Abstract
Tissue-resident stem cells may enter a dormant state, also known as quiescence, which allows them to withstand metabolic stress and unfavorable conditions. Similarly, hibernating mammals can also enter a state of dormancy used to evade hostile circumstances, such as food shortage and low ambient temperatures. In hibernation, the dormant state of the individual and its cells is commonly known as torpor, and is characterized by metabolic suppression in individual cells. Given that both conditions represent cell survival strategies, we here compare the molecular aspects of cellular quiescence, particularly of well-studied hematopoietic stem cells, and torpor at the cellular level. Critical processes of dormancy are reviewed, including the suppression of the cell cycle, changes in metabolic characteristics, and cellular mechanisms of dealing with damage. Key factors shared by hematopoietic stem cell quiescence and torpor include a reversible activation of factors inhibiting the cell cycle, a shift in metabolism from glucose to fatty acid oxidation, downregulation of mitochondrial activity, key changes in hypoxia-inducible factor one alpha (HIF-1α), mTOR, reversible protein phosphorylation and autophagy, and increased radiation resistance. This similarity is remarkable in view of the difference in cell populations, as stem cell quiescence regards proliferating cells, while torpor mainly involves terminally differentiated cells. A future perspective is provided how to advance our understanding of the crucial pathways that allow stem cells and hibernating animals to engage in their ‘great slumbers.’
Highlights
The difference between life and death of individual cells or animals depends on their ability to survive, during periods of scarcity
Cellular quiescence in hematopoietic stem cells (HSCs) is associated with three key changes in cell physiology: (i) cell cycle arrest by inhibition of cyclindependent kinases (CDKs) upon an increase in expression of cyclin-dependent kinase inhibitors (CKIs), (ii) lowering of metabolism with a switch from carbohydrate to lipidbased metabolism and (iii) resistance to accumulating cellular damage conferred by differential expression of genes involved in apoptosis, proliferation and oxidative stress
In the presence of plentiful nutrients, growth factors activate transmembrane receptors, eliciting downstream signaling cascades, including the rat sarcoma oncogene (RAS) (Beauséjour et al, 2003), myelocytomatosis (Myc) (Rahl et al, 2010) and the serine/threonine-protein kinase B (PI3K/Akt) pathways. This is followed by sequential activation of the mitogen-activated protein kinases (MAPKs), which induce the transcription of cyclin D that binds to cyclin-dependent kinases (CDK) 4 and 6, forming activated complexes that initiate the downstream phosphorylation of DNA synthesis associated proteins (Seger and Krebs, 1995; Pimienta and Pascual, 2007; Risal et al, 2016; Seger and Wexler, 2016)
Summary
The difference between life and death of individual cells or animals depends on their ability to survive, during periods of scarcity. Some mammals may hibernate to cope with such conditions by suppressing metabolism in a state called torpor Given that they represent cell survival strategies triggered by external factors, cell quiescence and hibernation both deploy molecular adaptations to survive environmental stress such as low temperature and shortage of nutrients, and even increase their resistance to withstand periods of low oxygen supply. In both cases, phenotypic plasticity is of paramount importance to ensure survival, yet it is undocumented whether the mechanism governing entry or exit from cellular. We summarize mechanisms used in cellular quiescence and mammalian hibernation and use the collective findings to establish their resemblance
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