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
Cell-specific characterization of the placental methylome.
Yuan V and Hui D and Yin Y and Peñaherrera MS and Beristain AG and Robinson WP
Matrix 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
Maternal Obesity and the Uterine Immune Cell Landscape: The Shaping Role of Inflammation
International Journal of Molecular Sciences
Lauren E. St-Germain and Barbara Castellana and Jennet Baltayeva and Alexander G. Beristain
Low oxygen enhances trophoblast column growth by potentiating differentiation of the extravillous lineage and promoting LOX activity
Treissman, J. and Yuan, V. and Baltayeva, J. and Le, H.T. and Castellana, B. and Robinson, W.P. and Beristain, A.G.
Obesogenic 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.
Low 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
Regulation of Placental Extravillous Trophoblasts by the Maternal Uterine Environment.
Frontiers in immunology
Pollheimer J and Vondra S and Baltayeva J and Beristain AG and Knöfler M
ADAM8 localizes to extravillous trophoblasts within the maternal–fetal interface and potentiates trophoblast cell line migration through a ß1 integrin-mediated mechanism
MHR: Basic science of reproductive medicine
H T Le and J Atif and D L Mara and B Castellana and J Treissman and J Baltayeva and A G Beristain
Maternal 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 AG
A mouse model of maternal obesity leads to uterine natural killer (uNK) cell activation and uterine artery remodeling defects
Baltayeva J and Castellana B and Mara D and Christians JK and Beristain AG
Effects of diet-induced obesity on uterine natural killer cell function and placental development in early-mid pregnancy
Jennet Baltayeva and Barbara Castellana and Eunice Chin and Julian Christians and Alexander Beristain
Maternal 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
IFPA meeting 2016 workshop report III: Decidua-trophoblast interactions; trophoblast implantation and invasion; immunology at the maternal-fetal interface; placental inflammation.
Aplin JD and Beristain A and DaSilva-Arnold S and Dunk C and Duzyj C and Golos TG and Kemmerling U and Knöfler M and Mitchell MD and Olson DM and Petroff M and Pollheimer J and Reyes L and Lash GE
The Elsevier Trophoblast Research Award Lecture: Importance of metzincin proteases in trophoblast biology and placental development: a focus on ADAM12.
A Progesterone-CXCR4 Axis Controls Mammary Progenitor Cell Fate in the Adult Gland.
Stem cell reports
Shiah Y and Tharmapalan P and Casey A and Joshi P and McKee T and Jackson H and Beristain A and Chan-Seng-Yue M and Bader G and Lydon J and Waterhouse P and Boutros P and Khokha R
IGFBP-4 and -5 are expressed in first-trimester villi and differentially regulate the migration of HTR-8/SVneo cells.
Reproductive biology and endocrinology : RB&E
Activation of endocrine-related gene expression in placental choriocarcinoma cell lines following DNA methylation knock-down.
Molecular human reproduction
A disintegrin and metalloproteinase 12 (ADAM12) localizes to invasive trophoblast, promotes cell invasion and directs column outgrowth in early placental development.
Molecular human reproduction
Homotypic RANK signaling differentially regulates proliferation, motility and cell survival in osteosarcoma and mammary epithelial cells.
Journal of cell science
Prkar1a 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.
Cellular localization of gonadotropin-releasing hormone (GnRH) I and GnRH II in first-trimester human placenta and decidua.
The Journal of Clinical Endocrinology and Metabolism
Expression 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
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).Grants
NSERC 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)
ProjectResearch Group Members
Barbara Castellana, Research Associate
Ranwa Daker, Volunteer
Matthew Shannon, Graduate Student
Lauren St-Germain, Graduate Student
Jenna Treissman, Graduate Research Asst
Jasmin Waechter, Research Assistant, Masters student