Strategic development of stem cell-based therapies for vascular disease

Lead Research Organisation: University of Cambridge
Department Name: Surgery

Abstract

Diseases of the heart and circulatory system are the main cause of death in the UK. While improvements in lifestyle are benefiting people at risk for these diseases, many already suffer from previous illness and others will nevertheless experience life-threatening episodes. Our work will strive to harness recent developments in the field of stem cell research to benefit those at risk for heart and circulatory diseases. This will be accomplished by studying the fundamental processes of cell growth, specialization and function that can be done in the Petri dish using modern microscopy and also by other imaging techniques. We will study cells that make up the normal and diseased heart and also those that form the lining and walls of the blood vessels. We expect our studies to provide the insights for future methods for diagnosis and treatment of lung disease and atherosclerosis, which together account for most cardiovascular disease risk.

Technical Summary

Whilst stem cell research has great potential for translation into patient benefits, cell-based therapies are currently limited by lack of knowledge about human stem cell differentiation and about the extent and kinetics of integration and survival of transplanted tissues. Nonetheless, progeny obtained by in vitro differentiation of pluripotent stem cells can provide unprecedented cellular systems for understanding fundamental cardiovascular disease mechanisms, and for drug discovery and testing. Moreover, studies of endogenous tissue stem cells can provide key insights into their role in cardiovascular disease. We are establishing the Cambridge Cardiovascular Consortium to explore the interface between stem cells and cardiovascular medicine. The Consortium will focus on vascular disease, initially using pulmonary arterial hypertension (PAH) as a model, because its genetic basis is known, well-defined patient populations are available, and its molecular aetiology is highly relevant to other common vascular diseases, especially atherogenesis and vessel calcification. The strategic development of the Consortium will contribute great insight not only to PAH but also to vascular disease more broadly, and in future its infrastructure will serve studies of other cardiac and vascular diseases.

Publications

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Toshner M (2010) Endothelial progenitor cells in pulmonary hypertension - dawn of cell-based therapy? in International journal of clinical practice. Supplement

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Tucka J (2012) Cell death and survival signalling in the cardiovascular system. in Frontiers in bioscience (Landmark edition)

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Uryga A (2016) DNA Damage and Repair in Vascular Disease. in Annual review of physiology

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Vallier L (2015) Cell Cycle Rules Pluripotency. in Cell stem cell

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Warboys CM (2014) Disturbed flow promotes endothelial senescence via a p53-dependent pathway. in Arteriosclerosis, thrombosis, and vascular biology

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Wei Z (2014) Regulation of bone morphogenetic protein 9 (BMP9) by redox-dependent proteolysis. in The Journal of biological chemistry

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Yang J (2013) Id proteins are critical downstream effectors of BMP signaling in human pulmonary arterial smooth muscle cells. in American journal of physiology. Lung cellular and molecular physiology

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Yu E (2012) Mitochondria in vascular disease. in Cardiovascular research

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Yu EP (2014) Mitochondrial DNA damage and atherosclerosis. in Trends in endocrinology and metabolism: TEM

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Yu H (2015) Akt isoforms in vascular disease. in Vascular pharmacology

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Zhao J (2012) Late outgrowth endothelial progenitor cells engineered for improved survival and maintenance of function in transplant-related injury. in Transplant international : official journal of the European Society for Organ Transplantation

 
Description 'Development of a Novel Cellular Model for Analysis of Cardiomyocyte Defect in Pulmonary Arterial Hypertension'
Amount £10,891 (GBP)
Organisation University of Cambridge 
Department Isaac Newton Trust
Sector Academic/University
Country United Kingdom
Start 12/2011 
End 02/2012
 
Description 'Development of a drug-screening model of childhood pulmonary arterial hypertension using induced pluripotent stem cells.'
Amount £29,773 (GBP)
Organisation Robert McAlpine Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2013 
End 01/2014
 
Description 'Genetic engineering of pluripotent stem cells to model and develop treatments for pulmonary arterial hypertension',
Amount £107,437 (GBP)
Organisation The Dinosaur Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2014 
End 07/2016
 
Description BHF Studentship
Amount £126,863 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2014 
End 09/2017
 
Title 'Nuclear Reprogramming Substrate' 
Description Derivation of human induced pluripotent stem cells from endothelial progenitor cells 
IP Reference WO2012131387 
Protection Patent application published
Year Protection Granted 2011
Licensed No
Impact None yet defined
 
Title Populations of smooth muscle cells of specific embryonic lineages 
Description Populations of smooth muscle cells of specific embryonic lineages 
IP Reference GB1109882.9 
Protection Patent application published
Year Protection Granted 2011
Licensed No
Impact not yet known
 
Title Transcription factor mediated programming towards megakaryocytes 
Description Moreau T, Trotter MWB, Ouwehand W and Pedersen RA filed this application regarding a method for generating human megakaryocytes from human pluripotent stem cells using direct programming. 
IP Reference WO2013190296 
Protection Patent application published
Year Protection Granted 2012
Licensed No
Impact None to date
 
Company Name Definigen 
Description Research and experimental development on biotechnology 
Year Established 2011 
Impact Supplying chemically-defined medium and hepatocytes produced therefrom for drug discovery and toxicity testing.
Website http://www.definigen.com/