Mapping the temporal and spatial dynamics of the human endometrium in vivo and in vitro

The endometrium, the mucosal lining of the uterus, undergoes dynamic changes throughout the menstrual cycle in response to ovarian hormones. We have generated single-cell and spatial reference maps of the human uterus and 3D endometrial organoid cultures. We dissect the signalling pathways that determine cell fate of the epithelial lineages in the lumenal and glandular microenvironments. Our benchmark of the endometrial organoids highlights common pathways regulating the differentiation of secretory and ciliated lineage in vivo and in vitro. We show in vitro that downregulation of WNT or NOTCH pathways increases the differentiation efficiency along the secretory and ciliated lineages, respectively. These mechanistic insights provide a platform for future development of treatments for a range of common endometrial disorders including endometriosis and carcinoma.

[1]  G. Watts.  From vision to reality. , 1991, Nursing.

[2]  E. Jauniaux,et al.  Endometrial glands as a source of nutrients, growth factors and cytokines during the first trimester of human pregnancy: A morphological and immunohistochemical study , 2004, Reproductive biology and endocrinology : RB&E.

[3]  L. Giudice,et al.  Dickkopf-1, an inhibitor of Wnt signaling, is regulated by progesterone in human endometrial stromal cells. , 2006, The Journal of clinical endocrinology and metabolism.

[4]  R. Martin.  The evolution of human reproduction: a primatological perspective. , 2007, American journal of physical anthropology.

[5]  J. Brosens,et al.  A role for menstruation in preconditioning the uterus for successful pregnancy. , 2009, American journal of obstetrics and gynecology.

[6]  H. V. van Doorn,et al.  Progesterone Inhibition of Wnt/β-Catenin Signaling in Normal Endometrium and Endometrial Cancer , 2009, Clinical Cancer Research.

[7]  J. Brosens,et al.  Deregulation of the serum- and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure , 2011, Nature Medicine.

[8]  G. Wagner,et al.  The evolution of menstruation: a new model for genetic assimilation: explaining molecular origins of maternal responses to fetal invasiveness. , 2012, BioEssays : news and reviews in molecular, cellular and developmental biology.

[9]  H. Mollenkopf,et al.  The Notch and Wnt pathways regulate stemness and differentiation in human fallopian tube organoids , 2015, Nature Communications.

[10]  Patrik L. Ståhl,et al.  Visualization and analysis of gene expression in tissue sections by spatial transcriptomics , 2016, Science.

[11]  Lars E. Borm,et al.  Molecular Diversity of Midbrain Development in Mouse, Human, and Stem Cells , 2016, Cell.

[12]  Hui Zhao,et al.  Five endometrial cancer risk loci identified through genome-wide association analysis , 2016, Nature Genetics.

[13]  Dirk Timmerman,et al.  Development of organoids from mouse and human endometrium showing endometrial epithelium physiology and long-term expandability , 2017, Development.

[14]  C. Simón,et al.  Defective decidualization during and after severe preeclampsia reveals a possible maternal contribution to the etiology , 2017, Proceedings of the National Academy of Sciences.

[15]  Eric C. Huang,et al.  The Use of Endometrial Cancer Patient–Derived Organoid Culture for Drug Sensitivity Testing Is Feasible , 2017, International Journal of Gynecologic Cancer.

[16]  Bon-Kyoung Koo,et al.  Long-term, hormone-responsive organoid cultures of human endometrium in a chemically-defined medium , 2017, Nature Cell Biology.

[17]  Michael J. T. Stubbington,et al.  The Human Cell Atlas: from vision to reality , 2017, Nature.

[18]  Kerstin B. Meyer,et al.  Single-cell reconstruction of the early maternal–fetal interface in humans , 2018, Nature.

[19]  J. Sáez-Rodríguez,et al.  Benchmark and integration of resources for the estimation of human transcription factor activities , 2018, bioRxiv.

[20]  R. Mägi,et al.  GWAS meta-analysis highlights the hypothalamic-pituitary-gonadal axis (HPG axis) in the genetic regulation of menstrual cycle length , 2018, bioRxiv.

[21]  Peter Kraft,et al.  Identification of nine new susceptibility loci for endometrial cancer , 2018, Nature Communications.

[22]  H. Stefánsson,et al.  Large-scale genome-wide association meta-analysis of endometriosis reveals 13 novel loci and genetically-associated comorbidity with other pain conditions , 2018, bioRxiv.

[23]  K. Conrad,et al.  Evidence for shared molecular pathways of dysregulated decidualization in preeclampsia and endometrial disorders revealed by microarray data integration , 2019, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[24]  Richard Bonneau,et al.  High-definition spatial transcriptomics for in situ tissue profiling , 2019, Nature Methods.

[25]  T. Spencer,et al.  Self-renewing endometrial epithelial organoids of the human uterus , 2019, Proceedings of the National Academy of Sciences.

[26]  D. Timmerman,et al.  Patient-derived organoids from endometrial disease capture clinical heterogeneity and are amenable to drug screening , 2019, Nature Cell Biology.

[27]  Evan Z. Macosko,et al.  Slide-seq: A scalable technology for measuring genome-wide expression at high spatial resolution , 2019, Science.

[28]  C. Fiala,et al.  Oestrogen signalling drives ciliogenesis in human endometrial organoids. , 2019, Endocrinology.

[29]  Rafael A. Irizarry,et al.  Robust decomposition of cell type mixtures in spatial transcriptomics , 2020, Nature Biotechnology.

[30]  Omer Ali Bayraktar,et al.  Automation of Multiplexed RNAscope Single-Molecule Fluorescent In Situ Hybridization and Immunohistochemistry for Spatial Tissue Mapping. , 2020, Methods in molecular biology.

[31]  Giovanni Coppola,et al.  Astrocyte layers in the mammalian cerebral cortex revealed by a single-cell in situ transcriptomic map , 2020, Nature Neuroscience.

[32]  Tong Li,et al.  Comprehensive mapping of tissue cell architecture via integrated single cell and spatial transcriptomics , 2020, bioRxiv.

[33]  Mirjana Efremova,et al.  CellPhoneDB: inferring cell–cell communication from combined expression of multi-subunit ligand–receptor complexes , 2020, Nature Protocols.

[34]  Kieran R. Campbell,et al.  Single cell transcriptomes of normal endometrial derived organoids uncover novel cell type markers and cryptic differentiation of primary tumours , 2020, The Journal of pathology.

[35]  Evan Z. Macosko,et al.  Highly sensitive spatial transcriptomics at near-cellular resolution with Slide-seqV2 , 2020, Nature Biotechnology.

[36]  L. Giudice,et al.  Steroid hormones regulate genome-wide epigenetic programming and gene transcription in human endometrial cells with marked aberrancies in endometriosis , 2020, PLoS genetics.

[37]  Alyssa J. Miller,et al.  In Vitro and In Vivo Development of the Human Airway at Single-Cell Resolution. , 2020, Developmental cell.

[38]  Alistair R W Williams,et al.  Physiology of the endometrium and regulation of menstruation. , 2020, Physiological reviews.

[39]  Joseph Bergenstråhle,et al.  Single-cell and spatial transcriptomics enables probabilistic inference of cell type topography , 2020, Communications Biology.

[40]  S. Quake,et al.  Single-cell transcriptomic atlas of the human endometrium during the menstrual cycle , 2020, Nature Medicine.