Cell atlas of human uterus

Abstract

The human uterus is a highly dynamic tissue that undergoes repeated damage repair and regeneration during the menstrual cycle, which make it ideal model to study tissue regeneration and pathological process. Stem/progenitors were speculated to be involved in the regeneration of endometrial epithelial and pathogenesis of endometriosis. But the identity, microenvironment and regulatory mechanisms of the uterus epithelial stem/progenitors in vivo remain unclear. Here, we dissected the cell heterogeneities of the full-thickness human uterus epithelial cells (11 clusters), stroma cells (6 clusters), endothelial cells (5 clusters), smooth muscle cells (2 clusters), myofibroblasts (2 clusters) and immune cells (6 clusters) from 2735 single cell by single cell RNA-seq. Further analysis identified a unique ciliated epithelial cell cluster showing characteristics of stem/progenitors with properties of epithelial-mesenchymal transition (EMT) that mainly localized in the upper functionalis of the endometrium. Ordering the cell subpopulations along the pseudo-space revealed cell clusters possess cellular states of stress, inflammation and apoptosis in the upper functionalis cellular ecosystem of the endometrium. Connectivity map between the human uterus subpopulations revealed potential inflammatory (cytokines and chemokines) and developmental (WNT, FGF, VEGF) signals within the upper functionalis cellular ecosystem of the endometrium, especially from other epithelial clusters, regulating cell plasticity of the EMT-epithelial clusters. This study reconstructed the heterogeneities, space-specific distribution and connectivity map of human uterus atlas, which would provide insight in the regeneration of uterus endometria and reference for the pathogenesis of uterus.

Cells expressing PAX8 are the main source of homeostatic regeneration of adult mouse endometrial epithelium and give rise to serous endometrial carcinoma

“…In humans, such cells are commonly thought to be located in the basalis segment of the endometrial glands ( Nguyen et al, 2012 ; Patterson and Pru, 2013 ; Valentijn et al, 2013 ). However, according to a recent single-cell transcriptome study of secretory-phase human endometrium, cells showing characteristics of stem/progenitor cells are located in the upper region of the functionalis ( Wu et al, 2018 preprint). At the same time, several studies have suggested that endometrial epithelium can be regenerated by stem cells of either stromal/mesenchymal ( Huang et al, 2012 ; Patterson et al, 2013 ) or bone marrow cell origin ( Bratincsak et al, 2007 ; Du and Taylor, 2007 ; Ikoma et al, 2009 ; Mints et al, 2008 ; Taylor, 2004 ).…”

Identification of the lymphangioleiomyomatosis cell and its uterine origin

“…An understanding of the source of cells that infiltrate the lung has remained elusive, however, as have the mechanisms of tumorigenesis, metastasis, invasion, and cystic remodeling Krymskaya and McCormack, 2017;McCormack et al, 2012). In the present study, scRNA-seq analysis of LAM lesions identified unique, non-pulmonary mesenchymal cells, which we termed LAM CORE cells, that share a high degree of transcriptomic similarity to the LAM CORE cells in uterus of an S-LAM patient and with myometrial and stromal cells (express high level of MME, FN1, COL3A1, HOXA10) from normal human and mouse uteri (Mucenski et al, 2019;Wu et al, 2018) . A prominent neural crest signature was also identified in pulmonary and uterine LAM CORE cells and in normal uterus.…”

“…In addition, uterine myocyte, epithelial, immune, endothelial and several stromal cell subtypes were identified (Figure 6a; Figure S15). Endometrial epithelia (expressing high level of KRT8, KRT18, EPCAM, CLDN3) and stromal cells (expressing high level of MME, FN1, COL3A1, HOXA10, VIM ) were defined based on the gene markers from the human and mouse uterus altas (Mucenski et al, 2019;Wu et al, 2018) . Hierarchical clustering of major cell types from LAM lung and LAM uterus demonstrated close correlation of LAM CORE cells from both tissues (Figure 6b).…”

Northstar enables automatic classification of known and novel cell types from tumor samples

“…The widespread adoption of single-cell transcriptomics has led to a growing body of “atlas” datasets describing tissue heterogeneity with unprecedented resolution 1 . As atlas data across species 2 , tissues 3 – 7 , development 8 – 10 , and aging 4 , 11 are being amassed, a number of algorithms have been proposed to compare new data against reference data sets. The basic concept behind these efforts is to emulate the Basic Local Alignment Search Tool (BLAST) for nucleic acid and protein sequence matching 12 , except in gene expression space.…”