Critical requirement of VEGF-C in transition to fetal erythropoiesis

• Published in: Blood 2016-08, Vol.128 (5), p.710-720
• Main Authors: Fang, Shentong, Nurmi, Harri, Heinolainen, Krista, Chen, Shuo, Salminen, Essi, Saharinen, Pipsa, Mikkola, Hanna K.A., Alitalo, Kari
• Format: Article
• Language: English
• Subjects: Anemia - pathology; Animals; Apoptosis; Cell Lineage; Cell Proliferation; Embryo, Mammalian - metabolism; Erythroid Cells - metabolism; Erythropoiesis; Fetus - metabolism; Gene Deletion; Hepatocytes - metabolism; Integrin alpha4 - metabolism; Liver - blood supply; Liver - embryology; Macrophages - metabolism; Mice, Inbred C57BL; Organ Size; Vascular Endothelial Growth Factor C - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2015-12-687970

Vascular endothelial growth factor C (VEGF-C) is a major driver of lymphangiogenesis in embryos and adults. Vegfc gene deletion in mouse embryos results in failure of lymphangiogenesis, fluid accumulation in tissues, and lethality. The VEGF-C receptors VEGFR3 and VEGFR2 are required for embryonic blood vessel formation. The related VEGF is essential for both blood vessel formation and embryonic hematopoiesis, whereas the possible involvement of VEGF-C in hematopoiesis is unknown. Here we unveil a novel hematopoietic function of VEGF-C in fetal erythropoiesis. Deletion of Vegfc in embryonic day 7.5 (E7.5) embryos in the C57BL6 mouse genetic background led to defective fetal erythropoiesis, characterized by anemia and lack of enucleated red blood cells in blood circulation. Macrophages and erythroid cells in the fetal liver (FL) were also decreased after midgestation because of decreased cell proliferation and increased apoptosis. However, the Lin−Sca-1+c-Kit+ stem cell compartment in E14.5 FL was not affected by Vegfc deletion. VEGF-C loss did not disrupt the generation of primitive erythroid cells or erythro-myeloid progenitors (EMPs) in the yolk sac, but it decreased the expression of α4-integrin on EMPs and compromised EMP colonization of the FL. The distribution, maturation, and enucleation of primitive erythroblasts were also impaired by Vegfc deletion. In contrast, Vegfc deletion from E10.5 onward did not compromise definitive hematopoiesis in the liver, and Vegfc deletion in adult mice did not cause anemia. These results reveal an unexpected role for VEGF-C, a major lymphangiogenic growth factor, in the transition to FL erythropoiesis. •Vegfc is essential for mobilization, maturation, and enucleation of primitive erythroblasts.•Vegfc deletion compromises liver colonization by erythro-myeloid progenitors and subsequent macrophage/erythroid expansion.