The Evolution of Cell and Tissue Identity at the Maternal-Fetal Interface
Date of Award
Spring 2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Ecology and Evolutionary Biology
First Advisor
Wagner, Gunter
Abstract
One of the most compelling scientific questions is how complex phenotypes originate. The main driving question of my thesis is, how does a complex evolutionary novelty, the mammalian decidual-placental interface, comprised of highly interdependent and themselves novel interacting parts, come to be pieced together over the course of evolution? In this Dissertation, I developed and applied an approach to understand the evolutionary origin and subsequent diversification of cell-cell interaction systems (tissues) using the uterine decidua of placental mammals as my model system. The uterine decidua is perhaps the most recently evolved tissue type in the human body – a transient, pregnancy-specific transformed replacement of the endometrium comprising a constellation of specialized cells, including modified fibroblasts known as decidual stromal cells (DSC), macrophages (dMΦ), and natural killer (dNK) cells. Together, these cells function to orchestrate embryo implantation and regulate the immunological milieu of the uterus. Over the past few decades, the cardinal cell type of the decidua, the decidual stromal cell, has emerged as a paradigmatic evolutionary novelty for which the mechanistic underpinnings of its origin are known in increasing detail. I present evidence that the differentiation of the decidual stromal cell evolved from a modified response to prostaglandin E2 and progesterone, and that differentiating DSC pass through an intermediate state resembling the contractile myofibroblast which may recapitulate their evolutionary history. Using in vitro cell biology of endometrial fibroblasts, I identify a novel cis-regulatory genetic switch, where progesterone induces a switch from PTGER4 to PTGER2 as the dominant prostaglandin E2 receptor. Only PTGER2 is able to activate the downstream signaling cascade (cAMP/PKA) essential for decidual cell differentiation, unlike PTGER4. This mechanism is conserved in species spanning the Boreoeutheria clade of placental mammals but absent in the opossum, a marsupial. These findings suggest that the decidual stromal cell type arose, in part, by evolutionary changes in competence, i.e. changes in the plastic reactions to the cell type’s intra-organismal environment. Its origin allowed the decidual cell to integrate two sources of information – one indicating the temporal stage of the reproductive cycle, progesterone, and the other indicating contact with the fetus, prostaglandin E2. This created a competence for the decidual stroma to respond in an atypical way to inflammatory signaling than other fibroblasts of the body. Additionally, I use an extended analysis of the single-cell transcriptomic time course to capture gene expression dynamics during human decidual cell differentiation, and find that cells pass through an intermediate transition state where they express characteristic myofibroblast genes and become contractile. Myofibroblasts are part of the wound healing reaction and contract to close a lesion. This finding adds a new perspective to a long-supposed homology between decidual formation and the tissue-invariant process of fibroblast activation. In this light, the decidual response joins a growing number of examples of plastic responses forming the basis for the evolution of novel traits. In my last empirical project, I take the approach that the decidua is a novel tissue type, or collective of interacting cell types, and ask how the cells within this system have co-evolved with each other and with their counterpart during pregnancy, the fetal placenta. I trace the evolution of cell types and cell-cell signaling interactions in the fetal-maternal interface of species key events in the therian mammal phylogeny: the gray short-tailed opossum, a nondeciduate marsupial with noninvasive placentation, the Malagasy tailless tenrec, an afrotherian mammal with an ancestrally hemochorial placenta, and three members of Euarchontoglires with different patterns and degrees of placental invasiveness – the mouse, and the deeply invasive guinea pig and human. I find that Tenrec possesses a putatively natural killer cell-recruiting decidual cell resembling the recently discovered “Type II decidua” of the human, suggesting that this “pre-decidual” cell type may have been the initial decidual cell state to evolve in Placentalia before the prolactin-producing endocrine decidua in rodents and humans. I use this multi-species single-cell transcriptomic atlas to resolve homologies within trophoblast cell types, which are traditionally named by morphological appearance, and show that highly-invasive trophoblast shares a common transcriptomic signature across eutherians. Lastly, I utilize these newly collected comparative data to test long-standing theoretical hypotheses on the dynamics of fetal-maternal interaction evolution. I identify a consistent pattern of disambiguation between fetal and maternal signaling repertoires, enhanced by the evolution of fetal- or maternal-specific paralogs of ligand families undergoing gene duplication. I show that cell types at the very front of the interface – invasive trophoblast and decidua – display less cell autonomy and greater integration into cell-cell signaling networks. Lastly, I apply a phylogenetic framework to reconstruct the co-evolutionary dynamics of ligand-receptor signaling. My dissertation ends with more conceptual/review articles penned at different times in the course of investigation, the first on maternal contributions to the evolution of invasive placentation, the second contextualizing the discovery of fetal production of inflammatory signals in the opossum, and finally a conclusion. The trajectory of my PhD, therefore, has proceeded from the evolutionary understanding of cell type to explore a higher level of organization.
Recommended Citation
Stadtmauer, Daniel Joseph, "The Evolution of Cell and Tissue Identity at the Maternal-Fetal Interface" (2024). Yale Graduate School of Arts and Sciences Dissertations. 1502.
https://elischolar.library.yale.edu/gsas_dissertations/1502
