TGFb signaling instructs a conserved fibrosis-associated cell state marked by LRRC15

Area of Science:

• Cell Biology
• Immunology
• Pulmonary Medicine

Background:

• Myofibroblasts are crucial in chronic disease but often viewed as a uniform cell type.
• This homogeneity obscures critical functional differences vital for developing targeted therapies.
• Understanding myofibroblast heterogeneity is key to advancing fibrosis treatment.

Purpose of the Study:

• To define distinct myofibroblast cell states and their molecular regulators in idiopathic pulmonary fibrosis.
• To identify specific cell surface markers for these states.
• To explore the role of transforming growth factor beta (TGFb) signaling in myofibroblast differentiation.

Main Methods:

• Construction of a human lung stromal cell atlas for idiopathic pulmonary fibrosis.
• Transcriptional profiling to identify distinct myofibroblast states.
• Machine learning analysis using a human single-cell foundation model.

Main Results:

• Identification of two distinct myofibroblast transcriptional states with unique functions and markers.
• Fibroblast-specific TGFb signaling identified as the primary regulator switching cells from wound healing to profibrotic phenotypes.
• LRRC15 found to be a marker for myofibroblasts driving extracellular matrix remodeling, independent of inflammatory precursors.

Conclusions:

• Myofibroblast populations are heterogeneous, with distinct states driving fibrosis.
• Targeting TGFb signaling offers a potential therapeutic strategy for fibrosis.
• The findings have broad applicability to understanding chronic diseases involving myofibroblast activation.