Clonal Hematopoiesis Associated with TP53 Mutation Promotes Tissue Repair in Acute Cardiovascular Diseases

Clonal hematopoiesis (CH), arising from hematopoietic progenitor cells with acquired mutations, resulting in clonal expansion, and displaying functionally altered hematopoietic cells, is traditionally associated with adverse health outcomes of numerous conditions. However, CH may not always be pathological - our study found that CH promotes post-injury tissue regeneration, indicating the positive effects of CH. In mouse models of myocardial infarction, hindlimb ischemia, and muscle injury, we utilized competitive bone marrow transplantation to mimic CH with Trp53 mutation. Mice with CH demonstrated enhanced tissue repair compared to controls. Single-cell RNA sequencing of recovering tissues and residing hematopoietic cells indicated that mutant macrophages were associated with enhanced pro-angiogenic and phagocytic capability. Macrophages from CH mice showed increased expression of VEGF, contributing to improved tissue repair. Signaling analysis showed that suppressed E2F drives higher expression of Vegfa . These results suggest that CH may play a role in promoting recovery following ischemic injury and highlight its potential as a therapeutic strategy for improving outcomes in ischemic disease.