Rosenthal Group (Visiting)
Regenerative mechanisms in heart and skeletal muscle
Model of enhanced cardiac repair mediated by mIGF-1: Secreted locally by cardiomyocytes, transgenic mIGF-1 polarises invading macrophages to secrete their own mIGF-1, and stimulating RA synthesis in the epicardium, which induces new cardiomyocte formation in response to injury. In adjoining vasculature, mIGF-1 activates Sgk1, which induces Notch signalling in the vascular bed. This stimulates M2 macrophages to promote angiogenesis through endothelial cells and epicardial derivatives, with anastomosis by resident M2 macrophages.
Previous and current research
Our laboratory focuses on regenerative biology, which explores the processes that restore the architecture of damaged or degenerating tissues, oft en by recapitulating original embryonic development. Over the past decade we have used mouse genetics to enhance naturally acting signalling pathways that have proven highly effective in countering tissue decline. Local supplementation of Insulin-like Growth Factor-1 (IGF-1) propeptides orchestrates efficient repair of injured skeletal muscle tissues without scar formation, prevents age and heart failure-related muscle atrophy and enhances bone marrow cell recruitment to the damaged tissue. Importantly, neither fully processed IGF-1 nor systemically administered IGF-1 counteracts muscle loss.
Since IGF-1 curtails the expression of infl ammatory cytokines, we have investigated the role of the innate immune system in the regeneration process, using a genetic model in which prevention of macrophage polarisation blocks muscle regeneration. We have extended these findings to reveal the molecular and cellular mechanisms whereby localised IGF-1 propeptides induce eff ective tissue regeneration in the damaged heart. In our mouse model of enhanced cardiac repair, injury of the cardiomyocyte-specific mIGF-1 transgenic hearts activates a series of signalling intermediates, specifically in the epicardium - a layer of cells surrounding the heart that give rise to the coronary vasculature during embryogenesis. We are using mouse genetics to establish a role for exogenous or endogenous macrophages in promoting effective vascularisation and cardiomyocyte replacement in the uninjured and damaged heart. Supplemental mIGF-1 polarises macrophages to synthesise endogenous IGF-1 propeptides that target myocytes (improving survival by depressing NFkB protein turnover, activating SirT1 and inducing new muscle formation), endothelial cells (inducing cardiac regrowth by activating Sgk1 and Notch) and macrophages themselves (working indirectly to promote revascularisation, and directly as a stimulus to generate new muscle). We are pursuing the possibility that mIGF-1 potential progenitor cells for tissue regeneration may be disguised as components of the immune system, which can be coaxed into more productive engagement in the repair process with relatively simple, clinically applicable manipulations.
Future projects and goals
In our future research, we will exploit new conditional and inducible mouse genetic models and transgenic markers to characterise key cells and molecules governing the regeneration of mammalian tissues. We aim to defi ne the signalling mechanisms whereby selected growth factors and their intracellular intermediates modulate immune cell lineages in control inflammation and in promoting tissue repair. We hope to use this knowledge for developing clinically relevant interventions in ageing, injury and degenerative disease.