Decoding the stem cell quiescence cycle--lessons from yeast for regenerative biology

Abstract

In the past decade, major advances have occurred in the understanding of mammalian stem cell biology, but roadblocks (including gaps in our fundamental understanding) remain in translating this knowledge to regenerative medicine. Interestingly, a close analysis of the Saccharomyces cerevisiae literature leads to an appreciation of how much yeast biology has contributed to the conceptual framework underpinning our understanding of stem cell behavior, to the point where such insights have been internalized into the realm of the known. This Opinion article focuses on one such example, the quiescent adult mammalian stem cell, and examines concepts underlying our understanding of quiescence that can be attributed to studies in yeast. We discuss the metabolic, signaling and gene regulatory events that control entry and exit into quiescence in yeast. These processes and events retain remarkable conservation and conceptual parallels in mammalian systems, and collectively suggest a regulated program beyond the cessation of cell division. We argue that studies in yeast will continue to not only reveal fundamental concepts in quiescence, but also leaven progress in regenerative medicine.

Keywords: Adult stem cell; Metabolism; Quiescence; Regeneration; Signaling pathways; Yeast.

Fig. 1. Reversible withdrawal into a quiescence cycle is an active process.

(A) Schematic illustration of the quiescence cycle in context of the general cell cycle. Entry of cells into the quiescence cycle and ‘G0’ requires nutrient starvation (particularly in yeast cells) and other extrinsic cues, which both in yeast and mammalian cells might all funnel into regulating the activity of TOR, PKA and AMPK to permit induction of a quiescence program. Re-entry into the cell cycle requires nutrients and extrinsic cues. The systemic inputs required for triggering exit from proliferation, or re-entry into the cell cycle from quiescence remain poorly understood. Not all cells within a quiescent population will re-enter the cell cycle upon receiving appropriate cues and some cells appear to be uniquely adapted to re-enter the cell cycle. This program of reversible arrest includes induction of a quiescence program that involves an active suppression of alternative non-dividing fates (see B). Critical determinants of this program remain to be discovered. Nutrient-dependent commitment steps are illustrated in bold with black arrows. In proliferating populations, the decision to enter quiescence was traditionally thought to be in G1 (red arrowhead) when a cell assesses its cellular state in the context of external conditions, but recent evidence suggests that key control mechanisms might already be in place at the end of the preceding cell cycle (orange arrowhead). (B) Quiescence involves the induction of programs beyond mitotic arrest. Signatures of different phases of the quiescence cycle are illustrated. Cells entering G0 from G1 block alternate non-dividing states, such as senescence, death and differentiation. Even within such a population of non-dividing cells, there is heterogeneity in that only some cells are responsive to subsequent cues to be able to exit quiescence. To maintain the G0 state, cells induce survival pathways and nutrient uptake; they also must maintain identity and avoid precocious activation. Upon receiving an appropriate stimulus, which might include nutrient cues, the responsive cells (blue) within this population of cells will exit G0 and re-enter G1. Non-responsive cells are shown in red. Whether the heterogeneity arises from intrinsic variation in activation thresholds of key control mechanisms or temporal asynchrony of the population is not known.

Fig. 2. Conserved mechanisms might govern the entry into and exit from quiescence in stem cells.

Studies from yeast have elucidated the metabolic events and signaling pathways that control entry into quiescence during starvation (shown on the left). In particular, starvation strongly inhibits the TORC1 and PKA pathways, with an initial activation of the AMPK (Snf1) pathway. Exit from quiescence requires TORC1 activation, and an increase in the key metabolite acetyl-CoA, which regulates the activation of growth-promoting genes through specific acetylation events. Many parallels have been observed in adult mammalian stem cells (shown on the right). The population of yeast cells in G0 is heterogeneous, and only responsive cells (indicated in blue), which typically appear to have higher stores of carbon that can be converted into acetyl-CoA, exit quiescence upon stimulus (see also Fig. 1). Exit from quiescence in yeast correlates with increased TOR and PKA activity, and histone acetylation, which controls the transcription of growth-related genes. Several parallels appear to be conserved in mammalian adult stem cells, such as in the myoblast cell depicted on the right. However, unlike in yeast cells, the changes in carbon metabolism upon entry into quiescence and the role of the conserved energy-sensing kinase AMPK have not been well studied in mammalian cells. However, all three pathways identified in yeast have also been implicated in quiescence control in mammalian cells. Mammalian cell populations that enter quiescence are also heterogeneous and only responsive cells (in blue) exit quiescence upon sensing appropriate cues. Although recent studies have shown a crucial role for the mTORC1 pathway in exiting quiescence, other aspects observed in yeast cells (such as acetyl-CoA-dependent histone acetylation and gene activation) have not yet been investigated in mammalian cells. Indeed, several aspects of both metabolic events and signaling responses in stem cells remain unclear; however, owing to the high degree of conservation of these processes across different eukaryotes, it is likely that many of the pathways observed in yeast have similar roles in stem cells.