- Overview
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The human placenta is unique among eutherian mammals. One of the most striking distinctions in humans is the ability of specialized epithelial cells of the placenta (called trophoblasts) to acquire highly-invasive characteristics similar to invasive tumor cells. Invasive trophoblast populations play critical roles in remodeling the uterine microenvironment and facilitating nutrient and oxygen transfer between mother and developing baby. The success of placental formation (and pregnancy) is ultimately dictated by tight regulatory mechanisms that both promote and restrain differentiation of trophoblast subsets into highly-invasive populations. Conditions that suppress trophoblast differentiation impair vascular remodeling and lead to inadequate inter-villous blood perfusion, maternal hypertension and fetal stress.
A major focus of my lab investigates both the cellular and molecular processes that direct trophoblast cell biology in early placental development. Utilizing state of the art cell isolating techniques and three-dimensional culture systems, we investigate:
Trophoblast-intrinsic factors that regulate cell motility and early organ development
Maternal derived factors (predominantly immune cells) that play underlying roles in dictating trophoblast fitness and function
Global gene expression and gene regulatory mechanisms specific to highly-specialized invasive subsets of trophoblasts
- Publications
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Maternal obesogenic diet disrupts mid-gestation decidual immune and vascular homeostasis without impairing spiral artery remodelling
Christian J. Bellissimo and Erica Yeo and Tatiane A. Ribeiro and Patrycja A. Jazwiec and Chethana Ellewela and Jaskiran Bains and Ali A. Ashkar and Alexander G. Beristain and Dawn M.E. Bowdish and Deborah M. Sloboda
DOI: 10.1101/2024.09.10.612284
09/2024Single-cell assessment of primary and stem cell-derived human trophoblast organoids as placenta-modeling platforms
Developmental Cell
DOI: 10.1016/j.devcel.2024.01.023
2024Human organoid systems in modeling reproductive tissue development, function, and disease
Human Reproduction
DOI: 10.1093/humrep/dead085
2023Assessment of the human placental microbiome in early pregnancy
Frontiers in Medicine
DOI: 10.3389/fmed.2023.1096262
2023The application of epiphenotyping approaches to DNA methylation array studies of the human placenta
Epigenetics and Chromatin
DOI: 10.1186/s13072-023-00507-5
2023Cell trajectory modeling identifies a primitive trophoblast state defined by BCAM enrichment
Development (Cambridge)
Shannon, M.J. and Baltayeva, J. and Castellana, B. and Wächter, J. and McNeill, G.L. and Yoon, J.S. and Treissman, J. and Le, H.T. and Lavoie, P.M. and Beristain, A.G.
DOI: 10.1242/dev.199840
2022Transcriptomic mapping of the metzincin landscape in human trophoblasts
Gene Expression Patterns
W{\"a}chter, J. and Shannon, M.J. and Beristain, A.G.
DOI: 10.1016/j.gep.2022.119283
2022Single-Cell Assessment of Trophoblast Stem Cell-Based Organoids as Human Placenta-Modeling Platforms
SSRN
DOI: 10.2139/ssrn.4277949
2022Decidual innate immune cell kinetics following lipopolysaccharide challenge
bioRxiv
St-Germain, L.E. and Castellana, B. and Baltayeva, J. and Beristain, A.G.
DOI: 10.1101/2022.01.27.478092
2022Cell-specific characterization of the placental methylome.
BMC genomics
Yuan V and Hui D and Yin Y and Peñaherrera MS and Beristain AG and Robinson WP
DOI: 10.1186/s12864-020-07186-6
PubMed: 33407091
01/2021Single cell trajectory modeling identifies a primitive trophoblast state defined by BCAM enrichment
bioRxiv
Shannon, M. and Baltayeva, J. and Castellana, B. and Wächter, J. and Yoon, S. and Treissman, J. and Le, H. and Beristain, A.G.
DOI: 10.1101/2021.03.27.437349
2021Matrix metalloproteinase 15 plays a pivotal role in human first trimester cytotrophoblast invasion and is not altered by maternal obesity.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
DOI: 10.1096/fj.202000773r
PubMed: 32614494
07/2020Obesogenic diet exposure alters uterine natural killer cell biology and impairs vasculature remodeling in mice
Biology of Reproduction
Baltayeva, J. and Konwar, C. and Castellana, B. and Mara, D.L. and Christians, J.K. and Beristain, A.G.
DOI: 10.1093/biolre/ioz163
2020Low oxygen enhances trophoblast column growth by potentiating differentiation of the extravillous lineage and promoting LOX activity
Development (Cambridge)
Treissman, J. and Yuan, V. and Baltayeva, J. and Le, H.T. and Castellana, B. and Robinson, W.P. and Beristain, A.G.
DOI: 10.1242/dev.181263
2020Maternal obesity and the uterine immune cell landscape: The shaping role of inflammation
International Journal of Molecular Sciences
St-Germain, L.E. and Castellana, B. and Baltayeva, J. and Beristain, A.G.
DOI: 10.3390/ijms21113776
2020Low oxygen enhances trophoblast column growth by potentiating the extravillous lineage and promoting LOX activity
Jenna Treissman and Victor Yuan and Jennet Baltayeva and Hoa T. Le and Barbara Castellana and Wendy P. Robinson and Alexander G. Beristain
DOI: 10.1101/669796
06/2019ADAM8 localizes to extravillous trophoblasts within the maternal-fetal interface and potentiates trophoblast cell line migration through a ß1 integrin-mediated mechanism
Molecular Human Reproduction
Le, H.T. and Atif, J. and Mara, D.L. and Castellana, B. and Treissman, J. and Baltayeva, J. and Beristain, A.G.
DOI: 10.1093/molehr/gay034
2018Regulation of placental extravillous trophoblasts by the maternal uterine environment
Frontiers in Immunology
Pollheimer, J. and Vondra, S. and Baltayeva, J. and Beristain, A.G. and Knöfler, M.
DOI: 10.3389/fimmu.2018.02597
2018Maternal obesity alters uterine NK activity through a functional KIR2DL1/S1 imbalance
Immunology and Cell Biology
Castellana, B. and Perdu, S. and Kim, Y. and Chan, K. and Atif, J. and Marziali, M. and Beristain, A.G.
DOI: 10.1111/imcb.12041
2018Effects of diet-induced obesity on uterine natural killer cell function and placental development in early-mid pregnancy
Placenta
Jennet Baltayeva and Barbara Castellana and Eunice Chin and Julian Christians and Alexander Beristain
DOI: 10.1016/j.placenta.2017.07.210
09/2017Maternal obesity alters uterine NK cell activity through a functional KIR2DL1/S1 imbalance
Castellana B and Perdu S and Kim Y and Chan K and Atif J and Marziali M and Beristain AG
DOI: 10.1101/167213
07/2017ADAM28 localizes to HLA-G+ trophoblasts and promotes column cell outgrowth
Placenta
De Luca, L.C. and Le, H.T. and Mara, D.L. and Beristain, A.G.
DOI: 10.1016/j.placenta.2017.05.009
2017IFPA meeting 2016 workshop report III: Decidua-trophoblast interactions; trophoblast implantation and invasion; immunology at the maternal-fetal interface; placental inflammation
Placenta
DOI: 10.1016/j.placenta.2017.04.019
2017Maternal obesity drives functional alterations in uterine NK cells.
JCI insight
PubMed: 27699222
07/2016Maternal obesity drives functional alterations in uterine NK cells
JCI Insight
Perdu, S. and Castellana, B. and Kim, Y. and Chan, K. and DeLuca, L. and Beristain, A.G.
DOI: 10.1172/jci.insight.85560
2016Editorial: Uteroplacental mingling: Who’s kissing uNK?
Journal of Leukocyte Biology
Morgan, T.K. and Beristain, A.G.
DOI: 10.1189/jlb.1CE0316-162R
2016ADAM12 and PAPP-A: Candidate regulators of trophoblast invasion and first trimester markers of healthy trophoblasts
Cell Adhesion and Migration
Christians, J.K. and Beristain, A.G.
DOI: 10.1080/19336918.2015.1083668
2016A progesterone-CXCR4 axis controls mammary progenitor cell fate in the adult gland
Stem Cell Reports
Shiah, Y.-J. and Tharmapalan, P. and Casey, A.E. and Joshi, P.A. and McKee, T.D. and Jackson, H.W. and Beristain, A.G. and Chan-Seng-Yue, M.A. and Bader, G.D. and Lydon, J.P. and Waterhouse, P.D. and Boutros, P.C. and Khokha, R.
DOI: 10.1016/j.stemcr.2015.01.011
2015ADAM12-directed ectodomain shedding of E-cadherin potentiates trophoblast fusion
Cell Death and Differentiation
Aghababaei, M. and Hogg, K. and Perdu, S. and Robinson, W.P. and Beristain, A.G.
DOI: 10.1038/cdd.2015.44
2015Erratum: A progesterone-CXCR4 axis controls mammary progenitor cell fate in the adult gland (Stem Cell Reports (2015) 4 (313-322))
Stem Cell Reports
Shiah, Y.-J. and Tharmapalan, P. and Casey, A.E. and Joshi, P.A. and McKee, T.D. and Jackson, H.W. and Beristain, A.G. and Chan-Seng-Yue, M.A. and Bader, G.D. and Lydon, J.P. and Waterhouse, P.D. and Boutros, P.C. and Khokha, R.
DOI: 10.1016/j.stemcr.2015.02.020
2015PKA signaling drives mammary tumorigenesis through Src
Oncogene
Beristain, A.G. and Molyneux, S.D. and Joshi, P.A. and Pomroy, N.C. and Di Grappa, M.A. and Chang, M.C. and Kirschner, L.S. and Privé, G.G. and Pujana, M.A. and Khokha, R.
DOI: 10.1038/onc.2014.41
2015The Elsevier trophoblast research award lecture: Importance of metzincin proteases in trophoblast biology and placental development: A focus on ADAM12
Placenta
Aghababaei, M. and Beristain, A.G.
DOI: 10.1016/j.placenta.2014.12.016
2015A disintegrin and metalloproteinase 12 (ADAM12) localizes to invasive trophoblast, promotes cell invasion and directs column outgrowth in early placental development
Molecular Human Reproduction
Aghababaei, M. and Perdu, S. and Irvine, K. and Beristain, A.G.
DOI: 10.1093/molehr/gat084
2014IGFBP-4 and -5 are expressed in first-trimester villi and differentially regulate the migration of HTR-8/SVneo cells
Reproductive Biology and Endocrinology
Crosley, E.J. and Dunk, C.E. and Beristain, A.G. and Christians, J.K.
DOI: 10.1186/1477-7827-12-123
2014Activation of endocrine-related gene expression in placental choriocarcinoma cell lines following DNA methylation knock-down
Molecular Human Reproduction
Hogg, K. and Robinson, W.P. and Beristain, A.G.
DOI: 10.1093/molehr/gau020
2014Homotypic RANK signaling differentially regulates proliferation, motility and cell survival in osteosarcoma and mammary epithelial cells
Journal of Cell Science
Beristain, A.G. and Narala, S.R. and Di Grappa, M.A. and Khokha, R.
DOI: 10.1242/jcs.094029
2012Regulated expression of ADAMTS-12 in human trophoblastic cells: A role for ADAMTS-12 in epithelial cell invasion?
PLoS ONE
Beristain, A.G. and Zhu, H. and Leung, P.C.K.
DOI: 10.1371/journal.pone.0018473
2011Prkar1a is an osteosarcoma tumor suppressor that defines a molecular subclass in mice
Journal of Clinical Investigation
Molyneux, S.D. and Di Grappa, M.A. and Beristain, A.G. and McKee, T.D. and Wai, D.H. and Paderova, J. and Kashyap, M. and Hu, P. and Maiuri, T. and Narala, S.R. and Stambolic, V. and Squire, J. and Penninger, J. and Sanchez, O. and Triche, T.J. and Wood, G.A. and Kirschner, L.S. and Khokha, R.
DOI: 10.1172/JCI42391
2010Progesterone induces adult mammary stem cell expansion
Nature
Joshi, P.A. and Jackson, H.W. and Beristain, A.G. and Di Grappa, M.A. and Mote, P.A. and Clarke, C.L. and Stingl, J. and Waterhouse, P.D. and Khokha, R.
DOI: 10.1038/nature09091
2010Cellular localization of gonadotropin-releasing hormone (GnRH) I and GnRH II in first-trimester human placenta and decidua
Journal of Clinical Endocrinology and Metabolism
Chou, C.-S. and Beristain, A.G. and MacCalman, C.D. and Leung, P.C.K.
DOI: 10.1210/jc.2003-031636
2004Expression of Messenger RNA for ADAMTS Subtypes Changes in the Periovulatory Follicle after the Gonadotropin Surge and During Luteal Development and Regression in Cattle
Biology of Reproduction
Madan, P. and Bridges, P.J. and Komar, C.M. and Beristain, A.G. and Rajamahendran, R. and Fortune, J.E. and MacCalman, C.D.
DOI: 10.1095/biolreprod.102.013714
2003 - Research
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Identifying gene expression differences in subpopulations of trophoblasts in normal and pathological pregnancies
State of the art cell-sorting techniques and an understanding of unique cell surface expression markers on trophoblast subpopulations establishes an attractive method in identifying intrinsic trophoblast-specific genes in causative mechanisms in the development of pregnancy-related disorders. To this end, my lab is characterizing specialized trophoblast subpopulations within the placenta and maternal uterine tissue using state-of-the-art FACS-purification strategies. These studies are designed to answer questions directly related to:
Critical gene pathways essential in placental development, trophoblast differentiation, and trophoblast progenitor cell homeostasis.
Determining pathways dysregulated in pregnancy disorders (IUGR pregnancies and preeclampsia) and pregnancies associated with heightened risk of placental dysfunction (obesity).Examining the effects of obesity-associated inflammation on the maternal-fetal interface
Within the uterine microenvironment, maternal immune cells play a prominent role in regulating trophoblast function and survival. Abnormal changes in the balance of immune cell populations in utero can alter early placental development and have a direct effect on maternal health, fetal outcome and newborn health. Early stages of uterine arterial remodeling, trophoblast invasion and survival, as well as maternal tolerance of the fetal semi-allograft (half mom, half dad) are controlled by uterine immune cells, which are mainly comprised of decidual natural killer cells (dNKs; 70% of total immune cells), but also have significant numbers of myeloid-derived dendritic cells and macrophages (15%) and subsets of regulatory and effector T cell lymphocytes (10%). Alterations in immune cell composition and/or function at the fetal-maternal interface have major implications in trophoblast fitness and pregnancy outcome.
In healthy pregnancy, dNKs, macrophages and regulatory T lymphocytes (Tregs) adopt an immunoprotective role, limiting pro-inflammatory cytokine production and cytolytic/cytotoxic cellular immunity. However, a shift in balance towards pro-inflammatory cytokine producing immune cells within the uterine microenvironment is associated with impaired trophoblast function and survival, poor pregnancy outcome and compromised fertility. These correlations have been substantiated by experiments in mice showing that depletion of key protective/immunosuppressive immune cells leads to under-remodeled uterine arteries, under-perfused vessels, smaller litter sizes and increased fetal demise. Together, these findings indicate that changes in the uterine immune cell microenvironment may significantly alter early placentation.
In obesity, adipocyte expansion leads to heightened secretion pro-inflammatory factors like TNFa and IL-6 by fat cells (adipocytes), which together drive macrophage activation and contribute to the development of metabolic and immune syndromes. Obesity-associated inflammation is characterized by a subtle shift in the balance between different types of T lymphocytes (effector vs. regulatory), resulting in chronic low-level pro-inflammatory cytokine production, tissue cytotoxicity and apoptosis.
Work in my lab is currently profiling the uterine immune cell make-up in obese pregnant women in early pregnancy using a sophisticated multicolor flow cytometry approach. My lab is especially interested in understanding the importance of CD4+ T helper and immunosuppressive regulatory cells within the uterine environment with a particular focus on their roles in directing trophoblast survival and function.Examining the A Disintegrin And Metalloproteinase (ADAM) family in trophoblast biology
A specific focus of my research over the past year has examined the importance of the A Disintegrin And Metalloproteinase (ADAM) protease family member, ADAM12, in directing two cellular processes essential in placentation: cell invasion and cell fusion. Despite exceptionally high levels of ADAM12 expression in placental tissues, prior to my lab’s work, the biological significance of ADAM12 in trophoblast biology was unknown. Building upon my recent findings, my short-term objectives aim to characterize the molecular processes directed by ADAM12 in regulating trophoblast differentiation into invasive and multinuclear cell types.
As the biology of ADAM12-related genes in trophoblast function is unknown, I also aim to examine the importance of multiple ADAM family members in trophoblast biology using a global gene expression approach (see Aim 3 below). These extensive studies will inform us of the key ADAM proteases expressed in specific trophoblast subsets and the key signaling pathways and gene interactions linked to biological processes critical in early placental development (i.e. cell survival, proliferation, motility, cell fusion).GrantsNSERC Individual Discovery Grant
"Examining the importance of ADAM metalloproteinases in trophoblast biology" (2014-2019)
CIHR Operating Grant - Project
"Effects of obesity-associated inflammation on the maternal-fetal interface in early pregnancy" (2014-2019)
Research Group MembersGrace Bernard, Summer Student
Katie Cheah, Graduate Student
Burak Koksal, Graduate Student
Victoria Leonard
Gina McNeill
Elakkiya Prabaharan, Graduate Student
Matt Shannon, Graduate Student
Lauren St-Germain, Graduate Student
New research tools can shed light on an understudied organ essential to our lives
The placenta is essential to a healthy start in life. Despite its importance, little is known about it, including why it might not develop properly, which can lead to long-term health issues. Dr. Alexander Beristain’s lab is investigating two state-of-the-art stem cell-based tools that model a human placenta to find answers that can positively impact children’s health.
