Published online before print May 3, 2007, doi: 10.1161/01.RES.0000269182.22798.d9
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Submitted on July 4, 2006
Revised on March 30, 2007
Accepted on April 25, 2007
Generation of Functional Cardiomyocytes From Adult Mouse Spermatogonial Stem Cells
Kaomei Guan ;
From the Departments of Cardiology and Pneumology (K.G., S.W., B.U., L.S.M., D.K., G.H.) and Pathology (B.H.) and the Institute of Human Genetics (K.N., W.E.), Georg-August-University of Göttingen, Germany
* To whom correspondence should be addressed. E-mail: hasenfus{at}med.uni-goettingen.de.
Stem cell-based therapy is a promising approach for the treatment of heart failure. Adult stem cells with the pluripotency of embryonic stem cells (ESCs) would be an ideal cell source. Recently, we reported the successful establishment of multipotent adult germline stem cells (maGSCs) from mouse testis. These cultured maGSCs show phenotypic characteristics similar to ESCs and can spontaneously differentiate into cells from all 3 germ layers. In the present study, we used the hanging drop method to differentiate maGSCs into cardiomyocytes and analyze their functional properties. Differentiation efficiency of beating cardiomyocytes from maGSCs was similar to that from ESCs. The maGSC-derived cardiomyocytes expressed cardiac-specific L-type Ca2+ channels and responded to Ca2+ channel-modulating drugs. Cx43 was expressed at cell-to-cell contacts in cardiac clusters, and fluorescence recovery after photobleaching assay showed the presence of functional gap junctions among cardiomyocytes. Action potential analyses demonstrated the presence of pacemaker-, ventricle-, atrial-, and Purkinje-like cardiomyocytes. Stimulation with isoproterenol resulted in a significant increase in beating frequency, whereas the addition of cadmium chloride abolished spontaneous electrical activity. Confocal microscopy analysis of intracellular Ca2+ in maGSC-derived cardiomyocytes showed that calcium increased periodically throughout the cell in a homogenous fashion, pointing to a fine regulated Ca2+ release from intracellular Ca2+ stores. By using line-scan mode, we found rhythmic Ca2+ transients. Furthermore, we transplanted maGSCs into normal hearts of mice and found that maGSCs were able to proliferate and differentiate. No tumor formation was found up to 1 month after cell transplantation. Taken together, we believe that maGSCs provide a new source of distinct types of cardiomyocytes for basic research and potential therapeutic application.
Key words: spermatogonial stem cells • cardiac differentiation • gap junction • L-type Ca2+ channels • cell transplantation
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