Placenta

The Tree of Life

Ornella Parolini

• Publisher: CRC Press
• Year: 2016
• Print ISBN: 9780367658618
• eBook ISBN: 9781498788175
• Edition: 1
• Topic: Medicine
• Subtopic: Genetics in Medicine

Long regarded as biological waste, the placenta is gaining momentum as a viable product for clinical use. Due to their unique properties, placental cells and derivatives show great promise in curing various diseases. Utilizing contributions from world-renowned experts, Placenta: The Tree of Life considers the therapeutic potential of these cells. I

1 Structure and Development of the Human Placenta

Joanna L. James and Lawrence W. Chamley

CONTENTS

Preface

1.1 Overview of the Development of the Human Placenta

1.2 Preimplantation Development and Lineage Derivation

1.3 Decidua

1.4 The Early Postimplantation Placenta and Origins of the Fetal Membranes, Connecting Stalk, and Wharton’s Jelly

1.5 Development of the Villous Placenta

1.6 Origins of the Fetal Membranes

1.6.1 Amniotic Membrane

1.6.2 Chorionic Membrane

1.6.3 Membrane Fusion

1.7 Umbilical Cord and Wharton’s Jelly

1.8 Changes in the Anatomy of the Placenta During Gestation

1.9 Summary

References

PREFACE

The correct function of the human placenta is key for adequate nutrient and gas exchange between mother and baby, and thus for the overall success of pregnancy. The ability of the placenta to achieve appropriate transfer at the end of pregnancy depends on adequate placental development in early pregnancy. Despite the importance of early placental development, our understanding of the early gestation human placenta is limited by our inability to access early human implantation sites, and by a lack of suitable animal models with which to study the relatively unique process of human implantation. This chapter describes our current knowledge of how the placental cell lineages first arise from the blastocyst at the time of implantation, how the major structures of the placenta—the villi, the extraplacental membranes, and the umbilical cord—are formed during early pregnancy, and how these components function to ensure successful pregnancy.

1.1 OVERVIEW OF THE DEVELOPMENT OF THE HUMAN PLACENTA

The human placenta is a unique organ that bears limited anatomical resemblance to the placentae of common laboratory animals. Thus, it is often not possible to directly translate the functions of cells from animal placentae to equivalent human placental cells with any great confidence. The human placenta has a villous or branching structure and is hemochorial, meaning that the fetal trophoblast of the placenta is in direct contact with the maternal blood during most of pregnancy. The maternal face of the human placenta is lined by a single multinucleated cell layer called the syncytiotrophoblast; the syncytiotrophoblast is in direct contact with the maternal blood and thus forms the major exchange surface between mother and baby. Underlying the syncytiotrophoblast (on its fetal aspect) is a layer of actively proliferating mononuclear cytotrophoblasts that act as precursors and fuse into the overlying syncytiotrophoblast throughout pregnancy, allowing the continued expansion and regeneration of the mitotically inactive syncytiotrophoblast. In early pregnancy, cytotrophoblasts are also able to breach the syncytiotrophoblast and migrate out of the anchoring villi, where they differentiate to form columns of invasive extravillous trophoblasts that penetrate the maternal tissue of the uterine decidua. As they move away from the villi, the extravillous cytotrophoblasts lose their ability to proliferate and differentiate to an invasive phenotype. When this process first begins shortly after implantation, the extravillous trophoblasts move laterally around the implantation site to create a “cytotrophoblast shell” that encompasses the embryo. From this shell, extravillous trophoblasts continue to invade into the decidual stroma where they surround the maternal spiral arteries. A subset of extravillous trophoblasts, called endovascular trophoblasts, breech these vessels and migrate antidromically along the spiral arteries where they play key roles in replacing the endothelial cells that line the spiral arteries (Boyd and Hamilton 1970; Cartwright et al. 2010). Endovascular trophoblasts also act together with the trophoblasts that surround the spiral arteries to remove or dedifferentiate the arterial smooth muscle layer, rendering these vessels tonically inactive (France et al. 1986). These remodeling processes change the nature of blood flow within the spiral arteries to provide a constant and increased supply of blood to the placental surface as gestation progresses. In a normal pregnancy, this process, referred to as the “physiological changes of pregnancy,” continues until midgestation when the vessels are modified as far as a third of the length of their myometrial segments (Brosens et al. 1967). In pregnancies complicated by intrauterine growth restriction, preeclampsia, or both, these physiological changes are impaired (Robertson et al. 1967; Khong et al. 1986).

1.2 PREIMPLANTATION DEVELOPMENT AND LINEAGE DERIVATION

Following conception, the first few symmetric cell divisions of each blastomere of the zygote are identical, and all cells within it are thought to be totipotent. As the embryo begins to compact at the 16–32-cell (morula) stage, the blastomeres begin to show the first signs of polarity and differentiation (Nikas et al. 1996). The first clearly identifiable cell lineage differentiation event in human development occurs around 4 days postfertilization when the developing embryo progresses to the 64-cell stage and forms a blastocyst with a distinct inner cell mass that will develop into the embryo proper, and an outer single cell layer called the trophectoderm that will go on to form the trophoblast lineages of the placenta. The division of the blastocyst into the inner cell mass and trophectoderm is characterized by the upregulation of Cdx2, Gata2, and human chorionic gonadotropins (hCGs)-α and -β in the trophectoderm, and by a downregulation or loss of expression of Oct4 and Nanog, which in murine blastocysts, are then only observed in the inner cell mass (De Paepe et al. 2014). Trophectoderm lineage specification was thought to be irreversible, as demonstrated by the inability of inner cell mass–derived embryonic stem cell lines to colonize trophectoderm in murine blastocyst chimera experiments (Niwa et al. 2000; Rossant 2001). However, this absolute lineage commitment has been queried in other animal models, such as the cow, where Cdx2 does not completely repress the expression of Oct4, and Cdx2 expression is not an absolute requirement for trophectoderm differentiation (Berg et al. 2011; Goissis and Cibelli 2014). Similarly, it has been shown that trophectoderm from human blastocysts can be reaggregated into blastocyst-like structures that contain both trophectoderm and inner cell mass–like cells that express Nanog, indicating that human trophectoderm differentiation may also be reversible at this early stage (De Paepe et al. 2013).

By the time the blastocyst attaches to the endometrial epithelium around 7 days postfertilization, two morphologically and functionally distinct regions of the trophectoderm can be distinguished: (1) the polar trophectoderm that lies proximal to the inner cell mass and (2) the mural trophectoderm that stretches more thinly around the remainder of the blastocyst cavity. The inner cell mass of the preimplantation blastocyst is a pluripotent mass of cells, but it is likely that crosstalk between the inner cell mass and the underlying polar trophectoderm plays key roles in the further development of embryonic and placental cell lineages from both of these early populations. Therefore, it is important to be aware of key differences that exist between human and murine blastocysts and the modes of implantation in these species. In particular, in human blastocysts it is always the polar trophectoderm that adheres to the endometrial epithelium, whereas in the mouse, the mural trophectoderm at the abembryonic pole is adherent. The implications that this opposite orientation may have for differences in the regulation of lineage development between species remain unclear, but it is likely that inner cell mass–derived signaling molecules have quite different effects on trophectoderm-derived cells between mice and humans.

1.3 DECIDUA

In humans, the uterine endometrium is prepared every month to be receptive to an implanting blastocyst. This monthly process is called decidualization, and it occurs in each menstrual cycle, commencing around the time of ovulation. Decidualization in humans is driven primarily by a rise in progesterone levels from the corpus luteum following ovulation. Decidualization is characterized by the rapid proliferation of the epithelial and stromal cells of the endometrium; differentiation of the glandular epithelium into a highly secretory state; and finally, stromal cell differentiation in which the usually fibroblast-like stromal cells become plump and glycogen rich and take on a characteristic polygonal morphology (Salamonsen et al. 2009).Decidualization also involves the tightly regulated expression of specific adhesion molecules on endometrial epithelial cells that will facilitate the adhesion and attachment phases of implantation. The concurrent timing of this adhesion molecule expression and stromal cell differentiation ensures that the blastocyst is only able to implant into the decidua for a 2- to 4-day period known as the “implantation window.” Although ectopic pregnancies demonstrate that implantation, and even successful pregnancy, is possible in the absence of the decidua (Jackson et al. 1980; Martin et al. 1988), the success of decidualization is widely held to play an important role in implantation and the success of normal pregnancies.

1.4 THE EARLY POSTIMPLANTATION PLACENTA AND ORIGINS OF THE FETAL MEMBRANES, CONNECTING STALK, AND WHARTON’S JELLY

The very early stages of human placental development remain somewhat of an enigma, with as few as 15 normal human implantation sites from the previllous period in existence (Boyd and Hamilton 1970; James et al. 2012). Thus, our understanding of the events from implantation to around the fifth week of gestation (3 weeks postfertilization) are largely based on “snapshots” during this time, making it challenging to tease out a true functional understanding of the processes involved (James et al. 2012).

After adhesion, the blastocyst implants within the endometrium by actively invading into the decidua and remodeling the decidual extracellular matrix to allow the rapid expansion of the trophectoderm-derived components of the placenta (Boyd and Hamilton 1970). By day 9, the embryo has burrowed completely into the decidua, and the endometrial epithelium then heals over the implanted embryo. In contrast to other species, such as the ungulates that develop within the uterine cavity, human placental and embryonic development occurs entirely within the decidua.

1.5 DEVELOPMENT OF THE VILLOUS PLACENTA

As the blastocyst implants, the trophectoderm differentiates to form the first placental cell populations. The polar trophectoderm exhibits the greatest capacity for proliferation and invasion in human blastocysts, and by the eighth day postfertilization two primitive trophoblast populations are evident at the invading edge of the blastocyst: a mononuclear cytotrophoblast-like population and a multinucleated “primitive syncytium” (James et al. 2012). The primitive syncytium is thought to play an important role in expansion of the developing embryo by secreting several serine proteases (urokinasetype and tissue-type plasminogen activators), metalloproteinases (MMPs) (primarily MMP-2 and -9), and collagenases. These enzymes digest the deciduas, creating spaces what are referred to as lacunae. Processes of the primitive syncytium (called trabeculae) advance into the lacunae, thus expanding them and occasionally breaching maternal sinusoids (Hertig et al. 1956; Enders 1989). The primitive cytotrophoblasts rapidly proliferate, resulting in a convoluted layer of cells that begins to migrate into invaginations on the fetal aspect of the trabeculae (Boyd and Hamilton 1970). The formation of this bilayer of trophoblasts (around 12 days postfertilization) marks the beginning of the villous stage of placental development, and these structures are referred to as primary villi (Hertig 1968; Boyd and Hamilton 1970). The spaces between the villi (lacunae) are now referred to as the intervillous spaces.

The inner cell mass also undergoes many key differentiation events during this time. Upon first contact with the endometrial epithelium (7 days postfertilization), a layer of hypoblast (primary endoderm) becomes evident along the surface of the inner cell mass adjacent to the blastocyst cavity. By approximately 8 days postfertilization, a primitive amniotic cavity begins to develop within the inner cell mass, lined on one side by amnioblasts that will go on to form the amniotic membrane, and lined on the other side by the epiblast, a thick layer of columnar cells that together with the proliferating hypoblast form the bilaminar embryonic disk (Figure 1.1).

By 9 days postfertilization, the larger cavity in the embryo, now ...

Table of contents

• Cover
• Half Title
• Series Page
• Title Page
• Copyright Page
• Table of Contents
• Series Preface
• Preface
• Editor
• Contributors
• Chapter 1 Structure and Development of the Human Placenta
• Chapter 2 The Role of Mesenchymal Stem Cells in the Functions and Pathologies of the Human Placenta
• Chapter 3 The Roles of the Human Placenta in Fetal-Maternal Tolerance
• Chapter 4 The Human Placenta in Wound Healing: Historical and Current Approaches
• Chapter 5 Cell Populations Isolated from Amnion, Chorion, and Wharton’s Jelly of Human Placenta
• Chapter 6 The Immunomodulatory Features of Mesenchymal Stromal Cells Derived from Wharton’s Jelly, Amniotic Membrane, and Chorionic Villi: In Vitro and In Vivo Data
• Chapter 7 Use of Placenta-Derived Cells in Neurological Disorders
• Chapter 8 Use of Amnion Epithelial Cells in Metabolic Liver Disorders
• Chapter 9 The Use of Placenta-Derived Cells in Autoimmune Disorders
• Chapter 10 The Use of Placenta-Derived Cells in Inflammatory and Fibrotic Disorders
• Chapter 11 From Bench to Bedside: Strategy, Regulations, and Good Manufacturing Practice Procedures
• Chapter 12 Applications of Placenta-Derived Cells in Veterinary Medicine
• Index