Dr Matthew Hardman (BSc, PhD) - research

Cell Adhesion, Stem Cells, Wound Healing and Regeneration, Immunology, Adult/Tissue Stem Cells, Tissue Regeneration

The Role of Hormones in Delayed Wound Healing in the Elderly

Background. We are currently seeing a dramatic increase in the UK aged population. Aged skin takes longer to heal and elderly individuals are particularly susceptibible to developing non-healing skin wounds, eg. pressure sores or leg ulcers. Impaired healing results in substantial morbidity, mortality, and cost (in the US alone treatment of delayed wound healing is estimated to cost over $25 billion per year). Considering the high prevalence and extended time to heal, treatment modalities for chronic wounds are very limited. Our group has made major contributions to the understanding of delayed wound healing in the elderly.

Current projects

Hormones and Ageing. Prior studies published by our group have revealed a major and physiologically relevant role for gender hormones in regulating wound healing. We have shown that the vast majority of genes with altered expression in wounds from aged vs young males are estrogen regulated (80%), while few are known gerontogenes (3%) (Hardman & Ashcroft, 2008). In women the transition to delayed healing coincides with the menopause where hormone levels, particularly estrogen, rapidly fall. Estrogen replacement accelerates healing in both humans and animal models, with estrogen acting as a pleiotropic mediator, beneficially influencing multiple wound cell types (Emmerson et al., 2009). More recently we have identified differential roles for the two estrogen receptors (ERs) (Gilliver et al., 2010). There is a fundamental need to further elucidate cutaneous estrogen signalling with a view to selectively exploit the beneficial aspects to promote healing.

SERMs. Unfortunately there are substantial risks associated with the long term HRT. Thus, we are identifying alternative estrogen-like compounds capable of promoting healing while bypassing estrogen’s detrimental actions. We have primarily focused on selective ER modulators, revealing the novel therapeutic potential of two SERM currently in clinical use, tamoxifen and raloxifene (Hardman et al., 2008). More recently we have shown that the dietary phytoestrogen genistein also accelerates murine wound healing, dampening inflammation. The mode of action is complex, involving ER-independent effects (Emmerson et al., 2010). Thus, we propose that SERMs represent excellent candidates for therapeutic acceleration of delayed wound healing in the elderly population.

MIF as a key downstream mediator. We have shown that a small atypical pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) plays an extensive role in mediating the effects of estrogen on tissue repair (Hardman et al., 2005). Our recent work has shown that MIF is involved in numerous aspects of the cutaneous repair response, and that estrogen - MIF interaction is cell type specific (Emmerson et al, 2009). We are currently using genetically modified mice to investigate SERM/MIF interaction during wound repair.

Novel wound processes. By using a combination of estrogen signalling expertise combined with in vitro, ex vivo, pre-clinical, surgical and transgenic in vivo models we are probing the causes of delayed tissue repair in the elderly. Our current projects are investigating the contribution of estrogen-regulated changes in stem cell function, cell adhesion, extracellular matrix and inflammation to delayed tissue repair in the elderly.