Open AccessAngiogenesis is inhibitory for mammalian digit regeneration
Author(s) -
Yu Ling,
Yan Mingquan,
Simkin Jennifer,
Ketcham Paulina D.,
Leininger Eric,
Han Manjong,
Muneoka Ken
Publication year - 2014
Publication title -
regeneration
Language(s) - English
Resource type - Journals
ISSN - 2052-4412
DOI - 10.1002/reg2.24
Subject(s) - blastema , regeneration (biology) , angiogenesis , biology , microbiology and biotechnology , vascular endothelial growth factor , vascular endothelial growth factor a , fibroblast growth factor , bone morphogenetic protein , immunology , cancer research , vegf receptors , genetics , gene , receptor
The regenerating mouse digit tip is a unique model for investigating blastema formation and epimorphic regeneration in mammals. The blastema is characteristically avascular and we previously reported that blastema expression of a known anti‐angiogenic factor gene, Pedf , correlated with a successful regenerative response (Yu, L., Han, M., Yan, M., Lee, E. C., Lee, J. & Muneoka, K. (2010). BMP signaling induces digit regeneration in neonatal mice. Development, 137, 551–559). Here we show that during regeneration Vegfa transcripts are not detected in the blastema but are expressed at the onset of differentiation. Treating the amputation wound with vascular endothelial growth factor enhances angiogenesis but inhibits regeneration. We next tested bone morphogenetic protein 9 (BMP9), another known mediator of angiogenesis, and found that BMP9 is also a potent inhibitor of digit tip regeneration. BMP9 induces Vegfa expression in the digit stump suggesting that regenerative failure is mediated by enhanced angiogenesis. Finally, we show that BMP9 inhibition of regeneration is completely rescued by treatment with pigment epithelium‐derived factor. These studies show that precocious angiogenesis is inhibitory for regeneration, and provide compelling evidence that the regulation of angiogenesis is a critical factor in designing therapies aimed at stimulating mammalian regeneration.