Paul R Riley

University of Oxford, Oxford, England, United Kingdom

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Publications (58)450.44 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: To develop therapeutic strategies for the regeneration of lost heart muscle after myocardial infarction (MI), a source of functional new muscle cells and associated coronary vessels must be identified. The epicardium is a source of several cardiovascular cell types during heart development and is widely regarded as a resident progenitor population, which becomes dormant during adulthood. In adult mice, MI induces epicardial reactivation characterized by an upregulation of fetal genes and subsequent epicardium derived cell (EPDC) proliferation, migration, and differentiation. Determining whether the epicardium can be therapeutically targeted following cardiovascular disease requires an in vitro system for the study of adult human EPDCs (hEPDCs). This protocol describes techniques to establish and maintain human epicardium explant cultures from patient-derived right atrial appendage biopsies and documents methods to probe the resultant outgrowth of hEPDCs. The model facilitates a high-throughput approach to either genetic or chemical phenotypic screening for drug-like modifiers of hEPDC activation and potential cell fate. © 2015 by John Wiley & Sons, Inc.
    Current protocols in stem cell biology 11/2015; 35:2C.5.1-2C.5.12. DOI:10.1002/9780470151808.sc02c05s35
  • Sophie Norman · Paul R Riley ·
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    ABSTRACT: Lymphatic vessels are present throughout the entire body in all mammals and function to regulate tissue fluid balance, lipid transport and survey the immune system. Despite the presence of an extensive lymphatic plexus within the heart, until recently the importance of the cardiac lymphatic vasculature and its origins were unknown. Several studies have described the basic anatomy of the developing cardiac lymphatic vasculature and more recently the detailed development of the murine cardiac lymphatics has been documented, with important insight into their cellular sources during embryogenesis. In this review we initially describe the development of systemic lymphatic vasculature, to provide the background for a comparative description of the spatiotemporal development of the cardiac lymphatic vessels, including detail of both canonical, typically venous, and non-canonical (haemogenic endothelium) cellular sources. Subsequently, we address the response of the cardiac lymphatic network to myocardial infarction (heart attack) and the therapeutic potential of targeting cardiac lymphangiogenesis. This article is protected by copyright. All rights reserved.
    Clinical Anatomy 10/2015; DOI:10.1002/ca.22638 · 1.33 Impact Factor
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    ABSTRACT: Therapies that modulate inflammation and fibrosis have the potential to reduce the morbidity and mortality associated with chronic kidney disease (CKD). A promising avenue may be manipulating thymosin-β4, a naturally occurring peptide, which is the major G-actin sequestering protein in mammalian cells and a regulator of inflammation and fibrosis. Thymosin-β4 is already being tested in clinical trials for heart disease and wound healing. This editorial outlines the evidence that thymosin-β4 may also have therapeutic benefit in CKD.
    Expert opinion on biological therapy 06/2015; 15(S1):1-4. DOI:10.1517/14712598.2015.1009891 · 3.74 Impact Factor
  • Sveva Bollini · Paul R Riley · Nicola Smart ·
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    ABSTRACT: Introduction: Despite recent improvements in interventional medicine, cardiovascular disease still represents the major cause of morbidity worldwide, with myocardial infarction being the most common cardiac injury. This has sustained the development of several regenerative strategies based on the use of stem cells and tissue engineering approaches in order to achieve cardiac repair and regeneration by enhancing coronary neovascularization, modulating acute inflammation and supporting myocardial regeneration to provide new functional muscle. Areas covered: The actin monomer binding peptide, Thymosin β4 (Tβ4), has recently been described as a powerful regenerative agent with angiogenic, anti-inflammatory and cardioprotective effects on the heart and which specifically acts on its resident cardiac progenitor cells. In this review we will discuss the state of the art regarding the many roles of Tβ4 in preserving and regenerating the mammalian heart, with specific attention to its ability to activate the quiescent adult epicardium and specific subsets of epicardial progenitor cells for repair. Expert opinion: The therapeutic potential of Tβ4 for the treatment of cardiac failure is herein evaluated alongside existing, emerging and prospective novel treatments.
    Expert opinion on biological therapy 06/2015; 15(S1):1-12. DOI:10.1517/14712598.2015.1022526 · 3.74 Impact Factor
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    ABSTRACT: The lymphatic vasculature is a blind-ended network crucial for tissue-fluid homeostasis, immune surveillance and lipid absorption from the gut. Recent evidence has proposed an entirely venous-derived mammalian lymphatic system. By contrast, here we show that cardiac lymphatic vessels in mice have a heterogeneous cellular origin, whereby formation of at least part of the cardiac lymphatic network is independent of sprouting from veins. Multiple Cre-lox-based lineage tracing revealed a potential contribution from the putative haemogenic endothelium during development, and discrete lymphatic endothelial progenitor populations were confirmed by conditional knockout of Prox1 in Tie2(+) and Vav1(+) compartments. In the adult heart, myocardial infarction promoted a significant lymphangiogenic response, which was augmented by treatment with VEGF-C, resulting in improved cardiac function. These data prompt the re-evaluation of a century-long debate on the origin of lymphatic vessels and suggest that lymphangiogenesis may represent a therapeutic target to promote cardiac repair following injury.
    Nature 05/2015; 522(7554). DOI:10.1038/nature14483 · 41.46 Impact Factor
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    Megan Masters · Paul R. Riley ·
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    ABSTRACT: From historical studies of developing chick hearts to recent advances in regenerative injury models, the epicardium has arisen as a key player in heart genesis and repair. The epicardium provides paracrine signals to nurture growth of the developing heart from mid-gestation, and epicardium-derived cells act as progenitors of numerous cardiac cell types. Interference with either process is terminal for heart development and embryogenesis. In adulthood, the dormant epicardium reinstates an embryonic gene programme in response to injury. Furthermore, injury-induced epicardial signalling is essential for heart regeneration in zebrafish. Given these critical roles in development, injury response and heart regeneration, the application of epicardial signals following adult heart injury could offer therapeutic strategies for the treatment of ischaemic heart disease and heart failure.
    Stem Cell Research 11/2014; 13(3). DOI:10.1016/j.scr.2014.04.007 · 3.69 Impact Factor
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    ABSTRACT: Correct regulation of troponin and myosin contractile protein gene isoforms is a critical determinant of cardiac and skeletal striated muscle development and function, with misexpression frequently associated with impaired contractility or disease. Here we reveal a novel requirement for Prospero-related homeobox factor 1 (Prox1) during mouse heart development in the direct transcriptional repression of the fast-twitch skeletal muscle genes troponin T3, troponin I2, and myosin light chain 1. A proportion of cardiac-specific Prox1 knockout mice survive beyond birth with hearts characterized by marked overexpression of fast-twitch genes and postnatal development of a fatal dilated cardiomyopathy. Through conditional knockout of Prox1 from skeletal muscle, we demonstrate a conserved requirement for Prox1 in the repression of troponin T3, troponin I2, and myosin light chain 1 between cardiac and slow-twitch skeletal muscle and establish Prox1 ablation as sufficient to cause a switch from a slow- to fast-twitch muscle phenotype. Our study identifies conserved roles for Prox1 between cardiac and skeletal muscle, specifically implicated in slow-twitch fiber-type specification, function, and cardiomyopathic disease.
    Proceedings of the National Academy of Sciences 06/2014; 111(26). DOI:10.1073/pnas.1406191111 · 9.67 Impact Factor
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    ABSTRACT: The epicardium is a cellular source with the potential to reconstitute lost cardiovascular tissue following myocardial infarction. Here we show that the adult epicardium contains a population of CD45+ haematopoietic cells (HCs), which are located proximal to coronary vessels and encased by extracellular matrix (ECM). This complex tertiary structure is established during the regenerative window between post-natal days 1 and 7. We show that these HCs proliferate within the first 24 h and are released between days 2 and 7 after myocardial infarction. The ECM subsequently reforms to encapsulate HCs after 21 days. Vav1-tdTomato labelling reveals an integral contribution of CD45+ HCs to the developing epicardium, which is not derived from the proepicardial organ. Transplantation experiments with either whole bone marrow or a Vav1+ subpopulation of cells confirm a contribution of HCs to the intact adult epicardium, which is elevated during the first 24 weeks of adult life but depleted in aged mice.
    Nature Communications 06/2014; 5:4054. DOI:10.1038/ncomms5054 · 11.47 Impact Factor
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    Anke M Smits · Paul R. Riley ·
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    ABSTRACT: In the last decade, cell replacement therapy has emerged as a potential approach to treat patients suffering from myocardial infarction (MI). The transplantation or local stimulation of progenitor cells with the ability to form new cardiac tissue provides a novel strategy to overcome the massive loss of myocardium after MI. In this regard the epicardium, the outer layer of the heart, is a tractable local progenitor cell population for therapeutic pursuit. The epicardium has a crucial role in formation of the embryonic heart. After activation and migration into the developing myocardium, epicardial cells differentiate into several cardiac cells types. Additionally, the epicardium provides instructive signals for the growth of the myocardium and coronary angiogenesis. In the adult heart, the epicardium is quiescent, but recent evidence suggests that it becomes reactivated upon damage and recapitulates at least part of its embryonic functions. In this review we provide an update on the current knowledge regarding the contribution of epicardial cells to the adult mammalian heart during the injury response.
    04/2014; DOI:10.3390/jdb2020084
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    ABSTRACT: Cardiovascular disease remains the major cause of mortality and cardiac cell therapy has recently emerged as a paradigm for heart repair. The epicardium is a layer of mesothelial cells covering the heart that during development contributes to different cardiovascular lineages, including cardiomyocytes, but becomes quiescent after birth. We previously revealed that the peptide thymosin beta 4 (Tβ4) can reactivate the adult epicardium-derived cells (EPDCs) following myocardial infarction (MI) to proliferate and differentiate into cardiovascular derivatives. The aim of this study was to provide a lineage characterisation of the adult EPDCs relative to the embryonic epicardial lineage and to determine prospective cell fate biases within the activated adult population during cardiovascular repair. Wt1GFPCre/+ mice were primed with Tβ4 and MI induced by ligation of the left anterior descending coronary artery. Adult WT1+ GFP+ EPDCs were FACS-sorted 2, 4 and 7 days after MI. Embryonic WT1+ GFP+ EPDCs were isolated from embryonic hearts (E12.5) by FACS and sorted cells were characterised by real time qRT-PCR and immunostaining. Adult WT1+ GFP+ EPDCs were highly heterogeneous, expressing cardiac progenitor and mesenchymal stem markers. Based on the expression of Sca-1, CD44 and CD90 we identified different subpopulations of EPDCs of varying cardiovascular potential, based on marker gene profiles, with a molecular phenotype distinct from the source embryonic epicardial cells at E12.5. Thus, the activated adult WT1+ GFP+ cells are a heterogeneous population which when activated can restore an embryonic gene programme but do not revert entirely to adopt an embryonic phenotype. Potential biases in cardiovascular cell fate suggest discrete subpopulations of EPDCs might be clinically relevant for regenerative therapy.
    Stem cells and development 04/2014; 23(15). DOI:10.1089/scd.2014.0019 · 3.73 Impact Factor
  • Paul R Riley ·
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    ABSTRACT: Damage to the adult mammalian heart is irreversible, and lost cells are not replaced through regeneration. In neonatal mice, prior to P7, heart tissue can be regenerated after injury; however, the factors that facilitate cardiac regeneration in the neonatal heart are not known. In this issue of the JCI, Aurora and colleagues evaluated the immune response following myocardial infarction in P1 mice compared with that in P14 mice, which have lost their regenerative capacity, and identified a population of macrophages as mediators of cardiac repair. Further understanding of the immune modulators that promote the regenerative properties of this macrophage subset could potentially be exploited to recapitulate regenerative function in the adult heart.
    The Journal of clinical investigation 02/2014; 124(3):1-4. DOI:10.1172/JCI74418 · 13.22 Impact Factor
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    ABSTRACT: The downstream consequences of inflammation in the adult mammalian heart are formation of a non-functional scar, pathological remodelling and heart failure. In zebrafish, hydrogen peroxide released from a wound is the initial instructive chemotactic cue for the infiltration of inflammatory cells, however, the identity of a subsequent resolution signal(s), to attenuate chronic inflammation, remains unknown. Here we reveal that thymosin β4-sulfoxide lies downstream of hydrogen peroxide in the wounded fish and triggers depletion of inflammatory macrophages at the injury site. This function is conserved in the mouse and observed after cardiac injury, where it promotes wound healing and reduced scarring. In human T-cell/CD14+ monocyte co-cultures, thymosin β4-sulfoxide inhibits interferon-γ, and increases monocyte dispersal and cell death, likely by stimulating superoxide production. Thus, thymosin β4-sulfoxide is a putative target for therapeutic modulation of the immune response, resolution of fibrosis and cardiac repair.
    Nature Communications 07/2013; 4:2081. DOI:10.1038/ncomms3081 · 11.47 Impact Factor
  • Nicola Smart · Paul R Riley ·

    Circulation Research 02/2013; 112(3):e29-e30. DOI:10.1161/CIRCRESAHA.112.300555 · 11.02 Impact Factor
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    ABSTRACT: Efficient cardiac regeneration postinfarction (MI) requires the replacement of lost cardiomyocytes, formation of new coronary vessels and appropriate modulation of the inflammatory response. However, insight into how to stimulate repair of the human heart is currently limited. Using the embryonic paradigm of regeneration, we demonstrated that the actin-binding peptide thymosin β4 (Tβ4), required for epicardium-derived coronary vasculogenesis, can recapitulate its embryonic role and activate quiescent adult epicardial cells (EPDCs). Once stimulated, EPDCs facilitate neovascularization of the ischemic adult heart and, moreover, contribute bona fide cardiomyocytes. EPDC-derived cardiomyocytes structurally and functionally integrate with resident muscle to regenerate functional myocardium, limiting pathological remodeling, and effecting an improvement in cardiac function. Alongside pro-survival and anti-inflammatory properties, these regenerative roles, via EPDCs, markedly expand the range of therapeutic benefits of Tβ4 to sustain and repair the myocardium after ischemic damage.
    Annals of the New York Academy of Sciences 10/2012; 1269(1):92-101. DOI:10.1111/j.1749-6632.2012.06708.x · 4.38 Impact Factor
  • Nicola Smart · Karina N Dubé · Paul R Riley ·
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    ABSTRACT: While cardiovascular diseases remain the major worldwide cause of mortality and morbidity, there is an urgent need to tackle the clinical and economic burden of heart failure. Since the mammalian heart is unable to adequately regenerate beyond early postnatal stages, individuals surviving acute myocardial infarction are at risk of heart failure. Understanding the embryonic mechanisms of vasculogenesis and cardiogenesis, as well as the mechanisms retained for regeneration in species such as the zebrafish, will inform on strategies for human myocardial repair. Due to their fundamental role in heart development, epicardium-derived cells (EPDCs) have emerged as a population with potential to restore myocardium and coronary vasculature. The ability to revive ordinarily dormant EPDCs lies in the identification of key molecular cues used in the embryo to orchestrate cardiovascular development. One such stimulatory factor, Thymosin β4 (Tβ4), restores the quiescent adult epicardium to its pluripotent embryonic state. Tβ4 treatment of infarcted hearts induces dramatic EPDC proliferation and formation of a network of perfused, functional vessels to enhance blood flow to the ischaemic myocardium. Moreover, Tβ4 facilitates an epicardial contribution of mature de novo cardiomyocytes, structurally and functionally coupled with resident myocardium, which may contribute towards the functional improvement of Tβ4-treated hearts post-MI.
    Vascular Pharmacology 08/2012; 58(3). DOI:10.1016/j.vph.2012.08.001 · 3.64 Impact Factor
  • Paul R Riley ·
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    ABSTRACT: mt is a cross-disciplinary biomedical journal devoted to publishing the most exciting advances in pharmacology and therapeutics, as they pertain to advances in translational and clinical medicine. It is recognized as one of the most prestigious journals in the field. With an impact factor of 6.825*, mt ranks in the top 4.2% of scientific journals in the latest Science Citation Index. Published monthly online and in print.
    Molecular Therapy 07/2012; 20(7):1294-6. DOI:10.1038/mt.2012.121 · 6.23 Impact Factor
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    ABSTRACT: Compromised development of blood vessel walls leads to vascular instability that may predispose to aneurysm with risk of rupture and lethal hemorrhage. There is currently a lack of insight into developmental insults that may define the molecular and cellular characteristics of initiating and perpetrating factors in adult aneurismal disease. To investigate a role for the actin-binding protein thymosin β4 (Tβ4), previously shown to be proangiogenic, in mural cell development and vascular wall stability. Phenotypic analyses of both global and endothelial-specific loss-of-function Tβ4 mouse models revealed a proportion of Tβ4-null embryos with vascular hemorrhage coincident with a reduction in smooth muscle cell coverage of their developing vessels. Mechanistic studies revealed that extracellular Tβ4 can stimulate differentiation of mesodermal progenitor cells to a mature mural cell phenotype through activation of the transforming growth factor-beta (TGFβ) pathway and that reduced TGFβ signaling correlates with the severity of hemorrhagic phenotype in Tβ4-null vasculature. Tβ4 is a novel endothelial secreted trophic factor that functions synergistically with TGFβ to regulate mural cell development and vascular wall stability. These findings have important implications for understanding congenital anomalies that may be causative for adult-onset vascular instability.
    Circulation Research 06/2012; 111(4):e89-102. DOI:10.1161/CIRCRESAHA.111.259846 · 11.02 Impact Factor
  • Gemma M Balmer · Paul R Riley ·
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    ABSTRACT: Across biomedicine, there is a major drive to develop stem cell (SC) treatments for debilitating diseases. Most effective treatments restore an embryonic phenotype to adult SCs. This has led to two emerging paradigms in SC biology: the application of developmental biology studies and the manipulation of the SC niche. Developmental studies can reveal how SCs are orchestrated to build organs, the understanding of which is important in order to instigate tissue repair in the adult. SC niche studies can reveal cues that maintain SC 'stemness' and how SCs may be released from the constraints of the niche to differentiate and repopulate a 'failing' organ. The haematopoietic system provides an exemplar whereby characterisation of the blood lineages during development and the bone marrow niche has resulted in therapeutics now routinely used in the clinic. Ischaemic heart disease is a major cause of morbidity and mortality in humans and the question remains as to whether these principles can be applied to the heart, in order to exploit the potential of adult SCs for use in cardiovascular repair and regeneration.
    Journal of Cardiovascular Translational Research 06/2012; 5(5):631-40. DOI:10.1007/s12265-012-9386-3 · 3.02 Impact Factor
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    ABSTRACT: Nkx2.5 is one of the most widely studied cardiac-specific transcription factors, conserved from flies to man, with multiple essential roles in both the developing and adult heart. Specific dominant mutations in NKX2.5 have been identified in adult congenital heart disease patients presenting with conduction system anomalies and recent genome-wide association studies implicate the NKX2.5 locus, as causative for lethal arrhythmias ("sudden cardiac death") that occur at a frequency in the population of 1 in 1000 per annum worldwide. Haploinsufficiency for Nkx2.5 in the mouse phenocopies human conduction disease pathology yet the phenotypes, described in both mouse and man, are highly pleiotropic, implicit of unknown modifiers and/or factors acting in epistasis with Nkx2.5/NKX2.5. To identify bone fide upstream genetic modifier(s) of Nkx2.5/NKX2.5 function and to determine epistatic effects relevant to the manifestation of NKX2.5-dependent adult congenital heart disease. A study of cardiac function in prospero-related homeobox protein 1 (Prox1) heterozygous mice, using pressure-volume loop and micromannometry, revealed rescue of hemodynamic parameters in Nkx2.5(Cre/+); Prox1(loxP/+) animals versus Nkx2.5(Cre/+) controls. Anatomic studies, on a Cx40(EGFP) background, revealed Cre-mediated knock-down of Prox1 restored the anatomy of the atrioventricular node and His-Purkinje network both of which were severely hypoplastic in Nkx2.5(Cre/+) littermates. Steady state surface electrocardiography recordings and high-speed multiphoton imaging, to assess Ca(2+) handling, revealed atrioventricular conduction and excitation-contraction were also normalized by Prox1 haploinsufficiency, as was expression of conduction genes thought to act downstream of Nkx2.5. Chromatin immunoprecipitation on adult hearts, in combination with both gain and loss-of-function reporter assays in vitro, revealed that Prox1 recruits the corepressor HDAC3 to directly repress Nkx2.5 via a proximal upstream enhancer as a mechanism for regulating Nkx2.5 function in adult cardiac conduction. Here we identify Prox1 as a direct upstream modifier of Nkx2.5 in the maintenance of the adult conduction system and rescue of Nkx2.5 conduction disease phenotypes. This study is the first example of rescue of Nkx2.5 function and establishes a model for ensuring electrophysiological function within the adult heart alongside insight into a novel Prox1-HDAC3-Nkx2.5 signaling pathway for therapeutic targeting in conduction disease.
    Circulation Research 05/2012; 111(2):e19-31. DOI:10.1161/CIRCRESAHA.111.260695 · 11.02 Impact Factor

Publication Stats

2k Citations
450.44 Total Impact Points


  • 2012-2015
    • University of Oxford
      • Department of Physiology, Anatomy and Genetics
      Oxford, England, United Kingdom
  • 2005-2012
    • University College London
      • • Centre for Molecular Medicine
      • • Institute of Child Health
      Londinium, England, United Kingdom
  • 2010
    • University of Michigan
      • Department of Chemical Engineering
      Ann Arbor, Michigan, United States
  • 2008
    • Institute for Child Health Policy (ICHP)
      Гилфорд, Connecticut, United States
  • 2007
    • Harvard University
      • Department of Molecular and Cell Biology
      Cambridge, Massachusetts, United States
  • 2006
    • UCL Eastman Dental Institute
      Londinium, England, United Kingdom
    • MRC National Institute for Medical Research
      • Division of Developmental Biology
      Londinium, England, United Kingdom
  • 2004
    • WWF United Kingdom
      Londinium, England, United Kingdom
  • 2000
    • University of Toronto
      Toronto, Ontario, Canada
  • 1999
    • Samuel Lunenfeld Research Institute
      Toronto, Ontario, Canada