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Title: Leukocyte HMGB1 guides neoangiogenesis in regenerating skeletal muscle
Author: Campana, Lara
Awarding Body: Open University
Current Institution: Open University
Date of Award: 2012
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HMGB 1 is ubiquitously present in the cell nucleus and highly conserved among species. It is released by necrotic cells and actively secreted by immune cells in the extracellular environment, where it behaves as a DAMP (Damage-Associate Molecular Pattern). Up to now all studies addressing the role of HMGB 1 in wound healing have been carried out either in vitro or using pharmacological inhibitors. To assess the relative contribution of leukocyte HMGB 1 and of passively released HMGB 1 we have set up an ad hoc animal model. In this system, haematopoietic cells selectively lack HMGB 1 by transplanting Hmgb1+/+ or Hmgb1-/- foetal livers into WT recipients. The role of leukocyte HMGB 1 in tissue repair has been analyzed after skeletal muscle damage. I have used histological and magnetic resonance imaging (MRI) to non- invasively evaluate muscle inflammation and tissue architecture. In the absence of Hmgb 1, there is a lower number of regenerating fibres at day7 after injury and an aberrant repair with smaller fibres at day15. In vitro no differential effects of Hmgb1-/- and Hmgb1+/+ macrophages are detected on satellite cells differentiation/fusion, suggesting that events taking place in vivo are independent of the direct macrophage/satellite cell cross talk. No obvious differences are observed in the extent of leukocyte infiltration, as assessed both by cytofluorimetric and MRI analysis, , suggesting that leukocyte Hmgb 1 is not required for the attraction of inflammatory cells. qPCR unveils a role for leukocyte Hmgb 1 in the production of angiogenic stimuli such as Ang2 and TNFu, probably in a hypoxia-dependent manner. Accordingly, the number of CD31 cells is dramatically reduced in the absence of leukocyte Hmgb 1. Collectively our data suggest that HMGB1 secreted by leukocytes guides muscle regeneration through a paracnne role on vascular bed reconstitution.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available