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- PublicationROCK activity and the Gβγ complex mediate chemotactic migration of mouse bone marrow-derived stromal cellsBone marrow-derived stromal cells (BMSCs), also known as mesenchymal stem cells, are the focus of intensive efforts worldwide to elucidate their function and biology. Despite the importance of BMSC migration for their potential therapeutic uses, the mechanisms and signalling governing stem cell migration are still not fully elucidated. Methods: We investigated and detailed the effects of MCP-1 activation on BMSCs by using inhibitors of G protein-coupled receptor alpha beta (GPCR αβ), ROCK (Rho-associated, coiled-coil containing protein kinase), and PI3 kinase (PI3K). The effects of MCP-1 stimulation on intracellular signalling cascades were characterised by using immunoblotting and immunofluorescence. The effectors of MCP-1-mediated migration were investigated by using migration assays (both two-dimensional and three-dimensional) in combination with inhibitors. Results: We established the kinetics of the MCP-1-activated signalling cascade and show that this cascade correlates with cell surface re-localisation of chemokine (C motif) receptor 2 (CCR2) (the MCP-1 receptor) to the cell periphery following MCP-1 stimulation. We show that MCP-1-initiated signalling is dependent on the activation of βγ subunits from the GPCR αβγ complex. In addition, we characterise a novel role for PI3Kγ signalling for the activation of both PAK and ERK following MCP-1 stimulation. We present evidence that the Gβγ complex is responsible for PI3K/Akt, PAK, and ERK signalling induced by MCP-1 in BMSCs. Importantly, we found that, in BMSCs, inhibition of ROCK significantly inhibits MCP-1-induced chemotactic migration, in contrast to previous reports in other systems.Conclusions: Our results indicate differential chemotactic signalling in mouse BMSCs, which has important implications for the translation of in vivo mouse model findings into human trials. We identified novel components and interactions activated by MCP-1-mediated signalling, which are important for stem cell migration. This work has identified additional potential therapeutic targets that could be manipulated to improve BMSC delivery and homing.
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- PublicationIntroduction to Series on Mesenchymal Stromal (Stem) Cells—MSCs
- PublicationStem Cell Research & Therapy marks its first anniversaryJust over a year ago we launched Stem Cell Research & Therapy with the aim of it becoming the major forum for translational research into stem cell therapies . As we celebrate our first year of publication we look back at what we have achieved and how we hope to progress in our second year and beyond. Stem Cell Research & Therapy is an international, peer-reviewed, open access journal with a special emphasis on basic, translational, and clinical research into stem cell therapeutics, including animal models, and clinical trials. At launch we noted both the enormous potential of stem cell therapies and the major hurdles that have to be overcome . While the past year has seen continued legal turmoil regarding government funding of embryonic stem cell research in the USA , stem cell research continues to progress apace internationally.
Scopus© Citations 1 220
- PublicationLiposomal gene delivery mediated by tissue-engineered scaffoldsIn the absence of any ideal gene delivery carrier despite the recent explosion of novel carrier systems, the current trend is to explore the complementary synergy promised by a combination of delivery systems such as liposomes, which are the most widely researched versatile non-viral carriers, and tissue-engineered scaffolds with macrostructures of defined architecture comprised of natural or synthetic macromolecules. Here, we discuss the recent advances in liposomal gene delivery and the possible benefits of a combined liposome–scaffold approach, such as long-term expression, enhanced stability, reduction in toxicity and ability to produce spatio-temporal expression patterns. This approach is generating significant impact in the field as a result of its potential for extended localised gene delivery for applications in a variety of clinical conditions.
Scopus© Citations 72 1160
- PublicationInfluence of Referral to a Combined Diabetology and Nephrology Clinic on Renal Functional Trends and Metabolic Parameters in Adults With Diabetic Kidney DiseaseTo examine the impact of a diabetes renal clinic (DRC) on renal functional and metabolic indices in adults who have diabetes mellitus (DM) and chronic kidney disease (CKD).All patients evaluated at a DRC in a single tertiary referral center from January 1, 2008, to December 31, 2012, were identified. Serial renal and metabolic indices from January 1, 2004, to December 31, 2014, were recorded, and trends over time were analyzed by linear mixed-effects models.A total of 200 patients who had DM and CKD were identified and subdivided into 3 categories based on presumptive CKD etiology: 43 (21.5%) with type 1 DM (T1D) only, 127 (63.5%) with type 2 DM (T2D) only, and 30 (15.0%) with DM and an additional CKD etiology. Average annual absolute (mL/min per body surface area per year) and percentage (%/year) changes, respectively, in Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rate before vs after first DRC attendance were: -1.59 vs -3.10 (P=.31) and -1.22 vs -9.39 (P=.06) for T1D; -5.64 vs -3.07 (P=.004) and -10.88 vs -9.94 (P=.70) for T2D; and -6.50 vs +0.91 (P<.001) and -13.28 vs -2.29 (P=.001) for DM with an additional CKD etiology. Glycemic control worsened in those who had T2D, whereas trends in total cholesterol levels improved in those who had T1D.After first DRC attendance, the absolute rate of estimated glomerular filtration rate decline remained similar for those who had T1D, but it slowed for those who had T2D or DM with additional CKD etiology. Thus, benefits of combined diabetology and nephrology consultation may vary for different diabetic subpopulations.