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Chris Denning

Director of the University of Nottingham Biodiscovery Institute, Faculty of Medicine & Health Sciences

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Biography

Chris Denning is a Professor of Stem Cell Biology. and is Director of the University of Nottingham Biodiscovery Institute. He led the University's Research Priority Area in Regenerative Medicine & Stem Cells, and is now lead on the Interdisciplinary Research Cluster in End to End Therapeutics. His lab's interests are in cardiomyocyte (heart cell) differentiation of human pluripotent stem cells (hPSCs: human embryonic stem cells [hESCs] and human induced pluripotent stem cells [hiPSCs]) for use in drug screening and in production of new in vitro models of genetic-based cardiovascular disease. Broadly, the lab works in 3 main areas:

1) Disease modelling. Enabled via human induced pluripotent stem cells with or without additional manipulation by nuclease-mediated gene targeting technologies (including Cas9/CRISPR). As examples, the lab investigate diseases associated with defects in electrophysiology (e.g. long QT syndrome, CPVT, myotonic dystrophy), structure (e.g. myosin heavy chains, alpha-actin), survival (e.g. DMD) and signalling (e.g. b-adrenoceptors, GRK5). We also use gene targeting for knockout and knockin studies.

2) Platforms for cardiotoxicity evaluation. As an example, Chris leads the multinational CRACK-IT consortium, which aims to improve stem cell-cardiomyocyte models in the predictivity of drug-induced cardiotoxicity. The consortium includes 3 additional academic groups (Christine Mummery, Holland; Thomas Eschenhagen, Germany; Godfrey Smith, Scotland), 2 biotechs (ClydeBiosciences; Pluriomics) and Pharma (GlaxoSmithKline). This is facilitated by high throughput phenotyping platforms to assess changes in electrophysiology, calcium and contractility.

3) Automation and interdisciplinary approaches. Over the last 5 years, Chris has developed a £2M automation and phenotyping suite. This is embedded in a world-class stem cell culture facility, which includes 25 class II cell culture cabinets. This enables projects such as screening of an 83,000 compound library to find chemistries that improve cardiomyocyte maturity, as well as development of stem cell quality metrics. High throughput approaches have also enabled screening of polymer microarrays to identify chemistries that can alter stem cell and cardiomyocyte fate.

Appointments in brief:

  • PhD in Cancer Gene Therapy, Glasgow, 1997;
  • Postdoc: Institute for Stem Cell Research, Edinburgh 1997-98;
  • Postdoc: Roslin Institute 1998-2001;
  • Fellow (2001), Lecturer (2006), Reader (2008), Professor (2011) in Stem Cell Biology; from 2014 Head of Department of Stem Cell Biology, University of Nottingham

Education and appointments

First class hons in Biochemistry with Molecular Biology, University of Leeds 1994; PhD in Cancer Gene Therapy at Beatson Institute for Cancer Research, University of Glasgow, 1997; Postdoctoral Research Fellow - gene targeting in mouse ES cells, Institute for Stem Cell Research, University of Edinburgh, 1997-1998; Postdoctoral Research Fellow - gene targeting / cloning in somatic cells, Roslin Institute 1998-2001; Principal Investigator, University of Nottingham, 2001-2003; Medical Research Council Fellow, University of Nottingham, 2003-2006; Lecturer, University of Nottingham, 2006-2008; Reader, University of Nottingham 2008-2011; Professor in Stem Cell Biology, University of Nottingham 2011-

Expertise Summary

The lab uses automation and high content approaches to investigate impact of drug- and disease-induced perturbation of function of cardiomyocytes derived from stem cells. We have a world-class facility that comprises 25 class II cell culture cabinets, largely dedicated to stem cell biology. Within my own laboratory, specific technical expertise includes:

  • Derivation of human induced pluripotent stem cell (hiPSC) lines from healthy individuals of those harbouring genetic lesions
  • Culture and cardiomyocyte differentiation from 30-50 different human pluripotent stem cell (hPSC) lines, including hiPSCs and human embryonic stem cell (hESC) lines.
  • Genetic manipulation of stem cells, including targeted gene addition, deletion of polymorphic variation using the CRISPR/Cas9 system. Also, over expression and knockdown with lentiviral approaches
  • Robotic automation of hPSC culture and differentiation. As examples, we use our bespoke £1M Tecan Robotics facility for: 1) Development of quality metrics for automated hPSC scale up and bioprocess; 2) Screening of 83,000 compound library to improve maturity of hPSC-derived cardiomyocytes
  • Automated cardiomyocyte phenotyping. Our platforms include: 1) CellOPTIQ for optical imaging of calcium, voltage and contractility; 2) Manual and automated (Nanion Patchliner) for electrophysiology; 3) Multi electrode arrays for field potential analysis; 4) EnVision system for monitoring e.g. whole well calcium flux; 5) CardioExcyte for impedance measurement; 6) Seahorse bioanalyser for 96-well assessment of metabolic activity; 7) Operetta confocal plate reader for high content image analysis. In addition, we work with colleagues at Imperial College London and in Hamburg to use engineered heart tissue approaches to examine contraction in 3D constructs
  • Interdisciplinary approaches are a key area for the lab and a strength in Nottingham. For example, we have screened polymer microarrays to identify new substrate chemistries that enable manipulation of stem cell fate and cardiomyocyte function.
  • All standard cell and molecular analysis is available, including Q-PCR, FACS, electron microscopy, mass spec etc, while we tend to outsource RNAseq and proteomics

Teaching Summary

In 2007, the University of Nottingham developed a prestigious MSc / Masters Course in Stem Cell Technology. Chris was Course Director and Module Convenor from 2010-15. His main teaching includes

  • Human plurupotent stem cells (hPSCs), which include human embryonic stem cells and human induced pluripotent stem cells;
  • Maintenance of pluripotency and characterisation of hPSCs;
  • Methods of culture and automated scale up, including robotics, multi-well plates, and T-flasks
  • Genetic modification of hPSCs
  • Cardiomyocyte differentiation
  • Disease modelling and drug screening
  • International initiatives on hPSCs
  • Regulation of hPSCs, including distribution, patents and ethics
  • Practical classes in hPSC biology, culture, differentiation and characterisation

Research Summary

Chris' interests are in cardiomyocyte (heart cell) differentiation of human pluripotent stem cells (hPSCs: human embryonic stem cells [hESCs] and human induced pluripotent stem cells [hiPSCs]) for… read more

Selected Publications

Current Research

Chris' interests are in cardiomyocyte (heart cell) differentiation of human pluripotent stem cells (hPSCs: human embryonic stem cells [hESCs] and human induced pluripotent stem cells [hiPSCs]) for use in drug screening and in production of new in vitro models of genetic-based cardiovascular disease. Broadly, the lab works in 3 main areas:

1) Disease modelling. Enabled via human induced pluripotent stem cells with or without additional manipulation by nuclease-mediated gene targeting technologies (including Cas9/CRISPR). As examples, the lab investigate diseases associated with defects in electrophysiology (e.g. long QT syndrome, CPVT, myotonic dystrophy), structure (e.g. myosin heavy chains, alpha-actin), survival (e.g. DMD) and signalling (e.g. b-adrenoceptors, GRK5). We also use gene targeting for knockout and knockin studies.

Example publications:

  • Lin B, Li Y, Han L, Kaplan AD, Ao Y, Kalra S, Bett GC, Rasmusson RL, Denning C, Yang L. Modeling and studying mechanism of dilated cardiomyopathy using induced pluripotent stem cells derived from Duchenne Muscular Dystrophy (DMD) patients. Dis Model Mech. 8(5):457-66, 2015.
  • Matsa E, Dixon JE, Medway C, Georgiou O, Patel MJ, Morgan K, Kemp PJ, Staniforth A, Mellor I, Denning C. (2014). Allele-specific RNA interference rescues the long-QT syndrome phenotype in hiPSC cardiomyocytes. Eur Heart J. 35(16):1078-8. PMID: 23470493
  • Dick E, Kalra S, Anderson D, George V, Ritso M, Laval SH, Barresi R, Aartsma-Rus A, Lochmüller H, Denning C. (2013). Exon skipping and gene transfer restore dystrophin expression in hiPSC-cardiomyocytes harbouring DMD mutations. Stem Cells Dev. 22(20):2714-24. PMID: 23786351
  • Andrews et al., (2011). Screening a large, ethnically diverse population of human embryonic stem cells identifies a chromosome 20 minimal amplicon that confers a growth advantage (The International Stem Cell Initiative). Nature Biotechnology. 29(12):1132-44. PMID: 22119741
  • Matsa E, Rajamohan D, Dick E, Young L, Mellor I, Staniforth A, Denning C (2011). Drug evaluation in cardiomyocytes derived from human induced pluripotent stem cells carrying a long QT syndrome type 2 mutation. Eur Heart J. 32(8):952-62. PMID: 21367833

2) Platforms for cardiotoxicity evaluation. As an example, Chris leads the multinational CRACK-IT consortium, which aims to improve stem cell-cardiomyocyte models in the predictivity of drug-induced cardiotoxicity. The consortium includes 3 additional academic groups (Christine Mummery, Holland; Thomas Eschenhagen, Germany; Godfrey Smith, Scotland), 2 biotechs (ClydeBiosciences; Pluriomics) and Pharma (GlaxoSmithKline). This is facilitated by high throughput phenotyping platforms to assess changes in electrophysiology, calcium and contractility.

Example publications:

  • Rajamohan D, Kalra S, Hoang M, George V, Staniforth A, Russell H, Yang X, Denning C (2016). Automated electrophysiological and pharmacological evaluation of human pluripotent stem cell-derived cardiomyocytes Stem Cells and Development. 25(6):439-52. PMID:26906236
  • Berend J van Meer; Henk de Vries; Karl Firth; Jasper van Weerd; Leon G Tertoolen; Marcel Karperien; Pascal Jonkheijm; Chris Denning; Ad IJzerman; Christine Mummery. Small molecule absorption by PDMS in the context of drug response bioassays. Biochemical and Biophysical Research Communications. In Press
  • Denning C, Borgdorff V, Crutchley J, Firth KSA, George V, Kalra S, Kondrashov A, Hoang MD, Mosqueira D, Patel A, Prodanov L, Rajamohan D, Skarnes WC, Smith JGW, Young LE (2015). Cardiomyocytes from human pluripotent stem cells: From laboratory curiosity to industrial biomedical platform. Biochim Biophys Acta. Mol Cell Res 2015 pii: S0167-4889(15)00367-5 PMID: 26524115
  • Braam SR, Tertoolen L, Casini S, Matsa E, Lu HR, Teisman A, Passier R, Denning C, Gallacher DJ, Towart R, Mummery CL. (2013) Repolarization reserve determines drug responses in human pluripotent stem cell derived cardiomyocytes. Stem Cell Research. 10(1):48-56. PMID: 2308962

3) Automation and interdisciplinary approaches. Over the last 5 years, Chris has developed a £2M automation and phenotyping suite. This is embedded in a world-class stem cell culture facility, which includes 25 class II cell culture cabinets. This enables projects such as screening of an 83,000 compound library to find chemistries that improve cardiomyocyte maturity, as well as development of stem cell quality metrics. High throughput approaches have also enabled screening of polymer microarrays to identify chemistries that can alter stem cell and cardiomyocyte fate.

Example publications:

  • Dixon JE, Osman G, Morris GE, Markides H, Rotherham M, Bayoussef Z, El-Haj A, Denning C & Shakesheff KM. Highly Efficient Delivery of Functional Cargoes by the Synergistic Effect of GAG Binding Motifs and Cell-Penetrating Peptides. PNAS 2016;113(3):E291-9.
  • Patel AK, Celiz AD, Rajamohan D, Anderson DG, Langer R, Davies MC, Alexander MR, and Denning C. A defined synthetic substrate for serum free culture of human stem cell derived cardiomyocytes with improved sarcomeric integrity identified using combinatorial materials microarrays. Biomaterials. 61:257-65, 2015. PMID: 26005764
  • Celiz A, Smith JGW, Patel AK, Hook AL, Rajamohan D, George VT, Patel MJ, Epa VC, Singh T, Langer R, Anderson DG, Allen ND, Hay DC, Winkler DA, Barrett DA, Davies MC, Young LE, Denning C*, Alexander MR*. Discovery of a novel polymer for human pluripotent stem cell expansion and multi-lineage differentiation. Advanced Materials. 27(27):4006-12, 2015. PMID: 26033422
  • Celiz AD, Smith JGW, Langer R, Anderson DG, Barrett DA, Davies MC, Young LE, Denning C, Alexander MR. The Search for Materials for the Stem Cell Factories of the Future. Nature Materials 13(6):570-9. PMID: 24845996

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University of Nottingham
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