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Role of Hypoxia in Regulating Stromal-Epithelial Communication during Pregnancy

妊娠期缺氧在调节间质-上皮通讯中的作用

基本信息

批准号：
10406940
负责人：
MILAN K BAGCHI
金额：
$ 30.78万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-13 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10406940
关键词：
Address Amino Acids Animal Model Biology Cell Communication Cell Culture Techniques Cell secretion Cells Data Decidual Cell Reactions Defect Distant Down-Regulation Endometrial Endometrial Stromal Cell Endometrium Environment Epithelial Epithelial Cells Epithelial-Stromal Communication Exhibits Genomics Goals Human Hypoxia Hypoxia Inducible Factor In Vitro Infertility Link Mediating Messenger RNA Metabolic MicroRNAs Modeling Molecular Mus Paracrine Communication Pathway interactions Pregnancy Process Proteins Proteomics Regulation Reporting Research Role Signal Transduction Signaling Molecule Stromal Cells Supporting Cell Testing Time Tissues Transcript Uterus bHLH-PAS factor HLF blastocyst cell type early pregnancy exosome experimental study extracellular vesicles failure Implantation fetal implantation in vivo insight intercellular communication metabolomics microvesicles mouse model natural Blastocyst Implantation novel paracrine rab GTP-Binding Proteins response trafficking transcription factor

项目摘要

Implantation is initiated when the blastocyst attaches to the uterine luminal epithelium and subsequently penetrates into the underlying stroma to firmly embed into the endometrium. While many aspects of implantation remain unclear, emerging evidence indicates that intercellular communication between endometrial epithelial and stromal cells is vital for successful establishment of pregnancy. The paracrine signals that mediate this crosstalk remain poorly understood. Our recent studies revealed that the transcription factor, hypoxia-‐inducible factor 2 alpha (HIF2α), is induced selectively in endometrial stromal cells subjacent to the luminal epithelium at the time of implantation. This finding is significant because it is known for a long time that the maternal environment during implantation is hypoxic. To address the mechanisms of maternal adaptation to hypoxia during implantation, we generated Hif2αd/d mice that conditionally lack HIF2α in the endometrium. In these mice, the blastocysts are closely apposed to the uterine epithelium but fail to sustain firm attachment to it, resulting in implantation failure. The uterine stromal cells of Hif2αd/d mice exhibited downregulation of metabolic factors, such as lactate and a subset of amino acids, and a distinct set of Rab GTPases that regulate secretion of extracellular vesicles (EVs), including microvesicles and exosomes. The EVs are known to mediate a novel mechanism of cell-cell communication. That hypoxia promotes EV secretion by certain cells support the concept that HIF2α-driven EV secretion by the endometrial stromal cells represents a critical adaptive response that promotes intercellular communication during implantation. In the proposed study, we will employ the Hif2αd/d mouse model to test the hypothesis that HIF2α regulates a novel paracrine signaling mechanism under the hypoxic conditions of early pregnancy by controlling EV trafficking in the maternal tissue and that it directs transfer of key signaling molecules and metabolites from the stromal to luminal epithelial cells to influence epithelial functionality during implantation. We have proposed three specific aims to test this hypothesis. In Aim 1, we will investigate HIF2α-mediated EV trafficking in endometrial stromal cells and identify the resident molecular cargo in EVs. In Aim 2, we will investigate the effects of EVs and metabolic factors secreted from endometrial stromal cells on the functionality of epithelial cells. In Aim 3, we will investigate the role of HIF2α in regulating the secretory function of human endometrial stromal cells. A multi-pronged approach, utilizing a combination of (i) a unique animal model harboring a specific defect in adaptive response (ii) functional analyses using mouse and human primary endometrial cells, and (iii) genomic and proteomic analyses to understand cell-to-cell trafficking mechanisms, will enable us to provide answers to important unresolved questions regarding the impact of hypoxia on stromal-epithelial communication controlling endometrial function during early pregnancy.

当囊胚附着于子宫腔上皮并随后着床时开始着床