Abstract
ABSTRACTA 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 µm3 and trabecular thickness 0.05 ± 0.01 µm compared with control animals (4.3 ± 3.1 µm3, 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.
Highlights
A significant number of bone defects and fractures do not heal
AMD3100, (1,1-[1,4-Phenylenebis(methylene)] bis-1,4,8,11-tetraazacyclotetradecane octahydrochloride), is a bicyclam derivative that antagonises the CXCR4 receptor directly and mobilizes a population of CD34þ haematopoietic stem cells into the peripheral circulation. This occurs by highly selective, high affinity competitive blocking of the CXCR4 receptor which displaces stem cells from the bone marrow niche by disruption of their attraction to SDF1.14 haematopoietic stem cells have been successfully mobilized using GCSF or AMD3100 or a combination, work on Mesenchymal stem cell (MSC) and other progenitors is limited and these cells do not seem to be as migratory as hematopoietic stem cells, potentially due to their larger size, increased niche adherence and their limited number in the bone marrow stroma.[15]
This study has demonstrated a significant increase in peripheral blood circulating Peripheral Blood MSCs (PBMSCs) post Vascular Endothelial Growth Factor 165 (VEGF) and AMD3100 administration
Summary
A significant number of bone defects and fractures do not heal. In the USA, it is estimated that around 100,000 fractures per year go on to non-union.[1]. An intentional forced egress of cell ‘mobilization’ has been in clinical use for some time with haematopoietic stem cells for repopulation of the bone marrow after treatment for certain blood related malignancies.[12,13] AMD3100, (1,1-[1,4-Phenylenebis(methylene)] bis-1,4,8,11-tetraazacyclotetradecane octahydrochloride), is a bicyclam derivative that antagonises the CXCR4 receptor directly and mobilizes a population of CD34þ haematopoietic stem cells into the peripheral circulation This occurs by highly selective, high affinity competitive blocking of the CXCR4 receptor which displaces stem cells from the bone marrow niche by disruption of their attraction to SDF1.14 haematopoietic stem cells have been successfully mobilized using GCSF or AMD3100 or a combination, work on MSC and other progenitors is limited and these cells do not seem to be as migratory as hematopoietic stem cells, potentially due to their larger size, increased niche adherence and their limited number in the bone marrow stroma.[15] Pitchford’s seminal work on different mobilization protocols in mice, demonstrated that AMD3100 combined with VEGF rather than GCSF, preferentially mobilizes a population of MSCs rather than haematopoietic stem cells.[11]. The aim of this study was to investigate whether administration of VEGF with AMD3100, could mobilize MSCs into the peripheral circulation of rats, and to determine whether increasing the circulating levels of MSCs would improve fracture healing in a delayed union rat femoral fracture model
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