Cellular senescence, traditionally viewed as a consequence of proliferating and growing cells overwhelmed by extensive stresses and damage, has long been recognized as a critical cellular aging mechanism. Recent research, however, has revealed a novel pathway termed \"quiescence-origin senescence\", where cells directly transition into senescence from the quiescent state, bypassing cell proliferation and growth. This opinion paper presents a framework conceptualizing a continuum between quiescence and senescence with quiescence deepening as a precursor to senescence entry. We explore the triggers and controllers of this process and discuss its biological implications. Given that the majority of cells in the human body are dormant rather than proliferative, understanding quiescence-origin senescence has significant implications for tissue homeostasis, aging, cancer, and various disease processes. The new paradigm in exploring this previously overlooked senescent cell population may reshape our intervention strategies for age-related diseases and tissue regeneration.

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Quiescence is an important non-pathological state in which cells pause cell cycle progression temporarily, sometimes for decades, until they receive appropriate proliferative stimuli. Quiescent cells make up a significant proportion of the body, and maintaining genomic integrity during quiescence is crucial for tissue structure and function. While cells in quiescence are spared from DNA damage associated with DNA replication or mitosis, they are still exposed to various sources of endogenous DNA damage, including those induced by normal transcription and metabolism. As such, it is vital that cells retain their capacity to effectively repair lesions that may occur and return to the cell cycle without losing their cellular properties. Notably, while DNA repair pathways are often found to be downregulated in quiescent cells, emerging evidence suggests the presence of active or differentially regulated repair mechanisms. This review aims to provide a current understanding of DNA repair processes during quiescence in mammalian systems and sheds light on the potential pathological consequences of inefficient or inaccurate repair in quiescent cells.

Iron deficiency is a prevalent nutritional deficit associated with organ damage and dysfunction. Recent research increasingly associates iron deficiency with bone metabolism dysfunction, although the precise underlying mechanisms remain unclear. Some studies have proposed that iron-dependent methylation-erasing enzyme activity regulates cell proliferation and differentiation under physiological or pathological conditions. However, it remains uncertain whether iron deficiency inhibits the activation of quiescent mesenchymal stem cells (MSCs) by affecting histone demethylase activity. In our study, we identified KDM4D as a key player in the activation of quiescent MSCs. Under conditions of iron deficiency, the H3K9me3 demethylase activity of KDM4D significantly decreased. This alteration resulted in increased heterochromatin with H3K9me3 near the PIK3R3 promoter, suppressing PIK3R3 expression and subsequently inhibiting the activation of quiescent MSCs via the PI3K-Akt-Foxo1 pathway. Iron-deficient mice displayed significantly impaired bone marrow MSCs activation and decreased bone mass compared to normal mice. Modulating the PI3K-Akt-Foxo1 pathway could reverse iron deficiency-induced bone loss.

Animal oocytes face extreme challenges. They remain dormant in the body for long periods of time. To support offspring development and health, they need to store genetic material and maternal factors stably and at the same time manage cellular damage in a reliable manner. Recent studies have provided new insights on how oocytes cope with such challenges. This review discusses the many unusual or idiosyncratic nature of oocytes and how understanding oocyte biology can help us address issues of reproduction and intergenerational inheritance.

Signaling interactions are important during skeletal muscle regeneration, where muscle cells in distinct states (quiescent, reactivated, proliferating and differentiated) must coordinate their response to injury. Here, we probed the role of secreted small extracellular vesicles (sEV/exosomes) using a culture model of physiologically relevant cell states seen in muscle regeneration. Unexpectedly, G0 myoblasts exhibited enhanced secretion of sEV (∼150 nm) displaying exosome markers (Alix, TSG101, flotillin-1, and CD9), and increased expression of Kibra, a regulator of exosome biogenesis. Perturbation of Kibra levels confirmed a role in controlling sEV secretion rates. Purified sEVs displayed a common exosome marker-enriched proteome in all muscle cell states, as well as state-specific proteins. Exosomes derived from G0 cells showed an antioxidant signature, and were most strongly internalized by differentiated myotubes. Functionally, donor exosomes from all muscle cell states could activate an integrated Wnt reporter in target cells, but only G0-derived exosomes could induce myogenic differentiation in proliferating cells. Taken together, we provide evidence that quiescence in muscle cells is accompanied by enhanced secretion of exosomes with distinct uptake, cargo and signal activating features. Our study suggests the novel possibility that quiescent muscle stem cells in vivo may play a previously under-appreciated signaling role during muscle homeostasis.

Mating experience impacts the physiology and behavior of animals. Although mating effects of female Drosophila melanogaster have been studied extensively, the behavioral changes of males following copulation have not been fully understood. In this study, we characterized the mating-dependent behavioral changes of male flies, especially focusing on fly-to-fly interaction, and their dependence on rearing conditions. Our data demonstrate that male flies quiesce their courtship toward both females and males, as well as their locomotor activity. This post-copulatory quiescence appears to be contingent upon the presence of a peer, as minimal variation is noted in locomotion when the male is measured in isolation. Interestingly, copulated males influence a paired male without successful copulation to reduce his locomotion. Our findings point to a conditional behavioral quiescence following copulation, influenced by the presence of other flies.

Application of simultaneous multi-laser nanoparticle tracking analysis (NTA) to environmental water samples to investigate nonliving natural organic matter (NNOM) is introduced as an innovative method for observing particles directly in their native media. Multi-laser NTA results of particle visualization, particle number concentration, and particle size distribution elucidated particle dynamics in low and high total dissolved solids (TDS) aqueous environmental samples. A pond water sample and concentrate from a reverse osmosis (RO) treatment process (Stage 1) had 1.3 × 108 and 5.62 × 1019 particles/mL, respectively, (at time = 0) after filtration at 0.45 μm. Beyond the traditional applications for this instrument, this research presents novel evidence-based investigations that probe the existence of supramolecular structures in environmental waters during turbulence or quiescence. The pond water sample exhibited time-dependent aggregation as the volume distribution shifted to greater diameter during quiescence, compared to turbulence. Disaggregation (increased numbers of particles over time) was noted in the >250 nm to <600 nm region, and aggregation of >450 nm particles was also noted in the quiescent RO concentrate sample, indicative of depletion of small particles to form larger ones. Multi-laser NTA and dynamic light scattering (DLS) capabilities were compared and contrasted. DLS and NTA are different (complementary) particle sizing techniques. DLS yielded more information about the physical hydrogel in the NNOM hierarchy whereas multi-laser NTA better characterized meta-chemical and chemical hydrogel characteristics. Operationalization of innovation-moving from fundamental investigations to application-is supported by implementing novel analytical instrumentation as we address issues involving climate change, drought, and the scarcity of potable water. Multi-laser NTA can be used as a tool to study and optimize complex water and wastewater treatment processes. Questions about water treatment efficiencies, membrane fouling, assistance of pollutant transport, and carbon capture cycles affected by NNOM will benefit from insights from multi-laser NTA.

Dormancy in cancer is a clinical state in which residual disease remains undetectable for a prolonged duration. At a cellular level, rare cancer cells cease proliferation and survive chemotherapy and disseminate disease. We created a suspension culture model of high-grade serous ovarian cancer (HGSOC) dormancy and devised a novel CRISPR screening approach to identify survival genes in this context. In combination with RNA-seq, we discovered the Netrin signaling pathway as critical to dormant HGSOC cell survival. We demonstrate that Netrin-1, -3, and its receptors are essential for low level ERK activation to promote survival, and that Netrin activation of ERK is unable to induce proliferation. Deletion of all UNC5 family receptors blocks Netrin signaling in HGSOC cells and compromises viability during the dormancy step of dissemination in xenograft assays. Furthermore, we demonstrate that Netrin-1 and -3 overexpression in HGSOC correlates with poor outcome. Specifically, our experiments reveal that Netrin overexpression elevates cell survival in dormant culture conditions and contributes to greater spread of disease in a xenograft model of abdominal dissemination. This study highlights Netrin signaling as a key mediator HGSOC cancer cell dormancy and metastasis.
High-grade serous ovarian cancer (or HGSOC for short) is the fifth leading cause of cancer-related deaths in women. It is generally diagnosed at an advanced stage of disease when the cancer has already spread to other parts of the body. Surgical removal of tumors and subsequent treatment with chemotherapy often reduces the signs and symptoms of the disease for a time but some cancer cells tend to survive so that patients eventually relapse. The HGSOC cells typically spread from the ovaries by moving through the liquid surrounding organs in the abdomen. The cells clump together and enter an inactive state known as dormancy that allows them to survive chemotherapy and low-nutrient conditions. Understanding how to develop new drug therapies that target dormant cancer cells is thought to be an important step in prolonging the life of HGSOC patients. Cancer cells are hardwired to multiply and grow, so Perampalam et al. reasoned that becoming dormant poses challenges for HGSOC cells, which may create unique vulnerabilities not shared by proliferating cancer cells. To find out more, the researchers used HGSOC cells that had been isolated from patients and grown in the laboratory. The team used a gene editing technique to screen HGSOC cells for genes required by the cells to survive when they are dormant. The experiments found that genes involved in a cell signaling pathway, known as Netrin signaling, were critical for the cells to survive. Previous studies have shown that Netrin signaling helps the nervous system form in embryos and inhibits a program of controlled cell death in some cancers. Perampalam et al. discovered that Netrins were present in the environment immediately surrounding dormant HGSOC cells. Human HGSOC patients with higher levels of Netrin gene expression had poorer prognoses than patients with lower levels of Netrin gene expression. Further experiments demonstrated that Netrins help dormant HGSOC cells to spread around the body. These findings suggest that Netrin signalling may provide useful targets for future drug therapies against dormant cells in some ovarian cancers. This could include repurposing drugs already in development or creating new inhibitors of this pathway.

Stem cell therapy holds significant potential for skeletal muscle repair, with in vitro-generated human muscle reserve cells (MuRCs) emerging as a source of quiescent myogenic stem cells that can be injected to enhance muscle regeneration. However, the clinical translation of such therapies is hampered by the need for fetal bovine serum (FBS) during the in vitro generation of human MuRCs. This study aimed to determine whether fresh allogeneic human platelet-rich plasma (PRP) combined or not with hyaluronic acid (PRP-HA) could effectively replace xenogeneic FBS for the ex vivo expansion and differentiation of human primary myoblasts. Cells were cultured in media supplemented with either PRP or PRP-HA and their proliferation rate, cytotoxicity and myogenic differentiation potential were compared with those cultured in media supplemented with FBS. The results showed similar proliferation rates among human myoblasts cultured in PRP, PRP-HA or FBS supplemented media, with no cytotoxic effects. Human myoblasts cultured in PRP or PRP-HA showed reduced fusion ability upon differentiation. Nevertheless, we also observed that human MuRCs generated from PRP or PRP-HA myogenic cultures, exhibited increased Pax7 expression and delayed re-entry into the cell cycle upon reactivation, indicating a deeper quiescent state of human MuRCs. These results suggest that allogeneic human PRP effectively replaces FBS for the ex vivo expansion and differentiation of human myoblasts and favors the in vitro generation of Pax7High human MuRCs, with important implications for the advancement of stem cell-based muscle repair strategies.