title: Cardiac Repair With a Novel Population of Mesenchymal Stem Cells Resident in the Human Heart.
abstract: Cardiac resident stem cells (CRSCs) hold much promise to treat heart disease but this remains a controversial field. Here, we describe a novel population of CRSCs, which are positive for W8B2 antigen and were obtained from adult human atrial appendages. W8B2(+) CRSCs exhibit a spindle-shaped morphology, are clonogenic and capable of self-renewal. W8B2(+) CRSCs show high expression of mesenchymal but not hematopoietic nor endothelial markers. W8B2(+) CRSCs expressed GATA4, HAND2, and TBX5, but not C-KIT, SCA-1, NKX2.5, PDGFRα, ISL1, or WT1. W8B2(+) CRSCs can differentiate into cardiovascular lineages and secrete a range of cytokines implicated in angiogenesis, chemotaxis, inflammation, extracellular matrix remodeling, cell growth, and survival. In vitro, conditioned medium collected from W8B2(+) CRSCs displayed prosurvival, proangiogenic, and promigratory effects on endothelial cells, superior to that of other adult stem cells tested, and additionally promoted survival and proliferation of neonatal rat cardiomyocytes. Intramyocardial transplantation of human W8B2(+) CRSCs into immunocompromised rats 1 week after myocardial infarction markedly improved cardiac function (∼40% improvement in ejection fraction) and reduced fibrotic scar tissue 4 weeks after infarction. Hearts treated with W8B2(+) CRSCs showed less adverse remodeling of the left ventricle, a greater number of proliferating cardiomyocytes (Ki67(+) cTnT(+) cells) in the remote region, higher myocardial vascular density, and greater infiltration of CD163(+) cells (a marker for M2 macrophages) into the border zone and scar regions. In summary, W8B2(+) CRSCs are distinct from currently known CRSCs found in human hearts, and as such may be an ideal cell source to repair myocardial damage after infarction.
authors.affiliation: Department of Medicine, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: O'Brien Institute Department, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.
authors.forename: Priyadharshini
authors.initials: P
authors.lastname: Sivakumaran
authors.affiliation: Department of Surgery, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia.|Department of Cardiothoracic Surgery, St. Vincent's Hospital, Melbourne, Victoria, Australia.|Vascular and Cardiac Surgery, The Cardiovascular Research Centre (CvRC), Australian Catholic University, Fitzroy, Victoria, Australia.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Newcomb
authors.affiliation: Department of Medicine, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia.|O'Brien Institute Department, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.
authors.forename: Damián
authors.initials: D
authors.lastname: Hernandez
authors.affiliation: O'Brien Institute Department, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.
authors.forename: Nicole
authors.initials: N
authors.lastname: Harris
authors.affiliation: Department of Surgery, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia.|O'Brien Institute Department, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.
authors.forename: Ramin
authors.initials: R
authors.lastname: Khanabdali
authors.affiliation: Department of Ophthalmology, University of Melbourne, Melbourne, Victoria, Australia.|Centre for Eye Research Australia & Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.
authors.forename: Guei-Sheung
authors.initials: GS
authors.lastname: Liu
authors.affiliation: Department of Medicine, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Kelly
authors.affiliation: Department of Ophthalmology, University of Melbourne, Melbourne, Victoria, Australia.|Centre for Eye Research Australia & Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.
authors.forename: Alice
authors.initials: A
authors.lastname: Pébay
authors.affiliation: Department of Ophthalmology, University of Melbourne, Melbourne, Victoria, Australia.|Centre for Eye Research Australia & Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.
authors.forename: Alex W
authors.initials: AW
authors.lastname: Hewitt
authors.affiliation: School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Boyle
authors.affiliation: Developmental and Stem Cell Biology, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Harvey
authors.affiliation: Department of Surgery, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia.|O'Brien Institute Department, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.|AORTEC, Faculty of Health Sciences, Australian Catholic University, Fitzroy, Victoria, Australia.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Morrison
authors.affiliation: Cardiac Development, Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Elliott
authors.affiliation: Department of Surgery, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia.|Department of Ophthalmology, University of Melbourne, Melbourne, Victoria, Australia.|O'Brien Institute Department, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.|Centre for Eye Research Australia & Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Dusting
authors.affiliation: Department of Surgery, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia.|O'Brien Institute Department, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.
authors.forename: Shiang Y
authors.initials: SY
authors.lastname: Lim
mesh_terms: D000328:Adult; D053687:Adult Stem Cells / Q000637:transplantation; D000818:Animals; D000954:Antigens, Surface / Q000096:biosynthesis*; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D009203:Myocardial Infarction / Q000473:pathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000166:cytology; D051381:Rats
chemical_list: D000954:Antigens, Surface; D017077:Culture Media, Conditioned; D016207:Cytokines; C540400:W8B2 protein, human
keywords: Adult stem cells; Heart; Mesenchymal stem cell; Myocardial infarction; W8B2