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Sangfuang N, McCoubrey LE, Awad A, Marzorati M, Ghyselinck J, Verstrepen L, Munck JD, Medts JD, Gaisford S, Basit AW. Effects of senotherapeutics on gut microbiome dysbiosis and intestinal inflammation in Crohn's disease: A pilot study. Transl Res 2025; 278:36-47. [PMID: 39986536 DOI: 10.1016/j.trsl.2025.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 02/18/2025] [Accepted: 02/18/2025] [Indexed: 02/24/2025]
Abstract
Inflammatory Bowel Disease (IBD) is characterized by chronic inflammation in the gastrointestinal tract, and is usually accompanied by dysbiosis in the gut microbiome, a factor that contributes to disease progression. Excessive production of reactive oxygen species (ROS) because of gut microbiome dysbiosis-one of the hallmark features of IBD-promotes chronic inflammation and facilitates the transformation of normal cells into senescent cells. Cellular senescence is associated with the development of various chronic and age-related diseases. We hypothesise that senolytic agents, specifically dasatinib (D) and quercetin (Q), could have a beneficial effect on both the gut microbiome and intestinal cells in IBD. The modulatory effects of a combination of D + Q was assessed in the M-SHIME model with faecal microbiota sourced from Crohn's disease patients. D + Q significantly modulated butyrate and lactate levels in the samples from specific patients. In addition, metabolomic analysis showed that D + Q positively impacted the abundance of anti-inflammatory bacteria while also significantly reducing the several species of pathogenic bacteria. Findings from a Caco-2 cell/THP1 co-culture model of IBD demonstrated that D + Q exerted strong immunomodulatory effects on the gut epithelium, evidenced by reduced NF-kB activity, and lower levels of the pro-inflammatory markers TNF-α, CXCL-10, and MCP-1. Furthermore, D + Q induced the secretion of anti-inflammatory cytokines, including IL-6 and IL-10. However, it should be noted that D + Q also led to the secretion of the pro-inflammatory cytokines IL-8. These findings suggest that D + Q could offer a novel therapeutic approach for advanced IBD management by modulating both the gut microbiome and inflammatory pathways. The results support the potential repurposing of senotherapeutic agents as a strategy for addressing the chronic inflammation central to IBD pathogenesis.
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Affiliation(s)
| | - Laura E McCoubrey
- UCL School of Pharmacy, 29-39 Brunswick Square, London, WC1N 1AX, UK; Now at Drug Product Development, GSK R&D, Ware SG12 0GX, UK
| | - Atheer Awad
- UCL School of Pharmacy, 29-39 Brunswick Square, London, WC1N 1AX, UK; Department of Clinical, Pharmaceutical and Biological Sciences, University of Hertfordshire, College Lane, Hatfield AL10 9AB, UK
| | | | | | | | | | | | - Simon Gaisford
- UCL School of Pharmacy, 29-39 Brunswick Square, London, WC1N 1AX, UK
| | - Abdul W Basit
- UCL School of Pharmacy, 29-39 Brunswick Square, London, WC1N 1AX, UK.
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Andreoli V, Vetere A, Conti V, Gavezzoli M, Berni P, Ramoni R, Basini G, Nardini G, Pelizzone I, Grolli S, Di Ianni F. Mesenchymal stromal cell isolation from pond slider ( Trachemys scripta) adipose tissue obtained during routine neutering: a model for turtle species. Front Vet Sci 2025; 12:1546091. [PMID: 40177670 PMCID: PMC11963382 DOI: 10.3389/fvets.2025.1546091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Accepted: 02/25/2025] [Indexed: 04/05/2025] Open
Abstract
Introduction Mesenchymal stromal cells (MSCs) hold great clinical potential in veterinary regenerative medicine. However, a notable gap exists in the literature regarding the isolation and characterization of these cells in reptiles. The objective of this study was to evaluate the feasibility of isolating adipose tissue-derived mesenchymal stem cells (MSCs) from pond slider (Trachemys scripta) tissue samples collected during routine neutering procedures. Methods Adipose tissue samples were obtained from five animals and processed using an enzymatic procedure. The resulting cell suspension was subsequently cultured at 28°C in a controlled atmosphere with 5% CO2. The cell growth rates were evaluated through direct counting of cells up to passage 7. The colony-forming unit (CFU) capacity of MSCs was evaluated in low-density cell cultures, and the ability of the cells to differentiate into adipogenic, chondrogenic and osteogenic lineages was assessed. The cell phenotype was characterized at the molecular level using reverse transcription-polymerase chain reaction (RT-PCR) and amplicon sequencing, with a focus on markers commonly used for gene expression profiling of mammalian MSCs. Results The cells demonstrated the capacity to differentiate into adipogenic, chondrogenic, and osteogenic lineages. RT-PCR revealed the expression of CD105, CD73, CD44, and CD90, whereas CD34 and HLA-DRA were not expressed. Sequence homology analysis demonstrated that the amplicons matched the sequences reported in the Trachemys scripta whole-genome shotgun sequence. This study represents the first investigation aimed at the isolation, in vitro expansion, and characterization of reptile adipose tissue-derived MSCs. Discussion The results demonstrate the feasibility of isolating MSC-like cells from chelonian adipose tissue and underscore their potential for application in regenerative medicine for both companion reptiles and endangered wild species.
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Affiliation(s)
- Valentina Andreoli
- Department of Veterinary Medical Science, University of Parma, Parma, Italy
| | - Alessandro Vetere
- Department of Veterinary Medical Science, University of Parma, Parma, Italy
| | - Virna Conti
- Department of Veterinary Medical Science, University of Parma, Parma, Italy
| | - Martina Gavezzoli
- Department of Veterinary Medical Science, University of Parma, Parma, Italy
| | - Priscilla Berni
- Department of Veterinary Medical Science, University of Parma, Parma, Italy
| | - Roberto Ramoni
- Department of Veterinary Medical Science, University of Parma, Parma, Italy
| | - Giuseppina Basini
- Department of Veterinary Medical Science, University of Parma, Parma, Italy
| | | | - Igor Pelizzone
- Department of Veterinary Medical Science, University of Parma, Parma, Italy
| | - Stefano Grolli
- Department of Veterinary Medical Science, University of Parma, Parma, Italy
| | - Francesco Di Ianni
- Department of Veterinary Medical Science, University of Parma, Parma, Italy
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Gao X, Hu Y, Zhang Y, Huang Y, Zhang G, Zhang X, Zhou Y, Zhang D. A galactose-tethered tetraphenylethene prodrug mediated apoptosis of senescent cells for osteoporosis treatment. SCIENCE ADVANCES 2025; 11:eadr2833. [PMID: 39970227 PMCID: PMC11838013 DOI: 10.1126/sciadv.adr2833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 01/15/2025] [Indexed: 02/21/2025]
Abstract
Osteoporosis and bone injury healing in elderly patients are major medical challenges, often exacerbated by the accumulation of senescent cells. Herein, we show that TPE-Gal, which contains a tetraphenylethene unit and a galactose moiety, offers a promising molecular therapy designed to light up and eliminate senescent cells through a hydrolysis reaction catalyzed by β-galactosidase, an enzyme overexpressed in senescent cells. The reaction produces TPE-OH, which, in turn, increases reactive oxygen species levels within the senescent cells, leading to noninflammatory apoptosis of senescent cells. This targeted clearance mechanism helps to alleviate osteoporosis symptoms and promotes bone injury healing. Moreover, apoptotic vesicles, which are generated during the process, are partly phagocytosed by macrophages, mimicking physiological metabolic processes. This study opens new avenues for addressing bone health issues through the designed bioclearance of senescent cells, aligning with the body's natural pathways for maintaining homeostasis.
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Affiliation(s)
- Xin Gao
- Department of Prosthodontics, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, Beijing 100081, China
| | - Yichen Hu
- Beijing National Laboratory for Molecular Sciences, CAS Key Laboratories of Organic Solids and Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
- School of Chemical Sciences, University of Chinese Academy of Sciences, Beijing 100190, China
| | - Yingfei Zhang
- Department of Prosthodontics, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, Beijing 100081, China
| | - Yanyan Huang
- Beijing National Laboratory for Molecular Sciences, CAS Key Laboratories of Organic Solids and Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
- School of Chemical Sciences, University of Chinese Academy of Sciences, Beijing 100190, China
| | - Guanxin Zhang
- Beijing National Laboratory for Molecular Sciences, CAS Key Laboratories of Organic Solids and Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
- School of Chemical Sciences, University of Chinese Academy of Sciences, Beijing 100190, China
| | - Xiao Zhang
- Department of Prosthodontics, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, Beijing 100081, China
| | - Yongsheng Zhou
- Department of Prosthodontics, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, Beijing 100081, China
| | - Deqing Zhang
- Beijing National Laboratory for Molecular Sciences, CAS Key Laboratories of Organic Solids and Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
- School of Chemical Sciences, University of Chinese Academy of Sciences, Beijing 100190, China
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Pratsinis H, Mavrogonatou E, Zervou SK, Triantis T, Hiskia A, Kletsas D. Natural Product-Derived Senotherapeutics: Extraction and Biological Evaluation Techniques. Methods Mol Biol 2025; 2906:315-359. [PMID: 40082365 DOI: 10.1007/978-1-0716-4426-3_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2025]
Abstract
Selective targeting of senescent cells has been thus far considered a widespread preventive strategy, as well as a main or adjuvant therapy for age-associated diseases, fueling the research on the discovery of senotherapeutics (i.e., senolytic or senomorphic compounds). Given that until now no single senotherapeutic has been reported to exert a universal anti-senescence action due to the cell- /tissue-, and context-dependent specificity of such compounds, seeking novel selective senotherapeutics remains of great importance. In this chapter, a research strategy that could be followed to screen natural product collections for putative senotherapeutics with enhanced specificity and reduced toxicity is presented, from the extraction of the source material and the isolation and chemical characterization of the compounds of interest to their biological evaluation in vitro and in vivo.
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Affiliation(s)
- Harris Pratsinis
- Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos", Athens, Greece
| | - Eleni Mavrogonatou
- Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos", Athens, Greece
| | - Sevasti-Kiriaki Zervou
- Laboratory of Photo-Catalytic Processes and Environmental Chemistry, Institute of Nanoscience and Nanotechnology, National Centre of Scientific Research "Demokritos", Athens, Greece
| | - Theodoros Triantis
- Laboratory of Photo-Catalytic Processes and Environmental Chemistry, Institute of Nanoscience and Nanotechnology, National Centre of Scientific Research "Demokritos", Athens, Greece
| | - Anastasia Hiskia
- Laboratory of Photo-Catalytic Processes and Environmental Chemistry, Institute of Nanoscience and Nanotechnology, National Centre of Scientific Research "Demokritos", Athens, Greece
| | - Dimitris Kletsas
- Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos", Athens, Greece.
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Im GI. Clinical updates in mesenchymal stromal cell therapy for osteoarthritis treatment. Expert Opin Biol Ther 2025; 25:187-195. [PMID: 39710894 DOI: 10.1080/14712598.2024.2446612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 11/21/2024] [Accepted: 12/19/2024] [Indexed: 12/24/2024]
Abstract
INTRODUCTION Osteoarthritis (OA) is a common chronic musculoskeletal disease with heterogeneous clinical manifestations and variable responses to different treatments. Unfortunately, there is no effective disease modifying therapy at present that can alter the natural course of the disease. Cell therapy based on mesenchymal stromal cells (MSCs) may offer an attractive therapeutic option for OA with their multiple modes of action, particularly immune-regulatory and regenerative capacities. AREAS COVERED In this narrative review, updates on mode of action based on patient's data, factors that can influence the efficacy of MSC treatment, current status in clinical application of MSCs as seen from randomized, controlled OA trials are introduced as well as the author's perspectives in the future of MSCs as OA therapeutics. EXPERT OPINION Symptomatic relief is not sufficient to justify the high cost associated with culture-expanded stem cells. Its advantages and efficacy over simple and low risk/cost modalities should be seriously reevaluated. Also, as the short-term strategy, efforts should be made to lower the cost of MSC therapy. In the future, multiomics technology may help to predict that subgroup of patients who will favorably respond to stem cell treatment, which would enhance the cost effectiveness and therapeutic benefit of MSC therapy.
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Affiliation(s)
- Gun-Il Im
- Department of Orthopedics, Dongguk University Ilsan Hospital, Goyang, Republic of Korea
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Ivan A, Lukinich-Gruia AT, Cristea IM, Pricop MA, Calma CL, Simina AG, Tatu CA, Galuscan A, Păunescu V. Quercetin and Mesenchymal Stem Cell Metabolism: A Comparative Analysis of Young and Senescent States. Molecules 2024; 29:5755. [PMID: 39683913 DOI: 10.3390/molecules29235755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 12/02/2024] [Accepted: 12/05/2024] [Indexed: 12/18/2024] Open
Abstract
Quercetin is a natural flavonoid renowned for its potent antioxidant, anti-inflammatory, anti-diabetic, and antibacterial properties, making it a highly promising candidate for the treatment of various medical conditions. Our current study investigates the influence of quercetin on energy metabolism, fatty acid composition, oxidative stress gene expression, and sirtuin expression in early- and late-stage passages of stem cells derived from human exfoliated deciduous teeth (SHEDs). Mitochondrial respiration was analyzed by measuring oxygen consumption following a 24 h quercetin treatment, while fatty acid profiles were examined using gas chromatography-mass spectrometry (GC-MS). Additionally, quantitative PCR (qPCR) was used to assess the expression of oxidative stress genes and sirtuins. In younger SHEDs, quercetin enhances metabolic activity and mitochondrial respiration, although higher doses may decrease mitochondrial activity. Conversely, in older, senescent SHEDs, quercetin supports mitochondrial function at lower concentrations but appears to inhibit respiration at higher doses. These results suggest that quercetin may hold therapeutic potential for maintaining SHED viability and function, especially at lower doses in older cells. Further research is essential to fully elucidate a dose-dependent effect of quercetin and optimize its applications in regenerative medicine.
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Affiliation(s)
- Alexandra Ivan
- Department of Functional Sciences, Center of Immuno-Physiology (CIFBIOTEH), University of Medicine and Pharmacy "Victor Babes", Eftimie Murgu Sq. No. 2, 300041 Timisoara, Romania
- OncoGen Centre, Clinical County Hospital "Pius Branzeu", Blvd. Liviu Rebreanu 156, 300723 Timisoara, Romania
| | | | - Iustina-Mirabela Cristea
- OncoGen Centre, Clinical County Hospital "Pius Branzeu", Blvd. Liviu Rebreanu 156, 300723 Timisoara, Romania
| | - Maria-Alexandra Pricop
- OncoGen Centre, Clinical County Hospital "Pius Branzeu", Blvd. Liviu Rebreanu 156, 300723 Timisoara, Romania
- Department of Applied Chemistry and Environmental Engineering and Inorganic Compounds, Faculty of Industrial Chemistry, Biotechnology and Environmental Engeneering, Polytechnic University of Timisoara, Vasile Pârvan 6, 300223 Timisoara, Romania
| | - Crenguta Livia Calma
- Department of Functional Sciences, Center of Immuno-Physiology (CIFBIOTEH), University of Medicine and Pharmacy "Victor Babes", Eftimie Murgu Sq. No. 2, 300041 Timisoara, Romania
- OncoGen Centre, Clinical County Hospital "Pius Branzeu", Blvd. Liviu Rebreanu 156, 300723 Timisoara, Romania
| | - Alina-Georgiana Simina
- OncoGen Centre, Clinical County Hospital "Pius Branzeu", Blvd. Liviu Rebreanu 156, 300723 Timisoara, Romania
| | - Călin Adrian Tatu
- Department of Functional Sciences, Center of Immuno-Physiology (CIFBIOTEH), University of Medicine and Pharmacy "Victor Babes", Eftimie Murgu Sq. No. 2, 300041 Timisoara, Romania
- OncoGen Centre, Clinical County Hospital "Pius Branzeu", Blvd. Liviu Rebreanu 156, 300723 Timisoara, Romania
| | - Atena Galuscan
- Translational and Experimental Clinical Research Centre in Oral Health, Department of Preventive, Community Dentistry and Oral Health, "Victor Babes" University of Medicine and Pharmacy, 300040 Timisoara, Romania
- Department I, Department of Preventive, Community Dentistry and Oral Health, "Victor Babes" University of Medicine and Pharmacy, Eftimie Murgu Sq. No. 2, 300041 Timisoara, Romania
| | - Virgil Păunescu
- Department of Functional Sciences, Center of Immuno-Physiology (CIFBIOTEH), University of Medicine and Pharmacy "Victor Babes", Eftimie Murgu Sq. No. 2, 300041 Timisoara, Romania
- OncoGen Centre, Clinical County Hospital "Pius Branzeu", Blvd. Liviu Rebreanu 156, 300723 Timisoara, Romania
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Heinrichs DP, Maldonado VV, Ardana IKK, Porter RM, Samsonraj RM. Assessing the Effects of Dasatinib on Mesenchymal Stem/Stromal Cells. Cell Mol Bioeng 2024; 17:609-618. [PMID: 39926377 PMCID: PMC11799476 DOI: 10.1007/s12195-024-00830-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 10/11/2024] [Indexed: 02/11/2025] Open
Abstract
Introduction Progressive aging, or senescence, of mesenchymal stem/stromal cells (MSCs) is a major obstacle faced when trying to culture potent stem cells for use in therapy. Senescent cells are irreversibly nondividing cells that cease performing critical functional effects. Elimination of senescent cells using biochemical means, such as the use of senolytic drugs like dasatinib, may be useful in retaining the viable and proliferating populations of the cells. Methods An in vitro approach was used to investigate the effect of dasatinib on phenotypic, genotypic, and immunomodulatory functionality of osteogenic and adipogenic differentiated MSCs. Replicative senescence was achieved through multiple sub-culturing in vitro, then senescent and non-senescent cultures were treated with a standard dosage of dasatinib. MSCs were then differentiated into osteogenic, adipogenic or chondrogenic cultures using conditioned media to be tested for the three criteria being investigated. Results Significant changes were observed in these criteria, indicated by evidence gathered from proliferation and indoleamine 2,3 dioxygenase activity assays. Phenotypic results of dasatinib were shown to reduce the population of senescent MSCs while allowing non-senescent MSCs to continue differentiating and proliferating without interference from senescent cells. Genotypic results showed no change to upregulation in markers associated with osteogenic and adipogenic cells when exposed to dasatinib. Indoleamine Dioxygenase activity showed insignificant differences in cells exposed to dasatinib versus control groups, providing evidence against compromised cellular immune function. Conclusion This investigation provides insight into how dasatinib effects MSCs functional ability and provides a better understanding of the function of senolytic agents.
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Affiliation(s)
- David P. Heinrichs
- Department of Biomedical Engineering, Engineering Research Center, College of Engineering, University of Arkansas, 700 W Research Center Boulevard, Fayetteville, AR 72701 USA
| | - Vitali V. Maldonado
- Department of Biomedical Engineering, Engineering Research Center, College of Engineering, University of Arkansas, 700 W Research Center Boulevard, Fayetteville, AR 72701 USA
| | - I. Kade K. Ardana
- Cell and Molecular Biology Interdisciplinary Program, University of Arkansas, Fayetteville, AR 72701 USA
| | - Ryan M. Porter
- Department of Orthopedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR 72205 USA
| | - Rebekah M. Samsonraj
- Department of Biomedical Engineering, Engineering Research Center, College of Engineering, University of Arkansas, 700 W Research Center Boulevard, Fayetteville, AR 72701 USA
- Cell and Molecular Biology Interdisciplinary Program, University of Arkansas, Fayetteville, AR 72701 USA
- Department of Orthopedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR 72205 USA
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Matteini F, Montserrat‐Vazquez S, Florian MC. Rejuvenating aged stem cells: therapeutic strategies to extend health and lifespan. FEBS Lett 2024; 598:2776-2787. [PMID: 38604982 PMCID: PMC11586596 DOI: 10.1002/1873-3468.14865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 02/03/2024] [Accepted: 03/07/2024] [Indexed: 04/13/2024]
Abstract
Aging is associated with a global decline in stem cell function. To date, several strategies have been proposed to rejuvenate aged stem cells: most of these result in functional improvement of the tissue where the stem cells reside, but the impact on the lifespan of the whole organism has been less clearly established. Here, we review some of the most recent work dealing with interventions that improve the regenerative capacity of aged somatic stem cells in mammals and that might have important translational possibilities. Overall, we underscore that somatic stem cell rejuvenation represents a strategy to improve tissue homeostasis upon aging and present some recent approaches with the potential to affect health span and lifespan of the whole organism.
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Affiliation(s)
- Francesca Matteini
- Stem Cell Aging Group, Regenerative Medicine ProgramThe Bellvitge Institute for Biomedical Research (IDIBELL)BarcelonaSpain
- Program for Advancing the Clinical Translation of Regenerative Medicine of Catalonia (P‐CMR[C])BarcelonaSpain
| | - Sara Montserrat‐Vazquez
- Stem Cell Aging Group, Regenerative Medicine ProgramThe Bellvitge Institute for Biomedical Research (IDIBELL)BarcelonaSpain
- Program for Advancing the Clinical Translation of Regenerative Medicine of Catalonia (P‐CMR[C])BarcelonaSpain
| | - M. Carolina Florian
- Stem Cell Aging Group, Regenerative Medicine ProgramThe Bellvitge Institute for Biomedical Research (IDIBELL)BarcelonaSpain
- Program for Advancing the Clinical Translation of Regenerative Medicine of Catalonia (P‐CMR[C])BarcelonaSpain
- Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER‐BBN)MadridSpain
- The Catalan Institution for Research and Advanced Studies (ICREA)BarcelonaSpain
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Amiri F, Mistriotis P. Leveraging Cell Migration Dynamics to Discriminate Between Senescent and Presenescent Human Mesenchymal Stem Cells. Cell Mol Bioeng 2024; 17:385-399. [PMID: 39513008 PMCID: PMC11538215 DOI: 10.1007/s12195-024-00807-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Accepted: 06/11/2024] [Indexed: 11/15/2024] Open
Abstract
Purpose The suboptimal clinical performance of human mesenchymal stem cells (hMSCs) has raised concerns about their therapeutic potential. One major contributing factor to this issue is the heterogeneous nature of hMSCs. Senescent cell accumulation during stem cell expansion is a key driver of MSC heterogeneity. Current methodologies to eradicate senescent hMSCs have either shown limited success or lack clinical relevance. This study leverages the inherent capacity of hMSCs to migrate toward damaged tissues as a means to discern senescent from presenescent stem cells. Given the established deficiency of senescent cells to migrate through physiologically relevant environments, we hypothesized that a microfluidic device, designed to emulate key facets of in vivo cell motility, could serve as a platform for identifying presenescent cells. Methods We employed a Y-shaped microchannel assay, which allows fine-tuning of fluid flow rates and the degree of confinement. Results Highly migratory hMSCs detected by the device not only demonstrate increased speed, smaller size, and higher proliferative capacity but also manifest reduced DNA damage and senescence compared to non-migratory cells. Additionally, this assay detects presenescent cells in experiments with mixed early and late passage cells. The introduction of fluid flow through the device can further increase the fraction of highly motile stem cells, improving the assay's effectiveness to remove senescent hMSCs. Conclusions Collectively, this assay facilitates the detection and isolation of a highly potent stem cell subpopulation. Given the positive correlation between the migratory potential of administered MSCs and the long-term clinical outcome, delivering homogeneous, highly motile presenescent hMSCs may benefit patient outcomes. Supplementary Information The online version contains supplementary material available at 10.1007/s12195-024-00807-0.
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Affiliation(s)
- Farshad Amiri
- Department of Chemical Engineering, Auburn University, Auburn, AL USA
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Cifuentes SJ, Theran-Suarez NA, Rivera-Crespo C, Velez-Roman L, Thacker B, Glass C, Domenech M. Heparan Sulfate-Collagen Surface Multilayers Support Serum-Free Microcarrier Culture of Mesenchymal Stem Cells. ACS Biomater Sci Eng 2024; 10:5739-5751. [PMID: 39187752 DOI: 10.1021/acsbiomaterials.4c01008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/28/2024]
Abstract
The increasing cost of high-volume cultures and dependence on serum and growth factor supplementation limit the affordability of mesenchymal stromal cell (MSC) therapies. This has spurred interest in developing strategies that support adherent cell expansion while reducing raw material costs. Culture surfaces coated with sulfated glycosaminoglycans (GAGs), specifically heparan sulfate (HS), are an alternative to prolong growth factor retention in cell cultures. Unlike heparin, recombinant HS (rHS) offers strong binding affinity for multiple growth factors and extracellular matrix components, such as collagen I, without undesirable anticoagulant effects or xenobiotic health risks. The potential of rHS as a factor reservoir in MSC cultures remains underexplored. This study investigated the impact of rHS on the growth and anti-inflammatory properties of undifferentiated bone marrow MSCs in both planar and microcarrier-based cultures. It was hypothesized that rHS would enable MSC growth with minimal growth factor supplementation in a sulfation level-dependent manner. Cell culture surfaces were assembled via the layer-by-layer (LbL) method, combining alternating collagen I (COL) and rHS. These bilayers support cell adhesion and enable the incorporation of distinct sulfation levels on the culture surface. Examination of pro-mitogenic FGF and immunostimulatory IFN-γ release dynamics confirmed prolonged availability and sulfate level dependencies. Sulfated surfaces supported cell growth in low serum (2% FBS) and serum-free (SF) media at levels equivalent to standard culture conditions. Cell growth on rHS-coated surfaces in SF was comparable to that on heparin-coated surfaces and commercial surface-coated microcarriers in low serum. These growth benefits were observed in both planar and microcarrier (μCs) cultures. Additionally, rHS surfaces reduced β-galactosidase expression relative to uncoated surfaces, delaying cell senescence. Multivariate analysis of cytokines in conditioned media indicated that rHS-containing surfaces enhanced cytokine levels relative to uncoated surfaces during IFN-γ stimulation and correlated with decreased pro-inflammatory macrophage activity. Overall, utilizing highly sulfated rHS with COL reduces the need for exogenous growth factors and effectively supports MSC growth and anti-inflammatory potency on planar and microcarrier surfaces under minimal factor supplementation.
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Affiliation(s)
- Said J Cifuentes
- Bioengineering Graduate Program, University of Puerto Rico Mayaguez, Call Box 9000, Mayaguez, Puerto Rico 00681-9000, United States
- Bioengineering Department, Moffitt Cancer Center, Tampa, Florida 32611, United States
| | - Natalia A Theran-Suarez
- Chemical Engineering Department, University of Puerto Rico Mayaguez, 3550 General Atomics Ct, G02-102, Mayaguez, Puerto Rico 00681-9000, United States
| | - Carolina Rivera-Crespo
- Bioengineering Graduate Program, University of Puerto Rico Mayaguez, Call Box 9000, Mayaguez, Puerto Rico 00681-9000, United States
| | - Leonel Velez-Roman
- Bioengineering Graduate Program, University of Puerto Rico Mayaguez, Call Box 9000, Mayaguez, Puerto Rico 00681-9000, United States
| | - Bryan Thacker
- TEGA Therapeutics, Inc., 3550 General Atomics Ct, G02-102, San Diego, California 92121, United States
| | - Charles Glass
- TEGA Therapeutics, Inc., 3550 General Atomics Ct, G02-102, San Diego, California 92121, United States
| | - Maribella Domenech
- Bioengineering Graduate Program, University of Puerto Rico Mayaguez, Call Box 9000, Mayaguez, Puerto Rico 00681-9000, United States
- Chemical Engineering Department, University of Puerto Rico Mayaguez, 3550 General Atomics Ct, G02-102, Mayaguez, Puerto Rico 00681-9000, United States
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Sun R, Feng J, Wang J. Underlying Mechanisms and Treatment of Cellular Senescence-Induced Biological Barrier Interruption and Related Diseases. Aging Dis 2024; 15:612-639. [PMID: 37450933 PMCID: PMC10917536 DOI: 10.14336/ad.2023.0621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 06/21/2023] [Indexed: 07/18/2023] Open
Abstract
Given its increasing prevalence, aging is of great concern to researchers worldwide. Cellular senescence is a physiological or pathological cellular state caused by aging and a prominent risk factor for the interruption of the integrity and functionality of human biological barriers. Health barriers play an important role in maintaining microenvironmental homeostasis within the body. The senescence of barrier cells leads to barrier dysfunction and age-related diseases. Cellular senescence has been reported to be a key target for the prevention of age-related barrier diseases, including Alzheimer's disease, Parkinson's disease, age-related macular degeneration, diabetic retinopathy, and preeclampsia. Drugs such as metformin, dasatinib, quercetin, BCL-2 inhibitors, and rapamycin have been shown to intervene in cellular senescence and age-related diseases. In this review, we conclude that cellular senescence is involved in age-related biological barrier impairment. We further outline the cellular pathways and mechanisms underlying barrier impairment caused by cellular senescence and describe age-related barrier diseases associated with senescent cells. Finally, we summarize the currently used anti-senescence pharmacological interventions and discuss their therapeutic potential for preventing age-related barrier diseases.
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Affiliation(s)
- Ruize Sun
- Department of Neurology, Shengjing Hospital, Affiliated Hospital of China Medical University, Shenyang, China
| | - Juan Feng
- Department of Neurology, Shengjing Hospital, Affiliated Hospital of China Medical University, Shenyang, China
| | - Jue Wang
- Department of Neurology, Shengjing Hospital, Affiliated Hospital of China Medical University, Shenyang, China
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12
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Rasouli M, Naeimzadeh Y, Hashemi N, Hosseinzadeh S. Age-Related Alterations in Mesenchymal Stem Cell Function: Understanding Mechanisms and Seeking Opportunities to Bypass the Cellular Aging. Curr Stem Cell Res Ther 2024; 19:15-32. [PMID: 36642876 DOI: 10.2174/1574888x18666230113144016] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 10/28/2022] [Accepted: 11/23/2022] [Indexed: 01/17/2023]
Abstract
Undoubtedly, mesenchymal stem cells (MSCs) are the most common cell therapy candidates in clinical research and therapy. They not only exert considerable therapeutic effects to alleviate inflammation and promote regeneration, but also show low-immunogenicity properties, which ensure their safety following allogeneic transplantation. Thanks to the necessity of providing a sufficient number of MSCs to achieve clinically efficient outcomes, prolonged in vitro cultivation is indisputable. However, either following long-term in vitro expansion or aging in elderly individuals, MSCs face cellular senescence. Senescent MSCs undergo an impairment in their function and therapeutic capacities and secrete degenerative factors which negatively affect young MSCs. To this end, designing novel investigations to further elucidate cellular senescence and to pave the way toward finding new strategies to reverse senescence is highly demanded. In this review, we will concisely discuss current progress on the detailed mechanisms of MSC senescence and various inflicted changes following aging in MSC. We will also shed light on the examined strategies underlying monitoring and reversing senescence in MSCs to bypass the comprised therapeutic efficacy of the senescent MSCs.
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Affiliation(s)
- Mehdi Rasouli
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Yasaman Naeimzadeh
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Nader Hashemi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Simzar Hosseinzadeh
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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13
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Biţă A, Scorei IR, Ciocîlteu MV, Nicolaescu OE, Pîrvu AS, Bejenaru LE, Rău G, Bejenaru C, Radu A, Neamţu J, Mogoşanu GD, Benner SA. Nicotinamide Riboside, a Promising Vitamin B 3 Derivative for Healthy Aging and Longevity: Current Research and Perspectives. Molecules 2023; 28:6078. [PMID: 37630330 PMCID: PMC10459282 DOI: 10.3390/molecules28166078] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 08/09/2023] [Accepted: 08/14/2023] [Indexed: 08/27/2023] Open
Abstract
Many studies have suggested that the oxidized form of nicotinamide adenine dinucleotide (NAD+) is involved in an extensive spectrum of human pathologies, including neurodegenerative disorders, cardiomyopathy, obesity, and diabetes. Further, healthy aging and longevity appear to be closely related to NAD+ and its related metabolites, including nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). As a dietary supplement, NR appears to be well tolerated, having better pharmacodynamics and greater potency. Unfortunately, NR is a reactive molecule, often unstable during its manufacturing, transport, and storage. Recently, work related to prebiotic chemistry discovered that NR borate is considerably more stable than NR itself. However, immediately upon consumption, the borate dissociates from the NR borate and is lost in the body through dilution and binding to other species, notably carbohydrates such as fructose and glucose. The NR left behind is expected to behave pharmacologically in ways identical to NR itself. This review provides a comprehensive summary (through Q1 of 2023) of the literature that makes the case for the consumption of NR as a dietary supplement. It then summarizes the challenges of delivering quality NR to consumers using standard synthesis, manufacture, shipping, and storage approaches. It concludes by outlining the advantages of NR borate in these processes.
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Affiliation(s)
- Andrei Biţă
- Department of Pharmacognosy & Phytotherapy, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 2 Petru Rareş Street, 200349 Craiova, Dolj County, Romania; (A.B.); (L.E.B.); (G.D.M.)
- Department of Biochemistry, BioBoron Research Institute, S.C. Natural Research S.R.L., 31B Dunării Street, 207465 Podari, Dolj County, Romania; (M.V.C.); (G.R.); (J.N.)
| | - Ion Romulus Scorei
- Department of Biochemistry, BioBoron Research Institute, S.C. Natural Research S.R.L., 31B Dunării Street, 207465 Podari, Dolj County, Romania; (M.V.C.); (G.R.); (J.N.)
| | - Maria Viorica Ciocîlteu
- Department of Biochemistry, BioBoron Research Institute, S.C. Natural Research S.R.L., 31B Dunării Street, 207465 Podari, Dolj County, Romania; (M.V.C.); (G.R.); (J.N.)
- Department of Analytical Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 2 Petru Rareş Street, 200349 Craiova, Dolj County, Romania
| | - Oana Elena Nicolaescu
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 2 Petru Rareş Street, 200349 Craiova, Dolj County, Romania;
| | - Andreea Silvia Pîrvu
- Department of Biochemistry, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 2 Petru Rareş Street, 200349 Craiova, Dolj County, Romania;
| | - Ludovic Everard Bejenaru
- Department of Pharmacognosy & Phytotherapy, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 2 Petru Rareş Street, 200349 Craiova, Dolj County, Romania; (A.B.); (L.E.B.); (G.D.M.)
| | - Gabriela Rău
- Department of Biochemistry, BioBoron Research Institute, S.C. Natural Research S.R.L., 31B Dunării Street, 207465 Podari, Dolj County, Romania; (M.V.C.); (G.R.); (J.N.)
- Department of Organic Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 2 Petru Rareş Street, 200349 Craiova, Dolj County, Romania
| | - Cornelia Bejenaru
- Department of Pharmaceutical Botany, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 2 Petru Rareş Street, 200349 Craiova, Dolj County, Romania; (C.B.); (A.R.)
| | - Antonia Radu
- Department of Pharmaceutical Botany, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 2 Petru Rareş Street, 200349 Craiova, Dolj County, Romania; (C.B.); (A.R.)
| | - Johny Neamţu
- Department of Biochemistry, BioBoron Research Institute, S.C. Natural Research S.R.L., 31B Dunării Street, 207465 Podari, Dolj County, Romania; (M.V.C.); (G.R.); (J.N.)
- Department of Physics, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 2 Petru Rareş Street, 200349 Craiova, Dolj County, Romania
| | - George Dan Mogoşanu
- Department of Pharmacognosy & Phytotherapy, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 2 Petru Rareş Street, 200349 Craiova, Dolj County, Romania; (A.B.); (L.E.B.); (G.D.M.)
- Department of Biochemistry, BioBoron Research Institute, S.C. Natural Research S.R.L., 31B Dunării Street, 207465 Podari, Dolj County, Romania; (M.V.C.); (G.R.); (J.N.)
| | - Steven A. Benner
- Foundation for Applied Molecular Evolution (FfAME), 13709 Progress Avenue, Room N112, Alachua, FL 32615, USA;
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14
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Lee SS, Vũ TT, Weiss AS, Yeo GC. Stress-induced senescence in mesenchymal stem cells: Triggers, hallmarks, and current rejuvenation approaches. Eur J Cell Biol 2023; 102:151331. [PMID: 37311287 DOI: 10.1016/j.ejcb.2023.151331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 06/04/2023] [Accepted: 06/05/2023] [Indexed: 06/15/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have emerged as promising cell-based therapies in the treatment of degenerative and inflammatory conditions. However, despite accumulating evidence of the breadth of MSC functional potency, their broad clinical translation is hampered by inconsistencies in therapeutic efficacy, which is at least partly due to the phenotypic and functional heterogeneity of MSC populations as they progress towards senescence in vitro. MSC senescence, a natural response to aging and stress, gives rise to altered cellular responses and functional decline. This review describes the key regenerative properties of MSCs; summarises the main triggers, mechanisms, and consequences of MSC senescence; and discusses current cellular and extracellular strategies to delay the onset or progression of senescence, or to rejuvenate biological functions lost to senescence.
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Affiliation(s)
- Sunny Shinchen Lee
- Charles Perkins Centre, The University of Sydney, NSW 2006, Australia; School of Life and Environmental Sciences, The University of Sydney, NSW 2006, Australia
| | - Thu Thuy Vũ
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Viet Nam
| | - Anthony S Weiss
- Charles Perkins Centre, The University of Sydney, NSW 2006, Australia; School of Life and Environmental Sciences, The University of Sydney, NSW 2006, Australia; Sydney Nano Institute, The University of Sydney, NSW 2006, Australia
| | - Giselle C Yeo
- Charles Perkins Centre, The University of Sydney, NSW 2006, Australia; School of Life and Environmental Sciences, The University of Sydney, NSW 2006, Australia.
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15
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Copp G, Robb KP, Viswanathan S. Culture-expanded mesenchymal stromal cell therapy: does it work in knee osteoarthritis? A pathway to clinical success. Cell Mol Immunol 2023; 20:626-650. [PMID: 37095295 PMCID: PMC10229578 DOI: 10.1038/s41423-023-01020-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 03/29/2023] [Indexed: 04/26/2023] Open
Abstract
Osteoarthritis (OA) is a degenerative multifactorial disease with concomitant structural, inflammatory, and metabolic changes that fluctuate in a temporal and patient-specific manner. This complexity has contributed to refractory responses to various treatments. MSCs have shown promise as multimodal therapeutics in mitigating OA symptoms and disease progression. Here, we evaluated 15 randomized controlled clinical trials (RCTs) and 11 nonrandomized RCTs using culture-expanded MSCs in the treatment of knee OA, and we found net positive effects of MSCs on mitigating pain and symptoms (improving function in 12/15 RCTs relative to baseline and in 11/15 RCTs relative to control groups at study endpoints) and on cartilage protection and/or repair (18/21 clinical studies). We examined MSC dose, tissue of origin, and autologous vs. allogeneic origins as well as patient clinical phenotype, endotype, age, sex and level of OA severity as key parameters in parsing MSC clinical effectiveness. The relatively small sample size of 610 patients limited the drawing of definitive conclusions. Nonetheless, we noted trends toward moderate to higher doses of MSCs in select OA patient clinical phenotypes mitigating pain and leading to structural improvements or cartilage preservation. Evidence from preclinical studies is supportive of MSC anti-inflammatory and immunomodulatory effects, but additional investigations on immunomodulatory, chondroprotective and other clinical mechanisms of action are needed. We hypothesize that MSC basal immunomodulatory "fitness" correlates with OA treatment efficacy, but this hypothesis needs to be validated in future studies. We conclude with a roadmap articulating the need to match an OA patient subset defined by molecular endotype and clinical phenotype with basally immunomodulatory "fit" or engineered-to-be-fit-for-OA MSCs in well-designed, data-intensive clinical trials to advance the field.
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Affiliation(s)
- Griffin Copp
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, Toronto, ON, Canada
- Krembil Research Institute, University Health Network, Toronto, ON, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
| | - Kevin P Robb
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, Toronto, ON, Canada
- Krembil Research Institute, University Health Network, Toronto, ON, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
| | - Sowmya Viswanathan
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, Toronto, ON, Canada.
- Krembil Research Institute, University Health Network, Toronto, ON, Canada.
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada.
- Department of Medicine, Division of Hematology, University of Toronto, Toronto, ON, Canada.
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16
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Mesenchymal stromal cell senescence in haematological malignancies. Cancer Metastasis Rev 2023; 42:277-296. [PMID: 36622509 DOI: 10.1007/s10555-022-10069-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 11/17/2022] [Indexed: 01/10/2023]
Abstract
Acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL), and multiple myeloma (MM) are age-related haematological malignancies with defined precursor states termed myelodysplastic syndrome (MDS), monoclonal B-cell lymphocytosis (MBL), and monoclonal gammopathy of undetermined significance (MGUS), respectively. While the progression from asymptomatic precursor states to malignancy is widely considered to be mediated by the accumulation of genetic mutations in neoplastic haematopoietic cell clones, recent studies suggest that intrinsic genetic changes, alone, may be insufficient to drive the progression to overt malignancy. Notably, studies suggest that extrinsic, microenvironmental changes in the bone marrow (BM) may also promote the transition from these precursor states to active disease. There is now enhanced focus on extrinsic, age-related changes in the BM microenvironment that accompany the development of AML, CLL, and MM. One of the most prominent changes associated with ageing is the accumulation of senescent mesenchymal stromal cells within tissues and organs. In comparison with proliferating cells, senescent cells display an altered profile of secreted factors (secretome), termed the senescence-associated-secretory phenotype (SASP), comprising proteases, inflammatory cytokines, and growth factors that may render the local microenvironment favourable for cancer growth. It is well established that BM mesenchymal stromal cells (BM-MSCs) are key regulators of haematopoietic stem cell maintenance and fate determination. Moreover, there is emerging evidence that BM-MSC senescence may contribute to age-related haematopoietic decline and cancer development. This review explores the association between BM-MSC senescence and the development of haematological malignancies, and the functional role of senescent BM-MSCs in the development of these cancers.
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17
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Wong PF, Dharmani M, Ramasamy TS. Senotherapeutics for mesenchymal stem cell senescence and rejuvenation. Drug Discov Today 2023; 28:103424. [PMID: 36332835 DOI: 10.1016/j.drudis.2022.103424] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 10/04/2022] [Accepted: 10/27/2022] [Indexed: 11/06/2022]
Abstract
Mesenchymal stem cells (MSCs) are susceptible to replicative senescence and senescence-associated functional decline, which hampers their use in regenerative medicine. Senotherapeutics are drugs that target cellular senescence through senolytic and senomorphic functions to induce apoptosis and suppress chronic inflammation caused by the senescence-associated secreted phenotype (SASP), respectively. Therefore, senotherapeutics could delay aging-associated degeneration. They could also be used to eliminate senescent MSCs during in vitro expansion or bioprocessing for transplantation. In this review, we discuss the role of senotherapeutics in MSC senescence, rejuvenation, and transplantation, with examples of some tested compounds in vitro. The prospects, challenges, and the way forward in clinical applications of senotherapeutics in cell-based therapeutics are also discussed.
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Affiliation(s)
- Pooi-Fong Wong
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Wilayah Persekutuan Kuala Lumpur, Malaysia
| | - Murugan Dharmani
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Wilayah Persekutuan Kuala Lumpur, Malaysia
| | - Thamil Selvee Ramasamy
- Stem Cell Biology Laboratory, Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, 50603 Wilayah Persekutuan Kuala Lumpur, Malaysia.
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18
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Zamkova MA, Persiyantseva NA, Tatarskiy VV, Shtil AA. Therapy-Induced Tumor Cell Senescence: Mechanisms and Circumvention. BIOCHEMISTRY (MOSCOW) 2023; 88:86-104. [PMID: 37068872 DOI: 10.1134/s000629792301008x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/19/2023]
Abstract
Plasticity of tumor cells (multitude of molecular regulation pathways) allows them to evade cytocidal effects of chemo- and/or radiation therapy. Metabolic adaptation of the surviving cells is based on transcriptional reprogramming. Similarly to the process of natural cell aging, specific features of the survived tumor cells comprise the therapy-induced senescence phenotype. Tumor cells with this phenotype differ from the parental cells since they become less responsive to drugs and form aggressive progeny. Importance of the problem is explained by the general biological significance of transcriptional reprogramming as a mechanism of adaptation to stress, and by the emerging potential of its pharmacological targeting. In this review we analyze the mechanisms of regulation of the therapy-induced tumor cell senescence, as well as new drug combinations aimed to prevent this clinically unfavorable phenomenon.
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Affiliation(s)
- Maria A Zamkova
- Institute of Gene Biology, Russian Academy of Sciences, Moscow, 119334, Russia.
- Blokhin National Medical Research Center of Oncology, Moscow, 115478, Russia
| | - Nadezhda A Persiyantseva
- Institute of Gene Biology, Russian Academy of Sciences, Moscow, 119334, Russia
- Blokhin National Medical Research Center of Oncology, Moscow, 115478, Russia
| | - Victor V Tatarskiy
- Institute of Gene Biology, Russian Academy of Sciences, Moscow, 119334, Russia
| | - Alexander A Shtil
- Blokhin National Medical Research Center of Oncology, Moscow, 115478, Russia
- Institute of Cyber Intelligence Systems, National Research Nuclear University MEPHI, Moscow, 115409, Russia
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19
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Al-Azab M, Safi M, Idiiatullina E, Al-Shaebi F, Zaky MY. Aging of mesenchymal stem cell: machinery, markers, and strategies of fighting. Cell Mol Biol Lett 2022; 27:69. [PMID: 35986247 PMCID: PMC9388978 DOI: 10.1186/s11658-022-00366-0] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 07/18/2022] [Indexed: 02/08/2023] Open
Abstract
Human mesenchymal stem cells (MSCs) are primary multipotent cells capable of differentiating into osteocytes, chondrocytes, and adipocytes when stimulated under appropriate conditions. The role of MSCs in tissue homeostasis, aging-related diseases, and cellular therapy is clinically suggested. As aging is a universal problem that has large socioeconomic effects, an improved understanding of the concepts of aging can direct public policies that reduce its adverse impacts on the healthcare system and humanity. Several studies of aging have been carried out over several years to understand the phenomenon and different factors affecting human aging. A reduced ability of adult stem cell populations to reproduce and regenerate is one of the main contributors to the human aging process. In this context, MSCs senescence is a major challenge in front of cellular therapy advancement. Many factors, ranging from genetic and metabolic pathways to extrinsic factors through various cellular signaling pathways, are involved in regulating the mechanism of MSC senescence. To better understand and reverse cellular senescence, this review highlights the underlying mechanisms and signs of MSC cellular senescence, and discusses the strategies to combat aging and cellular senescence.
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20
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Malavolta M, Giacconi R, Piacenza F, Strizzi S, Cardelli M, Bigossi G, Marcozzi S, Tiano L, Marcheggiani F, Matacchione G, Giuliani A, Olivieri F, Crivellari I, Beltrami AP, Serra A, Demaria M, Provinciali M. Simple Detection of Unstained Live Senescent Cells with Imaging Flow Cytometry. Cells 2022; 11:cells11162506. [PMID: 36010584 PMCID: PMC9406876 DOI: 10.3390/cells11162506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 08/08/2022] [Accepted: 08/10/2022] [Indexed: 01/10/2023] Open
Abstract
Cellular senescence is a hallmark of aging and a promising target for therapeutic approaches. The identification of senescent cells requires multiple biomarkers and complex experimental procedures, resulting in increased variability and reduced sensitivity. Here, we propose a simple and broadly applicable imaging flow cytometry (IFC) method. This method is based on measuring autofluorescence and morphological parameters and on applying recent artificial intelligence (AI) and machine learning (ML) tools. We show that the results of this method are superior to those obtained measuring the classical senescence marker, senescence-associated beta-galactosidase (SA-β-Gal). We provide evidence that this method has the potential for diagnostic or prognostic applications as it was able to detect senescence in cardiac pericytes isolated from the hearts of patients affected by end-stage heart failure. We additionally demonstrate that it can be used to quantify senescence “in vivo” and can be used to evaluate the effects of senolytic compounds. We conclude that this method can be used as a simple and fast senescence assay independently of the origin of the cells and the procedure to induce senescence.
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Affiliation(s)
- Marco Malavolta
- Advanced Technology Center for Aging Research, IRCCS INRCA, 60121 Ancona, Italy
- Correspondence: ; Tel.: +39-0718004116
| | - Robertina Giacconi
- Advanced Technology Center for Aging Research, IRCCS INRCA, 60121 Ancona, Italy
| | - Francesco Piacenza
- Advanced Technology Center for Aging Research, IRCCS INRCA, 60121 Ancona, Italy
| | - Sergio Strizzi
- Advanced Technology Center for Aging Research, IRCCS INRCA, 60121 Ancona, Italy
| | - Maurizio Cardelli
- Advanced Technology Center for Aging Research, IRCCS INRCA, 60121 Ancona, Italy
| | - Giorgia Bigossi
- Advanced Technology Center for Aging Research, IRCCS INRCA, 60121 Ancona, Italy
| | - Serena Marcozzi
- Advanced Technology Center for Aging Research, IRCCS INRCA, 60121 Ancona, Italy
| | - Luca Tiano
- Department of Life and Environmental Sciences, Polytechnical University of Marche, 60121 Ancona, Italy
| | - Fabio Marcheggiani
- Department of Life and Environmental Sciences, Polytechnical University of Marche, 60121 Ancona, Italy
| | - Giulia Matacchione
- Department of Clinical and Molecular Sciences, DISCLIMO, Polytechnical University of Marche, 60121 Ancona, Italy
| | - Angelica Giuliani
- Department of Clinical and Molecular Sciences, DISCLIMO, Polytechnical University of Marche, 60121 Ancona, Italy
| | - Fabiola Olivieri
- Department of Clinical and Molecular Sciences, DISCLIMO, Polytechnical University of Marche, 60121 Ancona, Italy
- Center of Clinical Pathology and Innovative Therapy, IRCCS INRCA, 60121 Ancona, Italy
| | - Ilaria Crivellari
- Department of Medicine (DAME), University of Udine, 33100 Udine, Italy
| | | | - Alessandro Serra
- Luminex B.V., Het Zuiderkruis 1, 5215 MV ‘s-Hertogenbosch, The Netherlands
| | - Marco Demaria
- European Research Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen (UMCG), 9713 AV Groningen, The Netherlands
| | - Mauro Provinciali
- Advanced Technology Center for Aging Research, IRCCS INRCA, 60121 Ancona, Italy
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21
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Miura Y, Endo K, Komori K, Sekiya I. Clearance of senescent cells with ABT-263 improves biological functions of synovial mesenchymal stem cells from osteoarthritis patients. Stem Cell Res Ther 2022; 13:222. [PMID: 35658936 PMCID: PMC9166575 DOI: 10.1186/s13287-022-02901-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 05/14/2022] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Osteoarthritis (OA) is an age-related joint disease characterized by progressive cartilage loss. Synovial mesenchymal stem cells (MSCs) are anticipated as a cell source for OA treatment; however, synovial MSC preparations isolated from OA patients contain many senescent cells that inhibit cartilage regeneration through their senescence-associated secretory phenotype (SASP) and poor chondrogenic capacity. The aim of this study was to improve the biological function of OA synovial MSCs by removing senescent cells using the senolytic drug ABT-263. METHODS We pretreated synovial MSCs derived from 5 OA patients with ABT-263 for 24 h and then evaluated senescence-associated beta-galactosidase (SA-β-gal) activity, B cell lymphoma 2 (BCL-2) activity, apoptosis, surface antigen expression, colony formation ability, and multipotency. RESULTS The ABT-263 pretreatment significantly decreased the percentage of SA-β-gal-positive cells and BCL-2 expression and induced early- and late-stage apoptosis. Cleaved caspase-3 was expressed in SA-β-gal-positive cells. The pretreated MSCs formed greater numbers of colonies with larger diameters. The expression rate of CD34 was decreased in the pretreated cells. Differentiation assays revealed that ABT-263 pretreatment enhanced the adipogenic and chondrogenic capabilities of OA synovial MSCs. In chondrogenesis, the pretreated cells produced greater amounts of glycosaminoglycan and type II collagen and showed lower expression of senescence markers (p16 and p21) and SASP factors (MMP-13 and IL-6) and smaller amounts of type I collagen. CONCLUSION Pretreatment of synovial MSCs from OA patients with ABT-263 can improve the function of the cells by selectively eliminating senescent cells. These findings indicate that ABT-263 could hold promise for the development of effective cell-based OA therapy.
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Affiliation(s)
- Yugo Miura
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Kentaro Endo
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
| | - Keiichiro Komori
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Ichiro Sekiya
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
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22
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Li M, Jiang Y, Hou Q, Zhao Y, Zhong L, Fu X. Potential pre-activation strategies for improving therapeutic efficacy of mesenchymal stem cells: current status and future prospects. Stem Cell Res Ther 2022; 13:146. [PMID: 35379361 PMCID: PMC8981790 DOI: 10.1186/s13287-022-02822-2] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 03/20/2022] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cell (MSC)-based therapy has been considered as a promising approach targeting a variety of intractable diseases due to remarkable multiple effect of MSCs, such as multilineage differentiation, immunomodulatory property, and pro-regenerative capacity. However, poor engraftment, low survival rate of transplanted MSC, and impaired donor-MSC potency under host age/disease result in unsatisfactory therapeutic outcomes. Enhancement strategies, including genetic manipulation, pre-activation, and modification of culture method, have been investigated to generate highly functional MSC, and approaches for MSC pre-activation are highlighted. In this review, we summarized the current approaches of MSC pre-activation and further classified, analysed the scientific principles and main characteristics of these manipulations, and described the pros and cons of individual pre-activation strategies. We also discuss the specialized tactics to solve the challenges in this promising field so that it improves MSC therapeutic functions to serve patients better.
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Affiliation(s)
- Meirong Li
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and 4th Medical Center, PLA General Hospital and PLA Medical College, Beijing, China. .,PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing, China. .,Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences 2019RU051, Beijing, China.
| | - Yufeng Jiang
- Wound Repairing Department, PLA Strategic Support Force Characteristic Medical Center, Beijing, 100101, China
| | - Qian Hou
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and 4th Medical Center, PLA General Hospital and PLA Medical College, Beijing, China.,PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing, China.,Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences 2019RU051, Beijing, China
| | - Yali Zhao
- Central Laboratory, Trauma Treatment Center, Chinese PLA General Hospital, Hainan Hospital, Sanya, China
| | - Lingzhi Zhong
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and 4th Medical Center, PLA General Hospital and PLA Medical College, Beijing, China.,PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing, China.,Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences 2019RU051, Beijing, China
| | - Xiaobing Fu
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and 4th Medical Center, PLA General Hospital and PLA Medical College, Beijing, China. .,PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing, China. .,Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences 2019RU051, Beijing, China.
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23
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Ahmadinejad F, Bos T, Hu B, Britt E, Koblinski J, Souers AJ, Leverson JD, Faber AC, Gewirtz DA, Harada H. Senolytic-Mediated Elimination of Head and Neck Tumor Cells Induced Into Senescence by Cisplatin. Mol Pharmacol 2022; 101:168-180. [PMID: 34907000 PMCID: PMC8969145 DOI: 10.1124/molpharm.121.000354] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 11/25/2021] [Indexed: 01/10/2023] Open
Abstract
Therapeutic outcomes achieved in head and neck squamous cell carcinoma (HNSCC) patients by concurrent cisplatin-based chemoradiotherapy initially reflect both tumor regression and tumor stasis. However, local and distant metastasis and disease relapse are common in HNSCC patients. In the current work, we demonstrate that cisplatin treatment induces senescence in both p53 wild-type HN30 and p53 mutant HN12 head and neck cancer models. We also show that tumor cells can escape from senescence both in vitro and in vivo. We further establish the effectiveness of the senolytic, ABT-263 (Navitoclax), in elimination of senescent tumor cells after cisplatin treatment. Navitoclax increased apoptosis by 3.3-fold (P ≤ 0.05) at day 7 compared with monotherapy by cisplatin. Additionally, we show that ABT-263 interferes with the interaction between B-cell lymphoma-x large (BCL-XL) and BAX, anti- and pro-apoptotic proteins, respectively, followed by BAX activation, suggesting that ABT-263-induced apoptotic cell death is mediated through BAX. Our in vivo studies also confirm senescence induction in tumor cells by cisplatin, and the promotion of apoptosis coupled with a significant delay of tumor growth after sequential treatment with ABT-263. Sequential treatment with cisplatin followed by ABT-263 extended the humane endpoint to ∼130 days compared with cisplatin alone, where mice survived ∼75 days. These results support the premise that senolytic agents could be used to eliminate residual senescent tumor cells after chemotherapy and thereby potentially delay disease recurrence in head and neck cancer patients. SIGNIFICANCE STATEMENT: Disease recurrence is the most common cause of death in head and neck cancer patients. B-cell lymphoma-x large inhibitors such as ABT-263 (Navitoclax) have the capacity to be used in combination with cisplatin in head and neck cancer patients to eliminate senescent cells and possibly prevent disease relapse.
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Affiliation(s)
- Fereshteh Ahmadinejad
- Department of Human and Molecular Genetics, School of Medicine (F.A.), Philips Institute for Oral Health Research, School of Dentistry (T.B., E.B., A.C.F., H.H.), Cancer Mouse Models Core (B.H., J.K.), and Department of Pharmacology and Toxicology, School of Medicine (D.A.G.), Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia; and AbbVie, North Chicago, Illinois (A.J.S., J.D.L.)
| | - Tasia Bos
- Department of Human and Molecular Genetics, School of Medicine (F.A.), Philips Institute for Oral Health Research, School of Dentistry (T.B., E.B., A.C.F., H.H.), Cancer Mouse Models Core (B.H., J.K.), and Department of Pharmacology and Toxicology, School of Medicine (D.A.G.), Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia; and AbbVie, North Chicago, Illinois (A.J.S., J.D.L.)
| | - Bin Hu
- Department of Human and Molecular Genetics, School of Medicine (F.A.), Philips Institute for Oral Health Research, School of Dentistry (T.B., E.B., A.C.F., H.H.), Cancer Mouse Models Core (B.H., J.K.), and Department of Pharmacology and Toxicology, School of Medicine (D.A.G.), Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia; and AbbVie, North Chicago, Illinois (A.J.S., J.D.L.)
| | - Erin Britt
- Department of Human and Molecular Genetics, School of Medicine (F.A.), Philips Institute for Oral Health Research, School of Dentistry (T.B., E.B., A.C.F., H.H.), Cancer Mouse Models Core (B.H., J.K.), and Department of Pharmacology and Toxicology, School of Medicine (D.A.G.), Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia; and AbbVie, North Chicago, Illinois (A.J.S., J.D.L.)
| | - Jennifer Koblinski
- Department of Human and Molecular Genetics, School of Medicine (F.A.), Philips Institute for Oral Health Research, School of Dentistry (T.B., E.B., A.C.F., H.H.), Cancer Mouse Models Core (B.H., J.K.), and Department of Pharmacology and Toxicology, School of Medicine (D.A.G.), Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia; and AbbVie, North Chicago, Illinois (A.J.S., J.D.L.)
| | - Andrew J Souers
- Department of Human and Molecular Genetics, School of Medicine (F.A.), Philips Institute for Oral Health Research, School of Dentistry (T.B., E.B., A.C.F., H.H.), Cancer Mouse Models Core (B.H., J.K.), and Department of Pharmacology and Toxicology, School of Medicine (D.A.G.), Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia; and AbbVie, North Chicago, Illinois (A.J.S., J.D.L.)
| | - Joel D Leverson
- Department of Human and Molecular Genetics, School of Medicine (F.A.), Philips Institute for Oral Health Research, School of Dentistry (T.B., E.B., A.C.F., H.H.), Cancer Mouse Models Core (B.H., J.K.), and Department of Pharmacology and Toxicology, School of Medicine (D.A.G.), Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia; and AbbVie, North Chicago, Illinois (A.J.S., J.D.L.)
| | - Anthony C Faber
- Department of Human and Molecular Genetics, School of Medicine (F.A.), Philips Institute for Oral Health Research, School of Dentistry (T.B., E.B., A.C.F., H.H.), Cancer Mouse Models Core (B.H., J.K.), and Department of Pharmacology and Toxicology, School of Medicine (D.A.G.), Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia; and AbbVie, North Chicago, Illinois (A.J.S., J.D.L.)
| | - David A Gewirtz
- Department of Human and Molecular Genetics, School of Medicine (F.A.), Philips Institute for Oral Health Research, School of Dentistry (T.B., E.B., A.C.F., H.H.), Cancer Mouse Models Core (B.H., J.K.), and Department of Pharmacology and Toxicology, School of Medicine (D.A.G.), Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia; and AbbVie, North Chicago, Illinois (A.J.S., J.D.L.)
| | - Hisashi Harada
- Department of Human and Molecular Genetics, School of Medicine (F.A.), Philips Institute for Oral Health Research, School of Dentistry (T.B., E.B., A.C.F., H.H.), Cancer Mouse Models Core (B.H., J.K.), and Department of Pharmacology and Toxicology, School of Medicine (D.A.G.), Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia; and AbbVie, North Chicago, Illinois (A.J.S., J.D.L.)
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24
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Föger-Samwald U, Kerschan-Schindl K, Butylina M, Pietschmann P. Age Related Osteoporosis: Targeting Cellular Senescence. Int J Mol Sci 2022; 23:ijms23052701. [PMID: 35269841 PMCID: PMC8910503 DOI: 10.3390/ijms23052701] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 02/25/2022] [Accepted: 02/25/2022] [Indexed: 12/14/2022] Open
Abstract
Age-related chronic diseases are an enormous burden to modern societies worldwide. Among these, osteoporosis, a condition that predisposes individuals to an increased risk of fractures, substantially contributes to increased mortality and health-care costs in elderly. It is now well accepted that advanced chronical age is one of the main risk factors for chronical diseases. Hence, targeting fundamental aging mechanisms such as senescence has become a promising option in the treatment of these diseases. Moreover, for osteoporosis, the main pathophysiological concepts arise from menopause causing estrogen deficiency, and from aging. Here, we focus on recent advances in the understanding of senescence-related mechanisms contributing to age-related bone loss. Furthermore, treatment options for senile osteoporosis targeting senescent cells are reviewed.
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Affiliation(s)
- Ursula Föger-Samwald
- Medical Science and Human Medicine Study Programme, Karl Landsteiner University of Health Sciences, 3500 Krems an der Donau, Austria
- Correspondence:
| | | | - Maria Butylina
- Department of Pathophysiology and Allergy Research, Medical University of Vienna, 1090 Vienna, Austria; (M.B.); (P.P.)
| | - Peter Pietschmann
- Department of Pathophysiology and Allergy Research, Medical University of Vienna, 1090 Vienna, Austria; (M.B.); (P.P.)
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25
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Woo J, Shin S, Cho E, Ryu D, Garandeau D, Chajra H, Fréchet M, Park D, Jung E. Senotherapeutic-like effect of Silybum marianum flower extract revealed on human skin cells. PLoS One 2021; 16:e0260545. [PMID: 34914725 PMCID: PMC8675675 DOI: 10.1371/journal.pone.0260545] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 11/11/2021] [Indexed: 12/11/2022] Open
Abstract
Cellular senescence causes irreversible growth arrest of cells. Prolonged accumulation of senescent cells in tissues leads to increased detrimental effects due to senescence associated secretory phenotype (SASP). Recent findings suggest that elimination of senescent cells has a beneficial effect on organismal aging and lifespan. In this study, using a validated replicative senescent human dermal fibroblasts (HDFs) model, we showed that elimination of senescent cells is possible through the activation of an apoptotic mechanism. We have shown in this replicative senescence model, that cell senescence is associated with DNA damage and cell cycle arrest (p21, p53 markers). We have shown that Silybum marianum flower extract (SMFE) is a safe and selective senolytic agent targeting only senescent cells. The elimination of the cells is induced through the activation of apoptotic pathway confirmed by annexin V/propidium iodide and caspase-3/PARP staining. Moreover, SMFE suppresses the expression of SASP factors such as IL-6 and MMP-1 in senescent HDFs. In a co-culture model of senescent and young fibroblasts, we demonstrated that senescent cells impaired the proliferative capacities of young cells. Interestingly, when the co-culture is treated with SMFE, the cell proliferation rate of young cells is increased due to the decrease of the senescent burden. Moreover, we demonstrated in vitro that senescent fibroblasts trigger senescent process in normal keratinocytes through a paracrine effect. Indeed, the conditioned medium of senescent HDFs treated with SMFE reduced the level of senescence-associated beta-galactosidase (SA-β-Gal), p16INK4A and SASP factors in keratinocytes compared with CM of senescent HDFs. These results indicate that SMFE can prevent premature aging due to senescence and even reprograms aged skin. Indeed, thanks to its senolytic and senomorphic properties SMFE is a candidate for anti-senescence strategies.
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Affiliation(s)
- Jieun Woo
- BioSpectrum Life Science Institute, Yongin-si, Gyeonggi-do, Republic of Korea
| | - Seoungwoo Shin
- BioSpectrum Life Science Institute, Yongin-si, Gyeonggi-do, Republic of Korea
| | - Eunae Cho
- BioSpectrum Life Science Institute, Yongin-si, Gyeonggi-do, Republic of Korea
| | - Dehun Ryu
- BioSpectrum Life Science Institute, Yongin-si, Gyeonggi-do, Republic of Korea
| | | | | | | | - Deokhoon Park
- BioSpectrum Life Science Institute, Yongin-si, Gyeonggi-do, Republic of Korea
| | - Eunsun Jung
- BioSpectrum Life Science Institute, Yongin-si, Gyeonggi-do, Republic of Korea
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26
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Tumorigenic Aspects of MSC Senescence-Implication in Cancer Development and Therapy. J Pers Med 2021; 11:jpm11111133. [PMID: 34834485 PMCID: PMC8618265 DOI: 10.3390/jpm11111133] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 10/28/2021] [Accepted: 10/29/2021] [Indexed: 12/13/2022] Open
Abstract
As an organism ages, many physiological processes change, including the immune system. This process, called immunosenescence, characterized by abnormal activation and imbalance of innate and adaptive immunity, leads to a state of chronic low-grade systemic inflammation, termed inflammaging. Aging and inflammaging are considered to be the root of many diseases of the elderly, as infections, autoimmune and chronic inflammatory diseases, degenerative diseases, and cancer. The role of mesenchymal stromal/stem cells (MSCs) in the inflammaging process and the age-related diseases is not completely established, although numerous features of aging MSCs, including altered immunomodulatory properties, impeded MSC niche supporting functions, and senescent MSC secretory repertoire are consistent with inflammaging development. Although senescence has its physiological function and can represent a mechanism of tumor prevention, in most cases it eventually transforms into a deleterious (para-)inflammatory process that promotes tumor growth. In this review we are going through current literature, trying to explore the role of senescent MSCs in making and/or sustaining a microenvironment permissive to tumor development and to analyze the therapeutic options that could target this process.
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27
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Doolittle ML, Monroe DG, Farr JN, Khosla S. The role of senolytics in osteoporosis and other skeletal pathologies. Mech Ageing Dev 2021; 199:111565. [PMID: 34499959 DOI: 10.1016/j.mad.2021.111565] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/20/2021] [Accepted: 09/03/2021] [Indexed: 11/26/2022]
Abstract
The skeletal system undergoes irreversible structural deterioration with aging, leading to increased fracture risk and detrimental changes in mobility, posture, and gait. This state of low bone mass and microarchitectural changes, diagnosed as osteoporosis, affects millions of individuals worldwide and has high clinical and economic burdens. Recently, pre-clinical studies have linked the onset of age-related bone loss with an accumulation of senescent cells in the bone microenvironment. These senescent cells appear to be causal to age-related bone loss, as targeted clearance of these cells leads to improved bone mass and microarchitecture in old mice. Additionally, other pathologies leading to bone loss that result from DNA damage, such as cancer treatments, have shown improvements after clearance of senescent cells. The development of new therapies that clear senescent cells, termed "senolytics", is currently underway and may allow for the modulation of bone loss that results from states of high senescent cell burden, such as aging.
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Affiliation(s)
- Madison L Doolittle
- Kogod Center on Aging and Division of Endocrinology and Metabolism, Mayo Clinic, Rochester, MN, 55905, United States
| | - David G Monroe
- Kogod Center on Aging and Division of Endocrinology and Metabolism, Mayo Clinic, Rochester, MN, 55905, United States
| | - Joshua N Farr
- Kogod Center on Aging and Division of Endocrinology and Metabolism, Mayo Clinic, Rochester, MN, 55905, United States
| | - Sundeep Khosla
- Kogod Center on Aging and Division of Endocrinology and Metabolism, Mayo Clinic, Rochester, MN, 55905, United States.
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28
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Opportunities and Challenges in Stem Cell Aging. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1341:143-175. [PMID: 33748933 DOI: 10.1007/5584_2021_624] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Studying aging, as a physiological process that can cause various pathological phenotypes, has attracted lots of attention due to its increasing burden and prevalence. Therefore, understanding its mechanism to find novel therapeutic alternatives for age-related disorders such as neurodegenerative and cardiovascular diseases is essential. Stem cell senescence plays an important role in aging. In the context of the underlying pathways, mitochondrial dysfunction, epigenetic and genetic alterations, and other mechanisms have been studied and as a consequence, several rejuvenation strategies targeting these mechanisms like pharmaceutical interventions, genetic modification, and cellular reprogramming have been proposed. On the other hand, since stem cells have great potential for disease modeling, they have been useful for representing aging and its associated disorders. Accordingly, the main mechanisms of senescence in stem cells and promising ways of rejuvenation, along with some examples of stem cell models for aging are introduced and discussed. This review aims to prepare a comprehensive summary of the findings by focusing on the most recent ones to shine a light on this area of research.
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29
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Ngoi NY, Liew AQ, Chong SJF, Davids MS, Clement MV, Pervaiz S. The redox-senescence axis and its therapeutic targeting. Redox Biol 2021; 45:102032. [PMID: 34147844 PMCID: PMC8220395 DOI: 10.1016/j.redox.2021.102032] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 05/26/2021] [Accepted: 05/28/2021] [Indexed: 12/14/2022] Open
Abstract
Significance Cellular growth arrest, associated with ‘senescence’, helps to safeguard against the accumulation of DNA damage which is often recognized as the underlying mechanism of a wide variety of age-related pathologies including cancer. Cellular senescence has also been described as a ‘double-edged sword’. In cancer, for example, the creation of an immune-suppressive milieu by senescent tumor cells through the senescence-associated secretory phenotype contributes toward carcinogenesis and cancer progression. Recent advances The potential for cellular senescence to confer multi-faceted effects on tissue fate has led to a rejuvenated interest in its landscape and targeting. Interestingly, redox pathways have been described as both triggers and propagators of cellular senescence, leading to intricate cross-links between both pathways. Critical issues In this review, we describe the mechanisms driving cellular senescence, the interface with cellular redox metabolism as well as the role that chemotherapy-induced senescence plays in secondary carcinogenesis. Notably, the role that anti-apoptotic proteins of the Bcl-2 family play in inducing drug resistance via mechanisms that involve senescence induction. Future directions Though the therapeutic targeting of senescent cells as cancer therapy remains in its infancy, we summarize the current development of senotherapeutics, including recognized senotherapies, as well as the repurposing of drugs as senomorphic/senolytic candidates.
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Affiliation(s)
- Natalie Yl Ngoi
- Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore
| | - Angeline Qx Liew
- Integrative Science and Engineering Programme (ISEP), NUS Graduate School (NUSGS), National University of Singapore, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Stephen J F Chong
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Matthew S Davids
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Marie-Veronique Clement
- Integrative Science and Engineering Programme (ISEP), NUS Graduate School (NUSGS), National University of Singapore, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; NUS Medicine Healthy Longevity Program, National University of Singapore, Singapore
| | - Shazib Pervaiz
- Integrative Science and Engineering Programme (ISEP), NUS Graduate School (NUSGS), National University of Singapore, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; NUS Medicine Healthy Longevity Program, National University of Singapore, Singapore; NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore; National University Cancer Institute, National University Health System, Singapore; Faculté de Medicine, University of Paris, Paris, France.
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30
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Zhang Y, Tang LH, Lu J, Xu LM, Cheng BL, Xiong JY. ABT-263 enhanced bacterial phagocytosis of macrophages in aged mouse through Beclin-1-dependent autophagy. BMC Geriatr 2021; 21:225. [PMID: 33794800 PMCID: PMC8017763 DOI: 10.1186/s12877-021-02173-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 03/23/2021] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND Sepsis is a critical challenge for the older adults as the immune function is less responsive by aging. Although cell numbers seem preserved in the older adults, macrophages present age-related function decline, which including reduced chemokines, phagocytosis, and autophagy. ABT-263, an inhibitor of the anti-apoptotic protein Bcl-2, is reported had a senolytic effect which can selectively clear the senescent cells in vivo and rejuvenate the aged tissues. METHODS We treated the aged (12-16 months) and young (4-6 months) C57BL/6 mouse with ABT-263, then gave the animals cecal slurry injection to induce sepsis to observe the effect of senolytic compound ABT-263 on the survival rate of sepsis. Additionally, we isolated peritoneal macrophages from the aged mouse to investigate the cell function and molecular mechanism. 3-methyladenine (3-MA), a phosphatidylinositol 3-kinases (PI3K) inhibitor, and rapamycin, an autophagy-enhancer, were used to block or mimic the autophagy, respectively. RT-PCR and Western Blot were used to detect autophagy related gene and protein changes in sepsis. EGFP-expressing E. coli was used as a marker to evaluate the phagocytic ability of macrophages. RESULTS The results showed ABT-263 treatment improved the survival rate of sepsis in the aged mouse which related to autophagy, while blocking the autophagy can eliminate this effect. It is revealed that ABT-263 enhanced the phagocytic ability of the peritoneal macrophages by increasing the Trem-2 receptor. Additionally, ABT-263 blocked the binding of Bcl-2 to Beclin-1, thus induced Beclin-1-dependent autophagy. CONCLUSION ABT-263 enhanced the macrophage function in aged mouse by increasing the Trem-2 receptors and inducing a beclin-1-dependent autophagy, consequently, protected the aged mouse from sepsis.
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Affiliation(s)
- Yu Zhang
- Department of Anesthesiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Li-Hua Tang
- Department of Anesthesiology, The Second Hospital of Dalian Medical University, 467 Zhongshan Road, Dalian, ZIP: 116027, Liaoning, China
| | - Jia Lu
- Department of Anesthesiology, The Second Hospital of Dalian Medical University, 467 Zhongshan Road, Dalian, ZIP: 116027, Liaoning, China
| | - Li-Ming Xu
- Research Center, The Second Hospital of Dalian Medical University, Dalian, China
| | - Bao-Li Cheng
- Department of Anesthesiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jun-Yu Xiong
- Department of Anesthesiology, The Second Hospital of Dalian Medical University, 467 Zhongshan Road, Dalian, ZIP: 116027, Liaoning, China.
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31
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Rothmiller S, Jäger N, Meier N, Meyer T, Neu A, Steinritz D, Thiermann H, Scherer M, Rummel C, Mangerich A, Bürkle A, Schmidt A. Chronic senescent human mesenchymal stem cells as possible contributor to the wound healing disorder after exposure to the alkylating agent sulfur mustard. Arch Toxicol 2021; 95:727-747. [PMID: 33491125 PMCID: PMC7870771 DOI: 10.1007/s00204-020-02946-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 10/28/2020] [Indexed: 12/25/2022]
Abstract
Wound healing is a complex process, and disturbance of even a single mechanism can result in chronic ulcers developing after exposure to the alkylating agent sulfur mustard (SM). A possible contributor may be SM-induced chronic senescent mesenchymal stem cells (MSCs), unable to fulfil their regenerative role, by persisting over long time periods and creating a proinflammatory microenvironment. Here we show that senescence induction in human bone marrow derived MSCs was time- and concentration-dependent, and chronic senescence could be verified 3 weeks after exposure to between 10 and 40 µM SM. Morphological changes, reduced clonogenic and migration potential, longer scratch closure times, differences in senescence, motility and DNA damage response associated genes as well as increased levels of proinflammatory cytokines were revealed. Selective removal of these cells by senolytic drugs, in which ABT-263 showed initial potential in vitro, opens the possibility for an innovative treatment strategy for chronic wounds, but also tumors and age-related diseases.
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Affiliation(s)
- Simone Rothmiller
- Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstraße 11, 80937, Munich, Germany
- Molecular Toxicology Group, Department of Biology, University of Konstanz, 78457, Konstanz, Germany
| | - Niklas Jäger
- Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstraße 11, 80937, Munich, Germany
| | - Nicole Meier
- Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstraße 11, 80937, Munich, Germany
| | - Thimo Meyer
- Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstraße 11, 80937, Munich, Germany
| | - Adrian Neu
- Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstraße 11, 80937, Munich, Germany
| | - Dirk Steinritz
- Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstraße 11, 80937, Munich, Germany
- Walther-Straub-Institute of Pharmacology and Toxicology, University of Munich, Goethestr. 33, 80336, Munich, Germany
| | - Horst Thiermann
- Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstraße 11, 80937, Munich, Germany
| | - Michael Scherer
- Department of Traumatology and Orthopedics, HELIOS Amper Clinics, Krankenhausstraße 15, 85221, Dachau, Germany
| | - Christoph Rummel
- Department of Orthopedics and Sports Medicine, Wolfart Clinic, Waldstraße 7, 82166, Gräfelfing, Germany
| | - Aswin Mangerich
- Molecular Toxicology Group, Department of Biology, University of Konstanz, 78457, Konstanz, Germany
| | - Alexander Bürkle
- Molecular Toxicology Group, Department of Biology, University of Konstanz, 78457, Konstanz, Germany
| | - Annette Schmidt
- Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstraße 11, 80937, Munich, Germany.
- Faculty of Human Sciences, Institute for Sports Sciences, Universität Der Bundeswehr München, Werner-Heisenberg-Weg 39, 85577, Neubiberg, Germany.
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Deryabin PI, Shatrova AN, Borodkina AV. Apoptosis resistance of senescent cells is an intrinsic barrier for senolysis induced by cardiac glycosides. Cell Mol Life Sci 2021; 78:7757-7776. [PMID: 34714358 PMCID: PMC8629786 DOI: 10.1007/s00018-021-03980-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 09/24/2021] [Accepted: 10/13/2021] [Indexed: 01/10/2023]
Abstract
Targeted elimination of senescent cells, senolysis, is one of the core trends in the anti-aging therapy. Cardiac glycosides were recently proved to be a broad-spectrum senolytics. Here we tested senolytic properties of cardiac glycosides towards human mesenchymal stem cells (hMSCs). Cardiac glycosides had no senolytic ability towards senescent hMSCs of various origins. Using biological and bioinformatic approaches we compared senescence development in 'cardiac glycosides-sensitive' A549 and '-insensitive' hMSCs. The absence of senolysis was found to be mediated by the effective potassium import and increased apoptosis resistance in senescent hMSCs. Weakening "antiapoptotic defense" predisposes hMSCs to senolysis. We revealed that apoptosis resistance, previously recognized as a common characteristic of senescence, in fact, is not a general feature of senescent cells. Moreover, only apoptosis-prone senescent cells are sensitive to cardiac glycosides-induced senolysis. Thus, we can speculate that the effectiveness of senolysis might depend on whether senescent cells indeed become apoptosis-resistant as compared to their proliferating counterparts.
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Affiliation(s)
- Pavel I. Deryabin
- grid.418947.70000 0000 9629 3848Mechanisms of Cellular Senescence Group, Institute of Cytology of the Russian Academy of Sciences, Tikhoretsky Ave. 4, 194064 Saint Petersburg, Russia
| | - Alla N. Shatrova
- grid.418947.70000 0000 9629 3848Laboratory of Intracellular Membranes Dynamic, Institute of Cytology of the Russian Academy of Sciences, Tikhoretsky Ave. 4, 194064 Saint Petersburg, Russia
| | - Aleksandra V. Borodkina
- grid.418947.70000 0000 9629 3848Mechanisms of Cellular Senescence Group, Institute of Cytology of the Russian Academy of Sciences, Tikhoretsky Ave. 4, 194064 Saint Petersburg, Russia
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Hancox Z, Heidari Keshel S, Yousaf S, Saeinasab M, Shahbazi MA, Sefat F. The progress in corneal translational medicine. Biomater Sci 2020; 8:6469-6504. [PMID: 33174878 DOI: 10.1039/d0bm01209b] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cornea tissue is in high demand by tissue donation centres globally, and thus tissue engineering cornea, which is the main topic of corneal translational medicine, can serve as a limitless alternative to a donated human cornea tissue. Tissue engineering aims to produce solutions to the challenges associated with conventional cornea tissue, including transplantation and use of human amniotic membrane (HAM), which have issues with storage and immune rejection in patients. Accordingly, by carefully selecting biomaterials and fabrication methods to produce these therapeutic tissues, the demand for cornea tissue can be met, with an improved healing outcome for recipients with less associated harmful risks. In this review paper, we aim to present the recent advancements in the research and clinical applications of cornea tissue, applications including biomaterial selection, fabrication methods, scaffold structure, cellular response to these scaffolds, and future advancements of these techniques.
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Affiliation(s)
- Zoe Hancox
- Department of Biomedical and Electronics Engineering, School of Engineering, University of Bradford, Bradford, UK.
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Abruzzo PM, Canaider S, Pizzuti V, Pampanella L, Casadei R, Facchin F, Ventura C. Herb-Derived Products: Natural Tools to Delay and Counteract Stem Cell Senescence. Stem Cells Int 2020; 2020:8827038. [PMID: 33101419 PMCID: PMC7568162 DOI: 10.1155/2020/8827038] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 09/14/2020] [Accepted: 09/15/2020] [Indexed: 12/13/2022] Open
Abstract
Cellular senescence plays a very important role in organismal aging increasing with age and in age-related diseases (ARDs). This process involves physiological, structural, biochemical, and molecular changes of cells, leading to a characteristic trait referred to "senescence-associated secretory phenotype (SASP)." In particular, with aging, stem cells (SCs) in situ exhibit a diminished capacity of self-renewal and show a decline in their functionality. The identification of interventions able to prevent the accumulation of senescent SCs in the organism or to pretreat cultured multipotent mesenchymal stromal cells (MSCs) prior to employing them for cell therapy is a main purpose of medical research. Many approaches have been investigated and resulted effective to prevent or counteract SC senescence in humans, as well as other animal models. In this work, we have reviewed the chance of using a number of herb-derived products as novel tools in the treatment of cell senescence, highlighting the efficacy of these agents, often still far from being clearly understood.
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Affiliation(s)
- Provvidenza M. Abruzzo
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Silvia Canaider
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
- National Laboratory of Molecular Biology and Stem Cell Bioengineering-Eldor Lab, National Institute of Biostructures and Biosystems (NIBB), Innovation Accelerator, CNR, Via Piero Gobetti 101, 40129 Bologna, Italy
| | - Valeria Pizzuti
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Luca Pampanella
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Raffaella Casadei
- Department for Life Quality Studies (QuVi), University of Bologna, Corso D'Augusto 237, 47921 Rimini, Italy
| | - Federica Facchin
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
- National Laboratory of Molecular Biology and Stem Cell Bioengineering-Eldor Lab, National Institute of Biostructures and Biosystems (NIBB), Innovation Accelerator, CNR, Via Piero Gobetti 101, 40129 Bologna, Italy
| | - Carlo Ventura
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
- National Laboratory of Molecular Biology and Stem Cell Bioengineering-Eldor Lab, National Institute of Biostructures and Biosystems (NIBB), Innovation Accelerator, CNR, Via Piero Gobetti 101, 40129 Bologna, Italy
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Saleh T, Carpenter VJ, Tyutyunyk‐Massey L, Murray G, Leverson JD, Souers AJ, Alotaibi MR, Faber AC, Reed J, Harada H, Gewirtz DA. Clearance of therapy-induced senescent tumor cells by the senolytic ABT-263 via interference with BCL-X L -BAX interaction. Mol Oncol 2020; 14:2504-2519. [PMID: 32652830 PMCID: PMC7530780 DOI: 10.1002/1878-0261.12761] [Citation(s) in RCA: 108] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 06/11/2020] [Accepted: 07/07/2020] [Indexed: 01/14/2023] Open
Abstract
Tumor cells undergo senescence in response to both conventional and targeted cancer therapies. The induction of senescence in response to cancer therapy can contribute to unfavorable patient outcomes, potentially including disease relapse. This possibiliy is supported by our findings that tumor cells induced into senescence by doxorubicin or etoposide can give rise to viable tumors in vivo. We further demonstrate sensitivity of these senescent tumor cells to the senolytic ABT-263 (navitoclax), therefore providing a "two-hit" approach to eliminate senescent tumor cells that persist after exposure to chemotherapy or radiation. The sequential combination of therapy-induced senescence and ABT-263 could shift the response to therapy toward apoptosis by interfering with the interaction between BCL-XL and BAX. The administration of ABT-263 after either etoposide or doxorubicin also resulted in marked, prolonged tumor suppression in tumor-bearing animals. These findings support the premise that senolytic therapy following conventional cancer therapy may improve therapeutic outcomes and delay disease recurrence.
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Affiliation(s)
- Tareq Saleh
- Department of Basic Medical SciencesFaculty of MedicineThe Hashemite UniversityZarqaJordan
- Departments of Pharmacology & ToxicologySchool of MedicineMassey Cancer CenterVirginia Commonwealth UniversityRichmondVAUSA
| | - Valerie J. Carpenter
- Departments of Pharmacology & ToxicologySchool of MedicineMassey Cancer CenterVirginia Commonwealth UniversityRichmondVAUSA
| | - Liliya Tyutyunyk‐Massey
- Departments of Pharmacology & ToxicologySchool of MedicineMassey Cancer CenterVirginia Commonwealth UniversityRichmondVAUSA
| | - Graeme Murray
- Department of PhysicsVirginia Commonwealth UniversityRichmondVAUSA
| | | | | | - Moureq R. Alotaibi
- Department of Pharmacology and ToxicologyCollege of PharmacyKing Saud UniversityRiyadhSaudi Arabia
| | - Anthony C. Faber
- Philips Institute for Oral Health ResearchSchool of DentistryMassey Cancer CenterVirginia Commonwealth UniversityRichmondVAUSA
| | - Jason Reed
- Department of PhysicsVirginia Commonwealth UniversityRichmondVAUSA
| | - Hisashi Harada
- Philips Institute for Oral Health ResearchSchool of DentistryMassey Cancer CenterVirginia Commonwealth UniversityRichmondVAUSA
| | - David A. Gewirtz
- Departments of Pharmacology & ToxicologySchool of MedicineMassey Cancer CenterVirginia Commonwealth UniversityRichmondVAUSA
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Spehar K, Pan A, Beerman I. Restoring aged stem cell functionality: Current progress and future directions. Stem Cells 2020; 38:1060-1077. [PMID: 32473067 PMCID: PMC7483369 DOI: 10.1002/stem.3234] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 04/07/2020] [Accepted: 05/11/2020] [Indexed: 12/15/2022]
Abstract
Stem cell dysfunction is a hallmark of aging, associated with the decline of physical and cognitive abilities of humans and other mammals [Cell 2013;153:1194]. Therefore, it has become an active area of research within the aging and stem cell fields, and various techniques have been employed to mitigate the decline of stem cell function both in vitro and in vivo. While some techniques developed in model organisms are not directly translatable to humans, others show promise in becoming clinically relevant to delay or even mitigate negative phenotypes associated with aging. This review focuses on diet, treatment, and small molecule interventions that provide evidence of functional improvement in at least one type of aged adult stem cell.
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Affiliation(s)
- Kevin Spehar
- Epigenetics and Stem Cell Aging Unit, Translational Gerontology Branch, National Institute on Aging, NIH, BRC, Baltimore, Maryland
| | - Andrew Pan
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia
| | - Isabel Beerman
- Epigenetics and Stem Cell Aging Unit, Translational Gerontology Branch, National Institute on Aging, NIH, BRC, Baltimore, Maryland
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Cherif H, Bisson DG, Mannarino M, Rabau O, Ouellet JA, Haglund L. Senotherapeutic drugs for human intervertebral disc degeneration and low back pain. eLife 2020; 9:54693. [PMID: 32821059 PMCID: PMC7442487 DOI: 10.7554/elife.54693] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Accepted: 08/03/2020] [Indexed: 12/12/2022] Open
Abstract
Cellular senescence is a contributor to intervertebral disc (IVD) degeneration and low back pain. Here, we found that RG-7112, a potent mouse double-minute two protein inhibitor, selectively kills senescent IVD cells through apoptosis. Gene expression pathway analysis was used to compare the functional networks of genes affected by RG-7112, a pure synthetic senolytic with o-Vanillin a natural and anti-inflammatory senolytic. Both affected a functional gene network related to cell death and survival. O-Vanillin also affected networks related to cell cycle progression as well as connective tissue development and function. Both senolytics effectively decreased the senescence-associated secretory phenotype (SASP) of IVD cells. Furthermore, bioavailability and efficacy were verified ex vivo in the physiological environment of degenerating intact human discs where a single dose improved disc matrix homeostasis. Matrix improvement correlated with a reduction in senescent cells and SASP, supporting a translational potential of targeting senescent cells as a therapeutic intervention. Pain in the lower back affects about four in five people during their lifetime. Over time, the discs that provide cushioning between the vertebrae of the spine can degenerate, which can be one of the major causes of lower back pain. It has been shown that when the cells of these discs are exposed to different stress factors, they stop growing and become irreversibly dormant. Such ‘senescent’ cells release a range of proteins and small molecules that lead to painful inflammation and further degeneration of the discs. Moreover, it is thought that a high number of senescent cells may be linked to other degenerative diseases such as arthritis. Current treatments can only reduce the severity of the symptoms, but they cannot prevent the degeneration from progressing. Now, Cherif et al. set out to test the effects of two different compounds on human disc cells grown in the laboratory. One of the molecules studied, RG-7112, is a synthetic drug that has been approved for safety by the US Food and Drug Administration and has been shown to remove senescent cells. The other, o-Vanillin, is a natural compound that has anti-inflammatory and anti-senescence properties. The results showed that both compounds were able to trigger changes to that helped new, healthy cells to grow and at the same time kill senescent cells. They also reduced the production of molecules linked to inflammation and pain. Further analyses revealed that the compounds were able to strengthen the fibrous matrix that surrounds and supports the discs. Cherif et al. hope that this could form the basis for a new family of drugs for back pain to slow the degeneration of the discs and reduce pain. This may also have benefits for other similar degenerative diseases caused by cell senescence, such as arthritis.
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Affiliation(s)
- Hosni Cherif
- Orthopaedic Research Lab, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada.,McGill Scoliosis and Spine Group, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada
| | - Daniel G Bisson
- Orthopaedic Research Lab, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada.,McGill Scoliosis and Spine Group, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada
| | - Matthew Mannarino
- Orthopaedic Research Lab, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada.,McGill Scoliosis and Spine Group, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada
| | - Oded Rabau
- McGill Scoliosis and Spine Group, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada.,Shriner's Hospital for Children, 1003 Decarie Blvd, Montreal, Canada
| | - Jean A Ouellet
- McGill Scoliosis and Spine Group, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada.,Shriner's Hospital for Children, 1003 Decarie Blvd, Montreal, Canada
| | - Lisbet Haglund
- Orthopaedic Research Lab, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada.,McGill Scoliosis and Spine Group, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal, Canada.,Shriner's Hospital for Children, 1003 Decarie Blvd, Montreal, Canada
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Sharma AK, Roberts RL, Benson RD, Pierce JL, Yu K, Hamrick MW, McGee-Lawrence ME. The Senolytic Drug Navitoclax (ABT-263) Causes Trabecular Bone Loss and Impaired Osteoprogenitor Function in Aged Mice. Front Cell Dev Biol 2020; 8:354. [PMID: 32509782 PMCID: PMC7252306 DOI: 10.3389/fcell.2020.00354] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 04/21/2020] [Indexed: 12/02/2022] Open
Abstract
Senescence is a cellular defense mechanism that helps cells prevent acquired damage, but chronic senescence, as in aging, can contribute to the development of age-related tissue dysfunction and disease. Previous studies clearly show that removal of senescent cells can help prevent tissue dysfunction and extend healthspan during aging. Senescence increases with age in the skeletal system, and selective depletion of senescent cells or inhibition of their senescence-associated secretory phenotype (SASP) has been reported to maintain or improve bone mass in aged mice. This suggests that promoting the selective removal of senescent cells, via the use of senolytic agents, can be beneficial in the treatment of aging-related bone loss and osteoporosis. Navitoclax (also known as ABT-263) is a chemotherapeutic drug reported to effectively clear senescent hematopoietic stem cells, muscle stem cells, and mesenchymal stromal cells in previous studies, but its in vivo effects on bone mass had not yet been reported. Therefore, the purpose of this study was to assess the effects of short-term navitoclax treatment on bone mass and osteoprogenitor function in old mice. Aged (24 month old) male and female mice were treated with navitoclax (50 mg/kg body mass daily) for 2 weeks. Surprisingly, despite decreasing senescent cell burden, navitoclax treatment decreased trabecular bone volume fraction in aged female and male mice (−60.1% females, −45.6% males), and BMSC-derived osteoblasts from the navitoclax treated mice were impaired in their ability to produce a mineralized matrix (−88% females, −83% males). Moreover, in vitro administration of navitoclax decreased BMSC colony formation and calcified matrix production by aged BMSC-derived osteoblasts, similar to effects seen with the primary BMSC from the animals treated in vivo. Navitoclax also significantly increased metrics of cytotoxicity in both male and female osteogenic cultures (+1.0 to +11.3 fold). Taken together, these results suggest a potentially harmful effect of navitoclax on skeletal-lineage cells that should be explored further to definitively assess navitoclax’s potential (or risk) as a therapeutic agent for combatting age-related musculoskeletal dysfunction and bone loss.
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Affiliation(s)
- Anuj K Sharma
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Rachel L Roberts
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Reginald D Benson
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Jessica L Pierce
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Kanglun Yu
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Mark W Hamrick
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Meghan E McGee-Lawrence
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, United States.,Department of Orthopaedic Surgery, Augusta University, Augusta, GA, United States
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Saleh T, Bloukh S, Carpenter VJ, Alwohoush E, Bakeer J, Darwish S, Azab B, Gewirtz DA. Therapy-Induced Senescence: An "Old" Friend Becomes the Enemy. Cancers (Basel) 2020; 12:cancers12040822. [PMID: 32235364 PMCID: PMC7226427 DOI: 10.3390/cancers12040822] [Citation(s) in RCA: 185] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 03/21/2020] [Accepted: 03/25/2020] [Indexed: 01/10/2023] Open
Abstract
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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Affiliation(s)
- Tareq Saleh
- Department of Basic Medical Sciences, Faculty of Medicine, The Hashemite University, Zarqa 13133, Jordan; (T.S.); (S.D.)
| | - Sarah Bloukh
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman 11942, Jordan; (S.B.); (E.A.); (J.B.); (B.A.)
| | - Valerie J. Carpenter
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23284, USA;
| | - Enas Alwohoush
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman 11942, Jordan; (S.B.); (E.A.); (J.B.); (B.A.)
| | - Jomana Bakeer
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman 11942, Jordan; (S.B.); (E.A.); (J.B.); (B.A.)
| | - Sarah Darwish
- Department of Basic Medical Sciences, Faculty of Medicine, The Hashemite University, Zarqa 13133, Jordan; (T.S.); (S.D.)
| | - Belal Azab
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman 11942, Jordan; (S.B.); (E.A.); (J.B.); (B.A.)
- Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23284, USA
| | - David A. Gewirtz
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23284, USA;
- Correspondence:
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Neri S, Borzì RM. Molecular Mechanisms Contributing to Mesenchymal Stromal Cell Aging. Biomolecules 2020; 10:E340. [PMID: 32098040 PMCID: PMC7072652 DOI: 10.3390/biom10020340] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 02/13/2020] [Accepted: 02/19/2020] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are a reservoir for tissue homeostasis and repair that age during organismal aging. Beside the fundamental in vivo role of MSCs, they have also emerged in the last years as extremely promising therapeutic agents for a wide variety of clinical conditions. MSC use frequently requires in vitro expansion, thus exposing cells to replicative senescence. Aging of MSCs (both in vivo and in vitro) can affect not only their replicative potential, but also their properties, like immunomodulation and secretory profile, thus possibly compromising their therapeutic effect. It is therefore of critical importance to unveil the underlying mechanisms of MSC senescence and to define shared methods to assess MSC aging status. The present review will focus on current scientific knowledge about MSC aging mechanisms, control and effects, including possible anti-aging treatments.
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Affiliation(s)
- Simona Neri
- IRCCS Istituto Ortopedico Rizzoli, Laboratorio di Immunoreumatologia e Rigenerazione Tissutale, 40136 Bologna, Italy;
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Clinical Trials of Limbal Stem Cell Deficiency Treated with Oral Mucosal Epithelial Cells. Int J Mol Sci 2020; 21:ijms21020411. [PMID: 31936462 PMCID: PMC7014181 DOI: 10.3390/ijms21020411] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 01/04/2020] [Accepted: 01/07/2020] [Indexed: 12/11/2022] Open
Abstract
The corneal surface is an essential organ necessary for vision, and its clarity must be maintained. The corneal epithelium is renewed by limbal stem cells, located in the limbus and in palisades of Vogt. Palisades of Vogt maintain the clearness of the corneal epithelium by blocking the growth of conjunctival epithelium and the invasion of blood vessels over the cornea. The limbal region can be damaged by chemical burns, physical damage (e.g., by contact lenses), congenital disease, chronic inflammation, or limbal surgeries. The degree of limbus damage is associated with the degree of limbal stem cells deficiency (partial or total). For a long time, the only treatment to restore vision was grafting part of the healthy cornea from the other eye of the patient or by transplanting a cornea from cadavers. The regenerative medicine and stem cell therapies have been applied to restore normal vision using different methodologies. The source of stem cells varies from embryonic stem cells, mesenchymal stem cells, to induced pluripotent stem cells. This review focuses on the use of oral mucosa epithelial stem cells and their use in engineering cell sheets to treat limbal stem cell deficient patients.
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43
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Targeting normal and cancer senescent cells as a strategy of senotherapy. Ageing Res Rev 2019; 55:100941. [PMID: 31408714 DOI: 10.1016/j.arr.2019.100941] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 07/04/2019] [Accepted: 08/06/2019] [Indexed: 12/19/2022]
Abstract
Senotherapy is an antiageing strategy. It refers to selective killing of senescent cells by senolytic agents, strengthening the activity of immune cells that eliminate senescent cells or alleviating the secretory phenotype (SASP) of senescent cells. As senescent cells accumulate with age and are considered to be at the root of age-related disorders, senotherapy seems to be very promising in improving healthspan. Genetic approaches, which allowed to selectively induce death of senescent cells in transgenic mice, provided proof-of-concept evidence that elimination of senescent cells can be a therapeutic approach for treating many age-related diseases. Translating these results into humans is based on searching for synthetic and natural compounds, which are able to exert such beneficial effects. The major challenge in the field is to show efficacy, safety and tolerability of senotherapy in humans. The question is how these therapeutics can influence senescence of non-dividing post-mitotic cells. Another issue concerns senescence of cancer cells induced during therapy as there is a risk of resumption of senescent cell division that could terminate in cancer renewal. Thus, development of an effective senotherapeutic strategy is also an urgent issue in cancer treatment. Different aspects, both beneficial and potentially detrimental, will be discussed in this review.
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García-Sánchez D, Fernández D, Rodríguez-Rey JC, Pérez-Campo FM. Enhancing survival, engraftment, and osteogenic potential of mesenchymal stem cells. World J Stem Cells 2019; 11:748-763. [PMID: 31692976 PMCID: PMC6828596 DOI: 10.4252/wjsc.v11.i10.748] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 07/15/2019] [Accepted: 07/29/2019] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are promising candidates for bone regeneration therapies due to their plasticity and easiness of sourcing. MSC-based treatments are generally considered a safe procedure, however, the long-term results obtained up to now are far from satisfactory. The main causes of these therapeutic limitations are inefficient homing, engraftment, and osteogenic differentiation. Many studies have proposed modifications to improve MSC engraftment and osteogenic differentiation of the transplanted cells. Several strategies are aimed to improve cell resistance to the hostile microenvironment found in the recipient tissue and increase cell survival after transplantation. These strategies could range from a simple modification of the culture conditions, known as cell-preconditioning, to the genetic modification of the cells to avoid cellular senescence. Many efforts have also been done in order to enhance the osteogenic potential of the transplanted cells and induce bone formation, mainly by the use of bioactive or biomimetic scaffolds, although alternative approaches will also be discussed. This review aims to summarize several of the most recent approaches, providing an up-to-date view of the main developments in MSC-based regenerative techniques.
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Affiliation(s)
- Daniel García-Sánchez
- Department of Molecular Biology, Faculty of Medicine, University of Cantabria, Cantabria 39011, Spain
| | - Darío Fernández
- Laboratorio de Biología Celular y Molecular, Facultad de Odontología, Universidad Nacional del Nordeste, Corrientes W3400, Argentina
| | - José C Rodríguez-Rey
- Department of Molecular Biology, Faculty of Medicine, University of Cantabria, Cantabria 39011, Spain
| | - Flor M Pérez-Campo
- Department of Molecular Biology, Faculty of Medicine, University of Cantabria, Cantabria 39011, Spain.
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45
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Knoppert SN, Valentijn FA, Nguyen TQ, Goldschmeding R, Falke LL. Cellular Senescence and the Kidney: Potential Therapeutic Targets and Tools. Front Pharmacol 2019; 10:770. [PMID: 31354486 PMCID: PMC6639430 DOI: 10.3389/fphar.2019.00770] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 06/14/2019] [Indexed: 01/10/2023] Open
Abstract
Chronic kidney disease (CKD) is an increasing health burden (affecting approximately 13.4% of the population). Currently, no curative treatment options are available and treatment is focused on limiting the disease progression. The accumulation of senescent cells has been implicated in the development of kidney fibrosis by limiting tissue rejuvenation and through the secretion of pro-fibrotic and pro-inflammatory mediators termed as the senescence-associated secretory phenotype. The clearance of senescent cells in aging models results in improved kidney function, which shows promise for the options of targeting senescent cells in CKD. There are several approaches for the development of “senotherapies”, the most rigorous of which is the elimination of senescent cells by the so-called senolytic drugs either newly developed or repurposed for off-target effects in terms of selectively inducing apoptosis in senescent cells. Several chemotherapeutics and checkpoint inhibitors currently used in daily oncological practice show senolytic properties. However, the applicability of such senolytic compounds for the treatment of renal diseases has hardly been investigated. A serious concern is that systemic side effects will limit the use of senolytics for kidney fibrosis. Specifically targeting senescent cells and/or targeted drug delivery to the kidney might circumvent these side effects. In this review, we discuss the connection between CKD and senescence, the pharmacological options for targeting senescent cells, and the means to specifically target the kidney.
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Affiliation(s)
- Sebastian N Knoppert
- Department of Pathology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Floris A Valentijn
- Department of Pathology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Tri Q Nguyen
- Department of Pathology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Roel Goldschmeding
- Department of Pathology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Lucas L Falke
- Department of Pathology, University Medical Center Utrecht, Utrecht, Netherlands.,Department of Internal Medicine, Diakonessenhuis, University Medical Center Utrecht, Utrecht, Netherlands
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Fafián-Labora JA, Morente-López M, Arufe MC. Effect of aging on behaviour of mesenchymal stem cells. World J Stem Cells 2019; 11:337-346. [PMID: 31293716 PMCID: PMC6600848 DOI: 10.4252/wjsc.v11.i6.337] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2019] [Revised: 03/29/2019] [Accepted: 05/06/2019] [Indexed: 02/06/2023] Open
Abstract
Organs whose source is the mesoderm lineage contain a subpopulation of stem cells that are able to differentiate among mesodermal derivatives (chondrocytes, osteocytes, adipocytes). This subpopulation of adult stem cells, called "mesenchymal stem cells" or "mesenchymal stromal cells (MSCs)", contributes directly to the homeostatic maintenance of their organs; hence, their senescence could be very deleterious for human bodily functions. MSCs are easily isolated and amenable their expansion in vitro because of the research demanding to test them in many diverse clinical indications. All of these works are shown by the rapidly expanding literature that includes many in vivo animal models. We do not have an in-depth understanding of mechanisms that induce cellular senescence, and to further clarify the consequences of the senescence process in MSCs, some hints may be derived from the study of cellular behaviour in vivo and in vitro, autophagy, mitochondrial stress and exosomal activity. In this particular work, we decided to review these biological features in the literature on MSC senescence over the last three years.
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Affiliation(s)
- Juan Antonio Fafián-Labora
- Grupo de Terapia Celular y Medicina Regenerativa, Departamento de Fisioterapia, Ciencias Biomédicas y Medicina, Universidade da Coruña, A Coruña 15006, Spain
| | - Miriam Morente-López
- Grupo de Terapia Celular y Medicina Regenerativa, Departamento de Fisioterapia, Ciencias Biomédicas y Medicina, Universidade da Coruña, A Coruña 15006, Spain
| | - María C Arufe
- Grupo de Terapia Celular y Medicina Regenerativa, Departamento de Fisioterapia, Ciencias Biomédicas y Medicina, Universidade da Coruña, A Coruña 15006, Spain.
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Zhai W, Yong D, El-Jawhari JJ, Cuthbert R, McGonagle D, Win Naing M, Jones E. Identification of senescent cells in multipotent mesenchymal stromal cell cultures: Current methods and future directions. Cytotherapy 2019; 21:803-819. [PMID: 31138507 DOI: 10.1016/j.jcyt.2019.05.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 03/30/2019] [Accepted: 05/06/2019] [Indexed: 12/11/2022]
Abstract
Regardless of their tissue of origin, multipotent mesenchymal stromal cells (MSCs) are commonly expanded in vitro for several population doublings to achieve a sufficient number of cells for therapy. Prolonged MSC expansion has been shown to result in phenotypical, morphological and gene expression changes in MSCs, which ultimately lead to the state of senescence. The presence of senescent cells in therapeutic MSC batches is undesirable because it reduces their viability, differentiation potential and trophic capabilities. Additionally, senescent cells acquire senescence-activated secretory phenotype, which may not only induce apoptosis in the neighboring host cells following MSC transplantation, but also trigger local inflammatory reactions. This review outlines the current and promising new methodologies for the identification of senescent cells in MSC cultures, with a particular emphasis on non-destructive and label-free methodologies. Technologies allowing identification of individual senescent cells, based on new surface markers, offer potential advantage for targeted senescent cell removal using new-generation senolytic agents, and subsequent production of therapeutic MSC batches fully devoid of senescent cells. Methods or a combination of methods that are non-destructive and label-free, for example, involving cell size and spectroscopic measurements, could be the best way forward because they do not modify the cells of interest, thus maximizing the final output of therapeutic-grade MSC cultures. The further incorporation of machine learning methods has also recently shown promise in facilitating, automating and enhancing the analysis of these measured data.
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Affiliation(s)
- Weichao Zhai
- Leeds Institute of Rheumatic and musculoskeletal Medicine, Leeds, UK; Singapore Institute of Manufacturing Technology, A*STAR, Innovis, Singapore
| | - Derrick Yong
- Singapore Institute of Manufacturing Technology, A*STAR, Innovis, Singapore
| | - Jehan Jomaa El-Jawhari
- Leeds Institute of Rheumatic and musculoskeletal Medicine, Leeds, UK; Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Richard Cuthbert
- Leeds Institute of Rheumatic and musculoskeletal Medicine, Leeds, UK
| | - Dennis McGonagle
- Leeds Institute of Rheumatic and musculoskeletal Medicine, Leeds, UK
| | - May Win Naing
- Singapore Institute of Manufacturing Technology, A*STAR, Innovis, Singapore
| | - Elena Jones
- Leeds Institute of Rheumatic and musculoskeletal Medicine, Leeds, UK.
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Neri S. Genetic Stability of Mesenchymal Stromal Cells for Regenerative Medicine Applications: A Fundamental Biosafety Aspect. Int J Mol Sci 2019; 20:ijms20102406. [PMID: 31096604 PMCID: PMC6566307 DOI: 10.3390/ijms20102406] [Citation(s) in RCA: 105] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Revised: 05/08/2019] [Accepted: 05/10/2019] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem/stromal cells (MSC) show widespread application for a variety of clinical conditions; therefore, their use necessitates continuous monitoring of their safety. The risk assessment of mesenchymal stem cell-based therapies cannot be separated from an accurate and deep knowledge of their biological properties and in vitro and in vivo behavior. One of the most relevant safety issues is represented by the genetic stability of MSCs, that can be altered during in vitro manipulation, frequently required before clinical application. MSC genetic stability has the potential to influence the transformation and the therapeutic effect of these cells. At present, karyotype evaluation represents the definitely prevailing assessment of MSC stability, but DNA alterations of smaller size should not be underestimated. This review will focus on current scientific knowledge about the genetic stability of mesenchymal stem cells. The techniques used and possible improvements together with regulatory aspects will also be discussed.
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Affiliation(s)
- Simona Neri
- Laboratorio di Immunoreumatologia e Rigenerazione Tissutale, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy.
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Yang YHK. Aging of mesenchymal stem cells: Implication in regenerative medicine. Regen Ther 2018; 9:120-122. [PMID: 30525083 PMCID: PMC6222976 DOI: 10.1016/j.reth.2018.09.002] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Revised: 08/30/2018] [Accepted: 09/13/2018] [Indexed: 12/15/2022] Open
Abstract
Multipotent mesenchymal stem cells (MSCs) represent a great candidate for various clinical applications including regenerative medicine. However, aging both in vivo and in vitro can significantly compromise MSC characteristics and performance. This paper highlights current thoughts on senescence-induced damage to MSCs that should be considered prior to their use for regeneration of different cells, tissues or organs.
Multipotent mesenchymal stem cells give rise to different cell lineages of mesodermal origin. Mesenchymal stem cells can undergo aging process during extensive in-vitro expansion. Senescence, both in vivo and in vitro, damages the regenerative and therapeutic potential of mesenchymal stem cells.
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Affiliation(s)
- Yueh-Hsun Kevin Yang
- Grove School of Engineering, The City University of New York - the City College, New York, NY 10031, USA
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