Identification of novel fibroblast subsets in diffuse cutaneous systemic sclerosis

Area of Science:

• Immunology and Dermatology
• Fibrotic Diseases
• Cell Biology

Background:

• Systemic sclerosis (SSc) is a fibrotic autoimmune disease characterized by excessive extracellular matrix (ECM) deposition and fibroblast activation.
• Understanding fibroblast heterogeneity is crucial for SSc pathogenesis and treatment.

Purpose of the Study:

• Identify novel fibroblast subpopulations in SSc.
• Determine the functional role of these subpopulations in disease progression.

Main Methods:

• Single-cell RNA sequencing of dermal fibroblasts from healthy donors and SSc patients.
• Protein-level verification of selected genes.
• siRNA knockdown experiments to assess functional roles.

Main Results:

• SSc fibroblasts exhibit significant heterogeneity with activated subsets overexpressing CD9 and four and a half LIM domain 1 (FHL1).
• CD9 and FHL1 upregulation observed in SSc patient skin fibroblasts; CD9 regulates FHL1 expression.
• FHL1 downregulation correlated with reduced VGLL3 expression, a known collagen synthesis regulator upregulated in SSc skin.

Conclusions:

• Novel SSc fibroblast subsets characterized by CD9 and/or FHL1 upregulation were identified.
• FHL1 plays a functional role in fibroblasts, regulating ECM production and linking to VGLL3.
• Findings suggest therapeutic strategies targeting fibroblast activation in SSc.