An estrogen-sensitive fibroblast population drives abdominal muscle fibrosis in an inguinal hernia mouse model

Tanvi Potluri, Matthew J. Taylor, Jonah J. Stulberg, Richard L. Lieber, Hong Zhao*, Serdar E. Bulun*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Greater than 25% of all men develop an inguinal hernia in their lifetime, and more than 20 million inguinal hernia repair surgeries are performed worldwide each year. The mechanisms causing abdominal muscle weakness, the formation of inguinal hernias, or their recurrence are largely unknown. We previously reported that excessively produced estrogen in the lower abdominal muscles (LAMs) triggers extensive LAM fibrosis, leading to hernia formation in a transgenic male mouse model expressing the human aromatase gene (Aromhum). To understand the cellular basis of estrogen-driven muscle fibrosis, we performed single-cell RNA sequencing on LAM tissue from Aromhum and wild-type littermates. We found a fibroblast-like cell group composed of 6 clusters, 2 of which were validated for their enrichment in Aromhum LAM tissue. One of the potentially novel hernia-associated fibroblast clusters in Aromhum was enriched for the estrogen receptor-α gene (Esr1hi). Esr1hi fibroblasts maximally expressed estrogen target genes and seemed to serve as the progenitors of another cluster expressing ECM-altering enzymes (Mmp3hi) and to upregulate expression of proinflammatory, profibrotic genes. The discovery of these 2 potentially novel and unique hernia-associated fibroblasts may lead to the development of novel treatments that can nonsurgically prevent or reverse inguinal hernias.

Original languageEnglish (US)
Article numbere152011
JournalJCI Insight
Volume7
Issue number9
DOIs
StatePublished - May 9 2022

Funding

This work was supported by the NIH R01 award DK121529 (to SEB and HZ). MJT was supported by Ruth L. Kirschstein National Research Service Award T32 DK007169. Single-cell sequencing was conducted by the Northwestern University NUSeq Core Facility, using the Core’s 10x Genomics Chromium supported by NIH 1S10OD025120. This work was also performed and analyzed at Northwestern University Pathology Core Facility, Center for Advanced Microscopy, and RHLCC Flow Cytometry Facility, which were supported by a grants P30 CA060553, NCI CA060553, 1S10OD011996-01, and 1S10OD026814-01. We thank Emily Stroup for her guidance with the analysis using Seurat.

ASJC Scopus subject areas

  • General Medicine

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