Effects of senolytic drugs on human mesenchymal stromal cells

Grezella, Clara; Fernández-Rebollo, Eduardo; Franzen, Julia; Ferreira, Mónica S. Ventura; Beier, Fabian; Wagner, Wolfgang

doi:10.1186/s13287-018-0857-6

Cited by 58 publications

(56 citation statements)

References 21 publications

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“…There is growing evidence that this phenomenon is also relevant in organismal aging and tumorigenesis (Childs et al 2015). Depletion of senescent cells might prolong healthy aging, and this raises high hopes for development of senolytic drugs (Jeon et al 2017;Kirkland et al 2017;Grezella et al 2018). In fact, replicative senescencein analogy to agingis associated with highly reproducible DNAm changes at specific sites in the genome Lowe et al 2015).…”

Section: Discussionmentioning

confidence: 99%

Epigenetic drift during long-term culture of cells in vitro

Franzen

Georgomanolis

Selich

et al. 2018

Preprint

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Replicative senescence of cells in culture is associated with highly reproducible DNA methylation (DNAm) changes at specific sites in the genome. Thus far, it is largely unclear if these epigenetic modifications are directly regulated, or if they are randomly evoked by other chromatin changes during long-term culture.We have identified CG dinucleotides (CpGs) that become continuously hyper-or hypomethylated in the course of culture expansion of mesenchymal stem cells (MSCs) and other cell types. These modifications provide a biomarker for replicative senescence and correlate with the number of passages in vitro. During reprogramming into induced pluripotent stem cells (iPSCs) senescence-associated DNAm is reversed simultaneously with pluripotency-associated DNAm changes. Bisulfite barcoded amplicon sequencing (BBA-seq) demonstrated that upon passaging the DNAm patterns of neighboring CpGs become more complex without evidence of continuous pattern development. Notably, BBA-seq of hairpin-linked DNA molecules demonstrated that many CpG dyads are methylated only on the forward or the reverse strand. This hemimethylation was conserved over many passages, indicating that it was not due to insufficient maintenance of DNAm patterns. Circularized chromatin conformation capture (4C) of senescence-associated CpGs revealed reproducible changes during senescence without evidence for preferential interaction between CpGs that become either hyper-or hypomethylated.Taken together, senescence-associated DNAm fluctuates stochastically at specific sites in the genome. Strand-specific DNAm and reproducible changes in 4C indicate that epigenetic modifications of these CG dyads are not regulated in a targeted manner but rather caused by passage-specific higher order chromatin conformation states.

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Section: Discussionmentioning

confidence: 99%

Epigenetic drift during long-term culture of cells in vitro

Franzen

Georgomanolis

Selich

et al. 2018

Preprint

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“…Dasatinib + Quercetin -Senescent HUVEC, senescent preadipocytes in vitro -Senescent MEFs, senescent bone marrow-derived murine mesenchymal stem cells in vivo -SA-β-gal positive muscle and fat tissue of irradiated single mouse limb -Progeroid Ercc1(−/∆) mice [186] -Senescent lung fibroblasts and epithelial cells in bleomycin-induced lung injury/idiopathic pulmonary fibrosis mouse model [18] -Senescent alveolar epithelial type (AT)II ex vivo in bleomycin-induced lung injury/idiopathic pulmonary fibrosis mouse model. [187] -Senescent medial aortal cells of aging mice and hypercholesterolemia (atherosclerosis) mouse models [188] -Senescent hepatocytes of dietary hepatic steatosis mouse model [189] -Radiation-induced senescent preadipocytes in vivo -Senescent cells in freshly isolated human omental adipose tissue of obese individuals ex vivo [190] -Arteriovenous fistula-chronic kidney disease mouse model [191] -20-month-old, transgenic tau NFT -Mapt 0/0 mice [192] -Aβ plaque-associated senescent oligodendrocyte progenitor cells in vivo -ZsGreen/APPPS1 p16 INK4 reporter Alzheimer's disease mouse model -Radiation-induced senescent N2a cells [193] -Uterine fibrosis mouse model [194] -Telomere dysfunction-induced senescent osteoblasts and osteocytes [195] Navitoclax (ABT263) -Radiation-induced, replication-exhausted and Ras-induced senescent WI38 fibroblasts in vitro -Radiation-induced senescent human IMR90 fibroblasts, human renal epithelial cells and mouse embryonic fibroblasts in vitro -Radiation-induced senescence in p16-3MR transgenic mouse model [196] -Radiation-induced senescent human umbilical vein epithelial cells, IMR90 human lung fibroblasts and mouse embryonic fibroblasts [197] -Radiation-induced senescent type II alveolar epithelial cells in vitro and in vivo [198] -Senescent pancreatic tissue of i4F mouse model [199] -Replicative-exhausted human mesenchymal stromal cells [200] -Aging-induced senescent cardiac myocytes -Myocardial infarction mouse model [201] -Senescent murine pancreatic β-cells in vitro and in vivo [202] -Aging mouse bone marrow stromal cells [203] -WIPI1 and SLITKR4 overexpression-induced senescent uterine leiomyoma spheroid model ex vivo [204]…”

Section: Senolytic Model/cell Line Referencementioning

confidence: 99%

Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy

Saleh

Bloukh

Carpenter

et al. 2020

Cancers

195

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For the past two decades, cellular senescence has been recognized as a central component of the tumor cell response to chemotherapy and radiation. Traditionally, this form of senescence, termed Therapy-Induced Senescence (TIS), was linked to extensive nuclear damage precipitated by classical genotoxic chemotherapy. However, a number of other forms of therapy have also been shown to induce senescence in tumor cells independently of direct genomic damage. This review attempts to provide a comprehensive summary of both conventional and targeted anticancer therapeutics that have been shown to induce senescence in vitro and in vivo. Still, the utility of promoting senescence as a therapeutic endpoint remains under debate. Since senescence represents a durable form of growth arrest, it might be argued that senescence is a desirable outcome of cancer therapy. However, accumulating evidence suggesting that cells have the capacity to escape from TIS would support an alternative conclusion, that senescence provides an avenue whereby tumor cells can evade the potentially lethal action of anticancer drugs, allowing the cells to enter a temporary state of dormancy that eventually facilitates disease recurrence, often in a more aggressive state. Furthermore, TIS is now strongly connected to tumor cell remodeling, potentially to tumor dormancy, acquiring more ominous malignant phenotypes and accounts for several untoward adverse effects of cancer therapy. Here, we argue that senescence represents a barrier to effective anticancer treatment, and discuss the emerging efforts to identify and exploit agents with senolytic properties as a strategy for elimination of the persistent residual surviving tumor cell population, with the goal of mitigating the tumor-promoting influence of the senescent cells and to thereby reduce the likelihood of cancer relapse.

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“…Our results demonstrate that replicative senescence has major impact on the metabolome with highly reproducible changes across different cell types and biological replica. Lee (Grezella et al, 2018;Zhu et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Senescence-associated metabolomic phenotype in primary and iPSC-derived mesenchymal stromal cells

Fernández-Rebollo

Franzen

Hollmann

et al. 2019

Preprint

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Long-term culture of primary cells is reflected by functional and secretory changes, which ultimately result in replicative senescence. In contrast, induced pluripotent stem cells (iPSCs) do not reveal any signs of cellular aging while in the pluripotency state, whereas little is known how they senesce upon differentiation. Furthermore, it is largely unclear how the metabolome of cells changes during replicative senescence and if such changes are consistent across different cell types. In this study, we have directly compared culture expansion of primary mesenchymal stromal cells (MSCs) and iPSC-derived MSCs (iMSCs) until they reached growth arrest after a mean of 21 and 17 cumulative population doublings, respectively. Both cell types acquired similar changes in morphology, in vitro differentiation potential, up-regulation of senescence-associated beta-galactosidase, and senescence-associated DNA methylation changes. Furthermore, MSCs and iMSCs revealed overlapping gene expression changes during culture expansion, particularly in functional categories related to metabolic processes. We subsequently compared the metabolome of MSCs and iMSCs at early and senescent passages and observed various significant and overlapping senescence-associated changes in both cell types, including down-regulation of nicotinamide ribonucleotide and up-regulation of orotic acid.Replicative senescence of both cell types was consistently reflected by the metabolic switch from oxidative to glycolytic pathways. Taken together, long-term culture of iPSCderived MSCs evokes very similar molecular and functional changes as observed in primary MSCs. Replicative senescence is associated with a highly reproducible senescence-associated metabolomics phenotype, which may be used to monitor the state of cellular aging.

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Effects of senolytic drugs on human mesenchymal stromal cells

Cited by 58 publications

References 21 publications

Epigenetic drift during long-term culture of cells in vitro

Epigenetic drift during long-term culture of cells in vitro

Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy

Senescence-associated metabolomic phenotype in primary and iPSC-derived mesenchymal stromal cells

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