Reduced WNT4 expression in normal skin fibroblasts leads to 'Dupuytren-like' changes in the transcriptome

Aoife O'Brien; Andrew Stevenson; Lucy Barrett; Nicholas B Lawler; Nicole Hortin; Zhenjun Deng; Amira Allahham; Fabio Quondamatteo; Nicole Smith; K Swaminathan Iyer; Fiona M Wood; Mark W Fear

doi:10.1016/j.heliyon.2024.e38016

Reduced WNT4 expression in normal skin fibroblasts leads to 'Dupuytren-like' changes in the transcriptome

Heliyon. 2024 Sep 17;10(18):e38016. doi: 10.1016/j.heliyon.2024.e38016. eCollection 2024 Sep 30.

Authors

Aoife O'Brien^{1

2}, Andrew Stevenson², Lucy Barrett², Nicholas B Lawler³, Nicole Hortin², Zhenjun Deng², Amira Allahham², Fabio Quondamatteo¹, Nicole Smith³, K Swaminathan Iyer³, Fiona M Wood^{2

4

5}, Mark W Fear^{2

5}

Affiliations

¹ Department of Anatomy and Regenerative Medicine, Royal College of Surgeons, Ireland.
² Burn Injury Research Unit (BIRU), School of Biomedical Sciences, University of Western Australia, Australia.
³ School of Molecular Sciences, The University of Western Australia, Perth, WA, 6009, Australia.
⁴ Burns Service of Western Australia, WA Department of Health, Perth, WA, Australia.
⁵ Fiona Wood Foundation, Murdoch, WA, Australia.

Abstract

Background: Dupuytren's disease (DD) is a fibro-proliferative disorder of unknown aetiology. Previous studies have implicated multiple WNT signalling genes/proteins in Dupuytren pathology, including WNT4. However, it is not yet clear whether WNT signalling dysregulation plays an important role in the initiation of the disease or progression. The aim of this study was to determine if loss of WNT4 expression triggered 'Dupuytren-like' changes in the transcriptome of healthy skin fibroblasts.

Methods: Fibroblasts were isolated from the wrists of healthy adult males and from the wrists and disease cord tissue from males in a family positive for Dupuytren's disease. Normal skin fibroblasts from healthy controls were treated with WNT4 siRNA and scrambled controls. RNASeq was used to analyse the transcriptomes of disease and non-disease fibroblasts from patients with Dupuytren's as well as in siRNA treated and non-treated control fibroblasts.

Results: Analysis of the transcriptomes from DD patient and normal skin fibroblasts showed significant differences, including in WNT4 expression. Downregulation of WNT4 in normal skin fibroblasts using siRNA led to 'DD-like' changes in the transcriptome.

Conclusion: In people susceptible to DD WNT4 is downregulated even in non-fibrotic fibroblasts. Knockdown of WNT4 in normal fibroblasts led to changes that made cells 'DD-like'. This study shows that WNT4 is down regulated in 'non-disease' cells, and that downregulating WNT4 in normal skin fibroblasts leads to widespread 'DD like' changes in the transcriptome, suggesting WNT4 downregulation is a key driver of DD.