Fibroblasts are not just fibroblasts: clear differences between dermal and pulmonary fibroblasts’ response to fibrotic growth factors

Abstract

Systemic Sclerosis (SSc) hallmark is skin fibrosis, but up to 80% of the patients have fibrotic involvement in the pulmonary system. Antifibrotic drugs which have failed in a general SSc population have now been approved in patients with SSc-associated interstitial lung disease (ILD). This indicates that the fibrotic progression and regulation of fibroblasts likely depend on local factors specific to the tissue type. This study investigated the difference between dermal and pulmonary fibroblasts in a fibrotic setting, mimicking the extracellular matrix. Primary healthy fibroblasts were grown in a crowded environment and stimulated with TGF-β1 and PDGF-AB. The viability, morphology, migration capacity, extracellular matrix formation, and gene expression were assessed: TGF-β1 only increased the viability in the dermal fibroblasts. PDGF-AB increased the migration capacity of dermal fibroblasts while the pulmonary fibroblasts fully migrated. The morphology of the fibroblasts was different without stimulation. TGF-β1 increased the formation of type III collagen in pulmonary fibroblasts, while PDGF-AB increased it in dermal fibroblasts. The gene expression trend of type VI collagen was the opposite after PDGF-AB stimulation. The fibroblasts exhibit different response profiles to TGF-β1 and PDGF-AB; this suggests that drivers of fibrosis are tissue-dependent, which needs to be considered in drug development.

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

“…The diversity across fibrotic diseases presents a challenge for designing broad-spectrum anti-fibrotic drugs. Even within a specific fibrotic disorder, such as SSc, there is substantial phenotypic diversity among fibroblasts from affected tissues ( 9 ). Nevertheless, myofibroblast differentiation is recognized as a common phenomenon that is shared among distinct fibrotic diseases and affected organs ( 10 ).…”