Transcriptomic analysis of primate placentas and novel rhesus trophoblast cell lines informs investigations of human placentation

Jimi L. Rosenkrantz,Lucia Carbone,Shawn L. Chavez,Victoria H. J. Roberts,Jessica E. Gaffney

doi:10.1186/s12915-021-01056-7

Jimi L. Rosenkrantz, Lucia Carbone + Show 3 more

Open Access

https://doi.org/10.1186/s12915-021-01056-7

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Abstract

BackgroundProper placentation, including trophoblast differentiation and function, is essential for the health and well-being of both the mother and baby throughout pregnancy. Placental abnormalities that occur during the early stages of development are thought to contribute to preeclampsia and other placenta-related pregnancy complications. However, relatively little is known about these stages in humans due to obvious ethical and technical limitations. Rhesus macaques are considered an ideal surrogate for studying human placentation, but the unclear translatability of known human placental markers and lack of accessible rhesus trophoblast cell lines can impede the use of this animal model.ResultsHere, we performed a cross-species transcriptomic comparison of human and rhesus placenta and determined that while the majority of human placental marker genes (HPGs) were similarly expressed, 952 differentially expressed genes (DEGs) were identified between the two species. Functional enrichment analysis of the 447 human-upregulated DEGs, including ADAM12, ERVW-1, KISS1, LGALS13, PAPPA2, PGF, and SIGLEC6, revealed over-representation of genes implicated in preeclampsia and other pregnancy disorders. Additionally, to enable in vitro functional studies of early placentation, we generated and thoroughly characterized two highly pure first trimester telomerase (TERT) immortalized rhesus trophoblast cell lines (iRP-D26 and iRP-D28A) that retained crucial features of isolated primary trophoblasts.ConclusionsOverall, our findings help elucidate the molecular translatability between human and rhesus placenta and reveal notable expression differences in several HPGs and genes implicated in pregnancy complications that should be considered when using the rhesus animal model to study normal and pathological human placentation.

Highlights

Proper placentation, including trophoblast differentiation and function, is essential for the health and wellbeing of both the mother and baby throughout pregnancy
In order to make the RNA-seq gene expression data comparable across species (Additional file 2), we limited our comparison to human protein-coding genes with ENSE MBL-defined “high-confidence” “one2one” rhesus orthologs and differentially expressed genes (DEGs) were identified by intersecting the results of two complementary differential expression (DE) analyses (Additional file 1: Fig. S2A)
Over-representation analysis (ORA) demonstrated that genes associated with pregnancy disorders including, “preeclampsia”, “HELLP syndrome”, “Gestational trophoblastic tumor”, and “Eclampsia” were upregulated in human compared to rhesus placenta (Additional file 1: Fig. S5; Additional file 10). These results provide a comprehensive list of differentially expressed Human placental marker gene (HPG) between human and rhesus placenta that should be considered when studying certain aspects of placentation in rhesus, those that are associated with Extravillous trophoblast (EVT) invasion, preeclampsia, or other placenta-related diseases

Summary

Introduction

Proper placentation, including trophoblast differentiation and function, is essential for the health and wellbeing of both the mother and baby throughout pregnancy. Placental abnormalities that occur during the early stages of development are thought to contribute to preeclampsia and other placenta-related pregnancy complications. Proper trophoblast differentiation and function are essential for normal placentation and fetal development throughout gestation. Abnormal placentation is the primary defect associated with major pregnancy complications, such as preeclampsia, fetal growth restriction, recurrent miscarriage, and still-birth [1]. The ethical and technical limitations of studying early human development have confined many human placentation investigations to late gestational stages closer to term. Early human placental development, including the origin and cause(s) of the placental abnormalities underlying major pregnancy complications, are poorly understood

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