Dr Andrew Smith

Profile

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).

Responsibilities

• Lecturer in Cardiovascular Science
• Leader for MBiol Programme in School of Biomedical Sciences
• Admissions Tutor for School of Biomedical Sciences

Research interests

Stem and progenitor cells in cardiovascular tissue: myocardial tissue maintenance

Cardiac tissue maintenance and repair

A main research interest in my group is in the role played by endogenous cardiac progenitor cells CPCs) 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 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 these cells' 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, USA, November 2015; Chicago IL, USA, November 2010) and the European Society for Cardiology Congress (London,UK,  August 2015). 

An additional important aspect of CPC 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. 

Cardiac Progenitor Cell roles in cardiotoxicity and phenotype changes due to tyrosine kinase inhibitors.

A particular focus at present is on the anti-cancer drugs and known cardiotoxins receptor tyrosine kinase inhibitors (RTKIs), specifically their effects on CPCs, using human eCSCs that have been isolated from tissue and grown in culture. Our first study has now been completed, examining the changes to CPC phenotype induced by RTKIs, 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 CPC-toxic of three RTKIs (sunitinib malate) impacts on the function of the whole heart. This may allow the identification of new avenues for treatment in the specific case of RTKI-induced cardiotoxicity or potentially a means to manipulate CPC biology with a view to using these cells’ regenerative potential to treat heart failure more broadly. This work was carried out in collaboration with Dr. Georgina Ellison-Hughes at King's College London, funded by Heart Research UK and the Rosetrees Trust, with early findings presented at: the British Society of Cardiovascular Research meeting (Leeds, September 2016) and the European Society of Cardiology Congress (Barcelona, August 2017), and the complete study presented at the Amercian Heart Association Scientific Sessions conference (Chicago IL, USA, November 2018) and the Physiological Society Life Sciences conference (Aberdeen, UK, July 2019). A complementary study examining the impact of tyrosine kinase inhibitors on adult cardiac fibroblasts has been completed and published (Burke et al., 2019, Toxicology In Vitro 58: 178-186). 

Cell death mechanisms in endogenous cardiac stem cells from tyrosine kinase inhibitors.

This study, building on the above now-completed study, is also now complete, using human CPCs isolated from tissue and grown in culture, to examine the mechanisms involved in the toxicity induced by tyrosine kinase inhibitors. The study focused on the cell death pathways involved and also examined associated alterations in intracellular calcium and levels of reactive oxygen species (ROS). This project used 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. The project was supervised by Dr. Smith in collaboration with Prof. Derek Steele, with funds from the School of Biomedical Sciences and the Leeds Anniversary Research Scholarship. Findings from this work have been presented at the Physiological Society Life Sciences conference (Aberdeen, UK, July 2019) and published as a pre-print on BioRxiv (Walmsley et al., ). 

Non-destructive cell biopsy by amphipathic polymers

Another 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. 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) and the Amercian Heart Association Scientific Sessions conference (Philadelphia, Pennsylvania, USA, November 2019), and published in November 2019 (Smith et al., 2019, Scientific Reports, 9(1): 1-10). 

This study has now been completed, but forms the basis for an on-going project in this research group, a follow-up project funded by Heart Research UK, to examine this method’s ability to actively obtain biomarkers of early vascular complications of diabetes mellitus. 

Recent Research group members

• Dr. Robert Walmsley (PhD project – LARS scholarship)
• Dr. Hanqing Zhao (BHF Research Project grant)
• Mr. Matthew Burke (School of Biomedical Sciences MBiol project funding)
• Dr. Huda Alfardus (HRUK Translational Research Project grant)

Collaborations

• Prof. Georgina M. Ellison-Hughes, King's College London, UK
• Mr. David O'Regan, Leeds General Infirmary, UK
• Mr. Sotiris Papaspyros, Leeds General Infirmary, UK
• Dr. Pilar Sepulveda, University of Valencia, Spain
• Dr. Ali Salehi-Reyhani, Imperial College London, UK

Publications

Smith AJ. (2021) Effects of cardiotoxins on cardiac stem and progenitor cell populations. (Review) Frontiers in Cardiovascular Medicine 8: 624028. 

Walmsley R, Steele DS, Ellison-Hughes GM, Smith AJ. (2021) Imatinib mesylate induces necroptotic cell death and impairs autophagic flux in human cardiac progenitor cells. (BioRxiv, published pre-print) 

Smith AJ, Wright KE, Muench SP, Schumann S, Whitehouse A, Porter KE, Colyer J. (2019) Styrene maleic acid recovers proteins from mammalian cells and tissues while avoiding significant cell death. Scientific Reports 9(1): 1-10

Torella D, Aquila I, Cianflore E, Scalise M, Marino F, Mancuso T, Agosti V, Filardo A, Smith AJ, Cappetta D, De Angelis A, Urbanek K, Isidori A, Torella M, Viglietto G, Nadal-Ginard B, Ellison-Hughes GM. (2019) c-kit Haploinsufficiency Impairs Adult Cardiac Stem Cell Growth, Myogenicity and Myocardial Regeneration. Cell Death & Disease 10, Article number: 436

Burke MJ, Walmsley R, Munsey T, Smith AJ. (2019) Toxicity of receptor tyrosine kinase inhibitors in adult rat cardiac fibroblasts. Toxicology In Vitro 58: 178-186

Sheard TMD, Hurley ME, Colyer J, White E, Pervolaraki E, Narayanasamy KK, Hou Y, Kirton HM, Yang Z, Hunter L, Shim J, Clowsley AH, Smith AJ, Baddeley D, Soeller C, Colman MA, Jayasinghe I. (2019) Three-Dimensional and Chemical Mapping of Intracellular Signalling Nanodomains in Health and Disease with Enhanced Expansion Microscopy. ACS Nano 13(2): 2143-2157

Vicinanza C, Aquila I, Scalise M, Cristiano F, Marino F, Cianflore E, Mancuso T, Marotta P, Sacco W, Lewis FC, Couch L, Shone V, Gritti G, Torella A, Smith AJ, Terracciano CMN, Britti D, Veltri P, Indolfi C, Nadal-Ginard B, Ellison-Hughes GM, Torella D (2017) 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(12): 2101-2116

Waring CD, Henning BJ, Smith AJ, Nadal-Ginard B, Torella D, Ellison GM (2015) Cardiac adaptations from 4 weeks of intensity-controlled vigorous exercise are lost after a similar period of detraining. Physiological Reports 3(2): e12302

Smith AJ, Lewis FC, Aquila I, Waring CD, Nocera A, Agosti V, Nadal-Ginard B, Torella D, Ellison GM (2014) Isolation and characterisation of resident endogenous c-kit-positive cardiac stem cells (eCSCs) from the adult mouse and rat heart. Nature Protocols 9(7): 1662-1681

Ellison GM, Smith AJ, Waring CD, Henning BJ, Burdina AO, Polydorou J, Vicinanza C, Lewis FC, Nadal-Ginard B, Torella D (2014)Chapter "Adult Cardiac Stem Cells: Identity, Location and Potential" in Adult Stem Cells (2^nd Ed) pp 47-90, edited by Kursad Turksen. Springer, New York

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 (2013) Adult c-kit^pos Cardiac Stem Cells Are Necessary and Sufficient for Functional Cardiac Regeneration and Repair. Cell 154(4): 827-42

Waring CD, Vicinanza C, Papalamprou A, Smith AJ, Purushothaman S, Goldspink DF, Nadal-Ginard B, Torella D, Ellison GM (2012) The adult heart responds to increased workload with physiologic hypertrophy, cardiac stem cell activation, and new myocyte formation. European Heart Journal: 35 (39), 2722-2731

Ellison GM, Torella D, Dellegrottaglie S, Perez-Martinez C, Perez de Prado A, Vicinanza C, Purushothaman S, Galuppo V, Iaconetti C, Waring CD, Smith A, Torella M, Cuellas Ramon C, Gonzalo-Orden JM, Agosti V, Indolfi C, Galiñanes M, Fernandez-Vazquez F, Nadal-Ginard B (2011) 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 58: 977-86

Kawaguchi N*, Smith AJ*, Waring CD, Hasan MK, Miyamoto S, Matsuoka R, Ellison GM (2010) c-kitpos GATA-4 high rat cardiac stem cells foster adult cardiomyocyte survival through IGF-1 paracrine signalling. PLoS One 5: e14297 *joint first author

Darlington LG, Forrest CM, Mackay GM, Smith RA, Smith AJ, Stoy N, Stone TW (2010) On the biological importance of the 3-hydroxyanthranilic acid: anthranilic acid ratio. International Journal of Tryptophan Research 3: 51-59

Smith AJ, Tauskela JS, Stone TW, Smith RA (2009) Preconditioning with 4-aminopyridine protects cerebellar granule neurones against excitotoxicity. Brain Research 1294: 165-175

Smith AJ, Smith RA, Stone TW (2009) 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

Smith AJ, Stone TW, Smith RA (2008) Preconditioning with NMDA protects against toxicity of 3-nitropropionic acid or glutamate in cultured cerebellar granule neurons. Neuroscience Letters 440: 294-298

Smith AJ, Stone TW, Smith RA (2007) Neurotoxicity of tryptophan metabolites. Biochemical Society Transactions 35: 1287-1289

Qualifications

• MBChB 2001, Aberdeen
• PhD 2008, Glasgow

Professional memberships

• Fellow of the Higher Education Academy, 2017
• Physiological Society (since 2007)

Student education

Current undergraduate projects under my supervision are examining: the alterations in protein expression found in non-destructive biopsies from endothelial cells grown in culture. This will build on our previous work using our newly-discovered method of sampling surface proteins without destroying the cells from which they are taken. Further projects are examining the impact of receptor tyrosine kinase inhibitors (RTKIs) on cell populations within cardiac tissue. The RTKIs are anti-cancer drugs with known cardiotoxic effects, these studies will examine their actions on cardiac fibroblasts and stem/progenitor cells.

Undergraduate project topics:

• Current undergraduate projects under my supervision are examining: the alterations in protein expression found in non-destructive biopsies from endothelial cells grown in culture. This will build on our previous work using our newly-discovered method of sampling surface proteins without destroying the cells from which they are taken.
• Further projects are examining the impact of receptor tyrosine kinase inhibitors (RTKIs) on cell populations within cardiac tissue. The RTKIs are anti-cancer drugs with known cardiotoxic effects, these studies will examine their actions on cardiac fibroblasts and stem/progenitor cells.

Postgraduate studentship areas:

• Determining the influence of cardiac stem and progenitor cells on new blood vessel formation 

• Identifying cardiac disease markers using non-lethal 'biopsy' of cells

See also:

• Faculty Graduate School

Research groups and institutes

• Cardiovascular
• Cardiac remodelling and repair
• Exercise and the failing heart
• Molecular machinery of muscle contraction

Projects

<li><a href="//phd.leeds.ac.uk/project/1909-cardiac-and-skeletal-muscle-progenitor-cells---driving-regeneration-ability-by-tryptophan-metabolites">Cardiac and skeletal muscle progenitor cells - driving regeneration ability by tryptophan metabolites</a></li>