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Expression of erythropoietin by the human placenta
Abstract
Circulating levels of maternal erythro‐poietin (EPO) rise during gestation due to increased biosynthesis of the hormone. Our objective was to investigate the human placenta as a potential extrarenal site of EPO production. Using two mono‐clonal antibodies recognizing different antigenic determinants, we identified immunoreactive EPO associated with villous cytotrophoblast, endovascular and intravascular cytotrophoblast, cytotrophoblast cell columns, and syncytiotrophoblast of first and second‐trimester placenta as well as syncytiotro‐ phoblast and extravillous cytotrophoblast of normal third‐trimester and preeclamptic placenta. In addi‐tion, cultured JAR (trophoblast‐derived) choriocar‐cinoma cells, cytotrophoblasts isolated from term placenta, villous core cells, and possibly other non‐ trophoblast cells within the decidual basal plate ex‐pressed immunoreactive EPO. Using reverse transcription‐polymerase chain reaction and EPO‐ specific primers, a 378 bp DNA product was ampli‐fied from placental tissues of various gestational ages, cytotrophoblasts isolated from term placenta, and JAR choriocarcinoma cells. The amplified product yielded restriction enzyme fragments of predicted sizes. On Southern analysis, hybridization was observed for two of these fragments in which the radiolabeled EPO cDNA probe did not overlap with the primer sequences. Finally, the JAR choriocarcinoma cells elaborated EPO into the culture medium as determined by enzyme‐linked immunosorbant assay and expressed EPO mRNA as determined by Northern analysis, both of which were stimulated by hypoxia (15‐20 torr). Taken together, these results suggest a new site of EPO expression: the trophoblast cell of the human placenta.—Conrad, K. P., Benyo, D. F., Westerhausen‐Larsen, A., Miles, T. M. Expression of erythropoietin by the human placenta. FASEB J. 10, 760‐766 (1996)
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“Finally, it is important to note that the placenta secretes a number of hormones that are traditionally associated with the hypoxic kidney, including erythropoietin, angiotensin II and adrenomedullin (123, 357).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [123]
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Items 101–138 of 138
Zubareva, E. V., Nadezhdin, S. V., Burda, Y. E., Nadezhdina, N. A., & Gashevskaya, A. S. (2019) · Research Results in Pharmacology · doi:10.3897/rrpharmacology.5.33457 · Cited by 7
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“This expectation is based on previous reports that EPO could be secreted by the placentae [28].”
Erythropoietin responses to progressive blood loss over 10 days in the ovine fetus
Sohl, B. D., Cheung, C. Y., Widness, J. A., et al. (2001) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.2001.281.4.r1051 · Cited by 7
“In the fetus, the placenta (which is fetal tissue), kidneys, and liver may all be major sources of circulating EPO because these tissues express EPO mRNA (7, 12, 24).”
BackgroundErythropoietin contributes to implantation: Ectopic hemoglobin synthesis in decidual cells of mice
Yasuda, Y., Sasaki, T., Takagawa, M., Maeda, M., Yasuda, M., Atsumi, T., Fujita, Y., & Fujita, H. (2007) · Congenital Anomalies · doi:10.1111/j.1741-4520.2006.00137.x · Cited by 6
“Moreover, the present findings provide an insight that non-hematopoietic expression of Epo and EpoR in such organs as the placenta (Conrad et al. 1996), brain (Digicaylioglu et al. 1995; Lin et al. 1996; Marti et al. 1996; Morishita et al. 1997) and uterine endometrium (Yasuda et al. 1998) may also…”
BackgroundKabyemela, E., Fried, M., Kurtis, J. D., Gwamaka, M., Gorres, J. P., Muehlenbachs, A., & Duffy, P. E. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.624136 · Cited by 5
“EPO does not cross the placenta (56) and therefore must emanate from fetal sources, such as kidneys, liver, and placenta which are known to express the EPO gene (57).”
BackgroundDavid, R. B., Sjaastad, Ø. V., Blom, A. K., et al. (2002) · Comparative Biochemistry and Physiology Part B Biochemistry and Molecular Biology · doi:10.1016/s1096-4959(02)00024-6 · Cited by 5
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Dame, C. (2006) · Birkhäuser-Verlag eBooks · doi:10.1007/3-7643-7543-4_4 · Cited by 5
Kasper, C. (2003) · Elsevier eBooks · doi:10.1016/b978-012689663-3/50011-9 · Cited by 5
Klemetti, M. M., Teramo, K. A., Kautiainen, H., Wasenius, N., Eriksson, J. G., & Laine, M. K. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.738570 · Cited by 5
“Although the organ that secretes the high concentrations of EPO into the fetal circulation in hypoxia remains elusive, the placenta is a strong candidate as the source tissue (19), based on studies in sheep (20) and in monochorionic twin pregnancies (21).”
BackgroundShim, S.-H., Kim, Y., Hwangbo, Y., Yoon, H. J., Kim, J. S., Lee, Y. J., Woo, Y. S., & Bahk, W. (2021) · Clinical Psychopharmacology and Neuroscience · doi:10.9758/cpn.2021.19.2.334 · Cited by 4
“A variety of organs, such as the placenta, testis, lung, spleen, and brain have been shown to express EPO [9,10].”
BackgroundErythropoietin is involved in hemoprotein syntheses in developing human decidua
Shiota, M., Yasuda, Y., Shimaoka, M., Tsuritani, M., Koike, E., Masaaki, O. I. K. I., Matsubara, J., Taketani, S., Murakami, H., Yamasaki, H., et al. (2012) · Congenital Anomalies · doi:10.1111/j.1741-4520.2012.00382.x · Cited by 3
Ogawa, A., Terada, S., Sakuragawa, N., et al. (2003) · Journal of Bioscience and Bioengineering · doi:10.1263/jbb.96.448 · Cited by 3
Delaney, K. M., Barad, A., Castillo, L. F., Hasund, C. M., Guillet, R., Pressman, E. K., Katzman, P. J., Ganz, T., Nemeth, E., & O'Brien, K. O. (2023) · Journal of Nutrition · doi:10.1016/j.tjnut.2023.05.023 · Cited by 4
Carretti, N. G., & Marca, A. L. (2002) · Gynecologic and Obstetric Investigation · doi:10.1159/000049407 · Cited by 3
Hemoglobinopathies in pregnancy
Adewoye, A. H., & Steinberg, M. H. (2006) · Cambridge University Press eBooks · doi:10.1017/cbo9780511526978.014 · Cited by 2
Herzog, M., & Jongsma, M. L. A. (2008) · Cited by 2
Human Amniotic Epithelial (HAE) Cells Produce Erythropoietin
Ogawa, A., Terada, S., Miki, M., et al. (2002) · Springer eBooks · doi:10.1007/978-94-017-0728-2_55 · Cited by 2
Molineux, G. (2006) · Birkhäuser-Verlag eBooks · doi:10.1007/3-7643-7543-4_7 · Cited by 2
Maternal Plasma Proteins Associated with Birth Weight: A Longitudinal, Large Scale Proteomic Study
Andresen, I. J., Westerberg, A. C., Roland, M. C. P., Zucknick, M., & Michelsen, T. M. (2025) · Journal of Proteome Research · doi:10.1021/acs.jproteome.4c00940 · Cited by 1
“However, as EPO is expressed by the placenta, 72,79 increased levels in maternal blood could reflect increased placental size or increased placental metabolic activity.”
Kurtz, A., Wenger, R. H., & Eckardt, K. (2012) · Elsevier eBooks · doi:10.1016/b978-0-12-381462-3.00092-6 · Cited by 2
Papworth, K. (2011) · KTH Publication Database DiVA (KTH Royal Institute of Technology) · Cited by 1
Rodríguez, L., & Javier, Ó. (2010) · TDX (Tesis Doctorals en Xarxa)
Erythropoietin stimuliert die Knochenheilung der Maus
Speidel, V. (2012) · Publications of the UdS (Saarland University) · doi:10.22028/d291-21724
Tissue Protection and Regeneration Aided by Erythropoietin and Erythropoietin-derived Peptides
Fliser, D. (2010) · Elsevier eBooks · doi:10.1016/b978-0-12-380928-5.10005-3
Negative Regulatory Mechanisms Underlying EPO Receptor Signaling and Erythropoiesis
Richmond, T. D. (2010) · TSpace (University of Toronto)
Leptin in the perinatal period
Hytinantti, T. K. (2001) · Työväentutkimus Vuosikirja
Kowalska-Kańka, A., Maciejewski, T., & Niemiec, K. T. (2013)
Anemia and Progression of Chronic Kidney Disease
Fliser, D., & Bahlmann, F. H. (2010) · Humana Press eBooks · doi:10.1007/978-1-60761-857-7_31
“Additionally, recent studies could identify EPO expression in several extrarenal tissues and cell types, including astrocytes, neurons, the female genital tract, male reproductive organs, mammary glands, placental trophoblasts, bone marrowmacrophages, and erythroid progenitors [54–62].”
BackgroundEritropoietina:produção renal, anemia e cancro
Moreira, L. M. V. (2011) · Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) · doi:10.34626/adnj-sk50
STAT Signaling by Erythropoietin
Constantinescu, S. N., & Moucadel, V. (2003) · Springer eBooks · doi:10.1007/978-94-017-3000-6_36
Mechanisms of trophoblast differentiation and maternal–fetal interactions in the mouse
Cross, J. C. (2008) · CRC Press eBooks · doi:10.3109/9780203091500-37 · Cited by 1
Kurtz, A., & Eckardt, K. (2008) · Elsevier eBooks · doi:10.1016/b978-012088488-9.50098-x
Dias, L. C. (2020) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/t.17.2020.tde-12022020-175039
Mechanisms of trophoblast differentiationand maternal–fetal interactions in the mouse
Cross, J. C. (2008) · Reproductive medicine and assisted reproductive techniques series · doi:10.3109/9780203091500.032
Cellular determinants of parvovirus B19 infection in the human placentaPreprint
Suter, C., Kuffer, M., Bieri, J., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.09.12.675789
Cellular determinants of parvovirus B19 susceptibility in the human placenta
Suter, C., Kuffer, M., Bieri, J., et al. (2026) · PLoS Pathogens · doi:10.1371/journal.ppat.1013984
“Both Epo and EpoR are expressed by trophoblasts in the human placenta, where EpoR signaling contributes to critical processes such as cell survival, angiogenesis, placental development, and adaptation to hypoxic conditions [38,50].”
Kayıkcı, G. O., Dinç, G., Yaman, H., Ayan, S., & Güven, S. (2026) · Bratislavské lekárske listy/Bratislava medical journal · doi:10.1007/s44411-026-00812-x
Human Amniotic Epithelial (HAE) Cells Express Erythropoietin (EPO) and EPO-Receptor
Matsuura, K., Hoshika, A., Terada, S., et al. (2008) · Springer eBooks · doi:10.1007/0-306-46875-1_111
Metadata
- Authors
- Conrad, K. P., Benyo, D. F., Westerhausen‐Larsen, A., & Miles, T. M.
- Affiliations
- University of Pittsburgh (US)
- Magee‐Womens Research Institute and Department of Obstetrics, Gynecology and Reproductive Sciences University of Pittsburgh Pittsburgh Pennsylvania 15213 USA
- Corresponding author
- Conrad, Kirk P.
- ORCID
- Conrad, Kirk P.
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 1996-05
- Volume
- 10
- Issue
- 7
- Pages
- 760-768
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W1933030459
- Cited by
- 138
- References
- 0
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 1 · 2021: 3 · 2020: 4 · 2019: 2 · 2018: 4 · 2017: 2 · 2016: 1 · 2015: 3 · 2014: 1 · 2013: 3 · 2012: 8
- FWCI
- 2.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5k04hd001098-02)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD30325, R01HD030325, K04 HD-01098)
- Topics
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Keywords
- erythropoietin, placenta, trophoblast, cytotrophoblast, syncytiotrophoblast, extravillous cytotrophoblast, JAR choriocarcinoma cells, hypoxia, preeclampsia
- MeSH terms
- Enzyme-Linked Immunosorbent Assay, Erythropoietin, Female, Humans, Immunohistochemistry, Placenta, RNA, Messenger, Polymerase Chain Reaction
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