Integrating High-Throughput Approaches and in vitro Human Trophoblast Models to Decipher Mechanisms Underlying Early Human Placenta Development

Abstract

The placenta is a temporary but pivotal organ for human pregnancy. It consists of multiple specialized trophoblast cell types originating from the trophectoderm of the blastocyst stage of the embryo. While impaired trophoblast differentiation results in pregnancy disorders affecting both mother and fetus, the molecular mechanisms underlying early human placenta development have been poorly understood, partially due to the limited access to developing human placentas and the lack of suitable human in vitro trophoblast models. Recent success in establishing human trophoblast stem cells and other human in vitro trophoblast models with their differentiation protocols into more specialized cell types, such as syncytiotrophoblast and extravillous trophoblast, has provided a tremendous opportunity to understand early human placenta development. Unfortunately, while high-throughput research methods and omics tools have addressed numerous molecular-level questions in various research fields, these tools have not been widely applied to the above-mentioned human trophoblast models. This review aims to provide an overview of various omics approaches that can be utilized in the study of human in vitro placenta models by exemplifying some important lessons obtained from omics studies of mouse model systems and introducing recently available human in vitro trophoblast model systems. We also highlight some key unknown questions that might be addressed by such techniques. Integrating high-throughput omics approaches and human in vitro model systems will facilitate our understanding of molecular-level regulatory mechanisms underlying early human placenta development as well as placenta-associated complications.

Super-enhancer-associated transcription factors collaboratively regulate trophoblast-active gene expression programs in human trophoblast stem cells

“…We identified that the five TFs (FOS, GATA2, MAFK, TEAD4 and TFAP2C) are also key regulators in mouse TSCs. Since human and mouse placentas have common and distinct characteristics in structure and gene expression patterns ( 17–19 ), we compared the binding sites and the target genes of the five TFs between human and mouse TSCs to dissect the shared and unique functions of these TFs in each species. These TSC-pivotal TFs prefer to bind distal enhancers regardless of their origins (Figure 6A ).…”

“…Importantly, it is largely unknown to what extent key human TSC-active TFs share their targets and exert conserved or distinct functions between humans and mice. Even though human and mouse placentas play equivalent roles and have numerous functionally conserved genes, there are some discrepancies in their morphology, cellular organization and gene expression patterns ( 17–19 ). Considering these apparent differences, it is necessary to identify human TSC-specific enhancers, TFs and their targets in order to comprehensively understand the regulatory mechanisms underlying human placental development.…”

Multiomics Studies Investigating Recurrent Pregnancy Loss: An Effective Tool for Mechanism Exploration

“…During this process, the trophectoderm cells of the blastocyst differentiate into the extravillous trophoblast and the villous trophoblast (comprising the cytotrophoblast and syncytiotrophoblast), which form the major cell lineages of the placenta. Cytotrophoblasts can further differentiate into invasive extravillous trophoblasts ( 32 ). The proliferation and invasion of extravillous trophoblast cells into the decidua and the uterine myometrium are necessary for uterine spiral artery remodeling and establishing maternal-fetal circulation ( 33 ).…”

Stem Cell-Based Trophoblast Models to Unravel the Genetic Causes of Human Miscarriages

“…Although both mouse and human placentae are discoid in shape with a hemochorial gas–nutrient exchange, mouse model systems do not completely mimic the human placenta, with essential differences including gestational length, litter size, embryo architecture, trophoblast cell types, and tissue organization [ 76 ]. Furthermore, human and mouse TE establishment differ in terms of the expression of some crucial genes during the early development of the two species, as surveyed by [ 77 , 78 , 79 , 80 , 81 , 82 ]. Efforts to obtain human trophoblast stem cells (hTSCs) from blastocysts using culture conditions analogous to murine TSCs have not been successful [ 83 ].…”