TGFβ2-induced senescence during early inner ear development

Gibaja, Alejandro; Aburto, María Rodríguez; Pulido, Sara; Collado, Manuel; Hurlé, Juan M.; Varela-Nieto, Isabel; Magariños, Marta

doi:10.1038/s41598-019-42040-0

Cited by 47 publications

(41 citation statements)

References 44 publications

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“…Given that developmental senescence is found in some of the tissues that are most susceptible to mutation and birth defects, it is tempting to speculate that mis-regulation of senescence may be causally involved. Indeed, a number of studies in mouse models, including mice deficient in p63 (Keyes et al, 2005), PASG (Hells; Sun et al, 2004) and Brca1 (Cao et al, 2003), have shown how mutations that affect embryonic development also induce aberrant senescence, whereas recent studies using senolytics demonstrate how mis-regulation of the normal developmental process can cause patterning defects (Gibaja et al, 2019). A better appreciation of this link will further our understanding of senescence and its role in human health and disease.…”

Section: Discussionmentioning

confidence: 99%

“…This was primarily based on studies describing senescent cells in mouse embryos (Muñoz-Espin et al, 2013;Storer et al, 2013). However, cells bearing some or many features of senescence have also been described in human (Muñoz-Espin et al, 2013), chicken (Storer et al, 2013;Gibaja et al, 2019), quail (Nacher et al, 2006), Xenopus (Davaapil et al, 2017), axolotl (Davaapil et al, 2017;Villiard et al, 2017), zebrafish (Villiard et al, 2017) and naked mole rat (Zhao et al, 2018) embryos (Table 1).…”

Section: Developmental Senescencementioning

confidence: 99%

“…In addition, although p21-deficient animals are, for the most part, developmentally normal, it was shown that they have mild patterning defects in the limbs, kidneys and vagina (Muñoz-Espin et al, 2013;Storer et al, 2013). Furthermore, interference with the senescence program by chemical means (using TGFß or ERK inhibition), and more recently by senolytic treatment, leads to patterning defects (Muñoz-Espin et al, 2013;Storer et al, 2013;Davaapil et al, 2017;Gibaja et al, 2019).…”

Section: Developmental Senescencementioning

confidence: 99%

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Cellular senescence in development, regeneration and disease

2019

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Cellular senescence is a state comprising an essentially irreversible proliferative arrest combined with phenotypic changes and pronounced secretory activity. Although senescence has long been linked with aging, recent studies have uncovered functional roles for senescence in embryonic development, regeneration and reprogramming, and have helped to advance our understanding of this process as a highly coordinated and programmed cellular state. In this Primer article, we summarize some of the key findings in the field and attempt to explain them in a simple model that reconciles the normal and pathological roles for senescence. We discuss how a primary role of cellular senescence is to contribute to normal development, cell plasticity and tissue repair, as a dynamic and tightly regulated cellular program. However, when this process is perturbed, the beneficial effects turn detrimental and can contribute to disease and aging.

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Section: Discussionmentioning

confidence: 99%

Section: Developmental Senescencementioning

confidence: 99%

Section: Developmental Senescencementioning

confidence: 99%

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Cellular senescence in development, regeneration and disease

2019

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“…TGF-β1 levels were increased with aging (33), and in the ante-and postmortem sera from patients with AD, as well as in the postmortem cerebrospinal fluid of patients with AD (34). Furthermore, TGF-β is secreted as part of the SASP (3), and it can trigger senescence in neighboring cells (3,35,36). Our current study findings demonstrated that the TGF-β1-SMAD2/3 pathway is induced in 5xFAD astrocytes, and that inhibition of this pathway can reduce the expression of the senescence phenotype.…”

Section: Discussionmentioning

confidence: 99%

Astrocyte senescence in an Alzheimer’s disease mouse model is mediated by TGF-β1 and results in neurotoxicity

Amram

Iram

Lazdon

et al. 2019

Preprint

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Running title: Astrocyte senescence leads to neurotoxicity 2 ABBREVIATIONS: AD, Alzheimer's disease; Aβ, amyloid-β; SASP, senescence-associated secretory phenotype; CS, cellular senescence; AS, astrocyte senescence; NF-κB, kappa-lightchain-enhancer of activated B cells; IL-6, interleuken-6; TGF β1, transforming growth factor β; PBS, phosphate buffered saline; PDTC, pyrrolidinedithiocarbamic acid ammonium salt; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; WT, wild-type; Real-time polymerase chain reaction (RT-PCR) mRNA, messenger RNA; ELISA, enzyme-linked immunosorbent assay; WB, western blot; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; VEGF, vascular endothelial growth factor; BDNF, brain-derived neurotrophic factor; GFAP, glial fibrillary acidic protein 3 ABSTRACT: Alterations in astrocyte function such as a pro-inflammatory phenotype are associated with Alzheimer's disease (AD). We had shown impairments in the ability of aged astrocytes isolated from 5xFAD mice to clear and uptake amyloid-β (Aβ) as well as to support neuronal growth. Senescent cells accumulate with age and exhibit a senescence-associated secretory phenotype, which includes secretion of pro-inflammatory cytokines. In this study, we predicted that with age, astrocytes in 5xFAD mice would exhibit a cellular senescence phenotype that could promote neurodegeneration. We found an age-dependent increase in senescent astrocytes adjacent to Aβ plaques in 5xFAD mice. Inhibition of nuclear factor kappalight-chain-enhancer of activated B cells reduced interelukin-6 secretion by senescent astrocytes and resulted in improved neuronal support. Moreover, senescent astrocytes exhibited an increase in the induction of the TGF-β1-SMAD2/3 pathway, and inhibition of this pathway resulted in a reduction of cellular senescence. We also discovered that soluble Aβ42 induced astrocyte senescence in young naïve mice in a SMAD2/3-dependent manner. Our results suggest an important role of astrocyte senescence in AD and its role in mediating the neurotoxicity properties of astrocytes in AD and related neurodegenerative diseases.

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“…As we previously described, TGFβ2 is a potent regulator of cellular senescence during inner ear development, which has been proven to be an essential process for proper morphogenesis of the endolymphatic duct (Gibaja et al, 2019). We, therefore, aimed to investigate whether developing AVG neuroblasts in HH19 stages underwent cellular senescence regulated by TGFβ2.…”

Section: Tgfβ Pathway Does Not Induce Senescence In the Avgmentioning

confidence: 99%

Otic Neurogenesis Is Regulated by TGFβ in a Senescence-Independent Manner

Magariños

Barajas-Azpeleta

Varela-Nieto

et al. 2020

Front. Cell. Neurosci.

Self Cite

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Cellular senescence has classically been associated with aging. Intriguingly, recent studies have also unraveled key roles for senescence in embryonic development, regeneration, and reprogramming. Developmental senescence has been reported during embryonic development in different organisms and structures, such as the endolymphatic duct during inner ear development of mammals and birds. However, there is no study addressing the possible role of senescence on otic neurogenesis. TGFβ/SMAD is the best-known pathway linked to the induction of developmentally programmed cell senescence. Here, we studied if TGFβ2 induces cellular senescence during acoustic-vestibular-ganglion (AVG) formation. Using organotypic cultures of AVG, and characterizing different stages of otic neurogenesis in the presence of TGFβ2 and a selective TGF-β receptor type-I inhibitor, we show that TGFβ2 exerts a powerful action in inner ear neurogenesis but, contrary to what we recently observed during endolymphatic duct development, these actions are independent of cellular senescence. We show that TGFβ2 reduces proliferation, and induces differentiation and neuritogenesis of neuroblasts, without altering cell death. Our studies highlight the roles of TGFβ2 and cellular senescence in the precise regulation of cell fate within the developing inner ear and its different cell types, being their mechanisms of action highly cell-type dependent.

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TGFβ2-induced senescence during early inner ear development

Cited by 47 publications

References 44 publications

Cellular senescence in development, regeneration and disease

Cellular senescence in development, regeneration and disease

Astrocyte senescence in an Alzheimer’s disease mouse model is mediated by TGF-β1 and results in neurotoxicity

Otic Neurogenesis Is Regulated by TGFβ in a Senescence-Independent Manner

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