Background: Completed medical degree (MBChB, 2001) at the University of Aberdeen then worked clinically for some years. Carried out research PhD in Neuroscience and Biomedical Systems at the University of Glasgow (2008), then worked as a post-doctoral researcher at Liverpool John Moores University (2009-2013) and at King's College London (2013-2015).
Contact: Garstang 7.52b, +44(0) 113 34 39804,
Stem and progenitor cells in cardiovascular tissue: myocardial tissue maintenance
My interest is in the role played by endogenous cardiac stem cells (eCSCs) within the myocardium and their contribution to tissue in both normal myocardial function and in disease. It has been shown that these cells exhibit defining characteristics of stem cells and can develop into the main cell lineages found within the myocardium: cardiomyocytes, endothelial cells, smooth muscle cells and fibroblasts (Smith et al., 2014, Nature Protocols 9(7): 1662-1681) and can repair lost myocardial tissue following injury.
In my previous work in the laboratory of Dr. Georgina Ellison-Hughes at King's College London, we investigated the role of these cells in the post-injury setting, in particular their response to diffuse cardiac injury, showing that they play a critical role in myocardial tissue maintenance in this setting (Ellison et al., 2013, Cell 154(4): 827-42). In addition to this, we demonstrated that the application of growth factors via the cornoary blood supply can increase eCSCs' activity, in association with an improved tissue and functional recovery following myocardial infarction (Ellison et al., 2011, Journal of the American College of Cardiology 58: 977-86). I have presented this work at the American Heart Association Scientific Sessions conference (Orlando FL, November 2015; Chicago IL, November 2010) and the European Society for Cardiology Congress (London, August 2015).
An additional important aspect of eCSC biology is that these cells can be activated by physiological stimulus, specifically high-intensity exercise (Waring et al., 2012, European Heart Journal 35(39): 2722-2731). The mechanisms underlying this are of interest in my group, with funding applications in place to pursue this further, considering the roles of both cardiac and endothelial stem/progenitor cell populations.
My particular focus at present is on the anti-cancer drugs and known cardiotoxins receptor tyrosine kinase inhibitors (RTKIs), specifically their effects on eCSCs. I am interested in the RTKIs’ effects regarding both their impact on the viability and numbers of the eCSC population as a whole and their effects on eCSCs’ characteristics and their role in myocardial tissue maintenance. From this I intend to determine whether RTKI toxicity is due to their effects on eCSCs and to use this information to identify the role played by different RTK receptors in eCSC biology, in terms of how different second messenger systems associated with RTK receptors affect eCSCs’ characteristics and regenerative potential. This may allow the identification of new avenues for treatment in the specific case of RTKI-induced cardiotoxicity or potentially a means to manipulate eCSC biology with a view to using these cells’ regenerative potential to treat heart failure more broadly.
The second current area of investigation in my research group is continuing the development of a new method of non-destructive cell protein 'biopsy', in which we apply a novel chemical tool to sample proteins from cells without causing cell destruction. This is based around the use of an amphipathic polymer, which can extract cell proteins surrounded by a 'cuff' of membrane: we discovered for the first time that the application of this method allows the collection of cell proteins without the associated death of the cell. This first study has now been completed and we are developing further studies to exploit this finding and drive it towards further utilisation.
Dr. Georgina M. Ellison-Hughes, King's College London
Dr. Ali Salehi-Reyhani, Imperial College London
Cell death mechanisms in endogenous cardiac stem cells from tyrosine kinase inhibitors.
This study is currently on-going, using human eCSCs that have been isolated from tissue and grown in culture, to examine the mechanisms involved in the toxicity induced by tyrosine kinase inhibitors. Study will focus on the cell death pathways involved and will also examine associated alterations in intracellular calcium and levels of reactive oxygen species (ROS). This project involves isolation of human cells from tissue samples, cell culture, live staining and imaging in multi-well plates and confocal analysis, immunological labelling and molecular biology techniques; with considerable confocal microscope work to examine calcium and ROS labelling. This project is being supervised by Dr. Smith in collaboration with Prof. Derek Steele, and is funded by the School of Biomedical Sciences and the Leeds Anniversary Research Scholarship. The early findings from this work will be presented at the Physiological Society Future Physiology meeting in December 2017.
Endogenous cardiac stem cell phenotype changes due to tyrosine kinase inhibitors.
This study is in progress, using human eCSCs that have been isolated from tissue and grown in culture, to examine the changes to eCSC phenotype induced by tyrosine kinase inhibitors, including the impact on the cells' self-renewal, ability to differentiate, alteration of the pro-survival secretome released by the cells and the impact on internal cell signalling mechanisms. We have also determined that the most eCSC-toxic of three tyrosine kinase inhibitors (sunitinib malate) impacts on the function of the whole heart. This work is in collaboration with Dr. Georgina Ellison-Hughes at King's College London, is funded by Heart Research UK and the Rosetrees Trust, and findings have been presented at the British Society of Cardiovascular Research meeting (Leeds, September 2016) and the European Society of Cardiology Congress (Barcelona, August 2017).
Novel chemical methods to sample cell surface proteins.
This study is now completed, but forms the basis for further upcoming project in my research group. We used human cardiovascular cells, which had been isolated from clinical myocardial or vascular tissue samples and placed in culture. We applyied a novel chemical tool to in effect 'biopsy' the cell surface and obtain identifiable proteins, with the intention of obtaining marker proteins to characterise the cells, without affecting cell survival by this process. This project was successfully completed, in collaboration with Prof. John Colyer (Faculty of Biological Sciences) and Dr. Karen Porter (Faculty of Medicine and Health), with funding from the Wellcome Trust ISSF, and has been presented at the Nanoparticle technologies for membrane protein research meeting (Leeds Beckett University, June 2017).
BMSC1103 - Basic Laboratory and Scientific Skills
BMSC1110 - Foundations of Biomedical Sciences
BMSC2232 - Topics in Physiology
BMSC2235 - Molecular Neuroscience
BMSC3234/35/36 - Advanced Topics II
BMSC3301 - Research Project in Biomedical Sciences
BMSC5301M - Advanced Research Topics
BMSC5382M - Extended Research Project
DSUR1127 - Health and Health promotion
SPSC3328 - Sport Medicine, Health and Nutrition
Centre membership: The Multidisciplinary Cardiovascular Research Centre (MCRC)
Dr Kathleen Wright (Senior Scientific Officer in Cardiovascular Science)
Providing laboratory research support for multiple PIs, training new staff and laboratory/office management
Vicinanza C, Aquila I, Scalise M, Cristiano F, Marino F, Cianflone E, Mancuso T, Marotta P, Sacco W, Lewis FC, Couch L, Shone V, Gritti G, Torella A, Smith AJ, Terracciano CM, Britti D, Veltri P, Indolfi C, Nadal-Ginard B, Ellison-Hughes GM, Torella D Adult cardiac stem cells are multipotent and robustly myogenic: C-kit expression is necessary but not sufficient for their identification Cell Death and Differentiation 24 2101-2116, 2017
Waring CD, Henning BJ, Smith AJ, Nadal-Ginard B, Torella D, Ellison GM Cardiac adaptations from 4 weeks of intensity-controlled vigorous exercise are lost after a similar period of detraining Physiological Reports 3 e12302-e12302, 2015
Waring CD, Vicinanza C, Papalamprou A, Smith AJ, Purushothaman S, Goldspink DF, Nadal-Ginard B, Torella D, Ellison GM The adult heart responds to increased workload with physiologic hypertrophy, cardiac stem cell activation, and new myocyte formation European Heart Journal 35 2722-2731, 2014
Smith AJ, Lewis FC, Aquila I, Waring CD, Nocera A, Agosti V, Nadal-Ginard B, Torella D, Ellison GM Isolation and characterization of resident endogenous c-Kit<sup>+</sup>cardiac stem cells from the adult mouse and rat heart Nature Protocols 9 1662-1681, 2014
Ellison GM, Vicinanza C, Smith AJ, Aquila I, Leone A, Waring CD, Henning BJ, Stirparo GG, Papait R, Scarfò M, Agosti V, Viglietto G, Condorelli G, Indolfi C, Ottolenghi S, Torella D, Nadal-Ginard B Adult c-kit<sup>pos</sup>cardiac stem cells are necessary and sufficient for functional cardiac regeneration and repair Cell 154 827-842, 2013
Ellison GM, Torella D, Dellegrottaglie S, Perez-Martinez C, Perez de Prado A, Vicinanza C, Purushothaman S, Galuppo V, Iaconetti C, Waring CD, Smith AJ, Torella M, Cuellas Ramon C, Gonzalo-Orden JM, Agosti V, Indolfi C, Galinanes M, Fernandez-Vazquez F, Nadal-Ginard B Endogenous cardiac stem cell activation by insulin-like growth factor-1/hepatocyte growth factor intracoronary injection fosters survival and regeneration of the infarcted pig heart. Journal of the American College of Cardiology 977-986, 2011
Darlington LG, Forrest CM, Mackay GM, Smith RA, Smith AJ, Stoy N, Stone TW On the biological importance of the 3-hydroxyanthranilic acid: Anthranilic acid ratio International Journal of Tryptophan Research 3 51-59, 2010
Kawaguchi N, Smith AJ, Waring CD, Hasan MK, Miyamoto S, Matsuoka R, Ellison GM c-kit<sup>pos</sup>GATA-4 high rat cardiac stem cells foster adult cardiomyocyte survival through IGF-1 paracrine signalling PLoS ONE 5, 2010
Smith AJ, Tauskela JS, Stone TW, Smith RA Preconditioning with 4-aminopyridine protects cerebellar granule neurons against excitotoxicity. Brain research 1294 165-175, 2009
Smith AJ, Smith RA, Stone TW 5-Hydroxyanthranilic Acid, a Tryptophan Metabolite, Generates Oxidative Stress and Neuronal Death via p38 Activation in Cultured Cerebellar Granule Neurones Neurotoxicity Research 15 303-310, 2009
Smith AJ, Stone TW, Smith RA Preconditioning with NMDA protects against toxicity of 3-nitropropionic acid or glutamate in cultured cerebellar granule neurons Neuroscience Letters 440 294-298, 2008
Smith AJ, Aquila I, Henning BJ, Scalise M, Nadal-Ginard B, Ellison GM, Torella D Endogenous cardiac stem cells’ activation in response to injury potentiates their regenerative ability.
Smith AJ, Aquila I, Marino F, Scalise M, Henning BJ, Nadal-Ginard B, Ellison GM, Torella D In situ activation of endogenous cardiac stem cells alters their secretome, miRnome, potentiating their regenerative capacity on the injured heart.
Smith AJ, Wright KE, Ruchaya P, Nadal-Ginard B, Ellison-Hughes GM Cardiotoxic receptor tyrosine kinase inhibitors exert toxic effects on human cardiac stem cells and impair cardiac function