In this dissertation 1 use decidual stromal cells — a novel cell type that originated in the stem lineage of eutherian (placental) mammals - as a model to understand how and why new cells types originate in evolution. Decidual stromal cells differentiate from endometrial stromal fibroblasts during pregnancy in many eutherian mammals and are shed at the time of birth. They perform a variety of functions throughout pregnancy in human and mouse.
In the first chapter. 1 compare the life cycle of decidual stromal cells in major eutherian lineages and argue that their ancestral function was early in pregnancy, at the time of embryo implantation. Their functions later in pregnancy were likely acquired secondarily in some lineages. Embryo implantation, like decidual stromal cells, is a unique feature of eutherian pregnancy. Marsupials, The sister lineage of eutherians, are viviparous but the fetal-maternal attachment is limited to a brief period without implantation. In the second chapter, by transcriptomic comparison of implantation in eutherians and embryo attachment in opossum, a marsupial, I show that embryo implantation evolved through modification of an ancestral inflammatory response. The therian (marsupial and eutherian) ancestral mucosal inflammatory response induced by embryo attachment was modified in eutherian mammals such that one of its modules, viz. recruitment of neutrophils through IL17A signaling, was suppressed. Based on the findings in chapter 1, I hypothesized that the origin of decidual stromal cells brought about this suppression. An in vitro test for the effect of human decidual stromal cells on the differentiation of Th17 cells, the producers of IL17A, supported this hypothesis. These results show that the origin of decidual stromal cells enabled the evolution of embryo implantation and therefore paved the way for the evolution of prolonged eutherian pregnancy.
In the third and fourth chapters, I study pregnancy in the eutherian lineages of Xenarthra and Afrotheria, and compare the findings with those in other well-studied eutherian lineages to better understand the context in which decidual stromal cells originated. First, I provide a histological description of the fetal-maternal interface of the nine-banded armadillo (Xenarthra) and show that its placenta is more invasive than it was thought to be. Then, 1 describe the immune response during post-implantation stage of pregnancy in nine-banded armadillo and lesser hedgehog tenrec (Afrotheria) using transcriptomes of the uterus. Post-implantation pregnancy in these lineages is dominated by a non-inflammatory immune response — similar to the situation in human and mouse, although the immune cell types participating in this response are different.
In the fifth chapter, I elucidate the gene regulatory changes that enabled the origin of decidual stromal cells in eutherian mammals. Identity of a cell type is maintained by a core gene regulatory network composed of transcription factors. In this chapter, I first reconstruct the core regulatory network induced during the differentiation of human decidual stromal cells using a combination of functional genomic data (gene expression by RNA-seq, open chromatin landscape by ATAC-seq) and measuring the effect of siRNA-mediated knockdowns of core transcription factors on each other. Then, to understand how this core regulatory network arose in evolution, I compare it with the gene regulatory changes induced in the opossum endometrial stromal fibroblasts upon treatment with decidualization stimuli. Opossum endometrial stromal fibroblasts cannot differentiate into decidual stromal cells, and can be used as a model for ancestral therian endometrial stromal fibroblasts. In response to decidualization stimuli, they activate many transcription factors typical of decidual stromal cells, but undergo stress-induced cell death instead, suggesting that the decidual stromal cell core regulatory network evolved through modification of an ancestral stress induced gene regulatory network.
|Advisor:||Wagner, Gunter P.|
|School Location:||United States -- Connecticut|
|Source:||DAI-B 80/07(E), Dissertation Abstracts International|
|Subjects:||Evolution and Development, Zoology, Immunology|
|Keywords:||Cell Type, Decidual, Embryo Implantation, Inflammation, Mammal, Pregnancy|
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