Homocysteine enhances neural stem cell autophagy in in vivo and in vitro model of ischemic stroke

Wang, Mengying; Liang, Xiao; Cheng, Man; Liu, Yang; Liu, Huan; Wang, Xuan; Sai, Na; Zhang, Xumei

doi:10.1038/s41419-019-1798-4

Cited by 85 publications

(59 citation statements)

References 38 publications

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“…We supplemented MT-speci ed inhibitor LUZ into cultured cells. We found The inhibitory regulation of PI3K/AKT/mTOR pathway can activate autophagy and as reported, several studies chose to target PI3K/AKT/mTOR pathway for autophagy regulation in stem cells [57][58][59].…”

Section: Discussionsupporting

confidence: 58%

Melatonin-induced Cell Rejuvenation from Long-term Ex-vivo passaging Functioned by its Restoration of Damaged Cell Autophagic Processes

Tan¹,

Xu²,

Dai³

et al. 2020

Preprint

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Background: Stem cells undergone long-term ex-vivo expansion are most likely functionally compromised (namely cellular senescence) in terms of their stem cell properties and therapeutic potentials. Due to the ability to attenuate cellular senescence, melatonin (MLT) has been proposed as an adjuvant across long-term cell expansion protocols, but the underlying mechanism remains largely unknown. Methods: Human periodontal ligament stem cells (PDLSCs) were isolated and cultured ex-vivo for 15 passages, and passage 2, 7 and 15 cells were used to interrogate the cellular senescence and alteration in cell autophagy during long-term expansion. The cellular senescence features were evidenced by senescence-associated β-galacotosidase (SA-β-gal) activity and the expression of senescence-related proteins including p53, p21, p16 and γ-H2AX. Electronic microscope was used to observe the autophagic vesicles. Adenovirus mRFP-GFP-LC3 was transfected to indicate the alteration of autophagic flux during long-term expansion, and the autophagy-associated proteins Atg7, Beclin-1, LC3-II and p62 were evaluated by Western blot. Results: It was found that long-term in-vitro passaging led to an accumulated SA-β-gal, elevated expressions of p53, p21, p16 and γ-H2AX, along with downregulated autophagy-associated proteins Atg7, Beclin-1 and LC3 as well as a mounting autophagy substrate p62. In accordance with expectation, supplemented with MLT not only ameliorated cells to a younger state but also restored the impaired autophagy level in senescent cells. Additionally, we demonstrated that autophagy inhibitor could block such MLT-induced cell rejuvenation. When the underlying signaling pathways involved was interrogated, we found that MLT receptor (MT) participated in mediating MLT-related autophagy restoration by regulating PI3K/AKT/mTOR signaling pathway.Conclusions: The present study suggests that MLT may rejuvenate long-term expansion-caused cellular senescence by restoring autophagy, more likely via PI3K/AKT/mTOR signaling pathway in an MT-dependent manner. This is the first report identifying the MT-dependent PI3K/AKT/mTOR signaling involved in MLT-induced autophagy alteration, pointing to a potential target for using autophagy-restoring agents such as MLT to develop optimized clinical-scale cell production protocols.

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Section: Discussionsupporting

confidence: 58%

Melatonin-induced Cell Rejuvenation from Long-term Ex-vivo passaging Functioned by its Restoration of Damaged Cell Autophagic Processes

Tan¹,

Xu²,

Dai³

et al. 2020

Preprint

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“…4a). Next, IGF-1, the activator of PI3K 29 , was applied for the rescue assays. As anticipated, IGF-1 treatment obviously reversed LINC01559 deficiency-restrained phosphorylation of PI3K, AKT and mTOR as well as the elevated PTEN level induced by LINC01159 inhibition (Fig.…”

Section: Linc01559 Accelerated Gc Progression By Activating Pi3k/ Aktmentioning

confidence: 99%

Exosome-transferred LINC01559 promotes the progression of gastric cancer via PI3K/AKT signaling pathway

Wang

et al. 2020

Cell Death Dis

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Increasing evidence indicates that long non-coding RNAs (lncRNAs) are associated with the progression of human cancers. However, the expression level and function of LINC01559 (long intergenic non-protein coding RNA 1559) in gastric cancer (GC) are rarely reported. Here we found that LINC01559 was upregulated in GC tissues based on GEPIA (Gene Expression Profiling Interactive Analysis) and TCGA (The Cancer Genome Atlas) databases. Also, LINC01559 was expressed at a lower level in GC cells than in mesenchymal stem cells (MSCs). In vitro experiments revealed that silencing LINC01559 remarkably hindered GC cell proliferation, migration and stemness. Then, we identified that LINC01559 was transmitted form MSCs to GC cells via the exosomes. Immunofluorescence staining and electron microscope validated the existence of exosomes in GC cells. Mechanistically, LINC01559 sponged miR-1343-3p to upregulate PGK1 (phosphoglycerate kinase 1), therefore activating PI3K/AKT pathway. Moreover, LINC01559 recruited EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) to PTEN (phosphatase and tensin homolog) promoter, inducing the methylation of PTEN promoter and finally resulting in PTEN repression. Of note, LINC01559 targeted both PGK1 and PTEN to promote GC progression by activating PI3K/AKT pathway. Taken together, our study demonstrated that LINC01559 accelerated GC progression via upregulating PGK1 and downregulating PTEN to trigger phosphatidylinositol 3-kinase/AKT serine/threonine kinase (PI3K/AKT) pathway, indicating LINC01559 as a potential biomarker for GC treatment.

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“…There were several reports linked to Hcy and abnormality of autophagy. Hcy enhanced autophagy in neural stem cells in the model of ischaemic stroke as well as in mouse liver 10,11 . However, Hcy inhibited autophagy in human neurons and mice 12 .…”

Section: Introductionmentioning

confidence: 95%

Decreased autophagy of vascular smooth muscle cells was involved in hyperhomocysteinemia‐induced vascular ageing

Yan

Cao

Zhen

et al. 2020

Clin Exp Pharma Physio

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Ageing and hyperhomocysteinemia (HHcy) are important risk factors for cardiovascular diseases (CVDs). HHcy affects the occurrence of vascular diseases in the elderly. So far, the mechanism of HHcy‐induced vascular ageing remains largely unknown. Autophagy level is significantly reduced in the ageing process, and restoring impaired autophagy to a normal state may be one of the possible ways to extend the expected longevity and lifespan in the future. In this study, we established the HHcy rat model by feeding a 2.5% methionine diet. Small animal ultrasound and the tail‐cuff method indicated that the vascular pulse wave velocity (PWV) and pulse pressure (PP) of HHcy rats were increased significantly compared with the control group. Vascular morphology and structure have been changed in HHcy rats, including lumen dilation, increased collagen fibre deposition and increased p53/p21/p16 expression. In vitro, under the stimulation of homocysteine (500 μmol/L, 24 hours), the rat vascular smooth muscle cells (VSMCs) presented senescence, which was characterized by the increased expression of ageing‐related markers, such as p16, p21 and p53 as well as increased senescence‐associated beta‐galactosidase (SA‐β‐gal) activity. Meanwhile, the autophagy level was decreased both in vivo and in vitro, shown as the increased level of autophagy substrate p62 and the reduced level of autophagy marker LC3 II/I in the thoracic aorta of HHcy rats and in Hcy‐treated VSMCs, respectively. The senescence phenotype of VSMCs was reversed by increased autophagy levels induced by rapamycin. Our findings indicate that decreased autophagy of VSMCs is involved in hyperhomocysteinemia‐induced vascular ageing.

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Homocysteine enhances neural stem cell autophagy in in vivo and in vitro model of ischemic stroke

Cited by 85 publications

References 38 publications

Melatonin-induced Cell Rejuvenation from Long-term Ex-vivo passaging Functioned by its Restoration of Damaged Cell Autophagic Processes

Melatonin-induced Cell Rejuvenation from Long-term Ex-vivo passaging Functioned by its Restoration of Damaged Cell Autophagic Processes

Exosome-transferred LINC01559 promotes the progression of gastric cancer via PI3K/AKT signaling pathway

Decreased autophagy of vascular smooth muscle cells was involved in hyperhomocysteinemia‐induced vascular ageing

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