Abstract
Dermal fibrosis is a cardinal feature of systemic sclerosis (SSc) for which there are limited effective disease-modifying therapies. SSc is characterized by dermal fibrosis accompanied by loss of dermal white adipose tissue (DWAT), yet the mechanisms linking adipocyte depletion to fibroblast activation remain unclear. Here we identify the transcription factor SIX1 as a central regulator coupling adipogenic repression with profibrotic signaling. SIX1 expression was increased in skin biopsies from 2 independent SSc cohorts and localized to fibroblast and perivascular stromal cells. In mice, ubiquitous or adipocyte-specific deletion of Six1 preserved DWAT, reduced collagen accumulation, and selectively decreased profibrotic mediators. In cultured fibroblasts, CRISPR/Cas9-mediated Six1 loss enhanced adipogenic markers while reducing profibrotic mediators and directly suppressed PAI-1 (SERPINE1) promoter activity. Together, these data position SIX1 as a transcriptional switch that promotes adipocyte reprogramming and fibrotic progression, and they highlight SIX1 inhibition as a potential therapeutic strategy to preserve adipocyte identity and limit dermal fibrosis.
Authors
Nancy Wareing, Tingting W. Mills, Scott Collum, Minghua Wu, Lucy Revercomb, René A. Girard, Hui Liu, Alexes Daquinag, Mikhail Kolonin, Marka Lyons, Brian Skaug, Weizhen Bi, Meer A. Ali, Haniyeh Koochak, Anthony R. Flores, Yuntao Yang, W. Jim Zheng, William R. Swindell, Shervin Assassi, Harry Karmouty-Quintana
Figure 10
PAI-1 levels are upregulated in bleomycin-induced skin fibrosis and track with SIX1 expression levels.
