Material-based deployment enhances efficacy of endothelial progenitor cells

Abstract

Cell-based therapies are attractive for revascularizing and regenerating tissues and organs, but clinical trials of endothelial progenitor cell transplantation have not resulted in consistent benefit. We propose a different approach in which a material delivery system is used to create a depot of vascular progenitor cells in vivo that exit over time to repopulate the damaged tissue and participate in regeneration of a vascular network. Microenvironmental conditions sufficient to maintain the viability and outward migration of outgrowth endothelial cells (OECs) have been delineated, and a material incorporating these signals improved engraftment of transplanted cells in ischemic murine hindlimb musculature, and increased blood vessel densities from 260 to 670 vessels per mm 2 , compared with direct cell injection. Further, material deployment dramatically improved the efficacy of these cells in salvaging ischemic murine limbs, whereas bolus OEC delivery was ineffective in preventing toe necrosis and foot loss. Finally, material deployment of a combination of OECs with another cell population commonly isolated from peripheral or cord blood, endothelial progenitor cells (EPCs) returned perfusion to normal levels in 40 days, and prevented toe and foot necrosis. Direct injection of an EPC/OEC combination was minimally effective in improving limb perfusion, and untreated limbs underwent autoamputation in 3 days. These results demonstrate that vascular progenitor cell utility is highly dependent on the mode of delivery, and suggest that one can create new vascular beds for a variety of applications with this material-controlled deployment of cells.biomaterial ͉ cell therapy ͉ ischemic diseases ͉ neovascularization ͉ regenerative medicine

The Role of Synthetic Extracellular Matrices in Endothelial Progenitor Cell Homing for Treatment of Vascular Disease

“…62 Albeit simple delivery routes, these methods of cellular infusion often have limited efficacy due to high cell death and poor recruitment and/or retention within the ischemic target. 2,70 In particular, the majority of systemically infused cells often get trapped in the microvasculature of other off-target organs/tissues. 27,64 For example, pulmonary passage is a major obstacle due to both the size of the cells and adhesion to the vascular endothelium.…”

“…7,56 While moderate therapeutic benefit has been achieved with bolus infusion (systemic or local), the lack of control over post-administered EPC survival, localization, fate, and functional activity poses major challenges and severely limits the degree of therapeutic benefit and clinical success. 64,70,78 Therefore, the efficacy of administered EPCs highly depends on the mode of delivery and subsequent control over administered cell fate after transplantation. 70 …”

“…64,70,78 Therefore, the efficacy of administered EPCs highly depends on the mode of delivery and subsequent control over administered cell fate after transplantation. 70 …”

“…3,29,35,63,87,89 In particular, outgrowth endothelial cells (OECs) or endothelial colony forming cells (ECFCs) are a specific subset of EPCs of solely endothelial lineage that directly participate in vessel formation in contrast to hematopoietic EPCs. 42,70,78,88,89 To date, no specific set of surface markers identifies a pure EPC population. 30,59,61,89 In fact, it has been shown that EPCs displaying the same set of surface markers contain separate subpopulations with a hierarchy of proliferative potential.…”

“…74 Implantation of OECs in ischemic tissue has demonstrated strong potential, but the poor survival, retention, and activity of transplanted cells still remains a large challenge for clinical success. 70,78 An attractive alternative that bypasses ex vivo cellular manipulation is to provide in situ tissue regeneration via controlled manipulation of endogenous EPC homing. 13 Regardless of the strategy employed, greater understanding of the mechanisms involved in EPC homing in both healthy and diseased states is critical in order to enhance efficacy of these strategies and maximize therapeutic benefit.…”