The Cellular Senescence Stress Response in Post-Mitotic Brain Cells: Cell Survival at the Expense of Tissue Degeneration

In 1960, Rita Levi-Montalcini and Barbara Booker made an observation that transformed neuroscience: as neurons mature, they become apoptosis resistant. The following year Leonard Hayflick and Paul Moorhead described a stable replicative arrest of cells in vitro, termed “senescence”. For nearly 60 years, the cell biology fields of neuroscience and senescence ran in parallel, each separately defining phenotypes and uncovering molecular mediators to explain the 1960s observations of their founding mothers and fathers, respectively. During this time neuroscientists have consistently observed the remarkable ability of neurons to survive. Despite residing in environments of chronic inflammation and degeneration, as occurs in numerous neurodegenerative diseases, often times the neurons with highest levels of pathology resist death. Similarly, cellular senescence (hereon referred to simply as “senescence”) now is recognized as a complex stress response that culminates with a change in cell fate. Instead of reacting to cellular/DNA damage by proliferation or apoptosis, senescent cells survive in a stable cell cycle arrest. Senescent cells simultaneously contribute to chronic tissue degeneration by secreting deleterious molecules that negatively impact surrounding cells. These fields have finally collided. Neuroscientists have begun applying concepts of senescence to the brain, including post-mitotic cells. This initially presented conceptual challenges to senescence cell biologists. Nonetheless, efforts to understand senescence in the context of brain aging and neurodegenerative disease and injury emerged and are advancing the field. The present review uses pre-defined criteria to evaluate evidence for post-mitotic brain cell senescence. A closer interaction between neuro and senescent cell biologists has potential to advance both disciplines and explain fundamental questions that have plagued their fields for decades.

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Epigenetic features in regulation of telomeres and telomerase in stem cells

Emerging Topics in Life Sciences ◽

10.1042/etls20200344 ◽

2021 ◽

Author(s):

Fatma Dogan ◽

Nicholas R. Forsyth

Keyword(s):

Stem Cells ◽

Telomere Length ◽

Cell Biology ◽

Replicative Senescence ◽

Telomerase Activity ◽

Cell Phenotype ◽

Tissue Degeneration ◽

Unique System ◽

Telomerase Regulation

The epigenetic nature of telomeres is still controversial and different human cell lines might show diverse histone marks at telomeres. Epigenetic modifications regulate telomere length and telomerase activity that influence telomere structure and maintenance. Telomerase is responsible for telomere elongation and maintenance and is minimally composed of the catalytic protein component, telomerase reverse transcriptase (TERT) and template forming RNA component, telomerase RNA (TERC). TERT promoter mutations may underpin some telomerase activation but regulation of the gene is not completely understood due to the complex interplay of epigenetic, transcriptional, and posttranscriptional modifications. Pluripotent stem cells (PSCs) can maintain an indefinite, immortal, proliferation potential through their endogenous telomerase activity, maintenance of telomere length, and a bypass of replicative senescence in vitro. Differentiation of PSCs results in silencing of the TERT gene and an overall reversion to a mortal, somatic cell phenotype. The precise mechanisms for this controlled transcriptional silencing are complex. Promoter methylation has been suggested to be associated with epigenetic control of telomerase regulation which presents an important prospect for understanding cancer and stem cell biology. Control of down-regulation of telomerase during differentiation of PSCs provides a convenient model for the study of its endogenous regulation. Telomerase reactivation has the potential to reverse tissue degeneration, drive repair, and form a component of future tissue engineering strategies. Taken together it becomes clear that PSCs provide a unique system to understand telomerase regulation fully and drive this knowledge forward into aging and therapeutic application.

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Extracellular matrix and cell signalling: the dynamic cooperation of integrin, proteoglycan and growth factor receptor

Journal of Endocrinology ◽

10.1530/joe-10-0377 ◽

2011 ◽

Vol 209 (2) ◽

pp. 139-151 ◽

Cited By ~ 617

Author(s):

Soo-Hyun Kim ◽

Jeremy Turnbull ◽

Scott Guimond

Keyword(s):

Growth Factor ◽

Cell Fate ◽

Cell Biology ◽

Heparan Sulphate ◽

Cell Signalling ◽

Growth Factor Receptor ◽

Animal Cells ◽

Structural Support

Extracellular matrices (ECM) are secreted molecules that constitute the cell microenvironment, composed of a dynamic and complex array of glycoproteins, collagens, glycosaminoglycans and proteoglycans. ECM provides the bulk, shape and strength of many tissues in vivo, such as basement membrane, bone and cartilage. In vitro, most animal cells can only grow when they are attached to surfaces through ECM. ECM is also the substrate for cell migration. However, ECM provides much more than just mechanical and structural support, with implications in developmental patterning, stem cell niches and cancer. ECM imparts spatial context for signalling events by various cell surface growth factor receptors and adhesion molecules such as integrins. The external physical properties of ECM may also have a role in the signalling process. ECM molecules can be flexible and extendable, and mechanical tension can expose cryptic sites, which could further interact with growth factors or their receptors. ECM proteins and structures can determine the cell behaviour, polarity, migration, differentiation, proliferation and survival by communicating with the intracellular cytoskeleton and transmission of growth factor signals. Integrins and proteoglycans are the major ECM adhesion receptors which cooperate in signalling events, determining the signalling outcomes, and thus the cell fate. This review focuses on the emerging concept of spatial cell biology of ECM, especially the current understanding of integrins and heparan sulphate proteoglycans as the essential cellular machineries that sense, integrate and respond to the physical and chemical environmental information either by directly connecting with the local adhesion sites or by regulating global cellular processes through growth factor receptor signalling pathways, leading to the integration of both external and internal signals in space and time.

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Evidence of the Cellular Senescence Stress Response in Mitotically Active Brain Cells—Implications for Cancer and Neurodegeneration

Life ◽

10.3390/life11020153 ◽

2021 ◽

Vol 11 (2) ◽

pp. 153

Author(s):

Gregory J. Gillispie ◽

Eric Sah ◽

Sudarshan Krishnamurthy ◽

Mohamed Y. Ahmidouch ◽

Bin Zhang ◽

...

Keyword(s):

Stress Response ◽

Neurodegenerative Diseases ◽

Cell Fate ◽

Cellular Senescence ◽

Stress Responses ◽

Cellular Stress ◽

Surrounding Tissue ◽

Brain Cells ◽

Cell Fate Decisions ◽

The Brain

Cellular stress responses influence cell fate decisions. Apoptosis and proliferation represent opposing reactions to cellular stress or damage and may influence distinct health outcomes. Clinical and epidemiological studies consistently report inverse comorbidities between age-associated neurodegenerative diseases and cancer. This review discusses how one particular stress response, cellular senescence, may contribute to this inverse correlation. In mitotically competent cells, senescence is favorable over uncontrolled proliferation, i.e., cancer. However, senescent cells notoriously secrete deleterious molecules that drive disease, dysfunction and degeneration in surrounding tissue. In recent years, senescent cells have emerged as unexpected mediators of neurodegenerative diseases. The present review uses pre-defined criteria to evaluate evidence of cellular senescence in mitotically competent brain cells, highlights the discovery of novel molecular regulators and discusses how this single cell fate decision impacts cancer and degeneration in the brain. We also underscore methodological considerations required to appropriately evaluate the cellular senescence stress response in the brain.

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Angptl2 is a Marker of Cellular Senescence: The Physiological and Pathophysiological Impact of Angptl2-Related Senescence

International Journal of Molecular Sciences ◽

10.3390/ijms222212232 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12232

Author(s):

Nathalie Thorin-Trescases ◽

Pauline Labbé ◽

Pauline Mury ◽

Mélanie Lambert ◽

Eric Thorin

Keyword(s):

Cell Fate ◽

Cellular Senescence ◽

Cellular Response ◽

Inflammatory Diseases ◽

Age Related ◽

A Cell ◽

Future Work ◽

The Impact

Cellular senescence is a cell fate primarily induced by DNA damage, characterized by irreversible growth arrest in an attempt to stop the damage. Senescence is a cellular response to a stressor and is observed with aging, but also during wound healing and in embryogenic developmental processes. Senescent cells are metabolically active and secrete a multitude of molecules gathered in the senescence-associated secretory phenotype (SASP). The SASP includes inflammatory cytokines, chemokines, growth factors and metalloproteinases, with autocrine and paracrine activities. Among hundreds of molecules, angiopoietin-like 2 (angptl2) is an interesting, although understudied, SASP member identified in various types of senescent cells. Angptl2 is a circulatory protein, and plasma angptl2 levels increase with age and with various chronic inflammatory diseases such as cancer, atherosclerosis, diabetes, heart failure and a multitude of age-related diseases. In this review, we will examine in which context angptl2 was identified as a SASP factor, describe the experimental evidence showing that angptl2 is a marker of senescence in vitro and in vivo, and discuss the impact of angptl2-related senescence in both physiological and pathological conditions. Future work is needed to demonstrate whether the senescence marker angptl2 is a potential clinical biomarker of age-related diseases.

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Engineered illumination devices for optogenetic control of cellular signaling dynamics

10.1101/675892 ◽

2019 ◽

Cited By ~ 1

Author(s):

Nicole A. Repina ◽

Thomas McClave ◽

Xiaoping Bao ◽

Ravi S. Kane ◽

David V. Schaffer

Keyword(s):

Cell Fate ◽

High Throughput ◽

Protein Interactions ◽

Cell Biology ◽

Low Cost ◽

Optical Design ◽

Embryonic Stem ◽

Protein Protein Interactions ◽

Optogenetic Control

ABSTRACTSpatially and temporally varying patterns of morphogen signals during development drive cell fate specification at the proper location and time. However, currentin vitromethods typically do not allow for precise, dynamic, spatiotemporal control of morphogen signaling and are thus insufficient to readily study how morphogen dynamics impact cell behavior. Here we show that optogenetic Wnt/β-catenin pathway activation can be controlled at user-defined intensities, temporal sequences, and spatial patterns using novel engineered illumination devices for optogenetic photostimulation and light activation at variable amplitudes (LAVA). The optical design of LAVA devices was optimized for uniform illumination of multi-well cell culture plates to enable high-throughput, spatiotemporal optogenetic activation of signaling pathways and protein-protein interactions. Using the LAVA devices, variation in light intensity induced a dose-dependent response in optoWnt activation and downstream Brachyury expression in human embryonic stem cells (hESCs). Furthermore, time-varying and spatially localized patterns of light revealed tissue patterning that models embryonic presentation of Wnt signalsin vitro. The engineered LAVA devices thus provide a low-cost, user-friendly method for high-throughput and spatiotemporal optogenetic control of cell signaling for applications in developmental and cell biology.

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Enteroendocrine Dynamics – New Tools Reveal Hormonal Plasticity in the Gut

Endocrine Reviews ◽

10.1210/endrev/bnaa018 ◽

2020 ◽

Vol 41 (5) ◽

pp. 695-706

Author(s):

Joep Beumer ◽

Helmuth Gehart ◽

Hans Clevers

Keyword(s):

Cell Fate ◽

Bone Morphogenetic Proteins ◽

Cell Biology ◽

Adult Stem Cell ◽

Cell Types ◽

Model Systems ◽

Enteroendocrine Cell ◽

Advantages And Disadvantages ◽

New Therapeutic Approaches

Abstract The recent intersection of enteroendocrine cell biology with single-cell technologies and novel in vitro model systems has generated a tremendous amount of new data. Here we highlight these recent developments and explore how these findings contribute to the understanding of endocrine lineages in the gut. In particular, the concept of hormonal plasticity, the ability of endocrine cells to produce different hormones over the course of their lifetime, challenges the classic notion of cell types. Enteroendocrine cells travel in the course of their life through different signaling environments that directly influence their hormonal repertoire. In this context, we examine how enteroendocrine cell fate is determined and modulated by signaling molecules such as bone morphogenetic proteins (BMPs) or location along the gastrointestinal tract. We analyze advantages and disadvantages of novel in vitro tools, adult stem cell or iPS-derived intestinal organoids, that have been crucial for recent findings on enteroendocrine development and plasticity. Finally, we illuminate the future perspectives of the field and discuss how understanding enteroendocrine plasticity can lead to new therapeutic approaches.

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Molecular and cell biology of brain tumor stem cells: lessons from neural progenitor/stem cells

Neurosurgical FOCUS ◽

10.3171/foc/2008/24/3-4/e24 ◽

2008 ◽

Vol 24 (3-4) ◽

pp. E25 ◽

Cited By ~ 14

Author(s):

Zhigang Xie ◽

Lawrence S. Chin

Keyword(s):

Stem Cells ◽

Brain Tumor ◽

Cell Fate ◽

Cell Biology ◽

Neural Progenitor ◽

Tumor Stem Cells ◽

Tumor Initiating Cells ◽

Brain Tumor Stem Cells

✓ The results of studies conducted in the past several years have suggested that malignant brain tumors may harbor a small fraction of tumor-initiating cells that are likely to cause tumor recurrence. These cells are known as brain tumor stem cells (BTSCs) because of their multilineage potential and their ability to self-renew in vitro and to recapitulate original tumors in vivo. The understanding of BTSCs has been greatly advanced by knowledge of neural progenitor/stem cells (NPSCs), which are multipotent and self-renewing precursor cells for neurons and glia. In this article, the authors summarize evidence that genetic mutations that deregulate asymmetric cell division by affecting cell polarity, spindle orientation, or cell fate determinants may result in the conversion of NPSCs to BTSCs. In addition, they review evidence that BTSCs and normal NPSCs may reside in similar vascularized microenvironments, where similar evolutionarily conserved signaling pathways control their proliferation. Finally, they discuss preliminary evidence that mechanisms of BTSC-associated infiltrativeness may be similar to those underlying the migration of NPSCs and neurons.

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Advances in Extracellular Matrix-Mimetic Hydrogels to Guide Stem Cell Fate

Cells Tissues Organs ◽

10.1159/000514851 ◽

2021 ◽

pp. 1-18

Author(s):

Ryan S. Stowers

Keyword(s):

Stem Cells ◽

Extracellular Matrix ◽

Stem Cell ◽

Cell Fate ◽

Cell Biology ◽

Stem Cell Differentiation ◽

Stem Cell Biology ◽

Stem Cell Fate ◽

Material Systems

In the fields of regenerative medicine and tissue engineering, stem cells offer vast potential for treating or replacing diseased and damaged tissue. Much progress has been made in understanding stem cell biology, yielding protocols for directing stem cell differentiation toward the cell type of interest for a specific application. One particularly interesting and powerful signaling cue is the extracellular matrix (ECM) surrounding stem cells, a network of biopolymers that, along with cells, makes up what we define as a tissue. The composition, structure, biochemical features, and mechanical properties of the ECM are varied in different tissues and developmental stages, and serve to instruct stem cells toward a specific lineage. By understanding and recapitulating some of these ECM signaling cues through engineered ECM-mimicking hydrogels, stem cell fate can be directed in vitro. In this review, we will summarize recent advances in material systems to guide stem cell fate, highlighting innovative methods to capture ECM functionalities and how these material systems can be used to provide basic insight into stem cell biology or make progress toward therapeutic objectives.

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Enhanced Activity of Exportin-1/CRM1 in Neurons Contributes to Autophagy Dysfunction and Senescent Features in Old Mouse Brain

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/6682336 ◽

2021 ◽

Vol 2021 ◽

pp. 1-22

Author(s):

Elisa Gorostieta-Salas ◽

Daniel Moreno-Blas ◽

Cristian Gerónimo-Olvera ◽

Bulmaro Cisneros ◽

Felipe A. Court ◽

...

Keyword(s):

Cellular Senescence ◽

Brain Aging ◽

Autophagic Flux ◽

Proliferating Cells ◽

Neuronal Homeostasis ◽

Autophagic Degradation ◽

Vitro Model ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

Brain aging is characterized by dysfunctional autophagy and cellular senescence, among other features. While autophagy can either promote or suppress cellular senescence in proliferating cells, in postmitotic cells, such as neurons, autophagy impairment promotes cellular senescence. CRM1 (exportin-1/XPO1) exports hundreds of nuclear proteins into the cytoplasm, including the transcription factors TFEB (the main inducer of autophagy and lysosomal biogenesis genes) and STAT3, another autophagy modulator. It appears that CRM1 is a modulator of aging-associated senescence and autophagy, because pharmacological inhibition of CRM1 improved autophagic degradation in flies, by increasing nuclear TFEB levels, and because enhanced CRM1 activity is mechanistically linked to senescence in fibroblasts from Hutchinson–Gilford progeria syndrome patients and old healthy individuals; furthermore, the exogenous overexpression of CRM1 induced senescence in normal fibroblasts. In this work, we tested the hypothesis that impaired autophagic flux during brain aging occurs due to CRM1 accumulation in the brain. We found that CRM1 levels and activity increased in the hippocampus and cortex during physiological aging, which resulted in a decrease of nuclear TFEB and STAT3. Consistent with an autophagic flux impairment, we observed accumulation of the autophagic receptor p62/SQSTM1 in neurons of old mice, which correlated with increased neuronal senescence. Using an in vitro model of neuronal senescence, we demonstrate that CRM1 inhibition improved autophagy flux and reduced SA-β-gal activity by restoring TFEB nuclear localization. Collectively, our data suggest that enhanced CRM1-mediated export of proteins during brain aging perturbs neuronal homeostasis, contributing to autophagy impairment, and neuronal senescence.

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Cellular senescence is a central response to cytotoxic chemotherapy in high-grade serous ovarian cancer

10.1101/425199 ◽

2018 ◽

Cited By ~ 5

Author(s):

L. Calvo ◽

S. Cheng ◽

M. Skulimowski ◽

I. Clément ◽

L. Portelance ◽

...

Keyword(s):

Ovarian Cancer ◽

Dna Damage ◽

Cell Fate ◽

Cellular Senescence ◽

Response To Treatment ◽

High Grade ◽

Serous Ovarian Cancer ◽

Cell Fate Decisions ◽

Response To Chemotherapy

AbstractHigh-grade serous ovarian cancer (HGSOC) commonly responds to initial therapy, but this response is rarely durable. Understanding cell fate decisions taken by HGSOC cells in response to treatment could guide new therapeutic opportunities. Here we find that primary HGSOC cultures undergo therapy-induced senescence (TIS) in response to DNA damage induced by chemotherapy. HGSOC-TIS displays most senescence hallmarks including persistent DNA damage, senescence-associated inflammatory secretome, and selective sensitivity to senolytic Bcl-2 family inhibitors, suggesting avenues for preferential synergistic clearance of these cells. Comparison of pre- and post-chemotherapy HGSOC patient tissue samples revealed changes in senescence biomarkers suggestive of post-treatment “in patient” TIS, and a stronger TIS response in post-chemotherapy tissues correlated with better 5-year survival rates for patients. Together, these data suggest that the induction of cellular senescence in HGSOC cells accounts at least in part for beneficial cellular responses to treatment in patients providing a new therapeutic target.One Sentence SummaryCellular senescence is a central beneficial response to chemotherapy in high-grade serous ovarian cancer bothin vitroand in patient.

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