The role of oxygen as a regulator of stem cell fate during fracture repair in TSP2‐null mice |
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| Authors: | Darren Burke Michael Dishowitz Mariya Sweetwyne Emily Miedel Kurt D. Hankenson Daniel J. Kelly |
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| Affiliation: | 1. Trinity Centre for Bioengineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, , Dublin 2, Ireland;2. Department of Mechanical and Manufacturing Engineering, School of Engineering, Trinity College Dublin, , Dublin, Ireland;3. Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, , Philadelphia, Pennysylvania;4. Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, , Philadelphia, Pennysylvania;5. Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, , Philadelphia, Pennysylvania;6. Department of Clinical Studies‐New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, , Philadelphia, Pennysylvania;7. Department of Orthopaedic Surgery, Perelman School of Medicine University of Pennsylvania, , Philadelphia, Pennysylvania |
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| Abstract: | It is often difficult to decouple the relative importance of different factors in regulating MSC differentiation. Genetically modified mice provide model systems whereby some variables can be manipulated while others are kept constant. Fracture repair in thrombospondin‐2 (TSP2)‐null mice is characterized by reduced endochondral ossification and enhanced intramembranous bone formation. The proposed mechanism for this shift in MSC fate is that increased vascular density and hence oxygen availability in TSP2‐null mice regulates differentiation. However, TSP2 is multifunctional and regulates other aspects of the regenerative cascade, such as MSC proliferation. The objective of this study is to use a previously developed computational model of tissue differentiation, in which substrate stiffness and oxygen tension regulate stem cell differentiation, to simulate potential mechanisms which may drive alterations in MSC fate in TSP2‐null mice. Four models (increased cell proliferation, increased numbers of MSCs in the marrow decreased cellular oxygen consumption, and an initially stiffer callus) were not predictive of experimental observations in TSP2‐null mice. In contrast, increasing the rate of angiogenic progression led to a prediction of greater intramembranous ossification, diminished endochondral ossification, and a reduced region of hypoxia in the fracture callus similar to that quantified experimentally by the immunohistochemical detection of pimonidazole adducts that develop with hypoxia. This study therefore provides further support for the hypothesis that oxygen availability during early fracture healing is a key regulator of MSC bipotential differentiation, and furthermore, it highlights the advantages of integrating computational models with genetically modified mouse studies for further elucidating mechanisms regulating stem cell fate. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:1585–1596, 2013. |
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| Keywords: | tissue differentiation mesenchymal stem cell finite element model oxygen Thrombospondin‐2 |
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