Abstract
Secondary lymphedema is a debilitating condition driven by impaired regeneration of lymphatic vasculature following lymphatic injury, surgical removal of lymph nodes in cancer patients, or infection. However, the extent to which collecting lymphatic vessels regenerate following injury remains unclear. Here, we employed a novel mouse model of lymphatic injury in combination with state-of-the-art lymphatic imaging to demonstrate that the implantation of an optimized fibrin gel following lymphatic vessel injury leads to the reconnection of the injured lymphatic vessel network through sprouting lymphangiogenesis of initial-like lymphatic vessels from the ends of the collecting lymphatic vessels, resulting in the restoration of lymph flow to the draining lymph node. Mechanistically, we found that fibrin implantation elevates the tissue levels of CCL5, a potent immune cell-recruiting chemokine. Notably, injured vessels in CCL5-KO mice made fewer connections following fibrin gel implantation. These novel findings shed light on the mechanisms underlying lymphatic regeneration and suggest that enhancing CCL5 signaling may be a promising therapeutic strategy for enhancing lymphatic regeneration.
Data availability
All data generated by this study are available within the Article, Supplementary Information, or available from the authors upon request (submit requests to lmunn@mgh.harvard.edu, mrazavi2@unl.edu or tpadera@mgh.harvard.edu).
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Funding
National Institute of Health (NIH) F32HL156654 (MSR). National Institute of Health (NIH) R01CA284603 (LLM, TPP). National Institute of Health (NIH) R01CA284372 (TPP). National Institute of Health (NIH) R21AG072205 (TPP). National Institute of Health (NIH) R01HL128168 (LLM, TPP). National Institute of Health (NIH) R21EB031982 (LLM). National Institute of Health (NIH) R01CA247441 (LLM). Rullo Family MGH Research Scholar Award from the MGH Research Institute (TPP).
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Conceptualization: MSR, ZA, TPP, LLM. Methodology MSR, ZA, PL, NL, SN, KR, MO. Investigation: MSR, ZA, PL. Visualization: MSR, ZA. Supervision: TPP, LLM. Writing—– original draft: MSR, TPP, LLM– review & editing: All authors.
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LLM has equity in Bayer AG. The other authors declare no competing interests.
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Razavi, M.S., Lei, PJ., Amoozgar, Z. et al. Macrophages recruited by implanted fibrin gels promote regeneration of injured lymphatic vessels. Sci Rep (2026). https://doi.org/10.1038/s41598-026-39167-2
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DOI: https://doi.org/10.1038/s41598-026-39167-2
