Human myocardial-derived highly proliferative cells improve cardiac remodeling after myocardial infarction in mice.

Human highly proliferative cells (hHiPCs) isolated from the adult heart have progenitor and angiogenic properties. However, the mechanisms underlying hHiPCs in myocardial repair in vivo have yet to be investigated. We characterized the hHiPC proteome and secretome and found that hHiPCs express and secrete proangiogenic and proreparative proteins, including CXCL6, CTHRC1, and CD73, and are ontologically enriched in pathways related to cytokine signaling and glucose metabolism. Using publicly available single-cell data (GSE149699), we found that CXCL6, CTHRC1, and CD73 are also expressed in adult and neonatal cardiospheres, resembling a therapeutic cell population currently being tested in clinical trials. With the prominent role of these enriched secreted factors in cardiac repair and highly proliferative phenotype, we hypothesized that hHiPC injection would improve heart function following ischemic injury. Following experimental myocardial infarction (MI) in immunocompromised male and female mice, we found that intramyocardial injection of hHiPCs (2.5 × 10⁵ cells) resulted in ∼3.5% (∼8.7 × 10³ cells) survival in the host myocardium; however, hHiPC survival persisted throughout the acute phase of MI. To assess cardiac function after treatment, we found that hHiPCs improved fractional shortening by 21 and 28 days post-MI and prevented progressive ventricular remodeling compared with vehicle control treatment. Together, these data establish a role for hHiPCs in cardiac repair and lay the foundation for their investigation as a potential treatment for myocardial ischemic injury. SIGNIFICANCE STATEMENT: This study determined the unique novel properties of cardiac-derived human highly proliferative cells (hHiPCs) to survive over the acute inflammatory phase in the ischemic myocardium. hHIPCs were identified as potential candidates for cell-based therapy to create a long-term prohealing microenvironment by secreting proreparative proteins CXCL6, CTHRC1, and CD73.