A nucleolar weapon in our fight for regenerating adult hearts: nucleostemin and cardiac stem cells.

Ischemic diseases and heart failure remain the major causes of morbidity and mortality in the industrialized world. Several new therapeutic modalities have been developed to interfere with the response to injury and to improve cardiac function after ischemia or cardiomyopathy. Experimental and clinical studies demonstrated that the transplantation of bone marrow–derived or tissue-resident stem/progenitor cells in diseased hearts improves neovascularization and functional recovery.1 However, the recent discovery of cardiac stem cells (CSCs) in the adult heart poses the question whether activation of the endogenous pool of these resident stem cells may compensate for the loss of cardiac tissue after injury and improve functional recovery. Indeed, a genetic fate-mapping study elegantly demonstrated that stem cells or precursor cells significantly contributed to the replacement of adult mammalian cardiomyocytes after injury.2 Although it remains unclear to what extent cardiac regeneration in this genetic model was mediated by CSCs or circulating progenitor cell populations being attracted to the heart after injury, mounting evidence suggests that injury-associated signals activate CSCs in situ, which subsequently contribute to the refreshment of the injured heart.3 Obviously, to play a significant role in endogenous cardiac regeneration, the relatively small number of endogenous CSCs needs to be expanded after injury before differentiating into cardiac myocytes. However, the molecular mechanisms underlying the activation, expansion, and recruitment of resident CSCs after injury remain unclear. In the current issue of Circulation Research, Siddiqi et al provide an intriguing concept, which might help to mechanistically explain how proliferation of CSCs is regulated in response to injury.4 The authors investigated the cardiac expression of stem cell specific genes, involved in selfrenewal and proliferation, during cardiomyopathic injuries and found increased expression of the nucleolar protein nucleostemin—recently discovered in embryonic and adult stem cells as well as in cancer cell lines.5 Detailed expression analysis in the heart revealed that nucleostemin protein was expressed in the heart at birth but rapidly declined in the first weeks of postnatal life.4 However, nucleostemin was transiently reexpressed in the adult heart after acute myocardial infarction and other pathological challenges, such as pressure overload (Figure 1A). Interestingly, the transient reexpression of nucleostemin in c-kit CSCs may have contributed to their expansion after injury. Indeed, forced overexpression of nucleostemin in cultured CSCs significantly increased that proliferation, whereas cultured CSCs downregulated the expression of nucleostemin during cardiac differentiation (analogous to previous results in other adult stem cells5). Consistent with the concept that only a transient signal is required for expanding the stem cell pool, nucleostemin was expressed in vivo at maximum levels around 72 hours after injury and returned to baseline levels within days.4 Altogether, these data support the concept that a transient upregulation of nucleostemin promotes the proliferation of CSCs, whereas subsequent downregulation of its expression occurs before terminal differentiation. Obviously, these data are based on associations, and the causal role of nucleostemin for endogenous cardiac regeneration needs to be further tested in genetic animal models. Surprisingly, the expression of nucleostemin was not only increased in the c-kit CSCs, but also in selective cardiomyocytes after myocardial infarction or pressure-overload hypertrophy.4 The reexpression of nucleostemin in cardiomyocytes reminds to the well-established reactivation of the embryonic gene program during pathological hypertrophy; however, the functional relevance of this reexpression remains unknown. Indeed, in contrast to CSCs, forced overexpression of nucleostemin in cardiomyocytes failed to induce proliferation, and alternative functions of nucleostemin in cardiomyocytes were not studied. Generally, the molecular mechanisms of nucleostemin-mediated functions are not entirely clear. The protein consists of an N-terminal basic domain, which specifies nucleolar localization, and 2 GTP-binding motifs, which are involved in its interaction with p53.5 Removal of the GTP-binding motifs was shown to induce p53-dependent apoptosis indicating that nucleostemin might inhibit p53 activity.5 However, forced overexpression of nucleostemin in cardiomyocytes was insufficient to antagonize p53.4 Nucleostemin was also reported to delay cellular senescence in mouse embryonic fibroblasts.6 Consistent herewith, in CSCs, forced overexpression of nucleostemin resulted in the absence of telomere shortening despite increased proliferaThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Institute of Cardiovascular Regeneration (M.T., S.D.), Centre of Molecular Medicine, University of Frankfurt, Germany; Leibniz AG (M.T.), Institute of Cardiovascular Regeneration, Centre for Molecular Medicine, University Frankfurt, Germany; and Vesalius Research Center (M.T.), VIB, University of Leuven, Belgium. Correspondence to Stefanie Dimmeler, PhD, Institute of Cardiovascular Regeneration, Centre for Molecular Medicine, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. E-mail [email protected] (Circ Res. 2008;103:4-6.) © 2008 American Heart Association, Inc.