Adipose-derived regenerative cell therapy mitigates sepsis-induced cardiomyopathy through the induction of cardiac reparative lymphangiogenesis

Sepsis-induced cardiomyopathy (SICM) represents a critical unmet clinical challenge globally and is highlighted by the paucity of effective therapeutic interventions. Despite its clinical importance, the exacerbating factors and intricate underlying mechanisms remain largely unknown. Emerging evidence has highlighted the pivotal role of the cardiac lymphatic vasculature in cardiac homeostasis and repair, prompting investigations into its contributions during pathological states. In this study, we delineated the dynamics and functional significance of cardiac lymphatic vessels in SICM pathogenesis, and evaluated the therapeutic efficacy of targeted lymphangiogenesis as a novel strategy to improve poor prognosis. Using a lipopolysaccharide (LPS)-induced SICM mouse model, the evolution of cardiac lymphatic kinetics and observed reparative lymphangiogenesis was assessed in SICM. In addition, pharmacological inhibition of reparative lymphangiogenesis further exacerbated mortality rates in this model, thus highlighting its protective contributions. Adipose-derived regenerative cells (ADRCs) robustly enhance lymphangiogenesis in cardiac tissues during SICM. In vitro assays with lymphatic endothelial cells (LECs) confirmed that this lymphangiogenic potency is mediated, at least in part, by vascular endothelial growth factor-C (VEGF-C) secreted by ADRCs. Notably, ADRC-mediated therapeutic lymphangiogenesis restored cardiac function and mitigated adverse pathological remodeling as well as significantly improved the overall prognosis in SICM-affected animals. Our findings highlight the essential role of cardiac lymphatic vessels in improving SICM outcomes and indicate that ADRC-driven therapeutic lymphangiogenesis is a promising and innovative modality for treating this highly severe condition.