Abstract 9113: Therapeutic Neovascularization Targeting Notch Signaling
Implantation of mononuclear cells (MNC) has become a widely used method to induce therapeutic angiogenesis. However, according to multiple clinical trials published recently, MNC transplantation shows no beneficial effect upon approximately forty percent of the critical limb ischemia cases. To improve such outcomes, it may be a reasonable strategy to clarify the precise molecular mechanism underlying the therapeutic responsiveness, and to establish a novel molecular targeting therapy. Here, we show that Notch signaling can be a promising candidate. We previously reported that, in mice hind limb ischemia model, MNC therapy induced therapeutic muscle regeneration and neovascularization through activation of Notch signaling. We newly found that expression of Jagged-1, a Notch ligand, was significantly decreased in MNC harvested from patients who later suffered major limb amputation following cell therapy, indicating that Notch signaling has a pivotal role in the determination of therapeutic responsiveness by MNC implantation, also in a clinical setting. These results warranted us to further investigate and establish therapeutic neovascularization targeting Notch signaling. We first introduced Jagged-1 into hematopoietic cell line Ba/F3 with retrovirus, and transplanted them into ischemic limb of mice. The cells over-expressing Notch ligands were capable not only to enhance Notch signaling in ischemic muscle tissue, but also to significantly improve limb perfusion. To overcome safety concerns using viral constructs, we established another method utilizing agonistic antibody designed specifically against mice Notch-1 receptor. Like the retroviral cells, the antibody enhanced Notch signaling in ischemic muscle. When used in combination with MNC transplantation, the agonistic antibody significantly improved blood flow recovery from limb ischemia. These results warrant us to design a translational research that utilizes antibody medicine targeting Notch signaling for patients with critical limb ischemia.
- © 2011 by American Heart Association, Inc.