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Single-cell RNA sequencing and lineage tracing confirm mesenchyme to epithelial transformation (MET) contributes to repair of the endometrium at menstruation

The human endometrium experiences repetitive cycles of tissue wounding characterised by piecemeal shedding of the surface epithelium and rapid restoration of tissue homeostasis. In this study, we used a mouse model of endometrial repair and three transgenic lines of mice to investigate whether epith...

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Autores principales: Kirkwood, Phoebe M, Gibson, Douglas A, Shaw, Isaac, Dobie, Ross, Kelepouri, Olympia, Henderson, Neil C, Saunders, Philippa TK
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9873258/
https://www.ncbi.nlm.nih.gov/pubmed/36524724
http://dx.doi.org/10.7554/eLife.77663
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author Kirkwood, Phoebe M
Gibson, Douglas A
Shaw, Isaac
Dobie, Ross
Kelepouri, Olympia
Henderson, Neil C
Saunders, Philippa TK
author_facet Kirkwood, Phoebe M
Gibson, Douglas A
Shaw, Isaac
Dobie, Ross
Kelepouri, Olympia
Henderson, Neil C
Saunders, Philippa TK
author_sort Kirkwood, Phoebe M
collection PubMed
description The human endometrium experiences repetitive cycles of tissue wounding characterised by piecemeal shedding of the surface epithelium and rapid restoration of tissue homeostasis. In this study, we used a mouse model of endometrial repair and three transgenic lines of mice to investigate whether epithelial cells that become incorporated into the newly formed luminal epithelium have their origins in one or more of the mesenchymal cell types present in the stromal compartment of the endometrium. Using scRNAseq, we identified a novel population of PDGFRb + mesenchymal stromal cells that developed a unique transcriptomic signature in response to endometrial breakdown/repair. These cells expressed genes usually considered specific to epithelial cells and in silico trajectory analysis suggested they were stromal fibroblasts in transition to becoming epithelial cells. To confirm our hypothesis we used a lineage tracing strategy to compare the fate of stromal fibroblasts (PDGFRa+) and stromal perivascular cells (NG2/CSPG4+). We demonstrated that stromal fibroblasts can undergo a mesenchyme to epithelial transformation and become incorporated into the re-epithelialised luminal surface of the repaired tissue. This study is the first to discover a novel population of wound-responsive, plastic endometrial stromal fibroblasts that contribute to the rapid restoration of an intact luminal epithelium during endometrial repair. These findings form a platform for comparisons both to endometrial pathologies which involve a fibrotic response (Asherman’s syndrome, endometriosis) as well as other mucosal tissues which have a variable response to wounding.
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spelling pubmed-98732582023-01-25 Single-cell RNA sequencing and lineage tracing confirm mesenchyme to epithelial transformation (MET) contributes to repair of the endometrium at menstruation Kirkwood, Phoebe M Gibson, Douglas A Shaw, Isaac Dobie, Ross Kelepouri, Olympia Henderson, Neil C Saunders, Philippa TK eLife Medicine The human endometrium experiences repetitive cycles of tissue wounding characterised by piecemeal shedding of the surface epithelium and rapid restoration of tissue homeostasis. In this study, we used a mouse model of endometrial repair and three transgenic lines of mice to investigate whether epithelial cells that become incorporated into the newly formed luminal epithelium have their origins in one or more of the mesenchymal cell types present in the stromal compartment of the endometrium. Using scRNAseq, we identified a novel population of PDGFRb + mesenchymal stromal cells that developed a unique transcriptomic signature in response to endometrial breakdown/repair. These cells expressed genes usually considered specific to epithelial cells and in silico trajectory analysis suggested they were stromal fibroblasts in transition to becoming epithelial cells. To confirm our hypothesis we used a lineage tracing strategy to compare the fate of stromal fibroblasts (PDGFRa+) and stromal perivascular cells (NG2/CSPG4+). We demonstrated that stromal fibroblasts can undergo a mesenchyme to epithelial transformation and become incorporated into the re-epithelialised luminal surface of the repaired tissue. This study is the first to discover a novel population of wound-responsive, plastic endometrial stromal fibroblasts that contribute to the rapid restoration of an intact luminal epithelium during endometrial repair. These findings form a platform for comparisons both to endometrial pathologies which involve a fibrotic response (Asherman’s syndrome, endometriosis) as well as other mucosal tissues which have a variable response to wounding. eLife Sciences Publications, Ltd 2022-12-16 /pmc/articles/PMC9873258/ /pubmed/36524724 http://dx.doi.org/10.7554/eLife.77663 Text en © 2022, Kirkwood et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Medicine
Kirkwood, Phoebe M
Gibson, Douglas A
Shaw, Isaac
Dobie, Ross
Kelepouri, Olympia
Henderson, Neil C
Saunders, Philippa TK
Single-cell RNA sequencing and lineage tracing confirm mesenchyme to epithelial transformation (MET) contributes to repair of the endometrium at menstruation
title Single-cell RNA sequencing and lineage tracing confirm mesenchyme to epithelial transformation (MET) contributes to repair of the endometrium at menstruation
title_full Single-cell RNA sequencing and lineage tracing confirm mesenchyme to epithelial transformation (MET) contributes to repair of the endometrium at menstruation
title_fullStr Single-cell RNA sequencing and lineage tracing confirm mesenchyme to epithelial transformation (MET) contributes to repair of the endometrium at menstruation
title_full_unstemmed Single-cell RNA sequencing and lineage tracing confirm mesenchyme to epithelial transformation (MET) contributes to repair of the endometrium at menstruation
title_short Single-cell RNA sequencing and lineage tracing confirm mesenchyme to epithelial transformation (MET) contributes to repair of the endometrium at menstruation
title_sort single-cell rna sequencing and lineage tracing confirm mesenchyme to epithelial transformation (met) contributes to repair of the endometrium at menstruation
topic Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9873258/
https://www.ncbi.nlm.nih.gov/pubmed/36524724
http://dx.doi.org/10.7554/eLife.77663
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