(MRC DTP) In vivo imaging of macrophage behaviour during wound healing

Tissue repair and regeneration require dramatic and coordinated changes in cell behaviour in both wound-resident cells at the site of injury and in distant cells that respond to and are recruited to the injured tissue. In the last decade, the influence of inflammatory cells on wound healing has been shown to be highly significant, as they can function to promote or inhibit wound healing. Discovering the underlying mechanisms controlling the behaviour of inflammatory cells is pivotal to controlling these cells for therapeutic benefit. It is often very instructive to compare normal processes with diseased processes in order to understand how that process is regulated.

Diabetic patients and animal models have severely impaired wound healing and often develop chronic wounds. By comparing factors in diabetic wounds with normal wounds, we can begin to understand what is important for efficient wound healing and how to overcome impaired wound healing. Inflammatory cells from diabetic patients and animal models are dysfunctional and inhibit wound healing. Specifically, macrophages are critical inflammatory mediators in wounds, and adopt behaviours in response to dynamic environmental cues within the wound. Persistent macrophage infiltration correlates with impaired wound healing in diabetic humans, yet the influence of macrophages during the different stages of both healthy and diabetic wound healing is not fully understood. A major reason for this is that current methodology relies on a static “snapshot” pathology approach to elucidate macrophage behaviour in the wound, which often cannot detect dynamic and rapid changes in macrophage behaviour. In contrast, in vivo imaging techniques permit the real-time non-invasive investigation of biological processes at the cellular and molecular level, providing a better understanding of the underlying biology and evaluation of treatment response.

Specifically, this project would (1) utilise established macrophage-directed PET tracers for the novel purpose of tracking macrophage behaviour in diabetic and non-diabetic wounds in real time and (2) assess the response to immune-targeted therapies and (3) develop novel nanobody-based PET technology to visualise specific subsets of macrophages in wounds. These studies will be conducted in pre-clinical, mouse models.