Clonal Hematopoiesis Associated with TP53 and DNMT3A Mutations 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 associated with DNMT3A and TP53 promotes tissue regeneration after acute injury, indicating the positive effects of CH. Genetics analysis of 125,966 patients revealed that individuals with TET2 and JAK2 CH show worse prognosis in acute cardiovascular diseases, while no significant association was observed among individuals with DNMT3A and TP53 mutations. In mouse models of myocardial infarction, hindlimb ischemia, and muscle injury, we utilized competitive bone marrow transplantation to mimic CH with Dnmt3a and Trp53 mutations. Mice with CH demonstrated enhanced tissue repair compared to controls. Single-cell RNA sequencing of recovering tissues and residing hematopoietic cells indicated that clonal hematopoiesis was associated with the presence of diverse hematopoietic cell populations exhibiting pro-regenerative functions. Notably, macrophages from CH mice showed increased expression of VEGF, contributing to improved tissue repair. Signaling analysis showed that suppressed E2F family transcription factors drive 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.