Molecular signature of human endometrial stem/progenitor cells at the single cell level

  1. Harriet C. Fitzgerald
  2. Sally Mortlock
  3. Caitlin E. Filby
  4. Fiona L. Cousins
  5. Elizabeth Marquez-Garcia
  6. Katherine A. Wyatt
  7. Brett McKinnon
  8. Luk Rombauts
  9. Jim Tsaltas
  10. Grant W. Montgomery
  11. Caroline E Gargett
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Abstract

Human endometrium sheds and regenerates each month during the menstrual cycle. N-cadherin+(CDH2) glandular epithelial progenitors and SUSD2+MSC and their niches have been identified but their signaling interactions remain unknown. SSEA1+epithelial cells resurface the endometrium generating a new luminal epithelium each cycle. Based on these markers, we characterised the gene expression of human endometrial stem/progenitor cell-enriched populations derived from FACSorted hysterectomy endometrium by scRNAseq. Two of 10 epithelial clusters containedCDH2+SOX9+cells with highTRHandIHHexpression. N-cadherin and IHH, and SSEA1 and Hedgehog coreceptor BOC immunocolocalised in the basal layer of endometrial glands from which the new functional layer glands regenerate each menstrual cycle. Two of six mesenchymal clusters containedSUSD2+MSC, one with highMUSTN1expression. Epithelial progenitors and endometrial MSC transitioned to their respective progeny. We provide new insights into human endometrial stem/progenitor cell signaling pathways and niche interactions regulating their function.

Highlights

  • Enriching cell suspensions of human endometrial cells from hysterectomy tissues with CDH2+epithelial progenitors, SSEA-1+basalis epithelial cells and SUSD2+perivascular MSC enabled their gene profiling at the single cell level.

  • Multiple cell fate trajectory analyses showed thatCDH2+SOX9+epithelial cells andSUSD2+MYH11+MCAM+MUSTN1+MSC are the progenitors for human endometrial glandular and luminal epithelial cells, and stromal vascular cells, respectively.

  • EnrichedTRHexpression in human endometrial epithelial progenitors suggests a role in their progenitor function.

  • Interaction between IHH of SOX9+human endometrial epithelial progenitors with basalis fibroblasts and decidualized stroma and co-receptor BOC suggests IHH signalling may have a role in basalis epithelial migration to repair the luminal epithelium during menses.

eTOC blurb

Gargett and colleagues provide a molecular signature of human endometrial stem/progenitor cells by enriching 4 stem/progenitor populations from hysterectomies using known markers for scRNAseq analysis. The two epithelial and two MSC progenitor states identified transitioned to their differentiated progeny. IHH was validated as a key signalling molecule of epithelial progenitors in basal glands that interacted with BOC co-receptors.

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