Strategies to Stimulate Mobilization and Homing of Endogenous Stem and Progenitor Cells for Bone Tissue Repair

Abstract

The gold standard for the treatment of critical-size bone defects is autologous or allogenic bone graft. This has several limitations including donor site morbidity and the restricted supply of graft material. Cell-based tissue engineering strategies represent an alternative approach. Mesenchymal stem cells (MSCs) have been considered as a source of osteoprogenitor cells. More recently, focus has been placed on the use of endothelial progenitor cells (EPCs), since vascularization is a critical step in bone healing. Although many of these approaches have demonstrated effectiveness for bone regeneration, cell-based therapies require time consuming and cost-expensive in vitro cell expansion procedures. Accordingly, research is becoming increasingly focused on the homing and stimulation of native cells. The stromal cell-derived factor-1 (SDF-1) - CXCR4 axis has been shown to be critical for the recruitment of MSCs and EPCs. Vascular endothelial growth factor (VEGF) is a key factor in angiogenesis and has been targeted in many studies. Here, we present an overview of the different approaches for delivering homing factors to the defect site by absorption or incorporation to biomaterials, gene therapy, or via genetically manipulated cells. We further review strategies focusing on the stimulation of endogenous cells to support bone repair. Finally, we discuss the major challenges in the treatment of critical-size bone defects and fracture non-unions.

Keywords: bone repair; endothelial progenitor cells; homing; stem cells.

Figure 1

Cell therapy vs. homing and mobilization of native cells for bone regeneration. (A) For an autologous cell transplantation, donor cells have to be harvested and expanded in vitro before they are eventually re-transplanted in the patient. The amplified cells can be seeded on a biomaterial or incorporated in a carrier for local administration or injected in the circulation to increase the pool of available stem cells, which in turn may home to the defect site. (B) Homing factors are directly delivered to the defect site. The release and diffusion of the factor create a gradient subsequently attracting stem and progenitor cells from the local tissue environment or the circulation. (C) Native stem and progenitor cells may be mobilized into the circulation by the administration of a stimulation factor enhancing the level of available cells.