Neovascularization and the recruitment of CD31+ cells from the bone marrow are unique under regenerative but not wound repair conditions

The long-noted observation that endostatin is a potent inhibitor of tumor vasculature but has little or no effect on wound repair or pregnancy remains an “as of yet unexplained but remarkable phenomenon”([1][1]). However, there is another path to wound healing, epimorphic regeneration, and here we present data in mice demonstrating that endostatin is, in fact, a potent inhibitor of epimorphic regeneration. In this study, we show that a rege nerative response seen in the spontaneously regenerating MRL mouse involves CD31+ endothelial precursors that migrate from the bone marrow into the wound site and form new vessels, unlike that seen in the non-regenerating C57BL/6 mouse injury site. Furthermore, this appears to relate to the induction of HIF-1a, an inducer of regeneration ([2][2]). Inducing epimorphic regeneration in otherwise non-regenerating mice via an enhanced HIF-1a response by employing the PHD inhibitor 1,4-DPCA/hydrogel, a HIF-1a stabilizer, results in the same increased bone marrow-derived CD31+ endothelial precursor response and increased vasculogenesis. This regenerative response is completely blocked by endostatin, supporting the notion that vascularization induced during regeneration shares similarities to the tumor vasculature. ### Competing Interest Statement The authors have declared no competing interest. [1]: #ref-1 [2]: #ref-2