney or lungs within the mother. 1. However, harmful things such as viruses, CO, drugs, alcohol, poisons, microbiological organisms capable of moving on their own are able to penetrate the barrier 2. Bacteria usually do not make it through xix. Shown below is a schematic of the placenta in side view, fetal BV coming down into villi. 1. The villi form especially where maternal arterial blood is coming into the innervillus space xx. In between those fountains of maternal arterial blood villi do not form so the placental tissue doesn’t enlarge as much and will form partial septa xxi. Now if you think back when we looked at the placenta we looked rough on maternal aspect, the cotelydens and the spaces in between, 1. cotelydens form because of augmented villus formation takes up space triggered by maternal arterial blood 16 2. This is where we do not have input of arterial maternal blood therefore not as much villus formation and we develop then the septation around the cotelydens 17