Hypoxic and Normoxic Stem Cell Niches in the Aging IVIouse Heart

Brigham And Women'S Hospital, Boston MA

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Abstract

PROJECT SUMMARY (See instructions): 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.