VEGF with AMD3100 endogenously mobilizes mesenchymal stem cells and improves fracture healing

Abstract

A significant number of fractures develop non‐union. Mesenchymal stem cell (MSC) therapy may be beneficial, however, this requires cell acquisition, culture and delivery. Endogenous mobilization of stem cells offers a non‐invasive alternative. The hypothesis was administration of VEGF and the CXCR4 antagonist AMD3100 would increase the circulating pool of available MSCs and improve fracture healing. Ex‐breeder female wistar rats received VEGF followed by AMD3100, or sham PBS. Blood prepared for culture and colonies were counted. P3 cells were analyzed by flow cytometry, bi‐differentiation. The effect of mobilization on fracture healing was evaluated with 1.5 mm femoral osteotomy stabilized with an external fixator in 12–14 week old female Wistars. The mobilized group had significantly greater number of cfus/ml compared to controls, p = 0.029. The isolated cells expressed 1.8% CD34, 35% CD45, 61% CD29, 78% CD90, and differentiated into osteoblasts but not into adipocytes. The fracture gap in animals treated with VEGF and AMD3100 showed increased bone volume; 5.22 ± 1.7 µm 3 and trabecular thickness 0.05 ± 0.01 µm compared with control animals (4.3 ± 3.1 µm 3 , 0.04 ± 0.01 µm, respectively). Radiographic scores quantifying fracture healing (RUST) showed that the animals in the mobilization group had a higher healing score compared to controls (9.6 vs. 7.7). Histologically, mobilization resulted in significantly lower group variability in bone formation ( p = 0.032) and greater amounts of bone and less fibrous tissue than the control group. Clinical significance: This pre‐clinical study demonstrates a beneficial effect of endogenous MSC mobilization on fracture healing, which may have translation potential to prevent or treat clinical fractures at risk of delayed or non‐union fractures. © 2018 The Authors. Journal of Orthopaedic Research ® Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 37:1294–1302, 2019.

Stem cells in fracture healing

“…They stabilized with an external fixator a 1.5mm femoral osteotomy in rats. The bone volume was increased in animals treated with VEGF and AMD3100 30 .…”

Implementation of Endogenous and Exogenous Mesenchymal Progenitor Cells for Skeletal Tissue Regeneration and Repair

“…Strategies to enhance healing by mimicking the natural cellular processes that occur during skeletal development are actively being explored. Most notably, transplantation of tissue specific progenitor cells or stimulating the recruitment of endogenous/native progenitors are approaches that are utilized to enhance healing of skeletal tissues in preclinical models [15][16][17][18][19]. The self-renewal capacities of skeletal tissues diminish with aging.…”

Dual CXCR4 and E-Selectin Inhibitor, GMI-1359, Shows Anti-Bone Metastatic Effects and Synergizes with Docetaxel in Prostate Cancer Cell Intraosseous Growth

“…It was widely demonstrated that bone metastatic cancer cells displayed a characteristic pattern of homing in the long bones, with the majority of tumor cells seeded in the trabecular regions. In addition, it was showed that the mobilization of Human Stromal Cells (HSCs) from the niche resulted in increased numbers of tumour cells disseminated in trabecular regions [64]. It has been also demonstrated that the administration of the CXCR4 antagonist AMD3100 seems to increase the circulating pool of mesenchymal stromal cells (MSCs) improving the fracture healing [65] In addition it was also demonstrated that CXCR4 sustain osteogenic differentiation [66].…”