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

Abstract

ABSTRACTThe 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). 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). 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.