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      Human Cardiosphere-Derived Cells from Patients with Chronic Ischaemic Heart Disease Can Be Routinely Expanded from Atrial but Not Epicardial Ventricular Biopsies

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          Abstract

          To investigate the effects of age and disease on endogenous cardiac progenitor cells, we obtained right atrial and left ventricular epicardial biopsies from patients ( n = 22) with chronic ischaemic heart disease and measured doubling time and surface marker expression in explant- and cardiosphere-derived cells (EDCs, CDCs). EDCs could be expanded from all atrial biopsy samples, but sufficient cells for cardiosphere culture were obtained from only 8 of 22 ventricular biopsies. EDCs from both atrium and ventricle contained a higher proportion of c-kit+ cells than CDCs, which contained few such cells. There was wide variation in expression of CD90 (atrial CDCs 5–92 % CD90+; ventricular CDCs 11–89 % CD90+), with atrial CDCs cultured from diabetic patients ( n = 4) containing 1.6-fold more CD90+ cells than those from non-diabetic patients ( n = 18). No effect of age or other co-morbidities was detected. Thus, CDCs from atrial biopsies may vary in their therapeutic potential.

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          The online version of this article (doi:10.1007/s12265-012-9389-0) contains supplementary material, which is available to authorized users.

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          Adult cardiac stem cells are multipotent and support myocardial regeneration.

          The notion of the adult heart as terminally differentiated organ without self-renewal potential has been undermined by the existence of a subpopulation of replicating myocytes in normal and pathological states. The origin and significance of these cells has remained obscure for lack of a proper biological context. We report the existence of Lin(-) c-kit(POS) cells with the properties of cardiac stem cells. They are self-renewing, clonogenic, and multipotent, giving rise to myocytes, smooth muscle, and endothelial cells. When injected into an ischemic heart, these cells or their clonal progeny reconstitute well-differentiated myocardium, formed by blood-carrying new vessels and myocytes with the characteristics of young cells, encompassing approximately 70% of the ventricle. Thus, the adult heart, like the brain, is mainly composed of terminally differentiated cells, but is not a terminally differentiated organ because it contains stem cells supporting its regeneration. The existence of these cells opens new opportunities for myocardial repair.
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            Isolation and expansion of adult cardiac stem cells from human and murine heart.

            Cardiac myocytes have been traditionally regarded as terminally differentiated cells that adapt to increased work and compensate for disease exclusively through hypertrophy. However, in the past few years, compelling evidence has accumulated suggesting that the heart has regenerative potential. Recent studies have even surmised the existence of resident cardiac stem cells, endothelial cells generating cardiomyocytes by cell contact or extracardiac progenitors for cardiomyocytes, but these findings are still controversial. We describe the isolation of undifferentiated cells that grow as self-adherent clusters (that we have termed "cardiospheres") from subcultures of postnatal atrial or ventricular human biopsy specimens and from murine hearts. These cells are clonogenic, express stem and endothelial progenitor cell antigens/markers, and appear to have the properties of adult cardiac stem cells. They are capable of long-term self-renewal and can differentiate in vitro and after ectopic (dorsal subcutaneous connective tissue) or orthotopic (myocardial infarction) transplantation in SCID beige mouse to yield the major specialized cell types of the heart: myocytes (ie, cells demonstrating contractile activity and/or showing cardiomyocyte markers) and vascular cells (ie, cells with endothelial or smooth muscle markers).
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              Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction.

              Potential repair by cell grafting or mobilizing endogenous cells holds particular attraction in heart disease, where the meager capacity for cardiomyocyte proliferation likely contributes to the irreversibility of heart failure. Whether cardiac progenitors exist in adult myocardium itself is unanswered, as is the question whether undifferentiated cardiac precursor cells merely fuse with preexisting myocytes. Here we report the existence of adult heart-derived cardiac progenitor cells expressing stem cell antigen-1. Initially, the cells express neither cardiac structural genes nor Nkx2.5 but differentiate in vitro in response to 5'-azacytidine, in part depending on Bmpr1a, a receptor for bone morphogenetic proteins. Given intravenously after ischemia/reperfusion, cardiac stem cell antigen 1 cells home to injured myocardium. By using a Cre/Lox donor/recipient pair (alphaMHC-Cre/R26R), differentiation was shown to occur roughly equally, with and without fusion to host cells.
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                Author and article information

                Contributors
                +44-1865-282247 , +44-1865-282272 , Carolyn.Carr@dpag.ox.ac.uk
                Journal
                J Cardiovasc Transl Res
                J Cardiovasc Transl Res
                Journal of Cardiovascular Translational Research
                Springer US (Boston )
                1937-5387
                1937-5395
                3 July 2012
                3 July 2012
                October 2012
                : 5
                : 5
                : 678-687
                Affiliations
                [1 ]Department of Physiology, Anatomy and Genetics, University of Oxford, Sherrington Building, Parks Road, Oxford, OX1 3PT UK
                [2 ]Stem Cell Research Laboratory, NHS Blood and Transplant, John Radcliffe Hospital, Oxford, UK
                [3 ]Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK
                [4 ]Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK
                [5 ]Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang, Malaysia
                Article
                9389
                10.1007/s12265-012-9389-0
                3447135
                22752803
                1bac7987-2b16-4500-befc-4dec38589191
                © The Author(s) 2012
                History
                : 23 April 2012
                : 14 June 2012
                Categories
                Article
                Custom metadata
                © Springer Science+Business Media, LLC 2012

                Cardiovascular Medicine
                human,cardiosphere-derived cells,ischaemic heart disease,diabetes
                Cardiovascular Medicine
                human, cardiosphere-derived cells, ischaemic heart disease, diabetes

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