Senescence is a form of cell-cycle arrest linked to tumor suppression and aging. However, it remains controversial and has not been documented in nonpathologic states. Here we describe senescence as ...a normal developmental mechanism found throughout the embryo, including the apical ectodermal ridge (AER) and the neural roof plate, two signaling centers in embryonic patterning. Embryonic senescent cells are nonproliferative and share features with oncogene-induced senescence (OIS), including expression of p21, p15, and mediators of the senescence-associated secretory phenotype (SASP). Interestingly, mice deficient in p21 have defects in embryonic senescence, AER maintenance, and patterning. Surprisingly, the underlying mesenchyme was identified as a source for senescence instruction in the AER, whereas the ultimate fate of these senescent cells is apoptosis and macrophage-mediated clearance. We propose that senescence is a normal programmed mechanism that plays instructive roles in development, and that OIS is an evolutionarily adapted reactivation of a developmental process.
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•Cellular senescence is a normal, programmed, and instructive developmental process•Developmental senescence and oncogene-induced senescence share common signatures•p21 is a critical mediator of developmental senescence•Senescent cells are removed by apoptosis and macrophage-mediated clearance
During embryonic development, cellular senescence is prominent in signaling centers in the embryo, where it serves to instruct tissue pattering.
Senescence is a form of cell cycle arrest induced by stress such as DNA damage and oncogenes. However, while arrested, senescent cells secrete a variety of proteins collectively known as the ...senescence-associated secretory phenotype (SASP), which can reinforce the arrest and induce senescence in a paracrine manner. However, the SASP has also been shown to favor embryonic development, wound healing, and even tumor growth, suggesting more complex physiological roles than currently understood. Here we uncover timely new functions of the SASP in promoting a proregenerative response through the induction of cell plasticity and stemness. We show that primary mouse keratinocytes transiently exposed to the SASP exhibit increased expression of stem cell markers and regenerative capacity in vivo. However, prolonged exposure to the SASP causes a subsequent cell-intrinsic senescence arrest to counter the continued regenerative stimuli. Finally, by inducing senescence in single cells in vivo in the liver, we demonstrate that this activates tissue-specific expression of stem cell markers. Together, this work uncovers a primary and beneficial role for the SASP in promoting cell plasticity and tissue regeneration and introduces the concept that transient therapeutic delivery of senescent cells could be harnessed to drive tissue regeneration.
Cellular senescence and developmental defects Klein, Annabelle; Rhinn, Muriel; Keyes, William M.
The FEBS journal,
March 2023, 2023-03-00, 20230301, 2023-03-01, Letnik:
290, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Cellular senescence is a distinct state that is frequently induced in response to ageing and stress. Yet studies have also uncovered beneficial functions in development, repair and regeneration. ...Current opinion therefore suggests that timely and controlled induction of senescence can be beneficial, while misregulation of the senescence program, either through mis‐timed activation, or chronic accumulation of senescent cells, contributes to many disease states and the ageing process. Whether atypical activation of senescence plays a role in the pathogenesis of developmental defects has been relatively underexplored. Here, we discuss three recent studies that implicate ectopic senescence in neurodevelopmental defects, with possible causative roles for senescence in these birth defects. In addition, we highlight how the examination of senescence in other birth defects is warranted, and speculate that aberrantly activated senescence may play a much broader role in developmental defects than currently appreciated.
Cellular senescence is frequently induced in response to ageing and stress. Yet, studies have also uncovered beneficial functions in development, repair and regeneration. Therefore, timely and controlled induction of senescence can be beneficial, while misregulation of the senescence program contributes to disease and ageing. Here, we discuss recent studies that implicate ectopic senescence in neurodevelopmental defects and highlight how the examination of senescence in other birth defects is warranted.
Altered stem cell homeostasis is linked to organismal aging. However, the mechanisms involved remain poorly understood. Here we report novel alterations in hair follicle stem cells during skin aging, ...including increased numbers, decreased function, and an inability to tolerate stress. Performing high-throughput RNA sequencing on aging stem cells, cytokine arrays, and functional assays, we identify an age-associated imbalance in epidermal Jak-Stat signaling that inhibits stem cell function. Collectively, this study reveals a role for the aging epidermis in the disruption of cytokine and stem cell homeostasis, suggesting that stem cell decline during aging may be part of broader tumor-suppressive mechanisms.
Valproic acid (VPA) is a widely prescribed drug to treat epilepsy, bipolar disorder, and migraine. If taken during pregnancy, however, exposure to the developing embryo can cause birth defects, ...cognitive impairment, and autism spectrum disorder. How VPA causes these developmental defects remains unknown. We used embryonic mice and human organoids to model key features of VPA drug exposure, including exencephaly, microcephaly, and spinal defects. In the malformed tissues, in which neurogenesis is defective, we find pronounced induction of cellular senescence in the neuroepithelial (NE) cells. Critically, through genetic and functional studies, we identified p19Arf as the instrumental mediator of senescence and microcephaly, but, surprisingly, not exencephaly and spinal defects. Together, these findings demonstrate that misregulated senescence in NE cells can contribute to developmental defects.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Young mammals possess a limited regenerative capacity in some tissues, which is lost upon maturation. We investigated whether cellular senescence might play a role in such loss during liver ...regeneration. We found that following partial hepatectomy, the senescence-associated genes p21, p16
, and p19
become dynamically expressed in different cell types when regenerative capacity decreases, but without a full senescent response. However, we show that treatment with a senescence-inhibiting drug improves regeneration, by disrupting aberrantly prolonged p21 expression. This work suggests that senescence may initially develop from heterogeneous cellular responses, and that senotherapeutic drugs might be useful in promoting organ regeneration.
Senescence is a specialized form of cell cycle arrest induced in response to damage and stress. In certain settings, senescent cells can promote their own removal by recruitment of the immune system, ...a process that is thought to decline in efficiency with age. In this issue of
, Yin et al. (pp. 533-549) discover a surprising cross-talk where senescent cells instruct endothelial cells to help organize the clearance of the senescent population. This uncovers yet another layer of complexity in senescent cell biology, with implications for cancer treatment and aging.
Senescence-associated β-galactosidase (SAβ-gal) is a convenient histological technique used to identify senescent cells. Its ease of use is helpful to initially screen and detect senescent cells in ...heterogeneous cell populations both in vitro and in vivo. However, SAβ-gal staining is not an unequivocal marker of the senescent state, and diagnosis of such usually requires additional markers demonstrating an absence of proliferation and expression of cell-cycle inhibitors. Nonetheless, SAβ-gal remains one of the most widely used biomarkers of senescent cells. Recently, by measuring SAβ-gal activity, the expression of the cyclin-dependent kinase inhibitor p21 (waf1/cip1) and demonstrating a lack of proliferation, we identified senescent cells in the developing embryo. This chapter describes the methods for identifying cellular senescence in the embryo, detailing protocols for the detection of SAβ-gal activity in both sections and at the whole mount level, and immunohistochemistry protocols for the detection of additional biomarkers of senescence.
Despite the fact that the cell cycle is a fundamental process of life, a detailed quantitative understanding of gene regulation dynamics throughout the cell cycle is far from complete. Single-cell ...RNA-sequencing (scRNA-seq) technology gives access to these dynamics without externally perturbing the cell. Here, by generating scRNA-seq libraries in different cell systems, we observe cycling patterns in the unspliced-spliced RNA space of cell cycle-related genes. Since existing methods to analyze scRNA-seq are not efficient to measure cycling gene dynamics, we propose a deep learning approach (DeepCycle) to fit these patterns and build a high-resolution map of the entire cell cycle transcriptome. Characterizing the cell cycle in embryonic and somatic cells, we identify major waves of transcription during the G1 phase and systematically study the stages of the cell cycle. Our work will facilitate the study of the cell cycle in multiple cellular models and different biological contexts.
ZnT7 (Slc30a7) is a widely expressed zinc transporter involved in sequestration of zinc into the Golgi apparatus and vesicular compartments. znt7-knockout (KO) mice are mildly zinc-deficient and ...lean. Despite their lean phenotype, adult male znt7-KO mice are prone to insulin resistance. We hypothesized that fat partitioning from adipose to nonadipose tissues causes insulin resistance in znt7-KO mice. Here, we used biological and biochemical methods, including fatty acid and oxylipin profiling, EM, immunohistochemistry, quantitative RT-PCR, and Western blot analysis, to identify the underlying mechanism of insulin resistance in znt7-KO mice. We found that insulin resistance in this model was primarily associated with increased intracellular fatty acid levels in the skeletal muscle, which promoted intracellular lipid accumulation and production of bioactive lipid mediators, such as 12,13-dihydroxyoctadecanoic acid (12,13-DiHOME) and 12-hydroxyeicosatetraenoic acid (12-HETE). The expression of fatty acid–binding protein 3 (Fabp3) was dramatically up-regulated in the znt7-KO muscle cells accompanied by increased expression of Cd36, Slc27a1, and Slc27a4, the three major fatty acid transporters in the skeletal muscle. We also demonstrated that znt7-KO muscle cells had increased fatty acid oxidative capacity, indicated by enlarged mitochondria and increased mRNA or protein expression of key enzymes involved in the fatty acid mitochondrial shuttle and β-oxidation. We conclude that increased fatty acid uptake in the znt7-KO skeletal muscle is a key factor that contributes to the excessive intracellular lipid deposit and elevated production of bioactive lipid mediators. These mediators may play pivotal roles in oxidative stress and inflammation, leading to insulin resistance.