Placenta
Volume 26, Supplement , Pages S3-S9, April 2005

How to make a placenta: Mechanisms of trophoblast cell differentiation in mice – A Review

  • J.C. Cross

      Affiliations

    • Corresponding Author InformationCorresponding author. Tel.: +1 403 220 6876; fax: +1 403 270 0737.

Genes & Development Research Group, Department of Biochemistry and Molecular Biology, University of Calgary, Faculty of Medicine, HSC Room 2279, 3330 Hospital Drive N.W., Calgary, Alberta, T2N 4N1, Canada

Accepted 31 January 2005.

Article Outline

The word placenta is derived from the Latin term meaning ‘flat cake’. Despite the rather humble name, the placenta is an amazing organ that forms both the interface for selective delivery of nutrients from the mother to the fetus and also re-directs maternal metabolic, endocrine, cardiovascular and immune functions to promote fetal survival and growth. These two functions are fulfilled by different specialized trophoblast cell subtypes, and my laboratory has been studying how their formation and functions are regulated during placental development. Through molecular studies in cultured cells and tissues, genetic studies in mice, and comparative analysis of placentas from humans, rodents and farm animals, it is now possible to describe molecular pathways that control the development of all major trophoblast cell subtypes and structures of the placenta. The work has revealed an intricate complexity of cell–cell interactions, environmental factors, and molecular networks that control normal development.

Keywords: Development, Genetics, Genes, Differentiation, Trophoblast

 

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Introduction 

The last 10 years have seen a rapid evolution in our understanding of placental development. This has been driven in part by experimental embryology and the development of new culture systems that facilitate a cellular level of understanding, but also by the use of molecular biology and genetic approaches for the discovery of individual molecular pathways that are essential for development. The application of transgenic and gene knockout techniques in mice in particular has changed the face of our knowledge. Whereas we knew of less than five genes that were essential for placental development in 1994 [1], there are now over 100 (Table 1). While the functions of individual genes are interesting in their own ways, this article will review some of the remaining fundamental questions about placental development that my laboratory has been interested in trying to answer using the mouse as a model system:

(1)What are the cell types that make up the placenta and what is the cell lineage that underlies their formation? Anatomical descriptions have in large part described many of the cell types that make up the placenta and it is clear that there are a number of differentiated trophoblast cell subtypes that make up the placenta. In addition, though, molecular biology and studies that have localized gene expression patterns in the placenta have sometimes demonstrated that the repertoire of trophoblast cell subtypes is more complex than originally thought. Addressing how these diverse cell subtypes arise during development is difficult and often our understanding of how the single layered trophectoderm in the blastocyst diversifies into range of cell trophoblast subtypes in the mature placenta is incomplete or based on indirect evidence.

(2)How is the identity of different trophoblast cell subtypes determined during development, and are the molecular pathways conserved evolutionarily? Based largely on the analysis of knockout mice as well as gene mis-expression studies in trophoblast stem cells, it is now possible to describe most of the cell differentiation steps underlying mouse placental development in molecular terms. Unfortunately, there are only a limited number of studies that address whether the genes that are important for placental development in mice are likely to have a similar function in other species. However, human homologues for many of the genes are expressed in a pattern at least consistent with a conserved role [2]. Such studies have also helped to make comparisons between cell types across species, which has been a significant advance over comparative anatomy alone.

Table 1. Genes that show mutant mouse phenotypes in different aspects of placental development
Trophoblast stem cells
Activin, Cdx2, Eomes, Err2, Fgf4, Fgfr2, Dp1, Erk2, mTOR, Nipp1, Nodal, Talin

Trophoblast giant cells
Cyclin E1/E2, Hand1, I-mfa, Eed, Epcr, Fbw7, K18/19, Kip2, Lifr, Mfn2, Socs3

Spongiotrophoblast
Mash2, Egfr, Arnt, Nodal

Chorioallantoic attachment
Bmp5/7, Cdx2, Cyclin F, Cyr61, Dnmt, Edd, Err2, Fgfr2, Itga4, Lim1, Lpp3, Mrj, Nodal, Smad1, T, Tbx4, Vcam1, Zfp36L

Syncytiotrophoblast and labyrinth
α7 adrenergic receptors, Ap2g, Arnt, Chm, Cited1, Cited 2, Met, Ctbp2, Cx26, Cx31, Cx43, Dlx3, Egfr, Erk2, Erk5, Esx1, Fzd5, Gab1, Hey1/2, Hsp90b, Hgf, Igf2, Il10, Itgav, Itgb8, Junb, K8/18, Kip2, Lbp1a, Lifr, Mek1, Mekk3, Nex1, Nodal, Nte, Cul7, p38 MAPK, Kip2, Pdgfb, PKBa, Plk2, Pparg, RAP250, Rb, Rxra, Sos1, Tfeb, Vhl, Wnt2

Glycogen trophoblast differentiation
Igf2, Kip2

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Trophoblast cell subtypes and their developmental origins in mice 

After implantation, the simple trophectoderm surrounding the blastocyst goes on to differentiate into a variety of trophoblast cell subtypes each with specific functions (Figure 1). Much of our knowledge about the cell lineage – going from multi-potent trophoblast stem cells to the various differentiated trophoblast subtypes – is based on indirect studies. Trophoblast stem cells emerge from the polar trophectoderm that overlies the inner cell mass in the blastocyst. They proliferate in response to close contact with the inner cell mass, now known to be mediated by the growth factor FGF4 [3]. FGF4 continues to be expressed by the embryonic ectoderm after implantation and indeed FGF4-dependent trophoblast stem cell lines can be isolated from the adjacent trophoblast layer, called chorion trophoblast or extraembryonic ectoderm [4], [5]. Trophoblast stem cells can proliferate in culture for many generations and can differentiate into a range of differentiated trophoblast cell subtypes, both in vivo [4] and in vitro [6], [7], indicating that they are multi-potent. Importantly, trophoblast stem cell lines resembling those derived from blastocysts or early post-implantation chorion have not been successfully isolated from tissues older than embryonic day 7.5–8.0 [5]. This suggests that growth of the placenta after ∼E7.5 must be due to proliferation and differentiation of a distinct trophoblast progenitor cell type.

  • View full-size image.
  • Figure 1. 

    Overview of placental development in mice. (A) Morphological stages of early placental development. (B) Outline of the trophoblast cell lineage in mice. The dotted lines indicate signaling interactions that promote the specific differentiation step shown.

Trophoblast giant cells arise during two phases of development. Primary trophoblast giant cells arise from the direct differentiation of the 50 or so mural trophectoderm (the trophectoderm not overlying the inner cell mass) at the blastocyst stage [1], [8]. These cells exit the mitotic cell cycle and stop dividing, enlarge, and eventually go through rounds of DNA replication without intervening mitoses (endoreduplication) to become polyploid [9], [10], [11]. After implantation, the number of trophoblast giant cells increases to over 400 over the next several days [12], through the process of secondary giant cell differentiation in which cells of the ectoplacental cone are thought to differentiate into giant cells [1], [8]. There are no direct cell lineage tracing experiments to support this model. Nonetheless, the best evidence that cells of the ectoplacental cone differentiate into secondary giant cells is that cultured ectoplacental cone cells will spontaneously differentiate to giant cells. By contrast, cultured chorionic trophoblast cells differentiate into giant cells after proceeding through a stage in which they express genes typical of ectoplacental cells [13].

The functions of trophoblast giant cells are to first mediate the process of implantation and invasion of the conceptus into the uterus. Later they produce several hormones and cytokines that promote both local and systemic physiological adaptations in the mother including the regulation of maternal blood flow to the implantation site, production of progesterone from the ovary, lactogenesis and pancreatic islet hyperplasia [14], [15]. The majority of primary and secondary giant cells are morphologically similar and express genes in common. However, there are several genes which have been described that show heterogeneous patterns of expression [16], [17], implying an unsuspected level of sub-specialization.

Most trophoblast giant cells migrate only a short distance into the decidua. However, a subtype of trophoblast giant cell invades into the spiral arteries that bring maternal blood to the implantation site. In doing so, they establish the connection between the endothelial cell-lined arteries to the hemochorial blood spaces found in rodent and primate placentas [18]. The endovascular trophoblast giant cells express the Plf gene, a gene that in the placenta is otherwise specifically expressed in trophoblast giant cells. They are ‘atypical’ giant cells in that they are not nearly as large as the primary giant cells that surround the implantation site. There is no direct evidence as to where the endovascular trophoblast giant cells arise during development. However, they emerge from the edge of the ectoplacental cone and therefore are likely to be simply a subtype of secondary giant cell. In mice, they also appear several days before interstitial trophoblast invasion of the uterine wall occurs, implying that they traffic via an endo- or peri-vascular route from the start rather than as an end result of an initial interstitial route [18].

The ectoplacental cone also likely gives rise to the spongiotrophoblast layer (sometimes called the junctional zone). The evidence for this is based on expression patterns for genes that in the placenta are restricted to the ectoplacental cone and later the spongiotrophoblast (e.g., Flt1 and Tpbpa). However, it is notable that it is even unclear whether ectoplacental cone/spongiotrophoblast cells can proliferate. It has, for example, been shown that the spongiotrophoblast layer in rat contains a large proportion of polyploid cells that have arisen through endoreduplication [19], [20], indicating that these cells are post-mitotic. In the mature placenta, the spongiotrophoblast forms the middle layer of the placenta between the outermost giant cells and the innermost labyrinth. Its function is unknown, although it probably has a structural role and also produces several layer-specific secreted factors including anti-angiogenic factors that may prevent the growth of maternal blood vessels into the fetal placenta [15].

Glycogen trophoblast cells appear within the spongiotrophoblast layer starting after about embryonic day 12.5. They later invade into the uterus in a diffuse interstitial pattern and continue to express markers typical of spongiotrophoblast but not of trophoblast giant cells [18]. The developmental origin of these cells is not entirely clear, though it is likely that they represent a specialized subtype of spongiotrophoblast cell [18].

Syncytiotrophoblast cells form the nutrient transport surface within the labyrinth layer of the rodent placenta. They arise from the fusion of trophoblast cells that have left the cell cycle [8] and, as a result, syncytiotrophoblast cells contain multiple diploid nuclei. Syncytiotrophoblast differentiation does not begin until after attachment of the allantois to the chorion at embryonic day 8.5 implying that signals from the allantois may provide a signal to initiate the process. Indeed, whereas trophoblast stem cells readily differentiate into trophoblast giant cells in culture after withdrawal of FGF4 from the culture medium, less than 5% of cells differentiate into syncytiotrophoblast [7].

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Molecular mechanisms regulating differentiation of alternative trophoblast cell subtypes in mice 

Through gene knockout and transgenic studies in mice, as well as in vitro experiments in which genes have been mis-expressed, we now have a fairly long list of the genes/proteins that are important for development of the placenta. One of the important conclusions to emerge from these studies is that differentiation of alternative trophoblast cell subtypes is regulated by distinct molecular mechanisms (Table 1). In most cases, however, the individual genes have not been put into complete molecular pathways and in only a few cases do we have a fairly complete understanding of the overall molecular mechanisms.

Trophoblast stem cells 

Trophoblast stem cells are induced to proliferate and maintain their stem cell phenotype through the actions of FGF4 which activates signaling through the Fgfr2 receptor [4]. The identification of FGF4 as a critical factor was based on the findings that mutations in both the Fgf4 gene, which is expressed by embryonic ectoderm [21], [22], or the FGF receptor gene Fgfr2, which is expressed in trophectoderm [23], result in failure of trophoblast proliferation. The TGFβ related growth factor Nodal is also required to maintain trophoblast stem cell fate by cooperating with FGF signaling [24]. FGF signaling regulates the expression of the homeobox transcription factor genes Cdx2 [25] and Eomes [26] which are in turn required for maintenance of TS cell fate. The Err2 [27], [28] and AP-γ [29] transcription factor genes are also required for maintenance of the trophoblast stem cell fate and are regulated by FGF signaling. However, they appear to be required at a slightly later stage and null mutants arrest at a slightly later time than the Cdx2 and Eomes mutants.

Spongiotrophoblast and trophoblast giant cells 

Trophoblast giant cell differentiation is actively suppressed by FGF/Nodal signaling in trophoblast stem cells as withdrawal of these factors is sufficient to promote giant cell differentiation at a high rate [7]. While giant cell differentiation appears to be a ‘default pathway’ of trophoblast differentiation, it is regulated by the activity of a series of basic helix-loop-helix (bHLH) transcription factors. The Mash2 factor appears to suppress giant cell differentiation [12], [30], [31] and is able to maintain the proliferation of trophoblast cells in an FGF4-independent manner, albeit transiently [7]. Loss of Mash2 results in premature loss of the ectoplacental cone/spongiotrophoblast and an increase in trophoblast giant cell differentiation [32], [33], [34]. In contrast to Mash2, the Hand1 and Stra13 bHLH transcription factors promote giant cell differentiation and, when ectopically expressed in trophoblast stem cells, are sufficient to promote giant cell differentiation even if FGF4 is still present. This implies that suppressing Hand1 and Stra13 expression and/or activity in the trophoblast stem cell compartment is essential for normal placental development. The factors that regulate Hand1 gene expression are unknown at present. However, phosphorylation of the Hand1 protein can alter its transcriptional activity [35]. Stra13 is a retinoic acid-inducible bHLH transcription factor gene whose expression is induced during giant cell differentiation [7], and indeed retinoic acid treatment of trophoblast stem cells promotes a rapid arrest of cell proliferation and giant cell differentiation [36] similar to the effect of Stra13 over-expression [7]. While bHLH factors form dimers in general in order to bind DNA, the Hand1 and Stra13 proteins do not appear to interact directly [7].

In addition to cell intrinsic mechanisms, differentiation of spongiotrophoblast and giant cells is regulated by several extrinsic factors also. Tissue oxygen levels regulate the proliferation and differentiation of human trophoblast cells [37], [38]. Likewise in mice, mutation of the Arnt gene, which encodes a component of the hypoxia-inducible transcription factor Hif1, results in placental defects in which the spongiotrophoblast layer is diminished and giant cell numbers are increased [39]. Leukemia inhibitory factor (Lif) signaling also regulates trophoblast giant cell differentiation. Lif receptor mutant mice have late gestation placental defects [40], though not obviously specific to trophoblast giant cells. However, mutation of the Socs3 gene, which encodes a signaling adaptor protein that quenches signaling downstream of specific cytokine receptor including for Lif, results in increased trophoblast giant cell differentiation at the expense of being able to form a normal labyrinth layer [41]. This Socs3 mutant phenotype is suppressed when the Lif receptor is also mutated indicating that Lif over-stimulation is the real problem [41].

While the formation and maintenance of trophoblast giant and spongiotrophoblast cells is well understood at a molecular level, the factors that regulate their specialization into the invasive endovascular giant cell and interstitial glycogen trophoblast cell subtypes, respectively, are largely unknown. The only insights that we have at present are that the number of glycogen trophoblast cells is altered in Igf2 [42] and p57Kip2 [43] mutant mice. One issue, however, is that these cell populations have only recently been studied in much detail [44] and it is possible that some phenotypes have been overlooked in previously published studies.

The functions of the Mash2, Hand1 and Stra13 genes in regulating trophoblast differentiation in mice are likely conserved in other species as well, at least based on gene expression studies. The human MASH2 (HASH2), HAND1 and STRA13 genes are all expressed in early trophoblast derivatives. HASH2 transcripts have been detected in first trimester cytotrophoblast cells [45], [46]. HAND1 mRNA and protein expression has been detected in the trophectoderm of blastocysts [47], [48], but not in villous tissue or cytotrophoblast cells isolated from villous tissue [46], [47], [48]. Whether human HAND1 is expressed in trophoblast cells that invade the placental bed is not clear. Hand1 expression has also been detected in the placentas of sheep, cattle and horses [49]. STRA13 mRNA expression has been detected in both human placental tissue and in isolated cytotrophoblast cells that are differentiated into extravillous-like cells in vitro [46].

Syncytiotrophoblast 

The differentiation of syncytiotrophoblast is initiated and controlled by the activity of the Gcm1 transcription factor. Gcm1 mRNA expression occurs in small clusters of cells within the chorion layer as early as embryonic day 7.5, a layer that is otherwise comprised of trophoblast stem cells [50], [51]. The sites of expression later coincide with sites in the chorion where differentiation and villous morphogenesis begin [50]. In Gcm1 mutant mice, syncytiotrophoblast cells fail to form and villous morphogenesis is not initiated [50]. At a cellular level, Gcm1 is sufficient to promote differentiation of trophoblast stem cells towards the syncytiotrophoblast fate as ectopic expression is sufficient to force them out of the cell cycle, and to block their ability to differentiate into trophoblast giant cells [7]. In humans, GCM1 mRNA and protein are expressed in restricted clusters of villous cytotrophoblast cells reminiscent of the pattern in mice [52]. Consistent with a role in human syncytiotrophoblast differentiation, GCM1 can directly activate transcription of the human Syncytin gene [53], a gene encoding a cell surface, fusogenic protein [54].

As with the other trophoblast cell subtypes, intercellular signaling plays a critical role in syncytiotrophoblast differentiation and branching of the chorionic villi (for a more detailed review see [3]). The first requirement for signaling at the chorioallantoic interface is that while Gcm1 expression in mice appears in the chorion trophoblast cells prior to allantoic attachment, the maintenance of expression is dependent on signals from the allantois [17], [55]. The nature of the signal is unknown. However, it is clear that several signaling systems regulate the subsequent steps during branching morphogenesis of the chorioallantoic interface including Wnt/Fzd, FGF/Fgfr, EGF/Egfr and HGF/Met (Table 1).

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Conclusions 

Our understanding of placental development and of the molecules that regulate it has improved dramatically in the last decade. These studies have revealed several general conclusions. First, it is clear that development of the placenta occurs by progression through stereotypical steps. Second, we now know of several key molecular regulators underlying each step. This allows us to piece together the more complete picture through subsequent studies of identifying the upstream and downstream genes. Third, human homologues for several of the key mouse genes have been identified and it will be important to assess whether mis-expression of these genes is associated with human placental pathologies that affect specific cell types. So far there is already one study associating reduced expression of GCM1 with preeclampsia [56]. Fourth, in mice it appears that FGF-dependent, multi-potent trophoblast stem cells likely do not persist throughout gestation. This likely has important implications for investigators who are trying to derive trophoblast stem cell lines from humans and other species. Indeed, the mouse studies imply that much of the growth of the placenta after implantation is not due to trophoblast stem cells, but perhaps rather due to layer-specific progenitors. More work is needed in this area. Finally, normal development of several cell types in the placenta includes several non-cell autonomous mechanisms in which paracrine factors within the placenta itself and potentially also from the fetus and mother can alter the basic developmental program. Given this, it seems likely that some of what appear to be developmental defects in placentas may only be a secondary manifestation of a primary problem elsewhere.

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Acknowledgments 

I want to sincerely thank a long line of talented people who have worked in my lab as well as key collaborators who have contributed to my work on placental development over the last 10 years including Lee Adamson, Fran Allen, Lynn Anson-Cartwright, Tyler Davies, Kerri Dawson, Susan Fisher, Amanda Fortier, Colleen Geary, Naka Hattori, Myriam Hemberger, Martha Hughes, Patricia Hunter, Yong Lu, John Kingdom, Haruo Nakano, Hiroki Nakayama, David Natale, Paul Riley, Ian Scott, David Simmons, Maja Starovic, Lin Su, Erica Watson and Hiddy Yamamoto. Work from my laboratory has been funded by operating grants from the Canadian Institutes of Health Research (CIHR) and an establishment grant from the Alberta Heritage Foundation for Medical Research (AHFMR). JCC is a CIHR Investigator and AHFMR Senior Scholar.

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PII: S0143-4004(05)00047-0

doi:10.1016/j.placenta.2005.01.015

Placenta
Volume 26, Supplement , Pages S3-S9, April 2005

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