Age-related increase in Wnt inhibitor causes a senescence-like phenotype in human cardiac stem cells

Nakamura, Tamami; Hosoyama, Tohru; Murakami, Junichi; Samura, Makoto; Ueno, Koji; Kurazumi, Hiroshi; Suzuki, Ryo; Mikamo, Akihito; Hamano, Kimikazu

doi:10.1016/j.bbrc.2017.04.110

Cited by 16 publications

(17 citation statements)

References 24 publications

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“…In this regard, we observed an age-related increase in the protein levels of the Wnt antagonist SFRP-1 and SFRP-2, further suggesting that the aging-related decrease of Wnt activity is caused not only by structural component reduction or lack of activation signals, but also due to the increase of inhibitory signals. In this regard, an increase in the levels of SFRP1 has been related to cellular senescence on other cell types, including in Human Cardiac Stem Cells ( Nakamura et al, 2017 ), and fibroblasts ( Elzi et al, 2012 ). Recent studies also demonstrate that SFRP-1 is increased in the brain of patients with AD, binds to amyloid-β and accumulates in amyloid plaques.…”

Section: Discussionmentioning

confidence: 99%

Wnt Signaling Pathway Dysregulation in the Aging Brain: Lessons From the Octodon degus

Inestrosa

Tapia-Rojas

Lindsay

et al. 2020

Front. Cell Dev. Biol.

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Wnt signaling constitutes a fundamental cellular and molecular pathway, necessary from proper embryogenesis to function-maintenance of fully developed complex organisms. In this regard, Wnt pathway plays a crucial role in both the development of the central nervous system and in maintaining the structure and function of the neuronal circuits, and it has been suggested that its dysregulation is critical in the onset of several pathologies including cancer and neurodegenerative disorders, such as Alzheimer’s disease (AD). Due to its relevance in the maintenance of the neuronal activity and its involvement in the outbreak of devastating diseases, we explored the age-related changes in the expression of Wnt key components in the cortex and hippocampus of 7 to 72-months-old Octodon degus ( O. degus ), a Chilean long-living endemic rodent that has been proposed and used as a natural model for AD. We found a down-regulation in the expression of different Wnt ligands (Wnt3a, Wnt7a, and Wnt5a), as well as in the Wnt co-receptor LRP6. We also observed an increase in the activity of GSK-3β related to the down-regulation of Wnt activity, a fact that was confirmed by a decreased expression of Wnt target genes. Relevantly, an important increase was found in secreted endogenous Wnt inhibitors, including the secreted-frizzled-related protein 1 and 2 (SFRP-1 and SFRP-2) and Dickkopf-1 (Dkk-1), all them antagonists at the cell surface. Furthermore, treatment with Andrographolide, a labdane diterpene obtained from Andrographis paniculata , prevents Wnt signaling loss in aging degus . Taken together, these results suggest that during the aging process Wnt signaling activity decreases in the brain of O. degus .

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Section: Discussionmentioning

confidence: 99%

Wnt Signaling Pathway Dysregulation in the Aging Brain: Lessons From the Octodon degus

Inestrosa

Tapia-Rojas

Lindsay

et al. 2020

Front. Cell Dev. Biol.

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“…Due to the involvement of miR-142-3p in TGF-β signaling [26-28], we investigated the effects of miR-142-3p activation on the TGF-β3-induced SC barrier function breakdown in vitro . In primarily cultured SCs, a 24 h-treatment of TGF-β3 at 3 ng/ml led to a significant TJ barrier decrease, which was reflected by the TER value decrease by ∼40% (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…What interests us was the participation of miR-142-3p in TGF-β-regulated signaling pathways. For example, during region-dependent-chondrogenesis, miR-142-3p was involved in the limb type-specific effect of TGF-β3 on mesenchymal cells by modulating transcription of a disintegrin and metalloprotease (ADAM) [26]. In vascular smooth muscle cells (VSMCs), TGF-β could induce the expression of miR-142-3p, which inhibited cell migration and determined contractile phenotype of VSMCs by targeting at dedicator of cytokinesis 6 (DCK6) [27].…”

Section: Introductionmentioning

confidence: 99%

MiR-142-3p Inhibits TGF-β3-Induced Blood-Testis Barrier Impairment by Targeting Lethal Giant Larvae Homolog 2

Xu¹,

Wu²,

Fan³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Transforming growth factor-β3 (TGF-β3) has been proved to perturb the blood-testis barrier (BTB) by accelerating junction protein endocytosis in Sertoli cells (SCs) to accommodate the traversing of preleptotene spermatocytes across the BTB around stage VIII in rat. Yet the molecular network underlying the impairment of TGF-β3 on BTB integrity is not fully elucidated. Our study herein was designed to investigate the participation of microRNA-142-3p (miR-142-3p), which has been reported to affect TGF-β3 signaling via different pathways, during BTB dynamics and the corresponding mechanisms. Methods: MiRNA mimic or agomiRNA was co-administered with or without TGF-β3 in the cultured SCs or in the rat testis. The SC permeability barrier function was reflected by measuring the transepithelial resistance (TER) and the permeability of the sodium fluorescein (Na-F). The BTB integrity was detected by the permeation of biotin. A luciferase reporter assay was used to testify the potential target of miR-142-3p, lethal giant larvae 2 (Lgl2). Laser capture microdissection (LCM) was applied to acquire cell components of different stages of seminiferious tubules, followed by detection of the expression levels of miR-142-3p, TGF-β3, and Lgl2 by qPCR. The SC barrier function was also detected as above in the presence of TGF-β3 after Lgl2 knockdown. Results: We revealed a reversion of TGF-β3-induced BTB impairment after miR-142-3p treatment both in vitro and in vivo. Meanwhile, the activation of Cdc42 and reduction in occludin aroused by TGF-β3 were also reversed by miR-142-3p. The predicted binding of miR-142-3p with 3’-untranslated region (3’-UTR) of Lgl2, was verified by the luciferase assay. Moreover, an increased Lgl2 level in TGF-β3-treated SCs was found and correlated stage-specific expressions of TGF-β3, miR-142-3p, and Lgl2 were revealed. Knockdown of Lgl2 in SCs was shown to partially antagonize the BTB disruption mediated by TGF-β3. Conclusions: Collectively, our results suggest a resistance of miR-142-3p on the BTB impairment caused by TGF-β3 during the seminiferous epithelial cycle by targeting Lgl2.

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“…The Wnt/β-catenin signaling pathway is closely associated with ageing-associated impairments in cardiac regeneration and function (15). A previous study found that the canonical Wnt signaling pathway was involved in the senescence process of cardiac stem cells (CSCs) (16). As a post-transcriptional inhibitor of translation, β-catenin was initially identified as a direct transcriptional target of lincRNA-p21 (11).…”

Section: Introductionmentioning

confidence: 99%

Long intergenic non‑coding RNA‑p21 mediates cardiac senescence via the Wnt/β‑catenin signaling pathway in doxorubicin-induced cardiotoxicity

2017

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Doxorubicin (Dox)-induced cardiotoxicity has been a well‑known phenomenon to clinicians and scientists for decades. It has been confirmed that Dox‑dependent cardiotoxicity is accompanied by cardiac cellular senescence. However, the molecular mechanisms underlying Dox cardiotoxicity remains to be fully elucidated. Long non‑coding (lnc) RNAs regulate gene transcription and the fate of post‑transcriptional mRNA, which affects a broad range of age‑associated physiological and pathological conditions, including cardiovascular disease and cellular senescence. However, the functional role of lncRNAs in Dox‑induced cardiac cellular senescence remains largely unknown. Using the reverse transcription‑quantitative polymerase chain reaction method, the present study indicated that long intergenic non‑coding (linc) RNA‑p21 was highly expressed in Dox‑treated HL‑1 murine cardiomyocytes. Dox‑induced cardiac senescence was accompanied by decreased cellular proliferation and viability, increased expression of p53 and p16, and decreased telomere length and telomerase activity, while these effects were relieved by silencing endogenous lincRNA‑p21. We found that lincRNA‑p21 interacted with β‑catenin and that silencing β‑catenin abolished the anti‑senescent effect of lincRNA‑p21 silencing. It was observed that modulating lincRNA‑p21 to exert an anti‑senescent effect was dependent on decreasing oxidant stress. To conclude, the present findings suggest that lincRNA‑p21 may be involved in Dox‑associated cardiac cellular senescence and that silencing lincRNA‑p21 effectively protects against Dox cardiotoxicity by regulating the Wnt/β‑catenin signaling pathway and decreasing oxidant stress. Furthermore, modulating lincRNA‑p21 may have cardioprotective potential in patients with cancer receiving Dox treatment.

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Age-related increase in Wnt inhibitor causes a senescence-like phenotype in human cardiac stem cells

Cited by 16 publications

References 24 publications

Wnt Signaling Pathway Dysregulation in the Aging Brain: Lessons From the Octodon degus

Wnt Signaling Pathway Dysregulation in the Aging Brain: Lessons From the Octodon degus

MiR-142-3p Inhibits TGF-β3-Induced Blood-Testis Barrier Impairment by Targeting Lethal Giant Larvae Homolog 2

Long intergenic non‑coding RNA‑p21 mediates cardiac senescence via the Wnt/β‑catenin signaling pathway in doxorubicin-induced cardiotoxicity

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