Reversible Quiescence in Adult Stem Cells: A Profound Insight into Tissue Regeneration and Disease

Adult stem cells play a pivotal role in maintaining tissue homeostasis and repair throughout an organism’s life. These remarkable cells represent a small but critical pool within adult tissues, responsible for generating mature progeny and ensuring the continuous renewal of vital structures. To accomplish this task effectively, adult stem cells have developed a unique strategy – reversible quiescence.

In a new study published in the peer-reviewed Journal Neuroscience, PhD candidate Laura Blasco-Chamarro and Professor Isabel Fariñas from the University of Valencia in Spain have shed light on the fascinating world of reversible quiescence in adult stem cells (aNSCs). This research explores the dynamic state of aNSCs and its crucial role in tissue regeneration and disease. The study discusses the complexities of aNSCs, their activation and quiescence, and their contribution to the maintenance of various tissues, emphasizing the importance of this knowledge for potential therapeutic applications.

Cellular quiescence, in the context of adult stem cells, refers to a reversible state where cells temporarily exit the cell cycle and stop dividing while retaining the ability to resume proliferation when necessary. Unlike other non-proliferative conditions such as postmitotic differentiation or cellular senescence, quiescence equips these cells with the capacity to reactivate and contribute to tissue regeneration.

Quiescence is not a universal trait of all adult stem cells; it varies depending on the tissue in which they are found. Some stem cells can exist in either a quiescent or an activated state, with the proportions of these states adapted to the tissue’s specific needs. For instance, the intestine and the epidermis, exposed to constant environmental challenges, contain rapidly dividing stem cells, while skeletal muscle stem cells remain quiescent until tissue injury necessitates their activation.

Recent advancements in single-cell transcriptomic analysis have unveiled the unique molecular signature of quiescent stem cells. These cells display lower metabolic activity, reduced translation rates, and downregulated genes associated with DNA replication, cell-cycle progression, proliferation, and mitochondrial function. Despite not actively dividing, quiescent stem cells maintain metabolic activity to conserve energy and resources, preparing to respond to activating cues when required. This specialized molecular signature results from the interplay of tissue-specific stem cell transcription factors and discernible epigenetic modifications, highlighting the complexity of transcriptional regulation.

Remarkably, the levels of RNA and proteins within quiescent stem cells can differ significantly, indicating the pivotal role of post-transcriptional mechanisms in orchestrating and controlling the dormant state. Processes like translation repression and protein degradation are crucial for preserving quiescence. Additionally, autophagy and lysosomal pathways contribute to proteostasis and support quiescent stem cell function.

Recent studies have uncovered a surprising level of heterogeneity within quiescent stem cell populations. In some cases, stem cells can exist in different depths of quiescence, transitioning between shallow and deep quiescent states in response to specific cues. This variability raises intriguing questions about the role of primed or alerted stem cells, which exhibit characteristics between quiescent and activated states, in different tissues.

The identification and isolation of quiescent stem cells have been challenging but are essential for advancing our understanding of these cells and their potential therapeutic applications. Recent efforts have employed fluorescence-activated cell sorting (FACS) and surface markers to isolate subsets of quiescent and activated stem cells. This technology, combined with deep RNA sequencing, has enabled researchers to distinguish between different depths of quiescence.

Culturing quiescent stem cells in vitro remains a significant challenge, but recent progress has been made in modeling their behavior. By treating stem cells with specific signaling pathways, such as the bone morphogenetic protein (BMP) pathway, researchers have induced quiescence-like states that closely resemble their in vivo counterparts. These models provide valuable insights into the regulation of quiescence in vitro.

The study also discusses the quiescence of neural stem cells (NSCs) in the adult brain, a population of long-lasting cells that sustain the generation of new neurons, astrocytes, and oligodendrocytes throughout an organism’s lifespan. The heterogeneity of NSCs within the neurogenic niche is highlighted, as well as their distinct responses to various cues.

Aging has been shown to affect NSCs in the brain, leading to a progressive reduction in neurogenic output. While the number of proliferative cells decreases with age, active NSCs exhibit efficient cell cycle re-entry and transient expansion before lineage progression. However, recent studies suggest that aging leads to an increased proportion of NSCs with a quiescence-related molecular signature, rendering them less responsive to activation signals. This shift towards deeper quiescence ultimately results in diminished neurogenesis in the elderly.

Furthermore, the role of quiescence in tumorigenesis is explored, particularly in the context of glioblastoma, a highly malignant brain tumor. Glioblastoma has been linked to subependymal NSCs in both rodents and humans, and glioma stem cells (GSCs) share similarities with NSCs. Understanding the molecular mechanisms that govern quiescence may provide insights into the initiation, progression, and resistance of glioblastoma, paving the way for innovative therapeutic approaches.

The study of reversible quiescence in adult stem cells represents a fascinating journey into the intricacies of tissue regeneration, aging, and disease. The molecular signatures, post-transcriptional mechanisms, and heterogeneity of quiescent stem cells offer profound insights into their regulation and potential applications in regenerative medicine. Understanding the role of quiescence in neural stem cells and its implications for the aging brain and glioblastoma underscores the importance of this research in addressing critical challenges in neuroscience and medicine.