Morphological Reprogramming of Primary Cilia Length Mitigates the Fibrotic Phenotype in Fibroblasts Across Diverse Fibrotic Conditions

Abstract

Fibrosis is a hallmark of systemic sclerosis (SSc) and many diverse and incurable diseases. Myofibroblast activation, a common cellular phenomenon shared across fibrotic diseases, is marked by actin polymerization known to affect primary cilia (PC) length. We discovered that fibroblasts from diverse fibrotic conditions display significantly reduced PC length ex vivo. Treatment of healthy fibroblasts with profibrotic TGF-β1 induced PC shortening, while silencing ACTA2 in SSc skin fibroblasts caused PC elongation. Importantly, we found that PC length is negatively correlated with cellular expression of α-SMA in TGF-β1-stimulated healthy fibroblasts, or pharmacologically de-differentiated myofibroblasts. PC elongation by microtubule polymerization induction in SSc skin fibroblasts using LiCl or the HDAC6 inhibitor tubacin, reversed and mitigated fibrotic responses. Our results implicate a key role for microtubule polymerization in restraining fibrotic responses and suggest that modulation of PC dynamics may represent a potential therapeutic strategy for SSc and other treatment-resistant diseases associated with fibrosis.