• Beristain, Alexander G.

    Titles
    Investigator, BC Children's Hospital

    Assistant Professor, Department of Obstetrics and Gynecology, Experimental Medicine Program, Faculty of Medicine, University of British Columbia

    Degrees / Designations
    PhD
    Primary Area of Research
    Healthy Starts
    Secondary Area(s) of Research
    Phone
    604-875-3573
    Fax
    Lab Phone
    Assistant
    Domena Tu
    Assistant Phone
    604-875-2000 ext. 4974
    Mailing Address

    BC Children's Hospital Research Institute
    Room 371A
    950 West 28th Avenue
    Vancouver, BC  V5Z 4H4

    Affiliate Websites
    Research Areas

    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:

    1. Trophoblast-intrinsic factors that regulate cell motility and early organ development
    2. Maternal derived factors (predominantly immune cells) that play underlying roles in dictating trophoblast fitness and function
    3. Global gene expression and gene regulatory mechanisms specific to highly-specialized invasive subsets of trophoblasts
    Summary
    Current Projects

    1) 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).

    2) 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.

    3) 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).
    Selected Publications

    Hogg K, Robinson WP, Beristain AGActivation of endocrine-related gene expression in placental choriocarcinoma cell lines following DNA methylation knock-down. Molecular Human Reproduction (in revision January 2014).

    Beristain AG, Molyneux SD, Joshi PA, Pomroy NC, Di Grappa MA, Chang MC, Kirschner LS, Privé GG, Pujana MA, Khokha R. PKA signaling drives mammary tumorigenesis through Src. Oncogene. Accepted (December 2013).

    Aghababaei M, Perdu S, Irvine K, Beristain AGA disintegrin and metalloproteinase 12 (ADAM12) localizes to invasive trophoblast, promotes cell invasion and directs column outgrowth in early placental development. Mol Hum Reprod. 2013 Dec 5. [Epub ahead of print] PMID:24243624  

    Beristain AG, Narala SR, Di Grappa MA, Khokha R. Homotypic RANK signaling differentially regulates proliferation, motility and cell survival in osteosarcoma and mammary epithelial cells. J Cell Sci. 2012 Feb 15;125(Pt 4):943-55. doi: 10.1242/jcs.094029. Epub 2012 Mar 15. PMID:22421365

    Beristain AG, Zhu H, Leung PC. Regulated expression of ADAMTS-12 in human trophoblastic cells: a role for ADAMTS-12 in epithelial cell invasion? PLoS One. 2011 Apr 11;6(4):e18473. doi: 10.1371/journal.pone.0018473. PMID:21494557

    Molyneux SD, Di Grappa MA, Beristain AG, McKee TD, Wai DH, Paderova J, Kashyap M, Hu P, Maiuri T, Narala SR, Stambolic V, Squire J, Penninger J, Sanchez O, Triche TJ, Wood GA, Kirschner LS, Khokha R. Prkar1a is an osteosarcoma tumor suppressor that defines a molecular subclass in mice. J Clin Invest. 2010 Sep;120(9):3310-25. doi: 10.1172/JCI42391. Epub 2010 Aug 9. PMID:20697156

    Joshi PA, Jackson HW, Beristain AG, Di Grappa MA, Mote PA, Clarke CL, Stingl J, Waterhouse P, Khokha R. Progesterone induces adult mammary stem cell expansion. Nature. 2010 Jun 10;465(7299):803-7. doi: 10.1038/nature09091.

    Grants

    CIHR Operating Grant - Project: "Effects of obesity-associated inflammation on the maternal-fetal interface in early pregnancy" (2014-2019)

    NSERC Individual Discovery Grant: Project: "Examining the importance of ADAM metalloproteinases in trophoblast biology" (2014-2019)

    Honours & Awards
    Research Group Members