CD34⁺ cells contribute to cardiac remodeling during disease development.

CD34, once considered solely a hematopoietic stem cell marker, is now recognized as a lineage interface identifying distinct tissue-resident progenitor populations that critically influence cardiac homeostasis and pathological remodeling. It has been applied clinically for CD34-targeted therapies, such as cell-capture stents, G-CSF mobilization, and unselected CD34⁺ cell transplantation. However, they fail to discriminate between reparative and pathogenic subsets. Recent advances in lineage tracing, single-cell genomics, and human tissue studies have made major progress in this research field. It has been reported that (1) non-bone marrow-derived endothelial progenitor cells (EPCs) sustain vascular integrity and promote neovascularization; (2) hematopoietic progenitors give rise to inflammatory monocytes, neutrophils, and dendritic cells, orchestrating immune responses after injury; and (3) resident fibroblast progenitor cells (FPCs) differentiate into myofibroblasts and drive interstitial and perivascular fibrosis. During cardiac remodeling, it seems that all types of CD34⁺ cells were involved. In this Review, we integrate histological, mechanistic, and clinical evidence to delineate the diverse CD34⁺ lineages in cardiac remodeling. We discuss how to refine surface-marker panels for isolating endothelial-committed progenitors and exclusion of inflammatory and fibrogenic subsets during cardiac repair. We propose a paradigm shift from generic CD34⁺ cell enrichment toward lineage-specific therapeutic strategies.