Stem cell niches constitute interstitial microdomains, which integrate local and systemic cues regulating stem cell fate. In the myocardium, c-kit-positive cardiac stem cells (CSCs) are clustered in niches, which have been viewed as homogeneous compartments of rarely dividing cells. However, quiescent and active CSCs may coexist in the heart and inhabit distinct niches, representing an alternative model of tissue homeostasis. Quiescent CSCs may be responsible for the preservation of the undifferentiated stem cell pool within the myocardium, while the developmental choice of active CSCs is frequent replication with formation of a committed progeny. The hypothesis is raised that quiescent niches are characterized by a hypoxic microenvironment, while active niches are physiologically normoxic. CSCs in hypoxic niches proliferate rarely and, when needed, undergo a symmetric modality of CSC division with generation of two daughter stem cells. By this mechanism, CSCs in hypoxic niches may replenish depleted active niches, ensuring the homeostafic control of the young heart. With aging, the interdependence of hypoxic and normoxic niches may be partially lost, interfering with the physiological turnover of cardiomyocytes, and vascular endothelial cells and smooth muscle cells. Defects in tissue oxygenation may lead to an increase in the number of hypoxic niches so that CSCs nested in normoxic niches are forced to divide continuously and differentiate, leading to progressive telomere erosion and generation of a progeny that inherits the phenotypic properties of the aging mother cells. Conversely, CSCs residing in hypoxic niches retain a quiescent state and long telomeres, but cannot contribute to the renewal of cardiac cells and the generation of young specialized cells. The quiescent state of CSCs in hypoxic niches may depend on the expression of the hypoxia-inducible factor-la (HIFIa). HIFIa may downregulate miR-221/222 releasing the repressive function of these small RNAs on c-kit expression. Upregulation of c-kit preserves stemness and opposes lineage specification.

Public Health Relevance

This research aims at the identification of a pool of quiescent stem cells that retain a significant growth reserve late in life and, if activated, may rescue the cardiac senescent phenotype. This work may lead to the identification of novel strategies for the treatment of the aging myopathy, a major cause of death in the elderly.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-7)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
Borghetti, Giulia; Eisenberg, Carol A; Signore, Sergio et al. (2018) Notch signaling modulates the electrical behavior of cardiomyocytes. Am J Physiol Heart Circ Physiol 314:H68-H81
Wysoczynski, Marcin; Guo, Yiru; Moore 4th, Joseph B et al. (2017) Myocardial Reparative Properties of Cardiac Mesenchymal Cells Isolated on the Basis of Adherence. J Am Coll Cardiol 69:1824-1838
Sorrentino, Andrea; Signore, Sergio; Qanud, Khaled et al. (2016) Myocyte repolarization modulates myocardial function in aging dogs. Am J Physiol Heart Circ Physiol 310:H873-90
Meo, Marianna; Meste, Olivier; Signore, Sergio et al. (2016) Reduction in Kv Current Enhances the Temporal Dispersion of the Action Potential in Diabetic Myocytes: Insights From a Novel Repolarization Algorithm. J Am Heart Assoc 5:
Signore, Sergio; Sorrentino, Andrea; Borghetti, Giulia et al. (2015) Late Na(+) current and protracted electrical recovery are critical determinants of the aging myopathy. Nat Commun 6:8803
Moccetti, Tiziano; Leri, Annarosa; Goichberg, Polina et al. (2015) A Novel Class of Human Cardiac Stem Cells. Cardiol Rev 23:189-200
Leri, Annarosa; Rota, Marcello; Pasqualini, Francesco S et al. (2015) Origin of cardiomyocytes in the adult heart. Circ Res 116:150-66
Iso, Yoshitaka; Rao, Krithika S; Poole, Charla N et al. (2014) Priming with ligands secreted by human stromal progenitor cells promotes grafts of cardiac stem/progenitor cells after myocardial infarction. Stem Cells 32:674-83
Goichberg, Polina; Chang, Jerway; Liao, Ronglih et al. (2014) Cardiac stem cells: biology and clinical applications. Antioxid Redox Signal 21:2002-17
D'Amario, Domenico; Leone, Antonio M; Iaconelli, Antonio et al. (2014) Growth properties of cardiac stem cells are a novel biomarker of patients' outcome after coronary bypass surgery. Circulation 129:157-72

Showing the most recent 10 out of 25 publications