Clonal Hematopoiesis Instructs Maladaptive Tissue Repair to Promote Fibrosis
Year: 2026
Type: preprint
Abstract: Tissue repair is increasingly recognized as a systemic process influenced by age-associated changes beyond the injured organ itself. Clonal hematopoiesis of indeterminate potential (CHIP), a common consequence of somatic evolution in hematopoietic stem cells, has been linked to inflammatory disorders, yet whether it directly regulates tissue remodeling remains unclear. Here, we integrate population genomics, preclinical models, and human lung analyses to examine the role of CHIP in fibrotic lung disease. In large cohorts, idiopathic pulmonary fibrosis (IPF) was associated with a distinct CHIP mutational spectrum enriched for non- DNMT3A variants and for larger mutant clones. In mouse models, hematopoietic mutations exacerbated bleomycin-induced fibrosis and reprogrammed macrophages toward inflammatory, profibrotic states, including expansion of a distinct, injury-responsive SPP1 + population conserved in human disease. CHIP-associated macrophages were sufficient to directly promote fibroblast activation and alter epithelial differentiation, linking hematopoietic genotype to parenchymal remodeling. Consistently, a CHIP-derived macrophage transcriptional signature predicted adverse outcomes in independent IPF cohorts. Notably, immune and epithelial alterations were detectable even in the absence of overt injury, indicating that CHIP establishes a primed tissue environment permissive for maladaptive repair. Together, these findings identify clonal hematopoiesis as a systemic regulator of tissue repair and demonstrate that somatic evolution in blood can actively instruct organ remodeling through immune-parenchymal interactions. This framework supports the possibility that disease-associated selective pressures may shape clonal architecture with functional consequences for organ health.
Authors: Dongzhu Li, Ana C. Viñado, Paula Garcia-Olloqui, Sydney B. Montesi, Barry S. Shea, Leonard Christian, Iria Vazquez-Urio, Paula Aguirre-Ruiz, Beñat Ariceta, Manuela Neubert, Ashutosh Tripathy, Niloy Barua, Pablo S. Valera, Laura Vera, Eva Petri, Antje Prasse, Benjamin Seeliger, Amaia Vilas, Patxi San Martin, Maria José Calasanz, Felipe Prosper, Peter G. Miller, Werner Seeger, Florian H. Heidel, Jonas C. Schupp, Borja Saez, Ana Pardo-Saganta
Institutions: Justus-Liebig-Universität Gießen, German Center for Lung Research, Universities of Giessen and Marburg Lung Center, Cardio-Pulmonary Institute, Navarre Institute of Health Research, Clinica Universidad de Navarra, Centro de Investigación Médica Aplicada, Massachusetts General Hospital, Medizinische Hochschule Hannover, Universitätsmedizin Greifswald, Fraunhofer Institute for Toxicology and Experimental Medicine, Centro de Investigación Biomédica en Red de Cáncer, Broad Institute, Harvard University, Massachusetts Institute of Technology, Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Yale University
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7141219753