A compelling example of multi-nucleate cell benefit in mammals is the syncytiotrophoblast. Essential cell type of the placenta, arguably a successful pregnancy depends on healthy syncytiotrophoblasts.
When the human embryo contacts the maternal endometrial epithelium, placental trophoblast cells (mononuclear cytotrophoblasts) at the contact site fuse to form a syncytium of multi-nucleated cells called syncytiotrophoblasts.
An anatomically unique structure in the human body, syncytiotrophoblasts are ‘the outermost trophoblast-cell layer covering the chorionic villi that is formed by fusion of the underlying layer of mononuclear trophoblast cells to become a multinucleated syncytium, which forms a barrier between the fetus and the mother‘ (1). Functionally, their many unique attributes are likely the result of their multi-nuclear state.
Syncytiotrophoblasts signal the onset of pregnancy
~8 to 10 days post-fertilization, syncytiotrophoblasts secrete the hormone CG (chorionic gonadotrophin). A member of the glycoprotein hormone family (LH, luteinizing hormone, FSH, follicle stimulating hormone, TSH, thyroid stimulating hormone) (2), its presence in the blood and urine is the basis for many home pregnancy tests (3).
In humans, syncytiotrophoblasts are in direct contact with maternal blood and therefore, in direct contact with the systemic maternal immune system (see figure below from 4).
Syncytiotrophoblasts facilitate maternal-fetal communication
Estimated to be a relatively massive surface area of ~12m2 at term (5), the syncytiotrophoblast layer is the single largest mother-fetus interface. This large surface area is thus essential for critical functions such as bi-directional transport of nutrients and waste, and barrier function protecting the fetus against pathogens and toxins (5, 6).
Syncytiotrophoblasts are among the most important cells helping mould maternal immunity to accept the semi-allogeneic fetus
One of the enduring mysteries in immunology is successful pregnancy, specifically how the mother’s immune system tolerates a genetically dissimilar fetus. Fetus has antigens derived from both mother and father, hence it’s semi-allogeneic, i.e., partially, not completely, genetically different from the mother. This immunological difference between mother and fetus is the reason pregnancy’s often called a ‘natural transplant‘. While this question isn’t fully answered yet, syncytiotrophoblasts are definitely among the most important cells helping mould maternal anti-fetal immunity.
Unlike normal cells and tissues, syncytiotrophoblasts and underlying villous trophoblasts don’t express (MHC) molecules (called , HLA, in humans) (7, see table below from 8), key molecules necessary for T cell responses. In other words, syncytiotrophoblasts can’t present antigens to T cells, so stay hidden to them.
However, syncytiotrophoblasts express paternally-inherited minor histocompatibility antigens (9). This overturns the old notion that syncytiotrophoblasts are immunologically inert (see table below from 8). Rather they’re capable of eliciting immune responses from maternal immune cells, only they seem to be specific kinds of immune responses designed to be benign, not harmful, to the fetus, and likely indirectly, not directly, since they don’t express HLA. These molecules include unique immunoregulatory molecules such as IDO (2, 3-Indoleamine dioxygenase) (10), thought to be important in maternal immune tolerance of fetus. They also express the unique placenta-associated MHC called (11, 12), important for regulating natural killer (NK) cell functions.
Another unique feature, syncytiotrophoblast microvesicles (STBM), small vesicles <1µm in size, are continually shed into circulation. While their biological relevance is still not fully understood, STBM may sculpt maternal immunity to ensure a successful pregnancy, for e.g., by binding to B cells and monocytes, and altering their cytokine profiles (13, see figure below from 14). Conversely, stressed syncytiotrophoblasts (hypoxia, oxidative stress) are associated with , ‘toxicity of pregnancy’, a potentially dangerous condition associated with danger to both fetus and mother (8).
Syncytiotrohpblasts are the conduit for transfer of passive immunity (maternal antibodies) from mother to fetus
Noncytotoxic, i.e., non-complement fixing or non-damaging, IgG antibodies from maternal circulation reach fetal circulation via special neonatal Fc receptors on syncytiotrophoblasts (15, 16). Such passive immunity in the form of maternal antibodies is among the first line of defense for newborns as their immune systems, specifically their B cells, aren’t fully developed at birth.
Syncytiotrohpblasts are an effective barrier against mother to fetus infection (vertical transmission of infection)
An extremely important placental infection, Listeria monocytogenes is a food-borne bacterial pathogen that can spread from a pregnant woman to her fetus. Depending on the pregnancy stage, this infection can result in spontaneous abortion, stillbirth or preterm labor. A first trimester placental organ culture L. monocytogenes infection model showed that, in contrast to extravillous syncytiotrophoblasts, syncytiotrohoblasts are highly resistant to infection. Thus, they can protect the growing fetus against vertical L. monocytogenes transmission (17). This is a compelling example of the effective barrier function of syncytiotrophoblasts.
How syncytiotrohoblasts are formed, specifically the role of ancient endogenous retrovirus remnants, HERV-W, is explored in greater detail in these answers:,
In sum, benefits of the uniquely multi-nucleate syncytiotrophoblasts in human placenta are many and undeniable.
- Moffett, Ashley, and Charlie Loke. “Immunology of placentation in eutherian mammals.” Nature Reviews Immunology 6.8 (2006): 584-594.
- Maston, Glenn A., and Maryellen Ruvolo. “Chorionic gonadotropin has a recent origin within primates and an evolutionary history of selection.” Molecular Biology and Evolution 19.3 (2002): 320-335.
- Ehrenkranz, Joel RL. “Home and point-of-care pregnancy tests: a review of the technology.” Epidemiology 13.3 (2002): S15-S18.
- Jabrane‐Ferrat, Nabila, and Johan Siewiera. “The up side of decidual natural killer cells: new developments in immunology of pregnancy.” Immunology 141.4 (2014): 490-497.
- Benirschke, Kurt, Graham J. Burton, and Rebecca N. Baergen. “Early development of the human placenta.” Pathology of the human placenta. Springer Berlin Heidelberg, 2012. 41-53.
- Audus, Kenneth L., Michael J. Soares, and Joan S. Hunt. “Characteristics of the fetal/maternal interface with potential usefulness in the development of future immunological and pharmacological strategies.” Journal of Pharmacology and Experimental Therapeutics 301.2 (2002): 402-409.
- Hutter, Heinz, et al. “Expression of HLA class I molecules in human first trimester and term placenta trophoblast.” Cell and tissue research 286.3 (1996): 439-447.
- Chapter 8 – Immunology of Normal Pregnancy and Preeclampsia. Christopher W.G. Redman, Ian L. Sargent, Robert N. Taylor. P161-179. In Taylor, Robert N., et al., eds. Chesley’s Hypertensive Disorders in Pregnancy. Elsevier, 2014.
- Holland, Olivia J., et al. “Minor histocompatibility antigens are expressed in syncytiotrophoblast and trophoblast debris: implications for maternal alloreactivity to the fetus.” The American journal of pathology 180.1 (2012): 256-266.
- Sedlmayr, Peter, et al. “Localization of indoleamine 2, 3-dioxygenase in human female reproductive organs and the placenta.” Molecular human reproduction 8.4 (2002): 385-391.
- Morales, Pedro J., et al. “Placental cell expression of HLA-G2 isoforms is limited to the invasive trophoblast phenotype.” The Journal of Immunology 171.11 (2003): 6215-6224.
- Solier, Corinne, et al. “Secretion of pro‐apoptotic intron 4‐retaining soluble HLA‐G1 by human villous trophoblast.” European journal of immunology 32.12 (2002): 3576-3586.
- Ackerman, WEt, et al. “IFPA Meeting 2011 workshop report III: Placental immunology; epigenetic and microRNA-dependent gene regulation; comparative placentation; trophoblast differentiation; stem cells.” Placenta 33 (2012): S15-S22.
- Chapter 41 – Immunology of Pregnancy. Sarah A. Robertson, Margaret G. Petroff, Joan S. Hunt. P1835-1874. In Knobil and Neill’s Physiology of Reproduction (Fourth Edition), Elsevier, 2015.
- Simister, Neil E., et al. “An IgG‐transporting Fc receptor expressed in the syncytiotrophoblast of human placenta.” European journal of immunology 26.7 (1996): 1527-1531.
- Hsi, Bae-Li, Joan S. Hunt, and John P. Atkinson. “Differential expression of complement regulatory proteins on subpopulations of human trophoblast cells.” Journal of reproductive immunology 19.3 (1991): 209-223.
- Robbins, Jennifer R., et al. “Placental syncytiotrophoblast constitutes a major barrier to vertical transmission of Listeria monocytogenes.” PLoS Pathog 6.1 (2010): e1000732.