VEGF-C contributes to BM niche maintenance and regeneration after irradiation. Schematic models describing the BM microenvironment of ECs, LepR⁺ cells, HSCs, and the effects of VEGF-C. (A) During homeostasis, HSCs reside in and are maintained by the intact perivascular niche composed of ECs and LepR⁺ cells. VEGF-C from both LepR⁺ cells and ECs maintains an intact BM perivascular niche that is necessary for HSC maintenance. When Vegfc is deleted from ECs or LepR cells, genes related to interferon response are upregulated, and Cxcl12 and Pten are decreased in BM ECs and LepR⁺ cells, respectively, which leads to niche impairment and compromised HSC maintenance. (Bi) After irradiation and HSC transplantation, Vegfc expression in the niche is upregulated. Microenvironment-derived VEGF-C contributes to endothelial and LepR⁺ cell regeneration, which in turn is essential for HSC regeneration. (ii) When Vegfc is deleted from the BM microenvironment, genes related to inflammation are upregulated and the proliferation of ECs is decreased, which leads to impaired niche regeneration. Niche-derived hematopoietic regenerative factors are also decreased, resulting in a decreased recovery of HSCs. (iii) Overexpression of VEGF-C improves vascular regeneration, which leads to a better hematopoietic recovery after irradiation or transplantation.