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Title: Promoting fracture repair by inflammation-mediated recruitment of muscle derived stromal cells
Author: Glass, Graeme Ewan
ISNI:       0000 0004 2692 0315
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2010
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High energy open fractures are prone to delayed and non-union, necessitating secondary reconstruction or amputation and are associated with prolonged pain, disability and loss of income. Current strategies for accelerating healing require the addition of high concentrations of bone morphogenetic proteins or ex vivo expansion and/or viral transduction of autologous, marrow-derived stem cells for re-implantation. It is established that prompt cover with vascularised tissue is required to prevent bony infection. Coverage with muscle improves healing time and union strength in an experimental model but the reason for this finding remains unclear. The fracture environment, simulated by supernatant produced using human fractured bone fragments was found to promote the migration and osteogenic differentiation of human skeletal muscle derived cells (MDSC). These cells displayed a mesenchymal stromal phenotype. TNF-α and IL-6 promoted osteogenic differentiation of MDSC. TNF-α and IL-6 also promoted the migration of MDSC in vitro but did not appear to influence their proliferation. Using an in vivo periosteally stripped (high energy) fracture model, the P55 (TNF receptor-1) knockout exhibited early delay. Recombinant TNF-α promoted fracture healing in wild type mice but was inhibitory at high concentrations. The peri-fracture inflammatory infiltrate was comprised mainly of neutrophils. T cells were also present. Severe, combined immunodeficient mice exhibited delayed fracture healing. The study establishes the role of muscle derived stromal cells as an osteoprogenitor population, which may be important in healing high-energy fractures stripped of periosteum. These cells migrate and differentiate down an osteogenic lineage in response to TNF-α, present in the fracture environment. Fracture healing is critically dependent on TNF-α concentration locally and a high local concentration may be inhibitory. Fracture healing may be promoted by manipulating inflammation locally. Neutrophils and T cells are both potential sources of TNF-α.
Supervisor: Nanchahal, Jagdeep Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral