Investigating the efficacy and mechanism of action of mesenchymal stromal cell therapy in burn wound healing

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Whelan, Derek S.
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University College Cork
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Several studies suggest that mesenchymal stromal cell (MSC) therapy may be efficacious in accelerating wound healing. Which source of MSC is therapeutically superior has not been well established, especially in large clinically relevant animal models. We therefore investigated the efficacy of Bone marrow-MSC (BM-MSC) and Adipose-MSC (AD-MSC) in the treatment of burn wounds in a large porcine model. Donor matched allogeneic AD-MSC and BM-MSC were applied onto partial thickness burns within a fibrin hydrogel. MSC therapy was similarly efficacious in both groups, increasing wound closure, angiogenesis and collagen content, associated with increased wound maturity at two weeks. To augment this therapeutic response, priming of MSC with inflammatory cytokines was explored. Administration of MSC primed with TNFα resulted in a significant acceleration of burn wound closure, re-epithelialisation and increased angiogenesis, AD-MSC and BM-MSC were therapeutically equivalent in their response to TNFα. We hypothesised that MSC derived CCL-2 may be involved in the MSC therapeutic effect by facilitating macrophage repolarisation and may also play a role in TNFα pre-treatment as CCL2 is greatly induced by TNFα. To further delineate this mechanism, MSC isolated from CCL-2 deficient mice (CCL-2 KO) were applied to excisional wounds in wild-type (WT) mice. Interestingly, CCL-2 deficiency in MSC completely abrogated the therapeutic response compared to WT MSC. CCL-2 KO MSC were unable to repolarise macrophages to the same extent as WT and this was accompanied by a reduced angiogenesis and re-epithelialisation of the wounds at day 10. TNFα pre-treatment of WT MSC significantly increased therapeutic efficacy, resulting in complete re-epithelisation of all wounds by day 10. CCL-2 KO MSC responded somewhat, with increased CD206+ macrophages and reduced Ly6G+ neutrophils present within the wound, but this biology had no effect on re-epithelialisation.
Burns , Wound healing , MSC
Whelan, D. S. 2017. Investigating the efficacy and mechanism of action of mesenchymal stromal cell therapy in burn wound healing. PhD Thesis, University College Cork.