Limitations of the MRL mouse as a model for cardiac regeneration

Objective Myocardial repair following injury in mammals is restricted such that damaged areas are replaced by scar tissue, impairing cardiac function. MRL mice exhibit exceptional regenerative healing in an ear punch wound model. Some myocardial repair with restoration of heart function has also been reported following cryoinjury. Increased cardiomyocyte proliferation and a foetal liver stem cell population were implicated. We investigated molecular mechanisms facilitating myocardial repair in MRL mice to identify potential therapeutic targets in non-regenerative species. Methods Expressions of specific cell-cycle regulators that might account for regeneration (CDKs 1, 2, 4 and 6; cyclins A, E, D1 and B1; p21, p27 and E2F5) were compared by immunoblotting in MRL and control C57BL/6 ventricles during development. Flow cytometry was used to investigate stem cell populations in livers from foetal mice, and infarct sizes were compared in coronary artery-ligated and sham-treated MRL and C57BL/6 adult mice. Key findings No differences in the expressions of cell cycle regulators were observed between the two strains. Expressions of CD34+Sca1+ckit-, CD34+Sca1+ckit+ and CD34+Sca1-ckit+ increased in livers from C57BL/6 vs MRL mice. No differences were observed in infarct sizes, levels of fibrosis, Ki67 staining or cardiac function between MRL and C57BL/6 mice. Conclusions No intrinsic differences were observed in cell cycle control molecules or stem cell populations between MRL and control C57BL mouse hearts. Pathophysiologically relevant ischaemic injury is not repaired more efficiently in MRL myocardium, questioning the use of the MRL mouse as a reliable model for cardiac regeneration in response to pathophysiologically relevant forms of injury.

Canonical Wnt signalling induces satellite-cell proliferation during adult skeletal muscle regeneration

Satellite cells represent the stem cell population of adult skeletal muscle. The molecular mechanisms that control the proliferation of satellite cells are not well understood. In this study, we show that in response to injury, myofibres activate Wnt ligand transcription and activate a reporter cell line that is sensitive to the canonical Wnt-signalling pathway. Activated satellite cells on isolated cultured myofibres show robust expression of activated-β-catenin (Act-β-Cat), a key downstream transcriptional coactivator of canonical Wnt signalling. We provide evidence that the Wnt family of secreted glycoproteins act on satellite cells in a ligand-specific manner. Overexpression of Wnt1, Wnt3a or Wnt5a protein causes a dramatic increase in satellite-cell proliferation. By contrast, exposure of satellite cells to Wnt4 or Wnt6 diminishes this process. Moreover, we show that the prolonged satellite-cell quiescence induced by inhibitory Wnt is reversible and exposing inhibited satellite cells to stimulatory Wnt signalling restores their proliferation rate. Stimulatory Wnt proteins induce premature satellite cell BrdU incorporation as well as nuclear translocation of Act-β-Cat. Finally, we provide evidence that the Act-β-Cat translocation observed in single fibres during in vitro culture also occurs in cases of acute and chronic skeletal muscle regeneration in rodents and humans. We propose that Wnt proteins may be key factors that regulate the rate of satellite-cell proliferation on adult muscle fibres during the wound-healing response.

TRIM32 regulates skeletal muscle stem cell differentiation and is necessary for normal adult muscle regeneration

Limb girdle muscular dystrophy type 2H (LGMD2H) is an inherited autosomal recessive disease of skeletal muscle caused by a mutation in the TRIM32 gene. Currently its pathogenesis is entirely unclear. Typically the regeneration process of adult skeletal muscle during growth or following injury is controlled by a tissue specific stem cell population termed satellite cells. Given that TRIM32 regulates the fate of mammalian neural progenitor cells through controlling their differentiation, we asked whether TRIM32 could also be essential for the regulation of myogenic stem cells. Here we demonstrate for the first time that TRIM32 is expressed in the skeletal muscle stem cell lineage of adult mice, and that in the absence of TRIM32, myogenic differentiation is disrupted. Moreover, we show that the ubiquitin ligase TRIM32 controls this process through the regulation of c-Myc, a similar mechanism to that previously observed in neural progenitors. Importantly we show that loss of TRIM32 function induces a LGMD2H-like phenotype and strongly affects muscle regeneration in vivo. Our studies implicate that the loss of TRIM32 results in dysfunctional muscle stem cells which could contribute to the development of LGMD2H.

Critical success factors in urban brownfield regeneration: an analysis of ‘hardcore’ sites in Manchester and Osaka during the economic recession (2009–10)

Hardcore, or long-term derelict and vacant brownfield sites which are often contaminated, form a significant proportion of brownfield land in many cities, not only in the UK but also in other countries. The recent economic recession has placed the economic viability of such sites in jeopardy. This paper compares the approaches for bringing back hardcore brownfield sites into use in England and Japan by focusing on ten case studies in Manchester and Osaka, using an `agency'-based frame- work. The findings are set in the context of (i) national brownfield and related policy agendas; (ii) recent trends in land and property markets in both England and Japan; and (iii) city-level comparisons of brownfields in Manchester and Osaka. The research, which was conducted during 2009 ^ 10, suggests that hardcore brownfield sites have been badly affected by the recent recession in both Manchester and Osaka. Despite this, not only is there evidence that hardcore sites have been successfully regenerated in both cities, but also that the critical success factors (CSFs) operating in bringing sites back into use share a large degree of commonality. These CSFs include the presence of strong potential markets, seeing the recession as an opportunity, long-term vision, strong branding, strong partnerships, integrated development, and getting infrastructure into place. Finally, the paper outlines the policy implications of the research.

Housing supply and brownfield regeneration in a post-Barker world: is there enough brownfield land in England and Scotland?

The findings of the Barker review, which examined the reasons for the undersupply of UK housing, have important implications for the devolved constituents of the UK, including Scotland. This paper traces the emergence of the brownfi eld regeneration policy agenda across the UK and examines how the Barker review connects with this brownfi eld policy focus. The paper compares housing and brownfi eld policies and practices in England and Scotland, places them in an international context and elicits wider lessons for devolved governance in relation to housing policy, in terms of ‘centrist–local’ tensions. Estimates based on published data suggest that Barker’s emphasis on increased housing supply cannot easily be reconciled with the current emphasis on brownfi eld development and is likely to require a return to greenfield development in both countries.

The property development industry and sustainable urban brownfield regeneration in England: an analysis of case studies in Thames Gateway and Greater Manchester

The property development industry is a key actor in UK brownfield regeneration projects. UK policy has attempted to interlink ‘sustainable development’ and ‘sustainable brownfield’ policy agendas, which have found an additional focus through the UK government’s ‘Sustainable Communities Plan’, part of a growing international emphasis on sustainable development. This paper examines the emergence of these agendas and related policies, and the role of the property development industry in the regeneration of six differing brownfield sites, based in Thames Gateway and Greater Manchester. Using a conceptual framework, the paper investigates aspects of the sustainability of these projects and highlights key lessons from them for both the UK and overseas. The research is based on structured interviews with a variety of stakeholders, including developers, planners, consultants and community representatives to highlight emerging best practice and related policy implications.