Suppression of calcium-dependent membrane currents in human fibroblasts by replicative senescence and forced expression of a gene sequence encoding a putative calcium-binding protein.

Shi, Liu; Thweatt, Ray; Lumpkin, Charles K.; Goldstein, Samuel

doi:10.1073/pnas.91.6.2186

Cited by 17 publications

(6 citation statements)

References 40 publications

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“…It is also described to be a major early substrate for caspase‐8, which is required for actin reorganization during apoptosis . The downregulation of TRPC4 (a nonselective calcium‐permeable cation channel) is also biologically relevant in the context of senescence, since it is known that replicative senescence leads to the suppression of calcium‐dependent membrane currents in human fibroblasts . Reassuringly, real‐time RT‐PCR validated the differential expression of TRPC4 in both radiation‐ and replication‐induced senescent hMSCs.…”

Section: Discussionmentioning

confidence: 90%

Cell Senescence Abrogates the Therapeutic Potential of Human Mesenchymal Stem Cells in the Lethal Endotoxemia Model

et al. 2014

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Mesenchymal stem cells (MSCs) possess unique paracrine and immunosuppressive properties, which make them useful candidates for cellular therapy. Here, we address how cellular senescence influences the therapeutic potential of human MSCs (hMSCs). Senescence was induced in bone marrow-derived hMSC cultures with gamma irradiation. Control and senescent cells were tested for their immunoregulatory activity in vitro and in vivo, and an extensive molecular characterization of the phenotypic changes induced by senescence was performed. We also compared the gene expression profiles of senescent hMSCs with a collection of hMSCs used in an ongoing clinical study of Graft Versus Host disease (GVHD). Our results show that senescence induces extensive phenotypic changes in hMSCs and abrogates their protective activity in a murine model of LPS-induced lethal endotoxemia. Although senescent hMSCs retain an ability to regulate the inflammatory response on macrophages in vitro, and, in part retain their capacity to significantly inhibit lymphocyte proliferation, they have a severely impaired migratory capacity in response to proinflammatory signals, which is associated with an inhibition of the AP-1 pathway. Additionally, expression analysis identified PLEC, C8orf48, TRPC4, and ZNF14, as differentially regulated genes in senescent hMSCs that were similarly regulated in those hMSCs which failed to produce a therapeutic effect in a GVHD trial. All the observed phenotypic alterations were confirmed in replicative-senescent hMSCs. In conclusion, this study highlights important changes in the immunomodulatory phenotype of senescent hMSCs and provides candidate gene signatures which may be useful to evaluate the therapeutic potential of hMSCs used in future clinical studies.

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Section: Discussionmentioning

confidence: 90%

Cell Senescence Abrogates the Therapeutic Potential of Human Mesenchymal Stem Cells in the Lethal Endotoxemia Model

et al. 2014

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“…The physiological changes during cellular senescence are extensive, so it is conceivable that altered homeostasis of metals is a part of an overall metabolic disruption encountered during senescence. Some studies have reported altered metal homeostasis in human cells during cellular senescence (29,42). Because iron accumulates at both a greater rate and capacity than the other metals measured, and due to the relevance of iron to aging-related diseases, we focused on the changes in iron content during cellular senescence.…”

Section: Discussionmentioning

confidence: 99%

Iron Accumulation During Cellular Senescence in Human FibroblastsIn Vitro

Killilea¹,

Atamna²,

Liao

et al. 2003

Antioxidants & Redox Signaling

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Iron accumulates as a function of age in several tissues in vivo and is associated with the pathology of numerous age-related diseases. The molecular basis of this change may be due to a loss of iron homeostasis at the cellular level. Therefore, changes in iron content in primary human fibroblast cells (IMR-90) were studied in vitro as a model of cellular senescence. Total iron content increased exponentially during cellular senescence, resulting in 10-fold higher levels of iron compared with young cells. Low-dose hydrogen peroxide (H 2 O 2 ) induced early senescence in IMR-90s and concomitantly accelerated iron accumulation. Furthermore, senescence-related and H 2 O 2 -stimulated iron accumulation was attenuated by N-tert-butylhydroxylamine (NtBHA), a mitochondrial antioxidant that delays senescence in vitro. However, SV40-transformed, immortalized IMR-90s showed no time-dependent changes in metal content in culture or when treated with H 2 O 2 and/or NtBHA. These data indicate that iron accumulation occurs during normal cellular senescence in vitro. This accumulation of iron may contribute to the increased oxidative stress and cellular dysfunction seen in senescent cells.

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“…58 Gap junction assembly times increase by an order of magnitude and membrane permeability increases sharply 59. Specific inhibitors of calcium dependent membrane currents are induced 60. In addition, the glycation of corneal collagen produces an increase in intramolecular spacing 42.…”

Section: How Does Cell Senescence Affect the Cornea?mentioning

confidence: 99%