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Cellular and functional characterization of aging-independent senescent-like cells that modulate tissue repair

ABSTRACT: Cellular and functional characterization of aging-independent senescent-like cells that modulate tissue repair

PROVIDER: PRJNA1067582 | ENA |

REPOSITORIES: ENA

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Cellular and functional characterization of aging-independent senescent-like cells that modulate tissue repair

Project description:Cells expressing features of cellular senescence, including upregulation of p21 and p16, appear transiently following tissue injury, yet the properties of these cells or how they contrast with age-induced senescent cells remains unclear. Using skeletal fracture as a model of acute injury, we identified rapidly-appearing senescent-like cells, marked by p21 expression, that negatively affected fracture healing. p21+ callus cells, which consisted predominantly of neutrophils and osteochondroprogenitors, existed as transient cells specific to injury and expressed high levels of senescence-associated factors known to impair bone formation and induce paracrine senescence. Targeted genetic clearance of p21+ cells suppressed senescence-associated signatures within the fracture callus and accelerated fracture healing. By contrast, p21+ cell clearance did not alter bone loss due to aging; conversely, p16+ cell clearance, known to alleviate skeletal aging, did not affect fracture healing. Together, our findings establish contextual roles of senescent/senescent-like cells that may be leveraged for therapeutic opportunities.

2024-06-20 | GSE253863 | GEO

Accumulating DNA damage and insufficient DNA repair in senescent cells underlie persistent DNA damage signaling

Project description:Senescent cells are a major cause of organismal aging and a key target for anti-aging therapies. Persistent DNA damage signaling is a primary driver of the induction and maintenance of cellular senescence. However, many DNA damaging stimuli that induce senescence, such as irradiation or transient exposure to genotoxic drugs, are transient. The mechanisms underlying persistent damage signaling in senescent cells, and why senescent cells fail to repair damaged DNA, remain unknown. Here, we were able to assess the mechanisms underlying persistence of DNA damage and senescence maintenance by designing a precisely controllable senescence system that does not require potent stressors to induce senescence. We demonstrate that sustained mTORC1 signaling in senescent cells causes gradually accumulating DNA damage and an inflammatory response that maintains cell-cycle arrest. Markedly, activation of E2F transcription, which promotes expression of DNA repair proteins, can reverse accumulated DNA damage. Thus, persistent DNA damage signaling arises in senescent cells by uncoupling of mTORC1 and E2F signaling, whereby prolonged mTORC1 activity causes gradually increasing DNA damage that cannot be sufficiently repaired without induction of protective E2F target genes.

2023-06-01 | GSE153683 | GEO

miRNA and lncRNA expression networks modulate Cell Cycle and DNA repair inhibition in senescent prostate cells.

Project description:miRNA and lncRNA expression networks modulate Cell Cycle and DNA repair inhibition in senescent prostate cells.

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Impaired immune surveillance accelerates accumulation of senescent cells and aging [RNA-seq]

Project description:Cellular senescence is a stress response that imposes stable cell-cycle arrest in damaged cells, preventing their propagation in tissues. However, long-term presence of senescent cells might promote tissue degeneration and malignant transformation via secreted pro-inflammatory and matrix-remodeling factors. These factors lead to immune-cell recruitment and senescent-cell clearance. Senescent cells accumulate in tissues in advanced age. The extent of immune-system involvement in regulating age-related accumulation of senescent cells, and its consequences, are unknown. Here we show that mice with impaired cell cytotoxicity exhibit both higher senescent-cell tissue burden and chronic inflammation. They suffer from multiple age-related disorders and significantly lower survival. Strikingly, pharmacological elimination of senescent-cells by ABT-737 partially alleviates accelerated aging phenotype in these mice. In progeroid mice, impaired cell cytotoxicity further promotes senescent-cell accumulation and shortens lifespan. ABT-737 administration during the second half of life of these progeroid mice abrogates senescence signature and increases median survival. Our findings shed new light on mechanisms governing senescent-cell presence in aging, and could motivate new strategies for regenerative medicine.

2018-11-20 | GSE115401 | GEO

miRNA and lncRNA expression networks modulate Cell Cycle and DNA repair inhibition in senescent prostate cells. [RNA-Seq]

Project description:miRNA and lncRNA expression networks modulate Cell Cycle and DNA repair inhibition in senescent prostate cells. [RNA-Seq]

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miRNA and lncRNA expression networks modulate Cell Cycle and DNA repair inhibition in senescent prostate cells. [miRNA-Seq]

Project description:miRNA and lncRNA expression networks modulate Cell Cycle and DNA repair inhibition in senescent prostate cells. [miRNA-Seq]

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Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging

Project description:The accumulation of irreparable cellular damage restricts healthy lifespan after acute stress or natural aging. Senescent cells are thought to impair tissue function and their genetic clearance can successfully delay features of aging. Identifying how senescent cells avoid apoptosis would allow for the prospective design of anti-senescence compounds to address whether homeostasis can be restored. Here, we identify FOXO4 as a pivot in the maintenance of senescent cell viability. We designed a FOXO4-based peptide which selectively competes for interaction of FOXO4 with p53. In senescent cells, this results in p53 nuclear exclusion and cell-intrinsic apoptosis. Importantly, under conditions where it was well tolerated, the FOXO4 peptide restored liver function after Doxorubicin-induced chemotoxicity. Moreover, in fast aging XpdTTD/TTD, as well as in naturally aged mice the FOXO4 peptide could counteract the loss of fitness, fur density and renal function. Thus, it is possible to therapeutically target senescent cells and thereby effectively counteract senescence-associated loss of tissue homeostasis.

2017-03-01 | GSE94395 | GEO

Senescent cells suppress innate VSMC repair functions in atherosclerosis

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Oenothera effect on senescent NDHF

Project description:Accumulation of senescent dermal fibroblasts drives skin aging, impairing the integrity of the extracellular matrix (ECM) and the function of neighbouring cells. One of strategies to manipulate cell senescence include the reactivation of proliferation. Here, a data independent mass spectrometry based proteomic approach has been used to evaluate the effect of an hydrophilic Oenothera biennis cell culture extract (ObHEx) on senescent human dermal fibroblasts. It has been shown that the extract was able to affect the levels of 18 proteins which cluster together and point to mitosis pathways. Indeed the treatment with ObHEx increase the expression of CDK1, replicative helicase complex (MCM2, MCM3, MCM4, MCM5, MCM6, MCM7), condensin I complex (NCAPD2, NCAPH, NCAPG, SMC4, SMC2) and other proteins related to kinetochore (KNTC1, NUF2, TRIP13). This strongly suggests that ObHEx could restore the proliferation of senescent fibroblasts.

2023-03-10 | PXD034222 | Pride

Senescent cells suppress innate vascular smooth muscle cell repair functions

Project description:Senescent cells suppress innate vascular smooth muscle cell repair functions

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