Latest findings on the placenta from the point of view of immunology, tolerance and mesenchymal stem cells

Authors: K. Macholdová 1;  E. Macháčková 1;  V. Prošková 1;  I. Hromadníková 2;  R. Klubal 1
Authors‘ workplace: Medicínské centrum Praha, vedoucí pracoviště MUDr. R. Klubal 1;  Oddělení molekulární biologie a patologie buňky, 3. LF UK a Ústav pro péči o matku a dítě, Praha, přednosta doc. MUDr. J. Feyereisl, CSc. 2
Published in: Ceska Gynekol 2019; 84(2): 154-160


Objective: Overview of current placental findings from the point of view of immunology, tolerance and mesenchymal stem cells.

Type of study: Review.

Setting: Medicínské centrum Praha.

Conclusion: The placenta is an important organ that connects mother and developing fetus during pregnancy. For the uncomplicated course of pregnancy and fetal development the placental function is crucial. The placenta provides not only the replacement of breathing gases, nutrients and waste materials, but also creates an immunological interface between the mother and the fetus. Maternal tolerance towards the fetus carrying paternal antigens is induced at the fetomaternal interface due to the mutual molecular interactions. Immune tolerance at the interface between placenta and decidua is ensured mainly due to the expression of HLA-C, HLA-E, HLA-F, and HLA-G on trophoblasts and their interactions with receptors expressed on uterine NK cells. Regulatory T cells and DC-10 cells also play an important role at the fetomaternal interface on the mother‘s side of placenta. However, some fetal cells, such as Hofbauer cells or granulocytic myeloid-derived suppressor cells are also partially involved in inducement of maternal tolerance towards the fetus. Recently, considerable attention is also paid to mesenchymal stem cells derived from both placental and umbilical tissues. These mesenchymal stem cells play an important role in inducement of immune tolerance and exhibit better immunomodulatory properties than mesenchymal stem cells isolated from adult human tissues.


tolerance – Placenta – umbilical cord – immunology – mesenchymal stem cells – maternal fetal interface


1. Amodio, G., et al. HLA-G expressing DC-10 and CD4+ T cells accumulate in human decidua during pregnancy. Human Immunol, 2013, 74, 4, p. 406–411.

2. Blackburn, DG. Evolution of vertebrate viviparity and specializations for fetal nutrition: a quantitative and qualitative analysis. J Morphol, 2015, 276, 8, p. 961–990.

3. Burton, GJ., Jauniaux, E. What is the placenta?. Am J Obstet Gynecol, 2015, 213, 4, p. S6–e1.

4. Colonna, M., et al. Cutting edge: human myelomonocytic cells express an inhibitory receptor for classical and nonclassical MHC class I molecules. J Immunol, 1998, 160, 7, p. 3096–3100.

5. Darmochwal-Kolarz, D., et al. T CD3+CD8+ lymphocytes are more susceptible for apoptosis in the first trimester of normal human pregnancy. J Immunol Res, 2014.

6. Dominici, MLBK., et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy, 2006, 8, 4, p. 315–317.

7. El Omar, R., et al. Umbilical cord mesenchymal stem cells: the new gold standard for mesenchymal stem cell-based therapies? Tissue Engineering Part B: Reviews, 2014, 20, 5, p. 523–544.

8. Ferreira, LMR, et al. HLA-G: At the interface of maternal-fetal tolerance. Trends in Immunol, 2017, 38, 4, p. 272–286.

9. Figueiredo, AS., Schumacher, A. The T helper type 17/regulatory T cell paradigm in pregnancy. Immunology, 2016, 148, 1, p. 13–21.

10. Fu, Binqing, Haiming, Wei. Decidual natural killer cells and the immune microenvironment at the maternal-fetal interface. Science China Life Sciences, 2016, 59, 12, p. 1224–1231.

11. Gellersen, B., Brosens, J. Cyclic decidualization of the human endometrium in reproductive health and failure. Endocrine Rev, 2014, 35, 6, p. 851–905.

12. Goodridge, JP., et al. HLA-F and MHC class I open conformers are ligands for NK cell Ig-like receptors. J Immunol, 2013, p. 1300081.

13. Götherström, C., et al. Immunomodulatory effects of human foetal liver-derived mesenchymal stem cells. Bone Marrow Transplant, 2004, 33, 11, p. 1167.

14. Guernsey, MW., et al. Molecular conservation of marsupial and eutherian placentation and lactation. eLife, 2017, 6, p. e27450.

15. Hackmon, R., et al. Definitive class I human leukocyte antigen expression in gestational placentation: HLA-F, HLA-E, HLA-C, and HLA-G in extravillous trophoblast invasion on placentation, pregnancy, and parturition. Am J Reprod Immunol, 2017, 77, 6, p. e12643.

16. Hromadníková, I., et al. Detekce placentárně specifických mikroRNA v mateřské cirkulaci. Čes Gynek, 2010, 75, 3, p. 252–256.

17. Chavatte-Palmer, P., Tarrade, A. Placentation in different mammalian species. Ann d‘endocrinologie, Elsevier Masson, 2016, 77, 2.

18. Iida, Atsuo, Toshiyuki Nishimaki, Atsuko Sehara-Fujisawa. Prenatal regression of the trophotaenial placenta in a viviparous fish, Xenotoca eiseni. Sci Reports, 2015, 5, p. 7855.

19. Kim, Soo-Hwan, et al. Immunomodulatory effects of placenta-derived mesenchymal stem cells on t cells by regulation of FoxP3 expression. Placenta, 2018, 267, p. 15.

20. Kliman, HJ. Umbilical cord. Encyclopedia of Reproduction, 1998,4 , p. 915–923.

21. Köstlin, N., et al. Granulocytic myeloid-derived suppressor cells accumulate in human placenta and polarize toward a Th2 phenotype. J Immunol, 2016, 196, 3, p. 1132–1145.

22. Kumpel, BM., Manoussaka, MS. Placental immunology and maternal alloimmune responses. Vox Sanguinis, 2012, 102, 1, p. 2–12.

23. Lash, GE. Molecular cross-talk at the feto-maternal interface. Cold Spring Harbor Perspectives in Medicine, 2015, p. a023010.

24. Lee, N, et al. HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A. Proceedings of the National Academy of Sciences, 1998, 95, 9, p. 5199–5204.

25. Lide, B., et al. Intrahepatic persistent right umbilical vein and associated outcomes: a systematic review of the literature. J Ultrasound Med, 2016, 35, 1, p. 1–5.

26. Lim, J., et al. MSCs can be differentially isolated from maternal, middle and fetal segments of the human umbilical cord. Cytotherapy, 2016, 18, 12, p. 1493–1502.

27. Lozano, NA., et al. Expression of FcRn receptor in placental tissue and its relationship with IgG levels in term and preterm newborns. Am J Reprod Immunol, 2018, p. e12972.

28. Mareschi, K., et al. Immunoregulatory effects on T-lymphocytes by human mesenchymal stromal cells isolated from bone marrow, amniotic fluid, and placenta. Experimental Hematol, 2016, 44, 2, p. 138–150.

29. Moffett, A., Loke, C. Immunology of placentation in eutherian mammals. Nat Rev Immunol, 2006, 6, 8, p. 584.

30. Pijnenborg, R., et al. Evaluation of trophoblast invasion in placental bed biopsies of the baboon, with immunohistochemical localisation of cytokeratin, fibronectin, and laminin. J Med Primatol, 1996, 25, 4, p. 272–281.

31. Predanic, M. Sonographic assessment of the umbilical cord. Ultrasound Rev Obstet Gynecol, 2005, 5, 2, p. 105–110.

32. Ramhorst, R., et al. Modulation and recruitment of inducible regulatory T cells by first trimester trophoblast cells. Am J Reprod Immunol, 2012, 67, 1, p. 17–27.

33. Roberts, RM., Green, J., Schulz, LC. Evolution of the placenta. Reproduction, 2016, p. REP–16.

34. Robertson, SA., et al. Seminal fluid drives expansion of the CD4+ CD25+ T regulatory cell pool and induces tolerance to paternal alloantigens in mice. Biol Reprod, 2009, 80, 5, p. 1036–1045.

35. Sammar, M., et al. Expression of CD24 and Siglec-10 in first trimester placenta: implications for immune tolerance at the fetal-maternal interface. Histochem Cell Biol, 2017, 147, 5, p. 565–574.

36. Shah, NM., et al. Changes in T cell and dendritic cell phenotype from mid to late pregnancy are indicative of a shift from immune tolerance to immune activation. Frontiers Immunol, 2017, 8, p. 1138.

37. Simister, NE. Placental transport of immunoglobulin G. Vaccine, 2003, 21, 24, p. 3365–3369.

38. Somerset, DA., et al. Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T-cell subset. Immunology, 2004, 112, 1, p. 38–43.

39. Svensson-Arvelund, J., et al. The human fetal placenta promotes tolerance against the semiallogeneic fetus by inducing regulatory T cells and homeostatic M2 macrophages. J Immunol, 2015, p. 1401536.

40. Taylor, BD., et al. First and second trimester immune biomarkers in preeclamptic and normotensive women. Pregnancy Hypertension. Inter JWomen‘s Cardiovasc Health, 2016, 6, 4, p. 388–393.

41. Toldi, G., et al. The frequency of peripheral blood CD4+ CD25high FoxP3+ and CD4+ CD25? FoxP3+ regulatory T cells in normal pregnancy and pre?eclampsia. Am J Reprod Immunol, 2012, 68, 2, p. 175–180.

42. Troyer, DL., Weiss, ML. Concise review: Wharton‘s jelly-derived cells are a primitive stromal cell population. Stem Cells, 2008, 26, 3, p. 591–599.

43. Trundley, A., et al. Methods for isolation of cells from the human fetal-maternal interface. Placenta and trophoblast. Humana Press, 2006, p. 109–122.

44. Vince, GS., et al. Flow cytometric characterisation of cell populations in human pregnancy decidua and isolation of decidual macrophages. J Immunol Methods, 1990, 132, 2, p. 181–189.

45. Vokroj, J., Arnoštová, L. Preeklampsie – některé možnosti predikce. Čes Gynek, 2009, 74, 4, p. 256–261.

46. Wang, Hwai-Shi, et al. Mesenchymal stem cells in the Wharton‘s jelly of the human umbilical cord. Stem Cells, 2004, 22, 7, p. 1330–1337.

47. Wang, WJ., et al. Increased prevalence of T helper 17 (Th17) cells in peripheral blood and decidua in unexplained recurrent spontaneous abortion patients. J Reprod Immunol, 2010, 84, 2, p. 164–170.

48. Wang, XQ., et al. Trophoblast-derived CXCL16 induces M2 macrophage polarization that in turn inactivates NK cells at the maternal-fetal interface. Cellular Molecular Immunol, 2018, p. 1.

49. Zenclussen, AC., et al. Abnormal T-cell reactivity against paternal antigens in spontaneous abortion: adoptive transfer of pregnancy-induced CD4+ CD25+ T regulatory cells prevents fetal rejection in a murine abortion model. Am J Pathol., 2005, 166, 3, p. 811–822.

Paediatric gynaecology Gynaecology and obstetrics Reproduction medicine

Article was published in

Czech Gynaecology

Issue 2

2019 Issue 2

Most read in this issue
Forgotten password

Don‘t have an account?  Create new account

Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.


Don‘t have an account?  Create new account