Is Senescence-Associated β-Galactosidase a Reliable in vivo Marker of Cellular Senescence During Embryonic Development?

Mera-Rodríguez, José Antonio de; Álvarez-Hernán, Guadalupe; Gañán, Yolanda; Martı́n-Partido, Gervasio; Rodríguez-León, Joaquín; Francisco-Morcillo, Javier

doi:10.3389/fcell.2021.623175

Cited by 80 publications

(61 citation statements)

References 98 publications

(163 reference statements)

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“…SA-β-Gal is a lysosomal enzyme that hydrolyzes β-galactosidase into monosaccharides in senescent cells and in some post mitotic cells [ 39 ]. Its activity is correlated with its expression level in senescent cells [ 40 ].…”

Section: Resultsmentioning

confidence: 99%

HSP90 acts as a senomorphic target in senescent retinal pigmental epithelial cells

Chen

Peng

Wang

et al. 2021

Aging

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The senescence of retinal pigment epithelial (RPE) cells is associated with age-related macular degeneration (AMD), a leading cause of blindness in the world. HSP90 is a predominant chaperone that regulates cellular homeostasis under divergent physio-pathological conditions including senescence. However, the role of HSP90 in senescent RPE cells still remains unclear. Here, we reported that HSP90 acts as a senomorphic target of senescent RPE cells in vitro . Using H 2 O 2 -induced senescent ARPE-19 cells and replicative senescent primary RPE cells from rhesus monkey, we found that HSP90 upregulates the expression of IKKα, and HIF1α in senescent ARPE-19 cells and subsequently controls the induction of distinct senescence-associated inflammatory factors. Senescent ARPE-19 cells are more resistant to the cytotoxic HSP90 inhibitor IPI504 (IC50 = 36.78 μM) when compared to normal ARPE-19 cells (IC50 = 6.16 μM). Administration of IPI504 at 0.5–5 μM can significantly inhibit the induction of IL-1β, IL-6, IL-8, MCP-1 and VEGFA in senescent ARPE-19 and the senescence-mediated migration of retinal capillary endothelial cells in vitro . In addition, we found that inhibition of HSP90 by IPI504 reduces SA-β-Gal’s protein expression and enzyme activity in a dose-dependent manner. HSP90 interacts with and regulates SA-β-Gal protein stabilization in senescent ARPE-19 cells. Taken together, these results suggest that HSP90 regulates the SASP and SA-β-Gal activity in senescent RPE cells through associating with distinctive mechanism including NF-κB, HIF1α and lysosomal SA-β-Gal. HSP90 inhibitors (e.g. IPI504) could be a promising senomorphic drug candidate for AMD intervention.

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Section: Resultsmentioning

confidence: 99%

HSP90 acts as a senomorphic target in senescent retinal pigmental epithelial cells

Chen

Peng

Wang

et al. 2021

Aging

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“…(B) One of the most appreciated characteristic of senescence is an enhanced activity of the lysosomal senescence-associated beta-galactosidase (SA-βgal) enzyme, due to either increased expression of the gene GLB1 or increased lysosomal biogenesis ( 58 ). SA-βgal cleaves the β-D-galactose residues in β-D-galactosides, such as 5-bromo-4-chloro-3-indoyl-β-d-galactopyranoside (X-gal).…”

Section: Senescence and Its Hallmarksmentioning

confidence: 99%

“…In normal cells, SA-βgal is active at pH 4, but in senescent cells, its catalytic activity is detectable at suboptimal pH 6 ( 5 , 43 , 59 , 60 ). However, because of the robust signal detected with certain non-senescent, healthy cells in developing embryo, strong SA-βgal-positivity may not necessarily be the best indication of senescence ( 58 ).…”

Section: Senescence and Its Hallmarksmentioning

confidence: 99%

Senescence-Induced Chemoresistance in Triple Negative Breast Cancer and Evolution-Based Treatment Strategies

et al. 2021

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Triple negative breast cancer (TNBC) is classically treated with combination chemotherapies. Although, initially responsive to chemotherapies, TNBC patients frequently develop drug-resistant, metastatic disease. Chemotherapy resistance can develop through many mechanisms, including induction of a transient growth-arrested state, known as the therapy-induced senescence (TIS). In this paper, we will focus on chemoresistance in TNBC due to TIS. One of the key characteristics of senescent cells is a complex secretory phenotype, known as the senescence-associated secretory proteome (SASP), which by prompting immune-mediated clearance of senescent cells maintains tissue homeostasis and suppresses tumorigenesis. However, in cancer, particularly with TIS, senescent cells themselves as well as SASP promote cellular reprograming into a stem-like state responsible for the emergence of drug-resistant, aggressive clones. In addition to chemotherapies, outcomes of recently approved immune and DNA damage-response (DDR)-directed therapies are also affected by TIS, implying that this a common strategy used by cancer cells for evading treatment. Although there has been an explosion of scientific research for manipulating TIS for prevention of drug resistance, much of it is still at the pre-clinical stage. From an evolutionary perspective, cancer is driven by natural selection, wherein the fittest tumor cells survive and proliferate while the tumor microenvironment influences tumor cell fitness. As TIS seems to be preferred for increasing the fitness of drug-challenged cancer cells, we will propose a few tactics to control it by using the principles of evolutionary biology. We hope that with appropriate therapeutic intervention, this detrimental cellular fate could be diverted in favor of TNBC patients.

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“…This histochemical enzymatic indicator has been used to study certain aspects of cell and organism aging and several diseases, including cancers [ 3 , 4 ]. In addition to these pathological and non-pathological conditions in adult organisms, vertebrate embryos stained with β-gal-pH6 exhibit intense labeling in specific anatomical structures and locations [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. Embryonic senescent cells have been reported to be non-proliferative and subject to clearance from tissues after programmed cell death [ 6 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

“…However, some authors have concluded that β-gal-pH6 activity is enhanced under a variety of cellular physiological conditions, even in embryonic tissues. Endogenous histochemical staining is detected in the mouse visceral endoderm at early stages of development [ 14 ], in embryonic cardiomyocytes, skeletal muscle myofibers, osteoblasts, and cochlear hair cells [ 15 , 16 ], and embryonic macrophages [ 12 ]. Li et al, 2018 [ 17 ] establish a link between the concepts of cellular senescence and cell differentiation, showing that, at more advanced stages of development, β-gal-pH6 positive cells located in the apical ectodermal ridge of the limb re-enter the cell cycle, proliferate, and differentiate in epithelial cells.…”

Section: Introductionmentioning

confidence: 99%

Endogenous pH 6.0 β-Galactosidase Activity Is Linked to Neuronal Differentiation in the Olfactory Epithelium

Mera-Rodríguez

Álvarez-Hernán

Gañán

et al. 2022

Cells

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The histochemical detection of β-galactosidase enzymatic activity at pH 6.0 (β-gal-pH6) is a widely used biomarker of cellular senescence in aging tissues. This histochemical assay also detects the presence of programmed cell senescence during specific time windows in degenerating structures of vertebrate embryos. However, it has recently been shown that this enzymatic activity is also enhanced in subpopulations of differentiating neurons in the developing central nervous system in vertebrates. The present study addressed the histochemical detection of β-gal-pH6 enzymatic activity in the developing postnatal olfactory epithelium in the mouse. This activity was detected in the intermediate layer of the olfactory epithelium. As development progressed, the band of β-gal-pH6 labeling in this layer increased in width. Immunohistochemistry and lectin histochemistry showed the β-gal-pH6 staining to be strongly correlated with the immunolabeling of the olfactory marker protein (OMP) that identifies mature olfactory sensory neurons. The cell somata of a subpopulation of differentiated olfactory neurons that were recognized with the Dolichos biflorus agglutinin (DBA) were always located inside this band of β-gal-pH6 staining. However, the β-gal-pH6 histochemical signal was always absent from the apical region where the cytokeratin-8 positive supporting cells were located. Furthermore, no β-gal-pH6 staining was found in the basal region of the olfactory epithelium where PCNA/pHisH3 immunoreactive proliferating progenitor cells, GAP43 positive immature neurons, and cytokeratin-5 positive horizontal basal cells were located. Therefore, β-gal-pH6 seems to be linked to neuronal differentiation and cannot be regarded as a biomarker of cellular senescence during olfactory epithelium development in mice.

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Is Senescence-Associated β-Galactosidase a Reliable in vivo Marker of Cellular Senescence During Embryonic Development?

Cited by 80 publications

References 98 publications

HSP90 acts as a senomorphic target in senescent retinal pigmental epithelial cells

HSP90 acts as a senomorphic target in senescent retinal pigmental epithelial cells

Senescence-Induced Chemoresistance in Triple Negative Breast Cancer and Evolution-Based Treatment Strategies

Endogenous pH 6.0 β-Galactosidase Activity Is Linked to Neuronal Differentiation in the Olfactory Epithelium

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