Overview

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

Effects of diet-induced obesity on uterine natural killer cell function and placental development in early-mid pregnancy
Placenta
Jennet Baltayeva, Barbara Castellana, Eunice Chin, Julian Christians, Alexander Beristain
DOI: 10.1016/j.placenta.2017.07.210
09/2017

ADAM28 localizes to HLA-G+ trophoblasts and promotes column cell outgrowth.
Placenta
DOI: 10.1016/j.placenta.2017.05.009
PubMed: 28623976
07/2017

Editorial: Uteroplacental mingling: who's kissing uNK?
Journal of leukocyte biology
DOI: 10.1189/jlb.1ce0316-162r
PubMed: 27697917
10/2016

Maternal obesity drives functional alterations in uterine NK cells.
JCI insight
PubMed: 27699222
07/2016

ADAM12 and PAPP-A: Candidate regulators of trophoblast invasion and first trimester markers of healthy trophoblasts.
Cell adhesion & migration
DOI: 10.1080/19336918.2015.1083668
PubMed: 26417939
03/2016

ADAM12-directed ectodomain shedding of E-cadherin potentiates trophoblast fusion.
Cell death and differentiation
DOI: 10.1038/cdd.2015.44
PubMed: 25909890
12/2015

The Elsevier Trophoblast Research Award Lecture: Importance of metzincin proteases in trophoblast biology and placental development: a focus on ADAM12.
Placenta
DOI: 10.1016/j.placenta.2014.12.016
PubMed: 25589360
04/2015

A Progesterone-CXCR4 Axis Controls Mammary Progenitor Cell Fate in the Adult Gland.
Stem cell reports
DOI: 10.1016/j.stemcr.2015.01.011
PubMed: 28447939
03/2015

PKA signaling drives mammary tumorigenesis through Src.
Oncogene
DOI: 10.1038/onc.2014.41
PubMed: 24662820
02/2015

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
DOI: 10.1186/1477-7827-12-123
PubMed: 25475528
12/2014

Activation of endocrine-related gene expression in placental choriocarcinoma cell lines following DNA methylation knock-down.
Molecular human reproduction
DOI: 10.1093/molehr/gau020
PubMed: 24623739
07/2014

A disintegrin and metalloproteinase 12 (ADAM12) localizes to invasive trophoblast, promotes cell invasion and directs column outgrowth in early placental development.
Molecular human reproduction
DOI: 10.1093/molehr/gat084
PubMed: 24243624
03/2014

Homotypic RANK signaling differentially regulates proliferation, motility and cell survival in osteosarcoma and mammary epithelial cells.
Journal of cell science
DOI: 10.1242/jcs.094029
PubMed: 22421365
02/2012

Regulated expression of ADAMTS-12 in human trophoblastic cells: a role for ADAMTS-12 in epithelial cell invasion?
PloS one
DOI: 10.1371/journal.pone.0018473
PubMed: 21494557
04/2011

Prkar1a is an osteosarcoma tumor suppressor that defines a molecular subclass in mice.
The Journal of clinical investigation
DOI: 10.1172/jci42391
PubMed: 20697156
09/2010

Progesterone induces adult mammary stem cell expansion.
Nature
DOI: 10.1038/nature09091
PubMed: 20445538
06/2010

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
DOI: 10.1210/jc.2003-031636
PubMed: 15001648
03/2004

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
DOI: 10.1095/biolreprod.102.013714
PubMed: 12855604
11/2003

Research

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

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)

Research Group Members

Barbara Castellana Esteban
Jawairia Atif, Student
Jennet Baltayeva
Robert Hoyeck
Jenna Treissman
Vassilena Sharlandjieva