- Meeting abstract
- Open Access
Toward better understanding of the human placenta: development of “disease-in-a-dish” models
BMC Pregnancy and Childbirth volume 15, Article number: A6 (2015)
Many stillbirths result from pregnancy complications, whose root cause is abnormal development and function of the placenta . In order to prevent stillbirths, we need to have a better understanding of how the human placenta develops, both in normal and abnormal pregnancies. This lack of understanding of the human placenta has recently been acknowledged, and “The Human Placenta Project” launched, by the National Institute of Child Health and Human Development (NICHD) . In fact, the human placenta is difficult to study because of the lack of both “in vivo” animal models and placental cell lines able to be cultured “in vitro” in a tissue culture dish. Specifically, mice and rats have placentas which differ from the human both in structure and at the molecular level ; in addition, the human placental cell lines behave differently in culture, compared to the placental cells as they exist “in vivo” in the pregnant patient . Over the last 5 years, our laboratory has set out to use human pluripotent stem cells (hPSCs) to model placental development in a dish . “Pluripotent” stem cells have the ability to differentiate, or turn into, any cell type in the body, including the placental cell type, “trophoblast”[6, 7]. While initially hPSCs had to be derived from human embryos, in 2007, Yamanaka et al. developed a method for generating such cells from any proliferative cell type . hPSCs have now been derived from numerous cell types, including amnion cells of the placenta .
We have developed a method for step-wise differentiation of such hPSCs, first into trophoblast precursor cells and then into terminally differentiated, functional trophoblast, including multinucleated syncytiotrophoblast (STB) and invasive extravillous trophoblast (EVT). These two cell types are the functional units of the placenta: STB carry out nutrient and gas exchange, while the EVT invade the maternal uterus and establish blood flow to the feto-placental unit. Our differentiation method is both reproducible and highly efficient, with >95% of cells becoming trophoblast in the culture dish, based both on expression of specific genes and on functional assays such as secretion of the pregnancy hormone, hCG. We recently applied this method to hPSCs carrying a chromosomal aneuploidy, Trisomy 21 (T21). It is known that trophoblast isolated from T21 placentas have a defect in differentiation into multinucleated, hCG-secreting STB . We asked whether this defect could be reproduced in culture when differentiating T21 hPSCs into trophoblast. We observed that T21 hPSCs indeed show delayed differentiation into functional STB, secreting significantly less hCG into the media compared to trophoblast derived from hPSCs with a normal karyotype. These results confirm the utility of hPSCs in modeling human placenta, both during normal development and in disease. We are currently collecting and banking amnion epithelial cells from placentas of patients with pregnancy complications, focusing on early-onset severe preeclampsia, which is highly associated with both maternal and neonatal morbidity and mortality. We believe that, once reprogrammed into hPSCs, these cells hold great promise, both in advancing our understanding of the mechanisms of placental dysfunction, and also in providing a platform for drug screening to reverse the disease phenotype.
Flenady V, Koopmans L, Middleton P, Frøen JF, Smith GC, Gibbons K, Coory M, Gordon A, Ellwood D, Mcintyre HD, Fretts R, Ezzati M: Major risk factors for stillbirth in high-income countries: a systematic review and meta-analysis. Lancet. 2011, 377 (9774): 1331-40. 10.1016/S0140-6736(10)62233-7.
Guttmacher AE, Maddox YT, Spong CY: The Human Placenta Project: placental structure, development, and function in real time. Placenta. 2014, 35 (5): 303-4. 10.1016/j.placenta.2014.02.012.
Malassiné A, Frendo JL, Evain-Brion D: A comparison of placental development and endocrine functions between the human and mouse model. Hum Reprod Update. 2003, 9 (6): 531-9. 10.1093/humupd/dmg043.
Janneau JL, Maldonado-Estrada J, Tachdjian G, Miran I, Motté N, Saulnier P, Sabourin JC, Coté JF, Simon B, Frydman R, Chaouat G, Bellet D: Transcriptional expression of genes involved in cell invasion and migration by normal and tumoral trophoblast cells. J Clin Endocrinol Metab. 2002, 87 (11): 5336-9. 10.1210/jc.2002-021093.
Li Y, Moretto-Zita M, Soncin F, Wakeland A, Wolfe L, Leon-Garcia S, Pandian R, Pizzo D, Cui L, Nazor K, Loring JF, Crum CP, Laurent LC, Parast MM: BMP4-directed trophoblast differentiation of human embryonic stem cells is mediated through a DeltaNp63+ cytotrophoblast stem cell state. Development. 2013, 140: 3965-76. 10.1242/dev.092155.
Xu RH, Chen X, Li DS, Li R, Addicks GC, Glennon C, Zwaka TP, Thomson JA: BMP4 initiates human embryonic stem cell differentiation to trophoblast. Nat Biotechnol. 2002, 20: 1261-4. 10.1038/nbt761.
Amita M, Adachi K, Alexenko AP, Sinha S, Schust DJ, Schulz LC, Roberts RM, Ezashi T: Complete and unidirectional conversion of human embryonic stem cells to trophoblast by BMP4. Proc Natl Acad Sci USA. 2013, 110: E1212-21. 10.1073/pnas.1303094110.
Okita K, Yamanaka S: Induction of pluripotency by defined factors. Exp Cell Res. 2010, 316 (16): 2565-70. 10.1016/j.yexcr.2010.04.023.
Zhao HX, Li Y, Jin HF, Xie L, Liu C, Jiang F, Luo YN, Yin GW, Li Y, Wang J, Li LS, Yao YQ, Wang XH: Rapid and efficient reprogramming of human amnion-derived cells into pluripotency by three factors OCT4/SOX2/NANOG. Differentiation. 2010, 80 (2-3): 123-9. 10.1016/j.diff.2010.03.002.
Pidoux G, Gerbaud P, Cocquebert M, Segond N, Badet J, Fournier T, Guibourdenche J, Evain-Brion D: Review: Human trophoblast fusion and differentiation: lessons from trisomy 21 placenta. Placenta. 2012, 33 (Suppl A): S81-S86.
Rights and permissions
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
About this article
Cite this article
Parast, M.M. Toward better understanding of the human placenta: development of “disease-in-a-dish” models. BMC Pregnancy Childbirth 15 (Suppl 1), A6 (2015). https://doi.org/10.1186/1471-2393-15-S1-A6
- Human Placenta
- Pregnancy Complication
- Severe Preeclampsia
- Placental Cell