Placenta-Derived Organoids as an Evolutionary Model of the Maternal-Fetal Interface

Abstract

The placenta exhibits remarkable diversity across species containing distinct shapes, cellular layers, and the degree of maternal-fetal interdigitation. Despite this diversity of placental structure and cellular composition, the placenta has an evolutionarily conserved role as a protective barrier during mammalian pregnancy. While parallel evolution has altered the genetic composition of placentas across species, all eutherian placentas are comprised primarily of fetal-derived trophoblast cells. The trophoblast transcriptome among species remains largely unknown, owing at least in part to the lack of models that recapitulate the cellular composition of nonhuman placentas. Humans, rhesus macaques, and several bat species possess a hemochorial placenta, characterized by the direct contact of maternal blood and fetal tissues. In my dissertation work, I aimed to define the trophoblast gene expression signatures of rhesus macaques and Jamaican fruit bats and establish novel placental organoid model systems. To investigate these aims we derived, for the first time, rhesus macaque and Jamaican fruit bat (Jfb) placental organoid models. Multi-omic interrogation revealed that these organoids closely resembled the transcriptional profile of their tissues of origin. Utilizing our rhesus macaque placenta model, we found that rhesus trophoblast organoids (rTOs) recapitulate the multicellularity nature of the rhesus macaque placenta, including the differentiation of proliferating cytotrophoblasts into the multinucleated syncytiotrophoblast, and to extravillous trophoblast. Through high-throughput sequencing of Jamaican fruit bat placentas and our Jfb organoid model, we defined the bat trophoblast transcriptome. Comparative single-cell and single-nucleus RNA sequencing studies defined conserved and divergent trophoblast cell type-specific markers in both rhesus macaque and Jfb trophoblast cell lineages. Our findings underscore the power of organoid models in unraveling the intricacies of placental evolution across eutherian mammals, shedding light on fundamental aspects of reproductive biology.