Editors' ChoiceRegenerative Medicine

Home Is Where the Heart Is

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Science Translational Medicine  22 Jun 2011:
Vol. 3, Issue 88, pp. 88ec96
DOI: 10.1126/scitranslmed.3002784

If home is where the heart is, then regenerative medicine has moved into your chest cavity. Smart and colleagues now identify a resident stem or progenitor cell population that can terminally differentiate into heart muscle cells (cardiomyocytes) after a myocardial infarction (heart attack). These healing progenitor cells are not delivered, implanted, or transplanted—their home is in the heart itself.

In order to investigate the contribution of resident embryonic epicardial progenitor cells to repair of the adult heart, the authors sought to reactivate, in the adult mouse heart, the Wilms tumor gene (Wt1), which encodes a tumor suppressor protein that is a marker for cells of the embryonic epicardium, a membrane that surrounds the heart. Cumulative evidence indicates an epicardial origin for progenitor cells with a cardiomyocyte lineage, and the presence of Wt1 expression in a heart cell allows one to trace the cell’s origin to the adult heart epicardium. To this end, Smart and colleagues used previously described genetic mouse models in which epicardial marker proteins can be easily detected (“trace mice”). In these mice, one can trace both constitutive green fluorescent protein (GFP+)– and inducible pulse yellow fluorescent protein (YFP+)–labeling of Wt1-expressing progenitor cells in order to characterize the distribution of cardiomyocyte precursors in the adult animal.

In a process they call “priming,” the authors treated the trace mice with intraperitoneal injection of a peptide (Tβ4) from thymosin β4, an actin-binding protein that functions in cell migration and new blood vessel formation; Tβ4 has been shown to induce the adult epicardium to contribute coronary endothelial and smooth muscle cells to initiate vascular repair after injury. After priming or sham treatment, the mice were given a myocardial infarction by means of coronary artery ligation. The hearts were then assessed with a combination of fluorescence-activated cell sorting (FACS) analysis, immunofluorescence, and quantitative reverse transcription–polymerase chain reaction to look for markers of epicardial origin. Activation of Wt1 gave rise to cardiac progenitor cells in the injured hearts in numbers that increased over time. These progenitor cells differentiated into functional, structurally coupled cardiomyocytes, as shown by an increased presence of calcium transits across the Wt1+- and reporter-positive cells as compared with control cells. To rule out the possibility that traced resident cardiomyocytes were labeled by virtue of ectopic activation of the fluorophore in the hearts of trace mice, the authors transplanted FACS-isolated donor GFP+ cells into nontransgenic host hearts. Fluorescence in situ hybridization of the transplanted Wt1+GFP-labeled donor cells revealed differentiation to a myocyte fate in the absence of cell fusion. This indicates that the adult heart can respond to injury by recruiting Wt1+ progenitor cells without relying on fusion with a fully differentiated heart cell. Taken together, these findings confirm the progenitor cell source as the epicardium.

The new work by Smart et al. has important therapeutic implications for heart disease patients. The ability to repair the heart by stimulating a resident progenitor cell source avoids serious limitations such as low graft survival, restricted homing of progenitor cells to the site of injury, and host immune rejection. Although not specifically addressed in the paper, it is possible that this approach can restore cardiac function by terminally differentiating resident progenitor cells into functional cardiomyoctyes. This elegant combination of cardiology and regenerative medicine reaches beyond the realm of devices and reveals that the home of healing progenitor cells is where the heart is.

N. Smart et al., De novo cardiomyocytes from within the activated adult heart after injury. Nature 8 June 2011 (10.1038/nature10188). [Abstract]

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