Modeling preeclampsia using human induced pluripotent stem cells

Abstract

Preeclampsia (PE) is a pregnancy-specific hypertensive disorder, affecting up to 10% of pregnancies worldwide. The primary etiology is considered to be abnormal development and function of placental cells called trophoblasts. We previously developed a two-step protocol for differentiation of human pluripotent stem cells, first into cytotrophoblast (CTB) progenitor-like cells, and then into both syncytiotrophoblast (STB)- and extravillous trophoblast (EVT)-like cells, and showed that it can model both normal and abnormal trophoblast differentiation. We have now applied this protocol to induced pluripotent stem cells (iPSC) derived from placentas of pregnancies with or without PE. While there were no differences in CTB induction or EVT formation, PE-iPSC-derived trophoblast showed a defect in syncytialization, as well as a blunted response to hypoxia. RNAseq analysis showed defects in STB formation and response to hypoxia; however, DNA methylation changes were minimal, corresponding only to changes in response to hypoxia. Overall, PE-iPSC recapitulated multiple defects associated with placental dysfunction, including a lack of response to decreased oxygen tension. This emphasizes the importance of the maternal microenvironment in normal placentation, and highlights potential pathways that can be targeted for diagnosis or therapy, while absence of marked DNA methylation changes suggests that other regulatory mechanisms mediate these alterations.

Omics Approaches to Study Formation and Function of Human Placental Syncytiotrophoblast

“…For instance, hiPSCs generated from umbilical cords and exposed to culture conditions that promote trophoblast formation show stark differences in the transcriptome (as determined by RNA-seq) if the cords are collected from pregnancies with early onset preeclampsia. In particular, expression of genes associated with O 2 responsiveness and STB formation is impaired in cells from preeclampsia, without marked changes in the DNA methylome ( Sheridan et al, 2019 ; Horii et al, 2021 ).…”

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

“…Since hiPSCs can be used as starting cells in addition to preexisting hESCs, generation of patient-specific hTSLCs is feasible by sequential establishment of hiPSCs from patients' somatic cells followed by conversion of the hiPSCs to hTSLCs. In turn, the approaches using trisomy 21 hPSCs and PE-derived hiPSCs successfully model trophoblast differentiation defects (Horii et al, 2016(Horii et al, , 2021. Since many hiPSC lines have been established or can be established from human patients with various symptoms, similar approaches can be employed to understand previously unknown links between human diseases and the events during early placentation.…”

The Role of the 3Rs for Understanding and Modeling the Human Placenta

“…Horii et al have published reproducible models for differentiating human iPSCs into trophoblasts [ 60 ]. More recently, iPSC-derived trophoblasts have been used to study preeclampsia (PE), demonstrating changes in the syncytialization process, as well as differential gene expression in response to hypoxia [ 61 ]. This study underpins the utility of human iPSCs in studying placental disorders and gaining a better understanding of the pathways involved.…”

“…Modeling the transfer, and more generally the absorption, distribution, metabolism and excretion (ADME), of xenobiotics from the mother to fetus through the placenta has become one of the efforts in the DART field. To this end, different in silico approaches have been developed, such as statistics-based QSAR analysis and PBPK models [ 61 ].…”