Clonal Hematopoiesis Instructs Maladaptive Tissue Repair to Promote Fibrosis

Area of Science:

• Hematology
• Pulmonary Medicine
• Genomics

Background:

• Tissue repair is a systemic process influenced by aging.
• Clonal hematopoiesis of indeterminate potential (CHIP) is linked to inflammation but its role in tissue remodeling is unclear.

Purpose of the Study:

• To investigate the role of CHIP in fibrotic lung disease.
• To understand how hematopoietic mutations influence tissue repair and remodeling.

Main Methods:

• Population genomics, preclinical models, and human lung tissue analysis.
• Analysis of CHIP mutational spectrum in idiopathic pulmonary fibrosis (IPF) cohorts.
• Mouse models to study the effects of hematopoietic mutations on fibrosis and macrophage reprogramming.

Main Results:

• IPF cohorts showed a distinct CHIP mutational spectrum.
• Hematopoietic mutations in mice exacerbated fibrosis and promoted profibrotic macrophage states.
• CHIP-associated macrophages directly promoted fibroblast activation and altered epithelial differentiation.
• A CHIP-derived macrophage signature predicted adverse outcomes in IPF patients.

Conclusions:

• CHIP is a systemic regulator of tissue repair, influencing organ remodeling via immune-parenchymal interactions.
• Somatic evolution in blood can instruct organ repair, highlighting CHIP as a potential therapeutic target.
• CHIP establishes a primed tissue environment predisposing to maladaptive repair even without overt injury.