The cellular life span is structured around the cell cycle, a tightly regulated sequence of events leading to cell division. This cycle is divided into interphase and the M (mitosis) phase. Interphase consists of three stages: G1 (cell growth and preparation for DNA replication), S (DNA synthesis), and G2 (preparation for division). Cells that are not actively preparing to divide exit this cycle and enter a non-proliferative state called the G0 phase, also known as cellular quiescence. In G0, the cell remains metabolically active but halts all progression toward replication and division.
The Cell Cycle’s Restriction Point
The point where a cell decides whether to commit to division or enter the G0 state occurs during the G1 phase at a regulatory step known as the Restriction Point (R-point). Passing this point commits the cell to completing the rest of the cell cycle, regardless of external signals, making it an irreversible decision. A cell bypasses the R-point only if it receives sufficient external signals, primarily growth factors, and if its internal conditions are favorable.
In the absence of these growth signals, or in response to inhibitory signals, the cell exits the cycle and enters the G0 phase. This decision is controlled by a molecular braking system involving the retinoblastoma protein (Rb) and cyclin-dependent kinases (CDKs) partnered with cyclins. Growth factors activate Cyclin D-CDK4/6 complexes, which function to phosphorylate the Rb protein.
When Rb is unphosphorylated, it acts as a brake by binding to and inactivating the E2F transcription factors, which are necessary for expressing genes required for DNA synthesis in the S phase. The cell remains in G1 or enters G0 because replication machinery cannot be produced. Once Rb is phosphorylated by the cyclin-CDK complex, it releases E2F, allowing the transcription of S-phase genes and committing the cell past the R-point.
The Metabolic Activity of Quiescent Cells
The G0 state is one of active maintenance and survival. Cells in quiescence shift their metabolic priorities away from growth-related processes like DNA and protein synthesis toward cellular homeostasis and repair. This involves a general reduction in the rates of transcription and translation, which conserves cellular energy.
Quiescent cells typically have lower overall metabolic rates compared to rapidly dividing cells, with a reduced uptake of nutrients like glucose. Energy is redirected to maintaining membrane integrity, repairing incidental DNA damage, and performing the cell’s specialized tissue function. For instance, a quiescent liver cell still performs its detoxification roles, and a neuron continues to transmit signals.
The molecular profile of a G0 cell is distinct, marked by low levels of the cyclins and CDKs that drive the cell cycle forward. Conversely, there is an upregulation of specific proteins, such as cyclin-dependent kinase inhibitors (CKIs) like p27. These inhibitors actively maintain the quiescent state by blocking any residual CDK activity. This change in protein expression ensures the cell is poised for survival over proliferation, allowing it to persist for long periods while awaiting a change in environmental conditions.
Reversible and Irreversible G0 States
The duration and fate of a cell in G0 depend entirely on its cell type and its capacity to re-enter the proliferative cycle, categorizing the state into two main forms.
Reversible Quiescence
Reversible, or labile, quiescence allows cells to rapidly exit G0 and re-enter the G1 phase upon receiving external signals, such as growth factors. This state is exemplified by adult stem cells, which reside in G0 to maintain a reserve population, activating only when tissue repair or replacement is needed. Other reversibly quiescent cells include hepatocytes, which can quickly re-enter the cell cycle to regenerate liver tissue after injury. Lymphocytes also remain in G0 until they encounter a specific antigen, triggering rapid proliferation to mount an immune response.
Irreversible Quiescence
Irreversible, or stable, quiescence represents terminal differentiation where the cell permanently exits the cell cycle. Cells in this state have often lost the molecular machinery required to replicate their DNA and undergo division. Mature neurons and cardiac muscle cells (cardiomyocytes) are prime examples. These highly specialized cells must maintain their function without interruption for the organism’s entire life. Their inability to divide means that damage or loss to these cell populations cannot typically be restored through cell replacement.