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Adipocyte Progenitor Cells Embedded In Collagen Gels Accelerate Bone Formation In A Murine Calvarial Critical Defect Model
Michelle Griffin, MD PHD MRCS1,2, Nestor Diaz, BS1, Nicholas Guardino, BS1, Amanda Spielman, BS1, Darren Abbas, MD1, Derrick Wan, MD1, Michael Longaker, MD1.
1Stanford University, Stanford, CA, USA, 2University College London, London, United Kingdom.

PURPOSE:Techniques to restore bone formation following injury are under intense investigation and include the use of growth factors, osteoconductive scaffolds, osteoprogenitor cells, and distraction osteogenesis. Augmentation of bone formation with progenitor cell populations could provide a means to achieve bone formation following injury. Adipocyte progenitor cells (APCs) defined by flow-assisted cell sorting have been identified as cells with the ability to form vessels and adipocytes. The use of APCs in bone healing has not been investigated. Our study evaluates the ability of a specific subset of APCs to heal cavarial defects.
METHODS:APCs were isolated by fluorescence-activated cell sorting (FACS) according to a Sca1+, CD34+ and Pdgfra+ sorting strategy. APCs were seeded into collagen gels for 24 hours to allow for attachment. Adult C57Bl/6 mice (6-8-week-old) (n = 6) were then randomized to one of three conditions: 1. Calvarial (6mm) defect (Control group), 2. Calvarial defect with simultaneous treatment with a collagen gel seeded with isolated APCs (APC group), and 3. Calvarial defect with simultaneous treatment with a collagen gel alone (Gel group) (Fig.1A). Mice were euthanized at 12 weeks post the calvarial defect for histological and FACS analysis. MicroCT was collected at 0, 2, 4, 8, and 12 weeks to evaluate bone formation. Samples underwent immunofluorescent staining for vascularization (CD31 staining) and were imaged on a confocal microscope.
RESULTS:MicroCT confirmed bone formation was significantly greater in the APC group, compared to the Control and Gel group at 12 weeks (P < 0.05) (Fig.1B). Histological analysis by H&E and Pentachrome staining confirmed enhanced bone formation at 12 weeks compared to the Gel and Control group (P < 0.05). FACS analysis revealed the Sca1+, CD34+, Pdgfra+ remained at the defect site in the collagen gel at 12 weeks. The APC group also revealed greater vascularization with enhanced CD31 gene expression by RT-qPCR and protein expression by Immunohistochemistry than the Gel and Control group (P < 0.05).CONCLUSION: Our results suggest that APC represent a progenitor population that may enhance bone formation and vascularization. Collagen gels offer a feasible system for APC delivery to enhance bone formation following injury. Future work into understanding the mechanism by which APCs support bone formation may identify therapeutics targets to improve bone repair.


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