Targeted Clearance of Senescent Endothelium by GPNMB-Specific CAR-T Cells

Endothelial cells (ECs) serve as crucial components of blood vessels and are vital for preserving vascular health in humans. The aging of these cells significantly accelerates vascular aging. Factors released by aging ECs serve as key initiators of arterial dysfunction and various cardiometabolic diseases. As a result, the targeted removal of aging ECs from injured tissues could reduce these issues and potentially improve lifespan. In this research, we explored the therapeutic capabilities of chimeric antigen receptor (CAR)-T cells designed to focus on senescent cells as potential senolytic agents. We identified GPNMB, a transmembrane glycoprotein, as a protein characterized by extensive expression during cellular senescence. Our findings demonstrate that CAR-T cells specifically targeting GPNMB can efficiently remove senescent cells in vitro. In addition to this, the engineered CAR-T cells significantly clear replicative and doxorubicin (Dox)-induced senescent human umbilical vein ECs (HUVECs). Notably, these CAR-T cells successfully eradicated senescent HUVECs within a Matrigel matrix implanted subcutaneously in mice, thereby creating a simulated in vivo environment that mimics physiological conditions. The findings emphasize the possibilities of CAR-T cells in treating EC senescence.