Therapeutic Potential of Lymphatic Endothelial Progenitor Cells in Secondary Lymphedema: A Preclinical Murine Study

Background: Secondary lymphedema is a chronic complication of oncologic surgery and radiotherapy for which effective disease-modifying therapies remain lacking. While mesenchymal stem cells (MSCs) have shown partial benefit in experimental models, direct functional comparison with lineage-committed lymphatic endothelial progenitor cells (LEPCs) remains limited. Methods: Secondary lymphedema was induced in C57BL/6J mice by circumferential tail skin excision with disruption of superficial lymphatics. Animals received intradermal phosphate-buffered saline (PBS), MSCs, or adipose-derived LEPCs on postoperative days 1 and 7. Lymphatic function was longitudinally quantified using IVIS-based near-infrared indocyanine green (ICG) imaging with standardized region-of-interest analysis. Tail diameter was measured serially throughout follow-up as a complementary morphometric parameter. Tissue remodeling was assessed by Picrosirius Red staining and qualitative LYVE-1 immunofluorescence. Statistical analysis incorporated mixed-effects modeling to evaluate treatment group, sex, time, and their interaction terms, with estimation of effect sizes and 95% confidence intervals. Results: LEPC-treated mice demonstrated higher IVIS signal intensity than MSC- and PBS-treated animals, consistent with improved lymphatic transport at the injury site. Longitudinal tail diameter analysis showed a more favorable temporal profile in the LEPC group relative to controls, with exploratory analysis suggesting potential variations in temporal profiles between sexes that warrant further investigation in larger cohorts. Histologic analysis showed reduced non-tissue/void area and a more favorable qualitative pattern of LYVE-1 staining in LEPC-treated tissue. Conclusions: LEPC administration enhanced functional and structural recovery in a murine model of secondary lymphedema. These findings support further translational evaluation of LEPC-based approaches as a regenerative strategy for secondary lymphedema.