The placenta-specific proteome
The main function of the placenta is to connect the developing fetus to the mother via the umbilical cord to the uterine wall. The placenta undergoes rapid growth to harmonize with the requirements of the growing fetus and reaches a weight of approximately 500 grams at full term. The placenta mediates fetal nutrient uptake, waste elimination, and gas exchange via the maternal blood supply. The main cellular components of the highly vascularized placenta are trophoblasts, decidual cells, endothelial cells and primitive mesenchymal cells. Transcriptome analysis shows that 73% (n=14303) of all human proteins (n=19670) are expressed in the placenta and 494 of these genes show an elevated expression in the placenta compared to other tissue types.
The placenta transcriptome
Transcriptome analysis of the placenta can be visualized with regard to specificity and distribution of transcribed mRNA molecules (Figure 1). Specificity illustrates the number of genes with elevated or non-elevated expression in the placenta compared to other tissues. Elevated expression includes three subcategory types of elevated expression:
Distribution, on the other hand, visualizes how many genes that have, or do not have, detectable levels (NX≥1) of transcribed mRNA molecules in the placenta compared to other tissues. As evident in Table 1, all genes elevated in placenta are categorized as:
Figure 1. (A) The distribution of all genes across the five categories based on transcript specificity in placenta as well as in all other tissues. (B) The distribution of all genes across the six categories, based on transcript detection (NX≥1) in placenta as well as in all other tissues.
Table 1. Number of genes in the subdivided categories of elevated expression in placenta.
Table 2. The 12 genes with the highest level of enriched expression in placenta. "Tissue distribution" describes the transcript detection (NX≥1) in placenta as well as in all other tissues. "mRNA (tissue)" shows the transcript level in placenta as NX values. "Tissue specificity score (TS)" corresponds to the fold-change between the expression level in placenta and the tissue with second highest expression level.
Protein expression of genes elevated in placenta
In-depth analysis of the elevated genes in placenta using antibody-based protein profiling allowed us to create a map of where these proteins are expressed with regards to the different cellular compartments that constitute the placenta, i.e. cytotrophoblast cells, syncytiotrophoblast cells, extravillous trophoblast cells, decidual cells and blood vessels.
Proteins expressed in cytotrophoblasts
The placenta begins to develop upon implantation of the blastocyst (fertilized egg) as it attaches to the endometrium. The outer layer of the blastocyst consists of trophoblast cells, which also form the outer layers of the placenta. The trophoblast layer is further divided into two layers: the cytotrophoblast and the overlying syncytiotrophoblast layer. Examples of proteins expressed in cytotrophoblasts include the highly conserved PEG10, involved in cell proliferation, differentiation and apoptosis, and PAGE4, a member of the GAGE gene-family.
Proteins expressed in syncytiotrophoblasts
Syncytiotrophoblasts form when undifferentiated and highly proliferative cytotrophoblast fuse together. Syncytiotrophoblasts are specialized epithelial cells that cover the floating placental villi and are involved in maintaining pregnancy through the production of growth factors and hormones. Since the syncytiotrophoblasts are in direct contact with the maternal blood these cells are closely involved in the exchange of gas, nutrients and waste between the mother and the fetus. Examples of proteins expressed in syncytiotrophoblasts include CSH1, a member of the somatotropin/prolactin family of hormones, KISS1, a stimulator of gonadotropin secretion, and transcription factor GCM1, glial cells missing homolog 1.
Proteins expressed in extravillous trophoblasts
Extravillous trophoblasts are formed when cytotrophoblasts proliferate to form anchoring villi that attach to the uterine wall. From the anchoring villi, extravillous trophoblasts can form by detaching from the placental villi and migrate into the decidua. Examples of proteins expressed in extravillous trophoblast cells include PAPPA2, a metalloproteinase thought to be a local regulator of insulin-like growth factor (IGF), PRG2, a predominant constituent in the eosinophil granule and present in placenta where it exists as a complex with several other proteins including PAPPA, and HLA-G, a major histocompatibility complex (MHC) class I molecule, which plays a central role in the establishment of immune tolerance during pregnancy.
Proteins expressed in placental blood vessels and stroma
The placenta is highly vascularized with capillaries and blood vessels composed of endothelial cells, pericytes and vascular smooth muscle cells. Examples of proteins expressed in endothelial cells in the placenta include FCGR2B, a low affinity receptor for the Fc region of immunoglobulin gamma complexes involved in the phagocytosis of immune complexes and LIN28B, a suppressor of microRNA biogenesis. FBN2, a component of connective tissue microfibrils potentially involved in elastic fiber assembly, shows expression in the stroma of placental villi.
Proteins expressed in decidual cells
The decidua is the maternal part of the placenta. The decidua is derived from the maternal endometrium and includes specifically altered endometrial stromal cells that are formed in a response to progesterone in a process called decidualization. IGFBP1, expressed in decidual cells, is a secreted protein that binds both insulin-like growth factors I and II, and is also expressed in the uterus and liver.
Gene expression shared between placenta and other tissues
There are 99 group enriched genes expressed in placenta. Group enriched genes are defined as genes showing a 4-fold higher average level of mRNA expression in a group of 2-5 tissues, including placenta, compared to all other tissues.
In order to illustrate the relation of placenta tissue to other tissue types, a network plot was generated, displaying the number of genes with shared expression between different tissue types.
Figure 2. An interactive network plot of the placenta enriched and group enriched genes connected to their respective enriched tissues (grey circles). Red nodes represent the number of placenta enriched genes and orange nodes represent the number of genes that are group enriched. The sizes of the red and orange nodes are related to the number of genes displayed within the node. Each node is clickable and results in a list of all enriched genes connected to the highlighted edges. The network is limited to group enriched genes in combinations of up to 4 tissues, but the resulting lists show the complete set of group enriched genes in the particular tissue.
The placenta shares group enriched gene expression of a few genes with several other tissue types, but mostly with testis. One example of a group enriched gene expressed in the placenta and other tissues is CXorf67, previously uncharacterized, which is also expressed in testis. Another example is DLK1, a transmembrane protein involved in the differentiation of several cell types including adipocytes and neuroendocrine cells, also expressed in the adrenal gland.
The placenta is a temporary organ formed during pregnancy. It connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. The placenta consists of a fetal component, chorionic villi, which develops from the blastocyst that forms the fetus, and a maternal component, decidua, which develops from the maternal uterine tissue.
Besides supplying nutrients and oxygen to the fetus the placenta also metabolizes substances, protects against pathogens, is involved in maternal-fetal tolerance, and has endocrine functions where it for example produces several pregnancy-associated hormones and growth factors including human placental lactogen (hPL), human chorionic gonadotropin (hCG), placental growth hormone (PGH), corticotrophin-releasing hormone (CRH), gonadotrophin-releasing hormone (GnRH), thyrotrophin-releasing hormone (TRH), estrogen and progesterone.
The normal term placenta measures 15-20 cm in diameter, 1.5-3 cm in thickness and weighs approximately 450-600 grams. The main components are the chorionic villi protruding from the chorionic plate, decidual tissue, umbilical cord (54-61 cm in length, containing two umbilical arteries and one umbilical vein) and placental membranes. The placental membranes include the amnion (the innermost lining of the amniotic cavity composed of a single layer of flat epithelial cells) and the chorion (connective tissue that carries the fetal vasculature).
The main structure of the placenta is the villous "tree". The placenta villi can float freely in the intervillous space, or be attached to the decidua (anchoring villi) which provides structural stability for the placenta.
The cell types of the placenta villi include:
The other part of the placenta, the decidua, includes maternal decidual cells and vascular cells. Moreover there are extravillous trophoblast cells, of fetal origin, that migrate into the decidua and remodel uterine arteries.
Here, the protein-coding genes expressed in placenta are described and characterized, together with examples of immunohistochemically stained tissue sections that visualize corresponding protein expression patterns of genes with elevated expression in placenta.
Relevant links and publications
Uhlén M et al., Tissue-based map of the human proteome. Science (2015)