De novo cardiomyocytes from within the activated adult heart after injury

• Published in: Nature (London) 2011-06, Vol.474 (7353), p.640-644
• Main Authors: Smart, Nicola, Bollini, Sveva, Dubé, Karina N., Vieira, Joaquim M., Zhou, Bin, Davidson, Sean, Yellon, Derek, Riegler, Johannes, Price, Anthony N., Lythgoe, Mark F., Pu, William T., Riley, Paul R.
• Format: Article
• Language: English
• Subjects: 631/532/2118/2440; 692/699/75/2/1674; Adult Stem Cells - cytology; Animals; Biological and medical sciences; Cardiology. Vascular system; Cardiovascular diseases; Cell Differentiation; Cellular Reprogramming; Coronary heart disease; Gene Expression Regulation; Heart; Heart Injuries; Humanities and Social Sciences; letter; Medical sciences; Mice; multidisciplinary; Myocardial infarction; Myocardial Infarction - pathology; Myocytes, Cardiac - cytology; Myocytes, Cardiac - metabolism; Science; Science (multidisciplinary); Thymosin - metabolism; WT1 Proteins - genetics; WT1 Proteins - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature10188

Repairs of the heart The prospect of cell-based therapy in cardiovascular regenerative medicine comes a step closer with the demonstration that a peptide can stimulate a progenitor cell population in the adult heart to act as a source of new cardiomyocytes. The stem or progenitor cells, thought to be derived from the epicardium, are activated by the small actin monomer binding protein thymosin β4, which has previously been shown to restore vascular potential to adult epicardium-derived progenitor cells after injury. The discovery of a resident source of myocardial progenitors will stimulate a search for small molecules and other factors that promote optimal progenitor activation and replacement of destroyed myocardium. 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 1 . 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 2 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.