title: De novo cardiomyocytes from within the activated adult heart after injury.
abstract: A significant bottleneck in cardiovascular regenerative medicine is the identification of a viable source of stem/progenitor cells that could contribute new muscle after ischaemic heart disease and acute myocardial infarction. A therapeutic ideal--relative to cell transplantation--would be to stimulate a resident source, thus avoiding the caveats of limited graft survival, restricted homing to the site of injury and host immune rejection. Here we demonstrate in mice that the adult heart contains a resident stem or progenitor cell population, which has the potential to contribute bona fide terminally differentiated cardiomyocytes after myocardial infarction. We reveal a novel genetic label of the activated adult progenitors via re-expression of a key embryonic epicardial gene, Wilm's tumour 1 (Wt1), through priming by thymosin β4, a peptide previously shown to restore vascular potential to adult epicardium-derived progenitor cells with injury. Cumulative evidence indicates an epicardial origin of the progenitor population, and embryonic reprogramming results in the mobilization of this population and concomitant differentiation to give rise to de novo cardiomyocytes. Cell transplantation confirmed a progenitor source and chromosome painting of labelled donor cells revealed transdifferentiation to a myocyte fate in the absence of cell fusion. Derived cardiomyocytes are shown here to structurally and functionally integrate with resident muscle; as such, stimulation of this adult progenitor pool represents a significant step towards resident-cell-based therapy in human ischaemic heart disease.
authors.affiliation: Molecular Medicine Unit, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Smart
authors.forename: Sveva
authors.initials: S
authors.lastname: Bollini
authors.forename: Karina N
authors.initials: KN
authors.lastname: Dubé
authors.forename: Joaquim M
authors.initials: JM
authors.lastname: Vieira
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.forename: Sean
authors.initials: S
authors.lastname: Davidson
authors.forename: Derek
authors.initials: D
authors.lastname: Yellon
authors.forename: Johannes
authors.initials: J
authors.lastname: Riegler
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Price
authors.forename: Mark F
authors.initials: MF
authors.lastname: Lythgoe
authors.forename: William T
authors.initials: WT
authors.lastname: Pu
authors.forename: Paul R
authors.initials: PR
authors.lastname: Riley
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology*; D000818:Animals; D002454:Cell Differentiation; D065150:Cellular Reprogramming; D005786:Gene Expression Regulation; D006335:Heart Injuries; D051379:Mice; D009203:Myocardial Infarction / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D013947:Thymosin / Q000378:metabolism; D025721:WT1 Proteins / Q000235:genetics / Q000378:metabolism; D000099201:Thymosin beta(4)
chemical_list: D013947:Thymosin; D025721:WT1 Proteins; D000099201:Thymosin beta(4)