Combination of Injectable Multiple Growth Factor–Releasing Scaffolds and Cell Therapy as an Advanced Modality to Enhance Tissue Neovascularization

Abstract

Objective-Vasculogenic progenitor cell therapy for ischemic diseases bears great potential but still requires further optimization for justifying its clinical application. Here, we investigated the effects of in vivo tissue engineering by combining vasculogenic progenitors with injectable scaffolds releasing controlled amounts of proangiogenic growth factors. Methods and Results-We produced biodegradable, injectable polylactic coglycolic acid-based scaffolds releasing single factors or combinations of vascular endothelial growth factor, hepatocyte growth factor, and angiopoietin-1. Dual and triple combinations of scaffold-released growth factors were superior to single release. In murine hindlimb ischemia models, scaffolds releasing dual (vascular endothelial growth factor and hepatocyte growth factor) or triple combinations improved effects of cord blood-derived vasculogenic progenitors. Increased migration, homing, and incorporation of vasculogenic progenitors into the vasculature augmented capillary density, translating into improved blood perfusion. Most importantly, scaffold-released triple combinations including the vessel stabilizer angiopoietin-1 enhanced the number of perivascular smooth muscle actin ϩ vascular smooth muscle cells, indicating more efficient vessel stabilization. Conclusion-Vasculogenic

Nocturnal Hemodialysis Is Associated with Restoration of Early-Outgrowth Endothelial Progenitor-Like Cell Function

“…In contrast, Ang1 expression is often maintained for weeks after ischemia onset (23). Ang1 plays a critical role in the maturation of newly formed vascular networks in postnatal angiogenesis through the recruitment of pericytes (44) and has been shown to promote neovascularization in the setting of ischemia (45). Because exogenously administered earlyoutgrowth EPLCs have been shown to regulate host angiogenesis (41), the finding that NHD patient-derived cells, but not CHD patient-derived cells, upregulated endogenous Ang1 expression and ischemic neovascularization raises important mechanistic questions beyond the scope of the study presented here.…”

Therapeutic Angiogenesis: Foundations and Practical Application

“…Triple combinations resulted in signiicantly higher SMC counts indicating more eicient vessel stabilization due to angiopoietin-1 efects on perivascular cell chemotaxis [80].…”

Formation of Stable Vascular Networks in Engineered Tissues

“…The delivery of triple growth factors significantly enhanced the effect of cell therapy in multiple animal models, with increased progenitor cell incorporation, improved vessel function, and stabilization. (Saif et al, 2010) In addition to combined gene or protein delivery with cells, ECs and EPCs can also be genetically modified ex vivo prior to implantation to enhance vascular stabilization. For example, Bcl-2 is an anti-apoptosis protein that is upregulated during angiogenesis.…”

“…The chorioallantoic membrane (CAM) model with chicken or quail embryos is a simple method to evaluate vascularization in response to different therapies. (Saif et al, 2010;Stratman et al, 2010) After therapeutic agents injection or implantation, the angiogenic effect can be easily assessed by imaging vascular regions of the CAM. This model is cost efficient and easy to perform compared to other mammalian animal models.…”