Targeting senescent cells improves functional recovery after spinal cord injury

Paramos-de-Carvalho, Diogo; Martins, Isaura; Cristóvão, Ana Margarida; Dias, Ana Cristina; Neves-Silva, Dalila; Pereira, Telmo; Chapela, Diana; Farinho, Ana; Jacinto, António; Saúde, Leonor

doi:10.1016/j.celrep.2021.109334

Cited by 50 publications

(62 citation statements)

References 109 publications

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“…We gave new cohorts of young male and female mice SNI or sham surgeries and harvested lumbar spinal cord tissues from these animals 12–14 months later, or 2 months later. Spinal cords were stained with senescence‑associated β‑galactosidase (SA‑β‑gal) to reveal putatively senescent cells ( 28 ). A representative spinal cord image is shown in Figure 3A ; senescent cells were found throughout the spinal cord in the old cohort, but none at all in the young cohort (not shown).…”

Section: Resultsmentioning

confidence: 99%

Long-term male-specific chronic pain via telomere- and p53‑mediated spinal cord cellular senescence

Muralidharan¹,

Sotocinal²,

Yousefpour³

et al. 2022

Journal of Clinical Investigation

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Mice with experimental nerve damage can display long‑lasting neuropathic pain behavior. We show here that 4 months and later after nerve injury, male but not female mice displayed telomere length (TL) reduction and p53‑mediated cellular senescence in the spinal cord, resulting in maintenance of pain and associated with decreased lifespan. Nerve injury increased the number of p53‑positive spinal cord neurons, astrocytes, and microglia, but only in microglia was the increase male‑specific, matching a robust sex specificity of TL reduction in this cell type, which has been previously implicated in male‑specific pain processing. Pain hypersensitivity was reversed by repeated intrathecal administration of a p53‑specific senolytic peptide, only in male mice and only many months after injury. Analysis of UK Biobank data revealed sex-specific relevance of this pathway in humans, featuring male‑specific genetic association of the human p53 locus ( TP53 ) with chronic pain and a male-specific effect of chronic pain on mortality. Our findings demonstrate the existence of a biological mechanism maintaining pain behavior, at least in males, occurring much later than the time span of virtually all extant preclinical studies.

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Section: Resultsmentioning

confidence: 99%

Long-term male-specific chronic pain via telomere- and p53‑mediated spinal cord cellular senescence

Muralidharan¹,

Sotocinal²,

Yousefpour³

et al. 2022

Journal of Clinical Investigation

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“…After the destruction of the BSCB, peripheral immune cells are driven to the lesion site by the various chemokines and cytokines ( 34 , 35 ).These infiltrating peripheral immune cells will release some similar soluble factors, making them be the primary cellular source of these molecules at the lesion site ( 36 ). The first peripheral immune cells to infiltrate the injury site are neutrophils, which reach their peak at about 24h post-SCI ( 30 ).…”

Section: Inflammatory Response After Scimentioning

confidence: 99%

Neuroinflammation and Scarring After Spinal Cord Injury: Therapeutic Roles of MSCs on Inflammation and Glial Scar

Pang

Chen

et al. 2021

Front. Immunol.

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Transected axons are unable to regenerate after spinal cord injury (SCI). Glial scar is thought to be responsible for this failure. Regulating the formation of glial scar post-SCI may contribute to axonal regrow. Over the past few decades, studies have found that the interaction between immune cells at the damaged site results in a robust and persistent inflammatory response. Current therapy strategies focus primarily on the inhibition of subacute and chronic neuroinflammation after the acute inflammatory response was executed. Growing evidences have documented that mesenchymal stem cells (MSCs) engraftment can be served as a promising cell therapy for SCI. Numerous studies have shown that MSCs transplantation can inhibit the excessive glial scar formation as well as inflammatory response, thereby facilitating the anatomical and functional recovery. Here, we will review the effects of inflammatory response and glial scar formation in spinal cord injury and repair. The role of MSCs in regulating neuroinflammation and glial scar formation after SCI will be reviewed as well.

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“…Persistent senescent cells act as a determinant of the organ repair process ( Wyss–Coray, 2016 ). In a previous study, cell senescence was induced in SCI-regenerating zebrafish and SCI-scarred mice ( Paramos-de-Carvalho et al, 2021 ). Although the senescent cells induced in zebrafish were gradually eliminated, they were accumulated in mouse models over time.…”

Section: Discussionmentioning

confidence: 99%

“…Using distinct aging agents, senescent cells in SCI mice were removed and the functions were recovered. The functional recovery was linked with the inhibition of fibrotic scars and inflammatory response ( Paramos-de-Carvalho et al, 2021 ). Consistently, senescent cells were accumulated in the spinal cord of SCI mice.…”

Section: Discussionmentioning

confidence: 99%

Blockage of ERCC6 Alleviates Spinal Cord Injury Through Weakening Apoptosis, Inflammation, Senescence, and Oxidative Stress

Zou

Zhang²,

Zhang³

et al. 2022

Front. Mol. Biosci.

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Objective: Spinal cord injury (SCI) is a devastating disease resulting in lifelong disability, but the molecular mechanism remains unclear. Our study was designed to observe the role of excision repair cross-complementing group 6 (ERCC6) following SCI and to determine the underlying mechanism.Methods: SCI mouse models and LPS-induced microglia cell models were established. ERCC6 expression was blocked by ERCC6-siRNA-carrying lentivirus. Nissl staining was utilized for detecting neuronal damage, and apoptosis was analyzed with TUNEL and Western blotting (apoptotic markers). Immunofluorescence was used for measuring macrophage markers (CD68 and F4/80) and astrocyte and microglia markers (GFAP and Iba-1). Pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) were measured via ELISA. Senescent cells were estimated via SA-β-Gal staining as well as Western blot (senescent markers p21 and p27). Oxidative stress was investigated by detecting the expression of 4-HNE, Nrf2, and Keap1, and intracellular ROS levels.Results: ERCC6 expression was remarkably upregulated both in the spinal cord of SCI mice and LPS-induced microglia cells. ERCC6 deficiency alleviated neuronal damage and apoptosis. Macrophage infiltration and inflammatory response were suppressed by si-ERCC6 treatment. Moreover, ERCC6 blockage ameliorated astrocyte and microglia activation and cell senescence in the damaged spinal cord. Excessive oxidative stress was significantly decreased by ERCC6 knockdown in SCI.Conclusion: Collectively, ERCC6 exerts crucial functions in mediating physiological processes (apoptosis, inflammation, senescence, and oxidative stress), implying that ERCC6 might act as a prospective therapeutic target against SCI.

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Targeting senescent cells improves functional recovery after spinal cord injury

Cited by 50 publications

References 109 publications

Long-term male-specific chronic pain via telomere- and p53‑mediated spinal cord cellular senescence

Long-term male-specific chronic pain via telomere- and p53‑mediated spinal cord cellular senescence

Neuroinflammation and Scarring After Spinal Cord Injury: Therapeutic Roles of MSCs on Inflammation and Glial Scar

Blockage of ERCC6 Alleviates Spinal Cord Injury Through Weakening Apoptosis, Inflammation, Senescence, and Oxidative Stress

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