Heart disease is one of the main causes of death in the UK and worldwide. At present no widely available, restorative option exists therefore new strategies are required to identify a safe and efficient way of treating heart failure.
In recent years, stem cells have emerged as a potentially valuable tool for the repair of damaged hearts. In particular a breakthrough discovery, which identified that stem cells could be generated from a patient's own skin cells, termed induced pluripotent stem cells (iPSCs). iPSCs have gained increasing recognition given their ability to generate new, patient-specific, cardiac muscle cells, which when delivered into damaged hearts improve cardiac function.
The focus of Dr Lewis-McDougall's research aims to understand the influence of donor age/disease on iPSC potential, identify the optimal iPSC progeny for cardiac repair and investigate extracellular vesicles as mediators of cardiac repair.
Biomarker discovery for Aortic Stenosis Management' with the following synopsis
Aortic stenosis (AS) occurs when one of the heart's valves narrows and blood cannot flow to the rest of the body normally. The disease can range from mild to severe and AS progression is unpredictable often occurring over many years. If severe aortic valve disease is left untreated this can lead to life-threatening problems, such as heart failure. Current treatments are limited to replacement of the faulty valve, ideally before the level of heart damage becomes too severe. However, predicting which patients will benefit from valve replacement and when to intervene is currently challenging due to lack of reliable clinical tools. In this project, we will follow patients before and after valve replacement, collecting information on how well their heart is functioning and their quality of life. Alongside this, we will comprehensively screen extracellular vesicles present in their blood to identify predictors of poor prognosis. Together this information will enable us to identify new markers associated with patient outcome, an important step towards the development of a much needed tool for AS disease management that can be used to identify the highest risk individuals for closer monitoring and timely intervention, improving patient outcomes.
Therapeutic potential of human induced pluripotent stem cell-derived cardiac progenitor cells: Direct comparison with endogenous cardiac progenitor cells from the same patients
Funded by The British Heart Foundation
The optimal iPSC progeny for cardiac repair is currently unknown and to date the majority of iPSC studies for cardiac repair have focused on generating fully differentiated iPSC-cardiomyocytes. While this approach has shown some promise, a major drawback is that only a single replacement cell type is delivered to the heart. Furthermore, iPSC-cardiomyocytes display an immature phenotype and their integration with the host myocardium often leads to arrhythmias.
Transplantation of Skeletal Muscle-Derived Sca-1+/PW1+/Pax7− Interstitial Cells (PICs) Improves Cardiac Function and Attenuates Remodeling in Mice Subjected to Myocardial Infarction.
Ruchaya PJ, Lewis-McDougall FC, Sornkarn N, Amin S, Grimsdell B, Shaalan A, Gritti G, Soe KT, Clark JE, Ellison-Hughes GM.
Receptor tyrosine kinase inhibitors negatively impact on pro-reparative characteristics of human cardiac progenitor cells.
AJ Smith, Ruchaya P, Walmsley R, Wright KE, Lewis-McDougall FC, Bond J, Ellison-Hughes GM
Cell barrier function of resident peritoneal macrophages in post-operative adhesions
Ito T, Shintani Y, Fields L, Shiraishi M, Podaru MN, Kainuma S, Yamashita K, Kobayashi K, Perretti M, Lewis-McDougall F, Suzuki K.
Epicardial placement of human MSC-loaded fibrin sealant films for heart failure: Preclinical efficacy and mechanistic data.
Fields L, Ito T, Kobayashi K, Ichihara Y, Podaru MN, Hussain M, Yamashita K, Machado V, Lewis-McDougall F, Suzuki K.
Aged-senescent progenitor cells contribute to impaired heart regeneration.
Lewis-McDougall FC, Ruchaya PJ, Domenjo-Vila E, Teoh TS, Cottle BJ, Clark JE, Punjabi PP, Awad W, Torella D, Tchkonia T, Kirkland JL, Ellison-Hughes GM.
Reparative macrophage transplantation for myocardial repair: a refinement of bone marrow mononuclear cell-based therapy.
Basic Res Cardiol.
Podaru M, Fields L, Kainuma S, Ichihara Y, Hussain M, Ito T, Kobayashi K, Mathur A, D’Acquisto F, Lewis-McDougall F, Suzuki K.
On-site fabrication of bi-layered adhesive mesenchymal stromal cell dressings for the treatment of heart failure.
Kobayashi K, Ichihara Y, Sato N, Umeda N, Fields L, Fukumitsu M, Tago Y, Ito T, Kainuma S, Podaru M, Lewis-McDougall FC, Yamahara K, Suzuki K.
Fibrin glue-aided, instant epicardial placement enhances the efficacy of mesenchymal stromal cell-based therapy for heart failure.
Kobayashi K, Ichihara Y, Tano N, Fields L, Ito T, Ikebe C, Lewis F, Yashiro K, Shintani Y, Uppal R, Suzuki K.
Transplantation of allogeneic PW1pos/Pax7neg interstitial cells
(PICs) enhance endogenous repair of injured porcine skeletal muscle.
JACC Basic Transl Sci.
Lewis FC, Henning BJ, Shone V, Marazzi G, Sassoon D, Tseng CCS, Chamuleau SAJ, NadalGinard B, Ellison-Hughes GM.
Active GSK3β and an intact beta-Catenin TCF complex are essential for the terminal differentiation of human myogenic progenitor cells.
Agley CC, Lewis FC*, Jaka O, Lazarus NR, Velloso C, Ellison-Hughes GM, Francis-West P, Harridge SDR (*joint first author).
Adult Cardiac Stem Cells are Multipotent and Robustly Myogenic: c-kit Expression is Necessary but not Sufficient for their Identification.
Cell Death Differ.
Vicinanza C, Aquila I, Scalise M, Cristiano F, Marino F, Cianflone E, Mancuso T, Sacco W, Lewis FC, Couch L, Shone V, Torella A, Smith A, Terracciano C, Britti D, Veltri P, Indolfi C, NadalGinard B, Ellison-Hughes GM, Torella D.
Skeletal muscle-derived interstitial progenitor cells (PICs) display stem cell properties, being clonogenic, self-renewing and multipotent in vitro and in vivo.
Stem Cell Res Ther.
Henning BJ, Lewis FC, Shone V, Ellison-Hughes GM.