Therapeutic potential of lymphatic endothelial progenitor cells in secondary lymphedema: a preclinical murine study

Background Secondary lymphedema is a chronic and disabling condition with scarce disease-modifying treatments, particularly after oncologic surgery or radiotherapy. Current management remains largely palliative rather than restorative. Regenerative medicine strategies are emerging as promising alternatives, and lymphatic endothelial progenitor cells (LEPCs) may support reconstruction of damaged lymphatic networks. Methods Secondary lymphedema was induced in C57BL/6J mice using standardized tail skin excision with interruption of superficial lymphatics. Animals received intradermal phosphate-buffered saline (PBS), mesenchymal stem cells (MSCs), or adipose-derived LEPCs on days 1 and 7 post-surgery. Lymphatic function was monitored longitudinally by IVIS-based near-infrared indocyanine green (ICG) imaging and serial tail circumference measurements. Lymphatic vessels were assessed by LYVE-1 immunofluorescence, and fibrosis by Picrosirius Red staining. Results LEPC treatment markedly improved functional lymphatic recovery, as evidenced by faster indocyanine green (ICG) transit on near-infrared imaging, and significantly reduced tail swelling compared with both the MSC and PBS groups. Immunofluorescence analysis revealed a higher density of LYVE-1⁺ lymphatic vessels in LEPC-treated tissue, supporting enhanced lymphatic network reconstruction. Conclusions LEPC administration significantly enhanced lymphatic repair and functional recovery in a murine model of secondary lymphedema. These findings reinforce LEPCs as a biologically targeted and potentially disease-modifying therapeutic option that deserves further translational evaluation.