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CAR T cells targeting uPAR are effective senolytics

ABSTRACT: Cellular senescence is a stress-response program characterized by stable cell cycle arrest and a secretory program that modulates the tissue microenvironment. Physiologically, senescence serves as a potent tumor suppressive mechanism that prevents the expansion of premalignant cells and plays a beneficial role in certain wound healing responses. Pathologically, the aberrant accumulation of senescent cells in response to chronic tissue damage produces an inflammatory milieu that contributes to diseases such as liver and lung fibrosis, atherosclerosis, diabetes and osteoarthritis. Accordingly, experimental approaches to eliminate senescent cells from damaged tissues in mice can ameliorate symptoms of these pathologies and even promote longevity. Here we test the therapeutic concept that chimeric antigen receptor (CAR) T cells targeting senescent cells can serve as effective senolytics. We identify the urokinase plasminogen activator receptor (uPAR) as a cell surface protein that is broadly induced during senescence and demonstrate that uPAR-specific CAR T cells efficiently target senescent cells in vitro and in vivo. Administration of uPAR-targeting CAR T cells improves the survival of mice harboring lung adenocarcinoma cells treated with a senescence inducing drug combination, and eliminates fibrosis in mice treated with carbon tetrachloride or on a non-alcoholic steatohepatitis (NASH)-inducing diet. These results establish the potential of senolytic CAR T therapy for a range of senescence-associated diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE145642 | GEO | 2020/04/18

REPOSITORIES: GEO

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CAR T cells targeting uPAR are effective senolytics

Project description:CAR T cells targeting uPAR are effective senolytics

| PRJNA607785 | ENA

Prophilactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction.

Project description:Senescent cells accumulate in organisms over time as a result of tissue damage and impaired immune surveillance and are thought to contribute to age-related tissue decline1,2. In agreement, genetic ablation studies reveal that elimination of senescent cells from aged tissues can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness3-7. While small-molecule drugs capable of eliminating senescent cells (known as ‘senolytics’) partially replicate these phenotypes, many have uncertain mechanisms of action and all require continuous administration to be effective. As an alternative approach, we previously developed a cell-based senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting uPAR, a cell-surface protein upregulated on senescent cells, and showed these can safely and efficiently eliminate senescent cells in young animals and reverse liver fibrosis8. We now show that uPAR-positive senescent cells accumulate during physiological aging and that they can be safely targeted with senolytic CAR T cells in aged animals. Treatment with anti uPAR CAR T cells ameliorates metabolic dysfunction by improving glucose tolerance and exercise capacity in physiological aging as well as in a model of metabolic syndrome. Importantly, the beneficial effects of senolytic CAR T cells are long lasting; single administration of a low dose is sufficient to achieve long-term therapeutic and preventive effects.

2023-12-08 | GSE243616 | GEO

Umbrella Cells, Bladder Uroepithelial Cells that Exhibit Senescence Features Throughout the Mouse Lifespan, Are Not Depleted by Senolytics

Project description:Lower urinary tract dysfunction (LUTD) increases with aging. Ensuing symptoms including incontinence greatly impact quality of life, isolation, depression, and nursing home admission. The aging bladder is hypothesized to be central to this decline, however, it remains difficult to pinpoint a singular strong driver of aging-related bladder dysfunction. Many molecular and cellular changes occur with aging, contributing to decreased resilience to internal and external stressors, affecting urinary control and exacerbating LUTD. In this study, we examined whether cellular senescence, a cell fate involved in the etiology of most aging diseases, contributes to LUTD. We found that umbrella cells (UCs), luminal barrier uroepithelial cells in the bladder, show senescence features over the mouse lifespan, identifying a novel non-aging related senescent cell population. While these senescent UCs may help maintain the blood-urine barrier, a novel example of beneficial senescence, they could also contribute to the generation of urothelial cancers and LUTD (antagonistic pleiotropy). These senescent UCs were not eliminated by the senolytic combination of Dasatinib and Quercetin, thus ensuring an intact blood-brain barrier when these agents are used in humans. We also tested the effect of a high fat diet and senescent cell transplantation on bladder function and showed that both models cause similar cystometric changes as natural aging in mice, with no effect of senolytics on HFD-induced changes. These findings illustrate the heterogeneity of cellular senescence in varied tissues, highlighting the importance of considering the safety of barrier cells in the bladder and possibly elsewhere during development and testing of future senolytics.

2024-02-01 | GSE247123 | GEO

Clearance of defective muscle stem cells by senolytics reduces the expression of senescence-associated secretory phenotype and restores myogenesis in myotonic dystrophy type 1

Project description:Muscle weakness and atrophy are clinical hallmarks of myotonic dystrophy type 1 (DM1). Muscle stem cells, which contribute to skeletal muscle growth and repair, are also affected in this disease. However, the molecular mechanisms leading to this defective activity and the impact on the disease severity are still elusive. Here, we explored through an unbiased approach the molecular signature leading to myogenic cell defects in DM1. Single cell RNAseq data revealed the presence of a specific subset of DM1 myogenic cells expressing a senescence signature, characterized by the high expression of genes related to senescence-associated secretory phenotype (SASP). This profile was confirmed using different senescence markers in vitro and in situ. Accumulation of intranuclear RNA foci in senescent cells, suggest that RNA-mediated toxicity contribute to senescence induction. High expression of IL-6, a prominent SASP cytokine, in the serum of DM1 patients was identified as a biomarker correlating with muscle weakness and functional capacity limitations. Drug screening revealed that the BCL-XL inhibitor (A1155463), a senolytic drug, can specifically target senescent DM1 myoblasts to induce their apoptosis and reduce their SASP. Removal of senescent cells re-established the myogenic function of the non-senescent DM1 myoblasts, which displayed improved proliferation and differentiation capacity in vitro; and enhanced engraftment following transplantation in vivo. Altogether this study presents a well-defined senescent molecular signature in DM1 untangling part of the pathological mechanisms observed in the disease; additionally, we demonstrate the therapeutic potential of targeting these defective cells with senolytics to restore myogenesis.

2023-05-05 | GSE208360 | GEO

Senolytics rescue blunted muscle hypertrophy in old mice

Project description:With aging, skeletal muscle plasticity is attenuated in response to exercise. Here, we report that senescent cells, identified using senescence markers senescence-associated β-Galactosidase (SA β-Gal) and p21 are very infrequent in resting muscle but emerge approximately two-weeks after a bout of resistance exercise in humans. We hypothesized that these cells contribute to blunted hypertrophic potential in old age. Using synergist ablation-induced mechanical overload of the plantaris muscle to model resistance training in adult (5-6 month) and old (23-24 month) male C57BL/6J mice, we found increased senescent cells in both age groups during hypertrophy. Consistent with the human data, there were negligible senescent cells in adult and old sham controls, but old mice had significantly more senescent cells 7- and 14-days following overload relative to young. Old mice had blunted whole muscle hypertrophy when compared to adult mice, along with smaller muscle fibers, specifically glycolytic Type 2x+2b fibers. To ablate senescent cells using a hit-and-run approach, old mice were treated with vehicle or a senolytic cocktail consisting of 5 mg/kg dasatinib and 50 mg/kg quercetin (D+Q) on day 7 and 10 during 14-days of overload; control mice underwent sham surgery with or without senolytic treatment. Old mice given D+Q had larger muscles and muscle fibers after 14 days of overload, fewer senescent cells when compared to vehicle-treated old mice, and changes in the expression of genes (i.e., Igf1, Ddit4, Mmp14) that are associated with hypertrophic growth . Our data collectively show that senescent cells emerge in human and mouse skeletal muscle following a hypertrophic stimulus, and that D+Q improves muscle growth in old mice.

2022-05-29 | GSE195707 | GEO

Transcriptomic profiling of human stromal cells in mouse xenografts upon treatment with chemotherapeutic drug and/or the senolytic agent procyanidin C1

Project description:Physical function declines in advanced age, portending disability, increased health expenditures, and clinical mortality. Cellular senescence leads to tissue dysfunction and contributes to the consequences of aging, but whether age-related pathologies including cancer can be alleviated by targeting senescent cells remains largely unclear. Long term retention of senescent cells in vivo, a process mainly attributed to high expression of BCL2 family proteins, causes chronical tissue damages mainly through the senescence-associated secretory phenotype (SASP). Indeed, senescent cells can be removed by several strategies, thus preventing appearance of chronic symptoms and prolonging healthspan. Strategies involving senolytics, which eliminate senescent cells by pharmacological actions, are recently emerging as a novel and prominent solution to ameliorate diverse age-related pathologies. Achieving the goal using synthetic or natural agents would generate a tremendous impact on the quality of life. We test the potential of procyanidin C1 (PCC1), a B type procyanidin flavonoid derived from plant sources including grape, apple and cocoa, in targeting senescent cells through inducing apoptosis and suppressing the pro-inflammatory phenotype. This study demonstrates the efficacy of PCC1 in restraining the SASP expression and minimizing the influence of senescent stromal cells in tumor microenvironment and provides a strong rationale for its future development in anti-aging industrial pipelines.

2021-10-04 | GSE178376 | GEO

Nano-encapsulated senolytics cocktail ameliorates germ cell senescence in female mice

Project description:Low-quality oocytes directly affect fertilization and embryo developmental ability, and further contributes to infertility in women. Dasatinib and quercetin, as a senolytics, has been explored extensively in various age-related diseases. Here, we report that nano-encapsulated senolytics cocktail (D+Q) efficaciously ameliorates the the quantity and quality of follicles and oocytes in vitro and in vivo. D+Q cocktail supplementation reduces the level of ROS in aged oocytes, decreases the frequency of fragmentation, maintains the spindle integrity, rescues mislocalized cortical granules, rescues mitochondrial membrane potential and alleviates DNA damage and apoptosis in vitro. Nano-encapsulated D+Q cocktail effectively ameliorates the fertility deficits in the cyclophosphamide-induced primary ovarian failure (POF) mice model. Moreover, RNA sequencing analysis shows that D+Q cocktail improves the fecundity of POF mice by increasing development gene expression and reduces the senescence-associated secretory phenotype (SASP) accumulation. Taken together, our data show that the D+Q cocktail helps to improve assisted reproductive technology and reproductive outcomes in POF.

2024-04-23 | GSE264327 | GEO

RNA seq on NEO2734, CFI-400945 or SASP treated cells

Project description:Senolytics, drugs that kill senescent cells, have been proposed to improve the response to pro-senescence cancer therapies. However, lack of broadly acting senolytic drugs remains a challenge. Using inducible CRISPR/Cas9-based genetic screens in different senescent cancer cell models, we identify here loss of the death receptor inhibitor cFLIP as a universal vulnerability of senescent cancer cells. Senescent cancer cells are primed for apoptotic death by NF-kB-mediated upregulation of death receptor DR5 and its ligand TRAIL but are protected from death by increased cFLIP. Activation of DR5 signaling by agonistic antibody, which can be enhanced further by suppression of cFLIP by BRD2 inhibition, leads to efficient killing of all senescent cancer cells tested. We validate this ?one-two punch? cancer therapy by combining pro-senescence therapy with DR5 activation in different animal models.

2022-08-24 | GSE191255 | GEO

Senescent cell elimination modifies features of Alzheimer’s disease in 3xTg-AD mice

Project description:Cellular senescence has been associated with neurodegenerative disease and clearance of senescent cells using genetic or pharmaceutical strategies (senolytics) has demonstrated beneficial effects in mouse models investigating individual disease etiologies of Alzheimer’s disease (AD). However, it has remained unclear if senescent cell clearance in a mouse model exhibiting both plaque and tau pathologies modifies the disease state (3xTg). Here, we show that treatment with senolytics (ABT263 (navitoclax) or a combination of dasatinib and quercetin (D+Q)) or transgenic removal of p16-expressing cells (via INK-ATTAC) reduced microgliosis and ameliorated both amyloid and tau pathology in 3xTg mice. Using RNA sequencing, we found evidence that synaptic dysfunction and neuroinflammation was attenuated with senescent cell removal. Unfortunately, these beneficial effects were not seen with short-term senolytic treatment in mice with more advanced disease. Overall, our results further corroborate the beneficial effects senescent cell clearance could have on AD and highlight the importance of early intervention for treatment of this debilitating disease.

2024-03-20 | GSE231332 | GEO

Characterization of fibrosis and senescence of human omental peritoneal mesothelial cells

Project description:Primary human omental mesothelial cells from multiple donors in a young (=normal) phase and senescent phase were treated with or without TGF-ß to induce fibrosis. Senescence was induced by up to 9 passages and confirmed by stopped cell division and positive senescence-associated β-galactosidase staining.

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