Adult Cardiac Stem Cell Aging: A Reversible Stochastic Phenomenon?

Abstract

Aging is by far the dominant risk factor for the development of cardiovascular diseases, whose prevalence dramatically increases with increasing age reaching epidemic proportions. In the elderly, pathologic cellular and molecular changes in cardiac tissue homeostasis and response to injury result in progressive deteriorations in the structure and function of the heart. Although the phenotypes of cardiac aging have been the subject of intense study, the recent discovery that cardiac homeostasis during mammalian lifespan is maintained and regulated by regenerative events associated with endogenous cardiac stem cell (CSC) activation has produced a crucial reconsideration of the biology of the adult and aged mammalian myocardium. The classical notion of the adult heart as a static organ, in terms of cell turnover and renewal, has now been replaced by a dynamic model in which cardiac cells continuously die and are then replaced by CSC progeny differentiation. However, CSCs are not immortal. They undergo cellular senescence characterized by increased ROS production and oxidative stress and loss of telomere/telomerase integrity in response to a variety of physiological and pathological demands with aging. Nevertheless, the old myocardium preserves an endogenous functionally competent CSC cohort which appears to be resistant to the senescent phenotype occurring with aging. The latter envisions the phenomenon of CSC ageing as a result of a stochastic and therefore reversible cell autonomous process. However, CSC aging could be a programmed cell cycle-dependent process, which affects all or most of the endogenous CSC population. The latter would infer that the loss of CSC regenerative capacity with aging is an inevitable phenomenon that cannot be rescued by stimulating their growth, which would only speed their progressive exhaustion. The resolution of these two biological views will be crucial to design and develop effective CSC-based interventions to counteract cardiac aging not only improving health span of the elderly but also extending lifespan by delaying cardiovascular disease-related deaths.

Figure 1

Schematic representation of the transitional sequence of cardiac stem cell-committed progeny. Quiescent, primitive, undifferentiated cardiac stem cells express Oct-4 (pink fluorescence), become activated, and start expressing c-kit (green fluorescence). In response to stress, these cells multiply and lose expression of Oct-4. The resulting c-kit pos/Oct-4 neg cells are still uncommitted to one specific cardiac cell lineage. After further expansion and differentiation, the cells induce expression of transcription factors specific to one cardiac lineage (GATA4, ETS1, or GATA6) and differentiate into one of the three cardiac cell types—cardiomyocytes, endothelial, and smooth muscle cells—respectively. These newly formed cardiac cells can undergo a few rounds of replication before becoming terminally differentiated. CSC: cardiac stem cell; vWF-VIII: von Willebrand factor VIII. Figure 1 is reproduced from Georgina M. Ellison et al., (under the Creative Commons Attribution License/public domain) [54].

Figure 2

c-Kit^pos CSCs are multipotent in vitro and in vivo. (a) Undifferentiated c-kit^pos (green) CSC-derived cardiospheres express multipotent stemness markers (c-kit, Oct-4, Sox-2, Klf-4, and Nanog) and Wnt3a (red). Bar = 50 μm. (b) CSC-derived contracting CMs in vitro express contractile proteins (actinin, cTnI, MHC, and cardiac actin) with coexpression of cardiac transcription factor (Gata-4). The CSC-derived CMs exhibit well-defined sarcomeric structures (z lines and dots) as well as gap junction formation (Cnx-43) between cells. DAPI stain nuclei are in blue. Bar = 20 μm. (c) Light microscopy image of freshly isolated adult cardiomyocytes from a dissociated rat heart 28 days after myocardial infarction (MI) and CSC GFP injection (MI + CSC GFP) shows a CSC-derived GFP-positive cardiomyocyte. (d) Confocal microscopy images show host-derived preexisting GFP^neg cardiomyocytes as compared to CSC-derived GFP^pos cardiomyocytes isolated from MI + CSC GFP rat hearts at 28 days after MI. Note that GFP^pos cardiomyocytes are of smaller size and mononucleated when compared to surviving binucleated GFP^neg cardiomyocytes of the host. (e) Representative confocal images show at high magnification a CSC-derived newly formed GFP^pos cardiomyocyte in the infarct border zone 28 days after MI treated with CSC GFP. Figure 2 is reproduced from Carla Vicinanza et al., (under the Creative Commons Attribution License/public domain) [55].

Figure 3

Schematic representation of the mechanisms implicated with adult stem cell senescence owing to tissue-specific stem/progenitor cell exhaustion in aging.

Figure 4

Schematic representation of the accumulation of “old” CSCs during cardiac homeostasis in aging and their impaired regenerative response after injury when compared to “healthy” young CSCs.