ATF6 safeguards organelle homeostasis and cellular aging in human mesenchymal stem cells

Wang, Si; Hu, Boqiang; Ding, Zicheng; Dang, Yujiao; Wu, Jun; Li, Di; Liu, Xiaoling; Xiao, Bailong; Zhang, Weiqi; Ren, Rui; Lei, Jinghui; Hu, Huifang; Chen, Chang; Chan, Piu; Liu, Dong; Qu, Jing; Tang, Fuchou; Liu, Guang Hui

doi:10.1038/s41421-017-0003-0

Cited by 51 publications

(46 citation statements)

References 67 publications

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“…Knocking down GPX7 in wild‐type HMSCs resulted in accelerated cellular aging (Figure 5f–h). To investigate whether the metformin‐Nrf2‐GPx7 pathway could protect HMSCs in an in vivo context, HMSCs were implanted into the tibialis anterior muscle of immune‐deficient mice, and their in vivo retention was measured by an in vivo imaging system (IVIS) (Kubben et al., 2016; Pan et al., 2016; Wang et al., 2018; Yang et al., 2017). Metformin‐treated HMSCs displayed delayed cellular attrition compared to vehicle‐treated cells (Figure 5i), whereas GPX7 ‐deficient HMSCs exhibited accelerated cell exhaustion in the in vivo microenvironment (Figure 5j).…”

Section: Resultsmentioning

confidence: 99%

Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

et al. 2018

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SummaryMetformin, an FDA‐approved antidiabetic drug, has been shown to elongate lifespan in animal models. Nevertheless, the effects of metformin on human cells remain unclear. Here, we show that low‐dose metformin treatment extends the lifespan of human diploid fibroblasts and mesenchymal stem cells. We report that a low dose of metformin upregulates the endoplasmic reticulum‐localized glutathione peroxidase 7 (GPx7). GP×7 expression levels are decreased in senescent human cells, and GPx7 depletion results in premature cellular senescence. We also indicate that metformin increases the nuclear accumulation of nuclear factor erythroid 2‐related factor 2 (Nrf2), which binds to the antioxidant response elements in the GPX7 gene promoter to induce its expression. Moreover, the metformin‐Nrf2‐GPx7 pathway delays aging in worms. Our study provides mechanistic insights into the beneficial effects of metformin on human cellular aging and highlights the importance of the Nrf2‐GPx7 pathway in pro‐longevity signaling.

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Section: Resultsmentioning

confidence: 99%

Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

et al. 2018

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“…CS patients frequently exhibit musculoskeletal abnormalities, such as kyphosis, contracture and osteoporosis (Hishiya and Watanabe, 2004;Karikkineth et al, 2017). MSCs are multipotent mesodermal cells that can differentiate into a variety of mesodermal cell types, including osteoblasts, chondrocytes, and adipocytes, which serve as a good cell model for investigating the accelerated degeneration of mesodermal tissues caused by genetic mutations (Liu et al, 2014;Zhang et al, 2015Zhang et al, , 2019Kubben et al, 2016;Li et al, 2016;Pan et al, 2016;Geng et al, 2018;Wang et al, 2018b;Wu et al, 2018;Yan et al, 2019). Therefore, we first differentiated CS-iPSCs and GC-iPSCs into MSCs to investigate whether ERCC6 mutations could result in accelerated attrition of the MSC pool.…”

Section: Alleviation Of Aging Defects In Gene-corrected Cs-mscsmentioning

confidence: 99%

“…The differentiation of CS-iPSCs and GC-iPSCs into MSCs was performed as previously described (Zhang et al, 2015;Pan et al, 2016;Wang et al, 2018b). Briefly, embryoid bodies were plated onto Matrigel-coated plates in differentiation medium (αMEM (Invitrogen) supplemented with 10% FBS (Gemcell), 10 ng/mL bFGF (Joint Protein Central, JPC), 5 ng/mL TGFβ (Human Zyme), 0.1 mmol/L NEAA (Gibco) and 1% penicillin/ streptomycin (Gibco)).…”

Section: Msc Generation and Characterizationmentioning

confidence: 99%

“…The differentiation potential of the MSCs towards chondrocytes, osteoblasts and adipocytes was evaluated by staining with Alcian blue (chondrogenesis), von Kossa (osteogenesis) and an oil red O (adipogenesis) kit (IHC World) after differentiation of the indicated lineage, as previously described (Zhang et al, 2015;Pan et al, 2016;Wang et al, 2018b).…”

Section: Msc Generation and Characterizationmentioning

confidence: 99%

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Rescue of premature aging defects in Cockayne syndrome stem cells by CRISPR/Cas9-mediated gene correction

Wang

Min

et al. 2019

Protein Cell

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Cockayne syndrome (CS) is a rare autosomal recessive inherited disorder characterized by a variety of clinical features, including increased sensitivity to sunlight, progressive neurological abnormalities, and the appearance of premature aging. However, the pathogenesis of CS remains unclear due to the limitations of current disease models. Here, we generate integration-free induced pluripotent stem cells (iPSCs) from fibroblasts from a CS patient bearing mutations in CSB/ERCC6 gene and further derive isogenic genecorrected CS-iPSCs (GC-iPSCs) using the CRISPR/Cas9 system. CS-associated phenotypic defects are recapitulated in CS-iPSC-derived mesenchymal stem cells (MSCs) and neural stem cells (NSCs), both of which display increased susceptibility to DNA damage stress. Premature aging defects in CS-MSCs are rescued by the targeted correction of mutant ERCC6. We next map the transcriptomic landscapes in CS-iPSCs and GC-iPSCs and their somatic stem cell derivatives (MSCs and

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“…As shown in Figure 6, we observed a statistically relevant increase of Mlinc.28428 expression in MSCs under replicative stress and in MSCs with CrisprCas9 depletion of genes with important role against senescence. In the Wang et al study [95], MSCs senescence was observed with the KO of ATF6 and the stress induced with tunicamycin (endoplasmic reticulum stress) and late passage (replicative stress). Mlinc.28428 expression increased with tunicamycin treatment, late passage and ATF6 KO.…”

Section: K-mers Analysis Of Markers In Functional Cell Situationmentioning

confidence: 99%

Detailed analysis of public RNAseq data and long non-coding RNA: a proposed enhancement to mesenchymal stem cell characterisation

Riquier

Mathieu

Boureux

et al. 2020

Preprint

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The development of RNA sequencing (RNAseq) and corresponding emergence of public datasets have created new avenues of transcriptional marker search. The long non-coding RNAs (lncRNAs) constitute an emerging class of transcripts with a potential for high tissue specificity and function. Using a dedicated bioinformatics pipeline, we propose to construct a cell-specific catalogue of unannotated lncRNAs and to identify the strongest cell markers. This pipeline uses ab initio transcript identification, pseudoalignment and new methodologies such as a specific k-mer approach for naive quantification of expression in numerous RNAseq data.For an application model, we focused on Mesenchymal Stem Cells (MSCs), a type of adult multipotent stem-cells of diverse tissue origins. Frequently used in clinics, these cells lack extensive characterisation. Our pipeline was able to highlight different lncRNAs with high specificity for MSCs. In silico methodologies for functional prediction demonstrated that each candidate represents one specific state of MSCs biology. Together, these results suggest an approach that can be employed to harness lncRNA as cell marker, showing different candidates as potential actors in MSCs biology, while suggesting promising directions for future experimental investigations.

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ATF6 safeguards organelle homeostasis and cellular aging in human mesenchymal stem cells

Cited by 51 publications

References 67 publications

Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

Rescue of premature aging defects in Cockayne syndrome stem cells by CRISPR/Cas9-mediated gene correction

Detailed analysis of public RNAseq data and long non-coding RNA: a proposed enhancement to mesenchymal stem cell characterisation

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