Biology subjects

Fortier, S. M.

Publications and source records attributed to Fortier, S. M..

3 recordsLinked to original sources

bioRxiv2026

Longitudinal Single-Cell RNA-seq Profiling of Lung Cell Phenotypes, Signaling, and Cross-talk During Fibrosis Resolution

Resolution of fibrosis following lung injury is distinguished from persistent/progressive parenchymal scarring through the timely clearance of aberrant cell types, removal of excess collagens, and regeneration of alveolar structure. The requisite signaling pathways, cellular cross-talk, and phenotypic shifts associated with, and required for, resolution of established lung fibrosis have not been well characterized. To address this critical knowledge gap, we performed longitudinal single-cell RNA sequencing of whole mouse lung digests obtained during spontaneously resolving fibrosis. We observed a putatively pro-fibrotic macrophage population emerge during peak fibrosis and undergo partial clearance during resolution. Our study also revealed conspicuous shifts in well-established pathways associated with tissue repair and fibrosis among immune, mesenchymal, and epithelial cells during spontaneous resolution. In addition to a decline in pro-fibrotic driver pathways, the putative anti-fibrotic pathways cAMP, HGF/MET, and TWEAK were enriched in several cell types during spontaneous resolution. CellChat analysis was used to predict the cellular senders and recipients of each pathway and characterize their longitudinal changes. Our characterization of the cellular and molecular dynamics in whole lungs during spontaneous fibrosis resolution provides a foundation for the identification of endogenous pathways that might be leveraged to treat pulmonary fibrosis.

cell biology↗

bioRxiv2025

Distinct cAMP regulation in scleroderma lung and skin myofibroblasts governs their dedifferentiation via p38α inhibition

Fibrosis in systemic sclerosis/scleroderma (SSc) is characterized by the progressive accumulation and persistence in multiple organs of pathologic fibroblasts whose contractile properties and exuberant secretion of collagens promote tissue stiffness and scarring. Identifying a tractable mechanism for inactivating and possibly clearing these ultimate effector cells of fibrosis, conventionally termed myofibroblasts (MFs), represents an appealing therapeutic strategy for patients with SSc. This can be accomplished by their phenotypic dedifferentiation, a process known to be promoted by generation of the intracellular second messenger cyclic AMP (cAMP). Notably, however, the abilities of SSc fibroblasts derived from different tissues to generate cAMP - and dedifferentiate in response to it - have never been directly characterized or compared. Here we compared these two processes in lung and skin MFs derived from patients with SSc. While directly increasing intracellular cAMP induced comparable dedifferentiation of lung and skin SSc MFs, dedifferentiation in response to the well-recognized cAMP stimulus prostaglandin E2 (PGE2) was diminished or absent in MFs from skin as compared to lung, in part due to differences in the expression of its target G protein-coupled receptors (GPCRs). Importantly, treatment with a phosphodiesterase 4 inhibitor rescued the dedifferentiating effects of PGE2 in skin SSc MFs. Finally, both cAMP-mediated and direct pharmacologic inhibition of the MAPK p38 promoted dedifferentiation of lung and skin SSc MFs. We conclude that activation of the cAMP pathway and its subsequent inhibition of p38 dedifferentiates SSc MFs from both lung and skin, and may thus represent a therapeutic strategy to alleviate multi-organ fibrosis in SSc.

molecular biology↗

bioRxiv2024

Morphological Reprogramming of Primary Cilia Length Mitigates the Fibrotic Phenotype in fibroblasts across diverse fibrotic conditions

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-{beta}1 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 -SMA in TGF-{beta}1-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. Teaser. PC length shortening is a hallmark of fibrosis.

cell biology↗