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Yang Y, Cai Q, Zhu M, Rong J, Feng X, Wang K. Exploring the double-edged role of cellular senescence in chronic liver disease for new treatment approaches. Life Sci 2025; 373:123678. [PMID: 40324645 DOI: 10.1016/j.lfs.2025.123678] [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: 02/06/2025] [Revised: 04/24/2025] [Accepted: 04/30/2025] [Indexed: 05/07/2025]
Abstract
Cellular senescence is a fundamental yet complex defense mechanism that restricts excessive proliferation, maintains cellular homeostasis under various stress conditions-such as oncogenic activation and inflammation-and serves as a dynamic stress response program involved in development, aging, and immunity. Its reversibility depends on essential maintenance components. Cellular senescence is a "double-edged sword": on one hand, it limits the malignant proliferation of damaged cells, thereby preventing tumor development. However, by retaining secretory functions, senescent cells can also induce persistent changes in the microenvironment and disrupt homeostasis, leading to tissue inflammation, fibrosis, and carcinogenesis. Senescence plays a critical role in the pathogenesis of various chronic liver diseases, including chronic viral hepatitis, liver fibrosis, and hepatocellular carcinoma. It exerts a dual influence by facilitating immune evasion and inflammation in chronic viral hepatitis, modulating hepatic stellate cell activity in fibrosis, and reshaping the tumor microenvironment to accelerate hepatocarcinogenesis. This article reviews the characteristics of cellular senescence and its role in the pathogenesis of these chronic liver diseases while exploring potential treatment and prevention strategies. The aim is to provide a comprehensive reference for future clinical and research investigations into chronic liver disease.
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Affiliation(s)
- Yiwen Yang
- Department of Hepatopancreatobiliary Surgery, Ningbo Medical Center Lihuili Hospital, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, China
| | - Qun Cai
- Department of Infectious Diseases and Liver Diseases, Ningbo Medical Center Lihuili Hospital, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, China
| | - Mingyan Zhu
- Department of Emergency, Ningbo Medical Center Lihuili Hospital, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, China
| | - Jianning Rong
- Department of Emergency, Ningbo Medical Center Lihuili Hospital, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, China
| | - Xudong Feng
- Department of Clinical Laboratory, Ningbo Medical Center Lihuili Hospital, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, China.
| | - Ke Wang
- Department of Hepatopancreatobiliary Surgery, Ningbo Medical Center Lihuili Hospital, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, China.
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2
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Tsoneva Y, Velikova T, Nikolaev G. Circadian clock regulation of myofibroblast fate. Cell Signal 2025; 131:111774. [PMID: 40169063 DOI: 10.1016/j.cellsig.2025.111774] [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: 12/04/2024] [Revised: 03/10/2025] [Accepted: 03/26/2025] [Indexed: 04/03/2025]
Abstract
Fibrosis-related disorders represent an increasing medical and economic burden on a worldwide scale, accounting for one-third of all disease-related deaths with limited therapeutic options. As central mediators in fibrosis development, myofibroblasts have been gaining increasing attention in the last 20 years as potential targets for fibrosis attenuation and reversal. While various aspects of myofibroblast physiology have been proposed as treatment targets, many of these approaches have shown limited long-term efficacy so far. However, ongoing research is uncovering new potential strategies for targeting myofibroblast activity, offering hope for more effective treatments in the future. The circadian molecular clock is a feature of almost every cell in the human body that dictates the rhythmic nature of various aspects of human physiology and behavior in response to changes in the surrounding environment. The dysregulation of these rhythms with aging is considered to be one of the underlying reasons behind the development of multiple aging-related chronic disorders, with fibrotic tissue scarring being a common pathological complication among the majority of them. Myofibroblast dysregulation due to skewed circadian clockwork might significantly contribute to fibrotic scar persistence. In the current review, we highlight the role of the circadian clock in the context of myofibroblast activation and deactivation and examine its dysregulation as a driver of fibrogenesis.
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Affiliation(s)
- Yoanna Tsoneva
- Department of Cell and Developmental Biology, Faculty of Biology, Sofia University "St. Kliment Ohridski", Bulgaria.
| | - Tsvetelina Velikova
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak str, 1407 Sofia, Bulgaria.
| | - Georgi Nikolaev
- Department of Cell and Developmental Biology, Faculty of Biology, Sofia University "St. Kliment Ohridski", Bulgaria.
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3
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Giroud J, Combémorel E, Pourtier A, Abbadie C, Pluquet O. Unraveling the functional and molecular interplay between cellular senescence and the unfolded protein response. Am J Physiol Cell Physiol 2025; 328:C1764-C1782. [PMID: 40257464 DOI: 10.1152/ajpcell.00091.2025] [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: 01/28/2025] [Revised: 02/12/2025] [Accepted: 04/14/2025] [Indexed: 04/22/2025]
Abstract
Senescence is a complex cellular state that can be considered as a stress response phenotype. A decade ago, we suggested the intricate connections between unfolded protein response (UPR) signaling and the development of the senescent phenotype. Over the past ten years, significant advances have been made in understanding the multifaceted role of the UPR in regulating cellular senescence, highlighting its contribution to biological processes such as oxidative stress and autophagy. In this updated review, we expand these interconnections with the benefit of new insights, and we suggest that targeting specific components of the UPR could provide novel therapeutic strategies to mitigate the deleterious effects of senescence, with significant implications for age-related pathologies and geroscience.
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Affiliation(s)
- Joëlle Giroud
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille, France
| | - Emilie Combémorel
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille, France
| | - Albin Pourtier
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille, France
| | - Corinne Abbadie
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille, France
| | - Olivier Pluquet
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille, France
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Huang X, Kui X, Ma J, Chen J, Huang Y, He B. Cyr61 promotes D-gal-induced aging C2C12 cell fibrosis by modulating Wnt/β-catenin signaling pathways. Mech Ageing Dev 2025; 225:112067. [PMID: 40339921 DOI: 10.1016/j.mad.2025.112067] [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: 03/04/2025] [Revised: 04/20/2025] [Accepted: 04/29/2025] [Indexed: 05/10/2025]
Abstract
Sarcopenia is characterized by age-related muscle mass/function loss and fibrosis. Satellite cell (SC) dysfunction during aging promotes fibrotic transdifferentiation and extracellular matrix (ECM) deposition. Cyr61, a pro-fibrotic matricellular protein, and Wnt/β-catenin signaling pathway are implicated in muscle regeneration-fibrosis balance, but their interaction in sarcopenia remains unclear. This study first compared the expression of Cyr61 and fibrosis markers (TGF-β1, collagen type I and III) in skeletal muscle of young and old mice. In vitro, D-gal-induced C2C12 aging models were used to assess Cyr61 and Wnt signaling pathway by proliferation/apoptosis assays, ECM analysis, and detecting the changes of myogenic/fibrotic markers (MyoD, α-SMA). Pathway modulation (FH535 inhibitor/LiCl activator) and combined with Cyr61 overexpression and knockout experiments defined mechanistic roles. Cyr61 was upregulated in skeletal muscle of aged mice, which was positively correlated with increased TGF-β1 and collagen deposition. In D-gal-induced C2C12 cells showed suppressed cell proliferation, increased apoptosis and enhanced ECM deposition, accompanied by elevated Cyr61. Cyr61 knockdown or Wnt signaling pathway inhibition (FH535) reversed fibrosis (α-SMA, collagen) and restored myogenesis (MyoD).This study reveals for the first time that Cyr61 drives sarcopenic fibrosis via Wnt/β-catenin activation, promoting myocyte-to-fibrotic transition. Targeting the Cyr61-Wnt axis may ameliorate age-related muscle degeneration, warranting translational validation in preclinical models.
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Affiliation(s)
- Xinchen Huang
- Department of Medical Imaging, The First Affiliated Hospital of Kunming Medical University, Kunming, China; Department of Radiology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaoling Kui
- Department of Medical Imaging, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jiyao Ma
- Department of Medical Imaging, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jiaxin Chen
- Department of Medical Imaging, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yilong Huang
- Department of Medical Imaging, The First Affiliated Hospital of Kunming Medical University, Kunming, China.
| | - Bo He
- Department of Medical Imaging, The First Affiliated Hospital of Kunming Medical University, Kunming, China.
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Lavarti R, Alvarez-Diaz T, Marti K, Kar P, Raju RP. The context-dependent effect of cellular senescence: From embryogenesis and wound healing to aging. Ageing Res Rev 2025; 109:102760. [PMID: 40318767 DOI: 10.1016/j.arr.2025.102760] [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: 01/02/2025] [Revised: 04/20/2025] [Accepted: 04/26/2025] [Indexed: 05/07/2025]
Abstract
Aging is characterized by a steady loss of physiological integrity, leading to impaired function and increased vulnerability to death. Cell senescence is a biological process that progresses with aging and is believed to be a key driver of age-related diseases. Senescence, a hallmark of aging, also demonstrates its beneficial physiological aspects as an anti-cancer, pro-regenerative, homeostatic, and developmental mechanism. A transitory response in which the senescent cells are quickly formed and cleared may promote tissue regeneration and organismal fitness. At the same time, senescence-related secretory phenotypes associated with extended senescence can have devastating effects. The fact that the interaction between senescent cells and their surroundings is very context-dependent may also help to explain this seemingly opposing pleiotropic function. Further, mitochondrial dysfunction is an often-unappreciated hallmark of cellular senescence and figures prominently in multiple feedback loops that induce and maintain the senescent phenotype. This review summarizes the mechanism of cellular senescence and the significance of acute senescence. We concisely introduced the context-dependent role of senescent cells and SASP, aspects of mitochondrial biology altered in the senescent cells, and their impact on the senescent phenotype. Finally, we conclude with recent therapeutic advancements targeting cellular senescence, focusing on acute injuries and age-associated diseases. Collectively, these insights provide a future roadmap for the role of senescence in organismal fitness and life span extension.
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Affiliation(s)
- Rupa Lavarti
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Tatiana Alvarez-Diaz
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Kyarangelie Marti
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Parmita Kar
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Raghavan Pillai Raju
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, United States; Charlie Norwood VA Medical Center, Augusta, GA, United States.
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Marjan T, Lafuente-Gómez N, Rampal A, Mooney DJ, Peyton SR, Qazi TH. Cell-Instructive Biomaterials with Native-Like Biochemical Complexity. Annu Rev Biomed Eng 2025; 27:185-209. [PMID: 39874600 PMCID: PMC12045723 DOI: 10.1146/annurev-bioeng-120823-020209] [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] [Indexed: 01/30/2025]
Abstract
Biochemical signals in native tissue microenvironments instruct cell behavior during many biological processes ranging from developmental morphogenesis and tissue regeneration to tumor metastasis and disease progression. The detection and characterization of these signals using spatial and highly resolved quantitative methods have revealed their existence as matricellular proteins in the matrisome, some of which are bound to the extracellular matrix while others are freely diffusing. Including these biochemical signals in engineered biomaterials can impart enhanced functionality and native-like complexity, ultimately benefiting efforts to understand, model, and treat various diseases. In this review, we discuss advances in characterizing, mimicking, and harnessing biochemical signals in developing advanced engineered biomaterials. An overview of the diverse forms in which these biochemical signals exist and their effects on intracellular signal transduction is also provided. Finally, we highlight the application of biochemically complex biomaterials in the three broadly defined areas of tissue regeneration, immunoengineering, and organoid morphogenesis.
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Affiliation(s)
- Tuba Marjan
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA;
| | - Nuria Lafuente-Gómez
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA;
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, Massachusetts, USA
| | - Akaansha Rampal
- Molecular and Cellular Biology Graduate Program, University of Massachusetts, Amherst, Massachusetts, USA
| | - David J Mooney
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA;
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, Massachusetts, USA
| | - Shelly R Peyton
- Molecular and Cellular Biology Graduate Program, University of Massachusetts, Amherst, Massachusetts, USA
- Department of Chemical Engineering, University of Massachusetts, Amherst, Massachusetts, USA
- Department of Biomedical Engineering, Tufts University, Medford, Massachusetts, USA;
| | - Taimoor H Qazi
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA;
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Nulty CD, Walton J, Erskine RM. Habitual Dietary Collagen Intake Is Lower in Females and Older Irish Adults Compared with Younger Males. J Nutr 2025; 155:1408-1416. [PMID: 40058700 DOI: 10.1016/j.tjnut.2025.03.002] [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: 12/13/2024] [Revised: 02/12/2025] [Accepted: 03/02/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Collagen ingestion reportedly benefits connective tissues, such as skin, bone, muscle, tendon, and ligament. However, the quantity of collagen intake in the diet of European adults is unknown. OBJECTIVES This study aims to investigate collagen intake in the habitual diets of Irish adults, and whether it differed according to sex and/or age. METHODS We conducted secondary analysis of the Irish National Adult Nutrition Survey, which assessed typical dietary intake using a 4-d food diary in 1500 adults, aged 18-90 y. We categorized participants into 3 age groups: young (18-39 y, n = 630), middle-aged (40-64 y, n = 644), and older (≥65 y, n = 226) adults. Collagen composition of each individual food item in the database was determined by applying a percentage collagen value from analytical sources, allowing computation of collagen mean daily intake (MDI), collagen MDI relative to body mass, and collagen/total protein MDI. Differences in intakes between age groups and sexes were evaluated using physical activity level as a covariate. RESULTS Collagen MDI for the entire population was 3.2 ± 2.0 g/d, representing 3.6% ± 1.9% total protein intake. Males had higher absolute and relative collagen MDI than females, regardless of age (4.0 ± 2.1 g/d compared with 2.3 ± 1.4 g/d, P < 0.001), whereas older adults had lower absolute collagen MDI than middle-aged adults (2.9 ± 1.8 g/d compared with 3.3 ± 2.0 g/d, P = 0.021). CONCLUSIONS Collagen intake in the Irish adult population was considered low (relative to total protein intake and to dose-response studies), particularly in females and older individuals. Increasing daily collagen intake may therefore be warranted to optimize the health of collagen-rich tissues.
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Affiliation(s)
- Christopher D Nulty
- School of Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, United Kingdom; Department of Health and Sport Science, South East Technological University, Carlow, Ireland
| | - Janette Walton
- School of Food and Nutritional Sciences, University College Cork, Cork, Republic of Ireland; Department of Biological Sciences, Munster Technological University, Cork, Republic of Ireland
| | - Robert M Erskine
- School of Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, United Kingdom; Institute of Sport, Exercise and Health, University College London, London, United Kingdom.
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8
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Kerek R, Sawma Awad J, Bassam M, Hajjar C, Ghantous F, Rizk K, Rima M. The multifunctional protein CCN1/CYR61: Bridging physiology and disease. Exp Mol Pathol 2025; 142:104969. [PMID: 40286773 DOI: 10.1016/j.yexmp.2025.104969] [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: 11/06/2024] [Revised: 04/16/2025] [Accepted: 04/18/2025] [Indexed: 04/29/2025]
Abstract
The matricellular protein CYR61/CCN1 is a member of the CCN protein family that plays significant roles in a broad range of physiological processes, including development, tissue repair, and inflammation, among others. CCN1 is also implicated in pathological conditions such as cancer and fibrosis. The diverse functions of CCN1 arise from its ability to bind different receptors located on many cell types, thereby activating diverse signaling pathways. The diverse, yet contradictory, functions mediated by CCN1 makes it a compelling target for investigation, as it offers the prospect of understanding fundamental cellular topics and their possible implications in various diseases. Recently, new cellular functions were attributed to CCN1, including senescence, pro-/anti- fibrosis, and rejuvenation. In this review, we discuss all these new findings along with the basic knowledge about CCN1 to provide an overall understanding of its conflicting roles and their potential corresponding mechanisms of action.
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Affiliation(s)
- Racha Kerek
- Department of Biological Sciences, Lebanese American University, Byblos, P.O. Box 36, Lebanon
| | - Joe Sawma Awad
- Department of Biological Sciences, Lebanese American University, Byblos, P.O. Box 36, Lebanon
| | - Mariam Bassam
- Department of Biological Sciences, Lebanese American University, Byblos, P.O. Box 36, Lebanon
| | - Carla Hajjar
- Department of Biological Sciences, Lebanese American University, Byblos, P.O. Box 36, Lebanon
| | - Fouad Ghantous
- Department of Biological Sciences, Lebanese American University, Byblos, P.O. Box 36, Lebanon
| | - Karelle Rizk
- Department of Biological Sciences, Lebanese American University, Byblos, P.O. Box 36, Lebanon
| | - Mohamad Rima
- Department of Biological Sciences, Lebanese American University, Byblos, P.O. Box 36, Lebanon.
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Guo W, Zhang C, Zhou Q, Chen T, Xu X, Zhang J, Yu X, Wu H, Zhang X, Ma L, Qian K, Klionsky DJ, Kang R, Kroemer G, Yu Y, Tang D, Wang J. Mitochondrial CCN1 drives ferroptosis via fatty acid β-oxidation. Dev Cell 2025:S1534-5807(25)00206-0. [PMID: 40280135 DOI: 10.1016/j.devcel.2025.04.004] [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: 10/08/2024] [Revised: 01/16/2025] [Accepted: 04/03/2025] [Indexed: 04/29/2025]
Abstract
Ferroptosis is a type of oxidative cell death, although its key metabolic processes remain incompletely understood. Here, we employ a comprehensive multiomics screening approach that identified cellular communication network factor 1 (CCN1) as a metabolic catalyst of ferroptosis. Upon ferroptosis induction, CCN1 relocates to mitochondrial complexes, facilitating electron transfer flavoprotein subunit alpha (ETFA)-dependent fatty acid β-oxidation. Compared with a traditional carnitine O-palmitoyltransferase 2 (CPT2)-ETFA pathway, the CCN1-ETFA pathway provides additional substrates for mitochondrial reactive oxygen species production, thereby stimulating ferroptosis through lipid peroxidation. A high-fat diet can enhance the anticancer efficacy of ferroptosis in lung cancer mouse models, depending on CCN1. Furthermore, primary lung cancer cells derived from patients with hypertriglyceridemia or high CCN1 expression demonstrate increased susceptibility to ferroptosis in vitro and in vivo. These findings do not only identify the metabolic role of mitochondrial CCN1 but also establish a strategy for enhancing ferroptosis-based anticancer therapies.
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Affiliation(s)
- Wanxin Guo
- Department of Clinical Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Congcong Zhang
- Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Qianjun Zhou
- Department of Surgical Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Tianxiang Chen
- Department of Surgical Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Xin Xu
- Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Jianfeng Zhang
- Department of Surgical Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Xuewen Yu
- Department of Surgical Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Han Wu
- Department of Surgical Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Xiao Zhang
- Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Lifang Ma
- Department of Clinical Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Kun Qian
- Institute of Medical Robotics and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Daniel J Klionsky
- Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris Cité, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, 94800 Villejuif, France; Department of Biology, Institut du Cancer Paris CARPEM, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France
| | - Yongchun Yu
- Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA.
| | - Jiayi Wang
- Department of Clinical Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Medical Science Laboratory, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
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10
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Nakata T, Kirita Y, Umehara M, Nakamura M, Sawai S, Minamida A, Yamauchi-Sawada H, Sunahara Y, Matoba Y, Okuno-Ozeki N, Nakamura I, Nakai K, Yagi-Tomita A, Yamashita N, Tamagaki K, Humphreys BD, Matoba S, Kusaba T. Injured tubular epithelia-derived CCN1 promotes the mobilization of fibroblasts toward injury sites after kidney injury. iScience 2025; 28:112176. [PMID: 40224016 PMCID: PMC11987671 DOI: 10.1016/j.isci.2025.112176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Revised: 01/28/2025] [Accepted: 03/04/2025] [Indexed: 04/15/2025] Open
Abstract
Humoral factors that prompt fibroblasts to migrate to an injury site at an appropriate time point are deemed indispensable for repair after kidney injury. We herein demonstrated the pivotal roles of injured tubule-derived cellular communication network factor 1 (CCN1) in the mobilization of fibroblasts to the injury site after kidney injury. Based on analyses of ligand-receptor interactions in vitro and tubular epithelial-specific transcriptomics in vivo, we identified the up-regulation of CCN1 during the early phases of kidney injury. CCN1 promotes fibroblast chemotaxis through focal adhesion kinase-extracellular signal-regulated kinase (ERK) signaling. In vivo analyses utilizing tubular-specific CCN1 knockout (KO) mice demonstrated the sparse accumulation of fibroblasts around injured sites after injury, resulting in ameliorated tissue fibrosis in CCN1-KO mice. These results reveal an epithelial-fibroblast CCN1 signaling axis that mobilizes fibroblasts to injured tubule early after acute injury but that promotes interstitial fibrosis at late time points.
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Affiliation(s)
- Tomohiro Nakata
- Department of Nephrolog, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yuhei Kirita
- Department of Nephrolog, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Minato Umehara
- Department of Nephrolog, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Masashi Nakamura
- Department of Nephrolog, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Shinji Sawai
- Department of Nephrolog, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Atsushi Minamida
- Department of Nephrolog, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hiroko Yamauchi-Sawada
- Department of Nephrolog, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yasuto Sunahara
- Department of Nephrolog, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yayoi Matoba
- Department of Nephrolog, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Natsuko Okuno-Ozeki
- Department of Nephrolog, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Itaru Nakamura
- Department of Nephrolog, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kunihiro Nakai
- Department of Nephrolog, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Aya Yagi-Tomita
- Department of Nephrolog, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Noriyuki Yamashita
- Department of Nephrolog, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Keiichi Tamagaki
- Department of Nephrolog, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Benjamin D. Humphreys
- Division of Nephrology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Satoaki Matoba
- Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tetsuro Kusaba
- Department of Nephrolog, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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11
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Li GH, Li YH, Yu Q, Zhou QQ, Zhang RF, Weng CJ, Ge MX, Kong QP. Unraveling the metabolic heterogeneity and commonality in senescent cells using systems modeling. LIFE MEDICINE 2025; 4:lnaf003. [PMID: 40224297 PMCID: PMC11992571 DOI: 10.1093/lifemedi/lnaf003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 01/16/2025] [Indexed: 04/15/2025]
Abstract
Cellular senescence is a key contributor to aging and aging-related diseases, but its metabolic profiles are not well understood. Here, we performed a systematic analysis of the metabolic features of four types of cellular senescence (replication, irradiation, reactive oxygen species [ROS], and oncogene) in 12 cell lines using genome-wide metabolic modeling and meta-analysis. We discovered that replicative and ROS-induced senescence share a common metabolic signature, marked by decreased lipid metabolism and downregulated mevalonate pathway, while irradiation and oncogene-induced senescence exhibit more heterogeneity and divergence. Our genome-wide knockout simulations showed that enhancing the mevalonate pathway, by administrating mevalonate for instance, could reverse the metabolic alterations associated with senescence and human tissue aging, suggesting a potential anti-aging or lifespan-extending effect. Indeed, the experiment in Caenorhabditis elegans showed that administrating mevalonate significantly increased the lifespan. Our study provides a new insight into the metabolic landscape of cell senescence and identifies potential targets for anti-aging interventions.
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Affiliation(s)
- Gong-Hua Li
- State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Key Laboratory of Healthy Aging Study, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China
| | - Yu-Hong Li
- College of Biological Resources and Food Engineering, Qujing Normal University, Qujing 655000, China
| | - Qin Yu
- State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Key Laboratory of Healthy Aging Study, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China
| | - Qing-Qing Zhou
- State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Key Laboratory of Healthy Aging Study, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China
| | - Run-Feng Zhang
- State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Key Laboratory of Healthy Aging Study, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China
| | - Chong-Jun Weng
- State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Key Laboratory of Healthy Aging Study, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China
| | - Ming-Xia Ge
- State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Key Laboratory of Healthy Aging Study, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China
| | - Qing-Peng Kong
- State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Key Laboratory of Healthy Aging Study, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China
- CAS Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China
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12
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Chandrasegaran S, Sluka JP, Shanley D. Modelling the spatiotemporal dynamics of senescent cells in wound healing, chronic wounds, and fibrosis. PLoS Comput Biol 2025; 21:e1012298. [PMID: 40233102 PMCID: PMC12052216 DOI: 10.1371/journal.pcbi.1012298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 05/05/2025] [Accepted: 03/25/2025] [Indexed: 04/17/2025] Open
Abstract
Cellular senescence is known to drive age-related pathology through the senescence-associated secretory phenotype (SASP). However, it also plays important physiological roles such as cancer suppression, embryogenesis and wound healing. Wound healing is a tightly regulated process which when disrupted results in conditions such as fibrosis and chronic wounds. Senescent cells appear during the proliferation phase of the healing process where the SASP is involved in maintaining tissue homeostasis after damage. Interestingly, SASP composition and functionality was recently found to be temporally regulated, with distinct SASP profiles involved: a fibrogenic, followed by a fibrolytic SASP, which could have important implications for the role of senescent cells in wound healing. Given the number of factors at play a full understanding requires addressing the multiple levels of complexity, pertaining to the various cell behaviours, individually followed by investigating the interactions and influence each of these elements have on each other and the system as a whole. Here, a systems biology approach was adopted whereby a multi-scale model of wound healing that includes the dynamics of senescent cell behaviour and corresponding SASP composition within the wound microenvironment was developed. The model was built using the software CompuCell3D, which is based on a Cellular Potts modelling framework. We used an existing body of data on healthy wound healing to calibrate the model and validation was done on known disease conditions. The model clearly shows how differences in the spatiotemporal dynamics of different senescent cell phenotypes lead to several distinct repair outcomes. These differences in senescent cell dynamics can be attributed to variable SASP composition, duration of senescence and temporal induction of senescence relative to the healing stage. The range of outcomes demonstrated strongly highlight the dynamic and heterogenous role of senescent cells in wound healing, fibrosis and chronic wounds, and their fine-tuned control. Further specific data to increase model confidence could be used to explore senolytic treatments in wound disorders.
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Affiliation(s)
| | - James P. Sluka
- Department of Intelligent Systems Engineering and Biocomplexity Institute, Indiana University Bloomington, Bloomington, Indiana, United States of America
| | - Daryl Shanley
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
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13
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Dworak H, Rozmaric T, Grillari J, Ogrodnik M. Cells of all trades - on the importance of spatial positioning of senescent cells in development, healing and aging. FEBS Lett 2025:10.1002/1873-3468.70037. [PMID: 40156464 PMCID: PMC7617592 DOI: 10.1002/1873-3468.70037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 02/28/2025] [Accepted: 03/04/2025] [Indexed: 04/01/2025]
Abstract
Biological processes are often spatially regulated, ensuring molecular and cellular events occur in their most strategically advantageous locations. Cellular senescence, marked by cell cycle arrest and hypersecretion, is recognized as an important part of physiological processes like development and healing, but it also contributes to aging and disease. However, the spatial distribution of senescent cells and its physiological and pathological impact remain unclear. Here we compile evidence on senescent cell localization in development, healing, and aging. We emphasize the significance of their spatial patterns and speculate on the effects of disrupted spatial positioning of senescence in relation to pathologies. To summarize the specific spatial functions of senescent cells, we propose to refer to them as 'barrier' and 'conductor' functions. The 'barrier' function of senescent cells, due to their altered morphology and apoptosis resistance, separates tissues and builds a border between two environments. The conductor function, with the secretion of signaling factors, influences the surrounding area and stimulates migration, differentiation, or proliferation, among other processes. Overall, this Review explores the spatial patterning of cellular senescence in biological processes, highlighting its dual roles as 'barrier' and 'conductor' functions, and examines the implications of senescent cell distribution in development, healing, aging, and disease.
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Affiliation(s)
- Helene Dworak
- Ludwig Boltzmann Institute for Traumatology. The Research Center in cooperation with AUVA, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Tomaz Rozmaric
- Ludwig Boltzmann Institute for Traumatology. The Research Center in cooperation with AUVA, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Johannes Grillari
- Ludwig Boltzmann Institute for Traumatology. The Research Center in cooperation with AUVA, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
- Institute of Molecular Biotechnology, BOKU University, Vienna, Muthgasse 18, Vienna, Austria
| | - Mikolaj Ogrodnik
- Ludwig Boltzmann Institute for Traumatology. The Research Center in cooperation with AUVA, Vienna, Austria
- Austrian Cluster for Tissue Regeneration, Vienna, Austria
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14
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Luo L, Yang H, Huang J, Chen D, He Y, Lin J, Zeng H, Hua C, Lin Z, Wu M, Ma Y, Deng Q, Liu M, Li S. Airway basal stem cell-derived extracellular vesicles modulate proliferation, migration and collagen deposition of fibroblasts. Stem Cell Res Ther 2025; 16:140. [PMID: 40102996 PMCID: PMC11921531 DOI: 10.1186/s13287-025-04268-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 03/06/2025] [Indexed: 03/20/2025] Open
Abstract
BACKGROUND Human bronchial epithelial cell-derived extracellular vesicles have demonstrated the ability to attenuate fibroblasts activation. However, the specific key effector cell populations mediating this inhibitory effect remain unidentified. Airway basal stem cells (BSCs), which serve as progenitor cells for bronchial epithelial cells, play a critical role in fibrotic remodeling processes and possess significant therapeutic potential. This study aimed to characterize BSC-derived extracellular vesicles (BSC-EVs) and investigate their regulatory influence on fibroblasts behavior. METHODS Airway BSCs were collected through bronchoscopic brushing and differential centrifugation. Fibroblasts were subsequently treated with BSC-EVs at various concentrations to evaluate their dose- and time-dependent effects in vitro. The proteomic composition of BSC-EVs was analyzed using four-dimensional data-independent acquisition quantitative mass spectrometry (4D-DIA). Moreover, a bleomycin-induced pulmonary fibrosis model was established to evaluate the safety and preliminary efficacy of BSC-EVs. RESULTS We successfully isolated and identified BSC-EVs, which expressed the nucleus-specific marker TP63, indicative of BSCs, but lacked the BSC marker KRT5. Our findings demonstrated that BSC-EVs enhanced fibroblasts proliferation and migration in a dose-dependent manner. Importantly, BSC-EVs significantly attenuated fibroblasts activation and promoted fibroblasts senescence. Utilizing 4D-DIA quantitative proteomics, we revealed that BSC-EVs modulate extracellular matrix remodeling processes and regulate the expression of key proteins, including collagen I/III and matrix metalloproteinases. Animal models utilizing intratracheal administration of BSC-EVs demonstrate efficient reduction of collagen deposition. CONCLUSION This study offers an extensive characterization of BSC-EVs, adhering to the guidelines set forth by MISEV2023. The findings underscore the significant therapeutic potential of BSC-EVs in the management of fibrotic diseases.
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Affiliation(s)
- Lisi Luo
- Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
- Guangzhou National Laboratory, Guangzhou International Bio Island, No. 9 XingDaoHuanBei Road, Guangzhou, 510005, Guangdong Province, China
- Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Huijie Yang
- Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
- Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Junfeng Huang
- Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
- Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Difei Chen
- Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
- Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yushan He
- Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
- Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Jinsheng Lin
- Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
- Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Haikang Zeng
- Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Chu Hua
- Guangzhou Medical University, Guangzhou, Guangdong, China
- Translatiaonl Research Centre of Regenrative Medicine and 3D Printing Technologies, Guangzhou Medical University, Guangzhou, China
| | - Zikai Lin
- Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
- Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Minting Wu
- Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yuqin Ma
- Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
- Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Qilin Deng
- Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
- Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Ming Liu
- Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
| | - Shiyue Li
- Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
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15
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Umrath F, Frick SL, Wendt V, Naros A, Zimmerer R, Alexander D. Inhibition of TGF-β signaling enhances osteogenic potential of iPSC-derived MSCs. Sci Rep 2025; 15:7814. [PMID: 40050624 PMCID: PMC11885616 DOI: 10.1038/s41598-025-89370-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 02/05/2025] [Indexed: 03/09/2025] Open
Abstract
Mesenchymal stem cells (MSCs) represent the most commonly utilized type of stem cell in clinical applications. However, variability in quality and quantity between different tissue sources and donors presents a significant challenge to their use. Induced pluripotent stem cells (iPSCs) are a promising and abundant alternative source of MSCs, offering a potential solution to the limitations of adult MSCs. Nevertheless, a standardized protocol for the differentiation of iPSCs into iPSC-derived mesenchymal stem cells (iMSCs) has yet to be established, as the existing methods vary significantly in terms of complexity, duration, and outcome. Many straightforward methods induce differentiation by culturing iPSCs in MSC media which are supplemented with fetal bovine serum (FBS) or human platelet lysate (hPL), followed by selection of MSC-like cells by passaging. However, in our hands, this approach yielded inconsistent quality of iMSCs, particularly in terms of osteogenic potential and premature senescence. This study examines the impact of the selective TGF-β inhibitor SB431542 on iMSC differentiation, demonstrating that TGF-β inhibition enhances osteogenic potential and reduces premature senescence. Additionally, we present a reliable, xeno-free method for producing high-quality iMSCs that can be adapted for Good Manufacturing Practice (GMP) compliance, thus enhancing the potential for clinical applications.
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Affiliation(s)
- Felix Umrath
- Department of Oral and Maxillofacial Surgery, University Hospital Tübingen, Osianderstr. 2-8, Tübingen, 72076, Germany.
- Department of Orthopedic Surgery, University Hospital Tübingen, Tübingen, Germany.
| | - Sarah-Lena Frick
- Department of Oral and Maxillofacial Surgery, University Hospital Tübingen, Osianderstr. 2-8, Tübingen, 72076, Germany
| | - Valerie Wendt
- Department of Oral and Maxillofacial Surgery, University Hospital Tübingen, Osianderstr. 2-8, Tübingen, 72076, Germany
| | - Andreas Naros
- Department of Oral and Maxillofacial Surgery, University Hospital Tübingen, Osianderstr. 2-8, Tübingen, 72076, Germany
| | - Rüdiger Zimmerer
- Department of Oral and Maxillofacial Surgery, University Hospital Tübingen, Osianderstr. 2-8, Tübingen, 72076, Germany
| | - Dorothea Alexander
- Department of Oral and Maxillofacial Surgery, University Hospital Tübingen, Osianderstr. 2-8, Tübingen, 72076, Germany
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16
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Fan J, Liu X, Guo SW. Hypermethylation of Klotho and Peroxisome Proliferator-Activated Receptor γ Concomitant with Overexpression of DNA Methyltransferase 1 in Adenomyosis. Reprod Sci 2025; 32:668-683. [PMID: 38816595 DOI: 10.1007/s43032-024-01599-4] [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: 02/29/2024] [Accepted: 05/14/2024] [Indexed: 06/01/2024]
Abstract
Cellular senescence is known to be involved in tissue repair, but its role in adenomyosis remains unclear. This study was tasked to evaluate the expression of Klotho, a well-known aging-suppressing protein, as well as PPARγ and DNMT1 in adenomyotic lesions (AD) in comparison with that of control endometrium (CT). We performed immunohistochemistry analysis of markers of cellular senescence p16 and p21, along with Klotho, PPARγ and DNMT1 in CT and AD samples, followed by the quantification of gene expression of Klotho, PPARγ and DNMT1 in epithelial organoids derived from AD and CT samples and methylation-specific PCR to evaluate promoter methylation status. The effect of forced expression and knockdown of DNMT1 on Klotho and PPARγ expression in ectopic endometrial epithelial cells was evaluated. We found that both p16 and p21 immunoreactivity in AD was significantly higher while that of Klotho and PPARγ was significantly lower than CT samples, which was concomitant with elevated immunoexpression of DNMT1. The results were confirmed by transcriptional analysis using epithelial organoids derived from AD and CT samples. In addition, the promoter regions of both Klotho and PPARγ genes were hypermethylated in AD as compared with CT, and treatment with HDAC and DNMT inhibitors reactivated the expression of both Klotho and PPARγ. Forced expression of DNMT1 resulted in downregulation of both Klotho and PPARγ but its knockdown increased their expression. Thus, overexpression of DNMT1 seems to facilitate the promoter hypermethylation of both Klotho and PPARγ in AD, resulting in their reduced expression that is suggestive of the role of senescence in adenomyosis.
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Affiliation(s)
- Jiao Fan
- Department of General Gynecology, Shanghai OB/GYN Hospital, Fudan University, Shanghai, 200011, China
| | - Xishi Liu
- Department of General Gynecology, Shanghai OB/GYN Hospital, Fudan University, Shanghai, 200011, China
| | - Sun-Wei Guo
- Research Institute, Shanghai Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China.
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17
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Tong H, Guo X, Chen L, Wang H, Hu X, He A, Li C, Zhang T, Kang J, Fu Y. Quercetin prevents the loss of chondrogenic capacity in expansion cultured human auricular chondrocytes by alleviating mitochondrial dysfunction. Regen Ther 2025; 28:358-370. [PMID: 39896443 PMCID: PMC11783217 DOI: 10.1016/j.reth.2025.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 12/25/2024] [Accepted: 01/04/2025] [Indexed: 02/04/2025] Open
Abstract
Objective To explore the characteristics of cellular senescence in human auricular chondrocytes during long-term in vitro culture and to evaluate the effects of anti-senescence treatments on enhancing their chondrogenic function. Methods Auricular chondrocytes exhibited senescence-related characteristics after prolonged expansion in culture. To identify senescence inducers, transcriptome sequencing was performed, with findings corroborated by transmission electron microscopy analyses. Quercetin was employed as an intervention to mitigate cellular senescence progression. The alterations in cellular senescence and mitochondrial function were evaluated. Regenerative cartilage tissue was developed through in vitro chondrogenic induction and in vivo implantation with GelMA hydrogel-loaded cells in nude mice. The impact of quercetin was substantiated through histological examinations. Results Mitochondrial dysfunction was a key characteristic of auricular chondrocytes after long-term expansion culture. Chondrocytes cultured with quercetin showed a lower proportion of senescent cells and reduced mitochondrial dysfunction. The chondrocytes cultured with continuous application of quercetin formed higher quality regenerative cartilage both in vitro and in vivo compared to the control group. Conclusion The results reveal that quercetin attenuates chondrocyte senescence by alleviating mitochondrial dysfunction, thereby preventing the loss of chondrogenic function in chondrocytes subjected to long-term expansion culture.
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Affiliation(s)
- Hua Tong
- Department of Facial Plastic and Reconstructive Surgery, Eye & ENT Hospital, Fudan University, Shanghai 200031, China
- ENT Institute, Eye & ENT Hospital, Fudan University, Shanghai 200031, China
| | - Xudong Guo
- School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Lili Chen
- Department of Facial Plastic and Reconstructive Surgery, Eye & ENT Hospital, Fudan University, Shanghai 200031, China
- ENT Institute, Eye & ENT Hospital, Fudan University, Shanghai 200031, China
| | - Honglei Wang
- Department of Facial Plastic and Reconstructive Surgery, Eye & ENT Hospital, Fudan University, Shanghai 200031, China
- ENT Institute, Eye & ENT Hospital, Fudan University, Shanghai 200031, China
| | - Xuerui Hu
- Department of Facial Plastic and Reconstructive Surgery, Eye & ENT Hospital, Fudan University, Shanghai 200031, China
- ENT Institute, Eye & ENT Hospital, Fudan University, Shanghai 200031, China
| | - Aijuan He
- Department of Facial Plastic and Reconstructive Surgery, Eye & ENT Hospital, Fudan University, Shanghai 200031, China
- ENT Institute, Eye & ENT Hospital, Fudan University, Shanghai 200031, China
| | - Chenlong Li
- Department of Facial Plastic and Reconstructive Surgery, Eye & ENT Hospital, Fudan University, Shanghai 200031, China
- ENT Institute, Eye & ENT Hospital, Fudan University, Shanghai 200031, China
| | - Tianyu Zhang
- Department of Facial Plastic and Reconstructive Surgery, Eye & ENT Hospital, Fudan University, Shanghai 200031, China
- ENT Institute, Eye & ENT Hospital, Fudan University, Shanghai 200031, China
- NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China
| | - Jiuhong Kang
- School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Yaoyao Fu
- Department of Facial Plastic and Reconstructive Surgery, Eye & ENT Hospital, Fudan University, Shanghai 200031, China
- ENT Institute, Eye & ENT Hospital, Fudan University, Shanghai 200031, China
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18
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Raissi-Dehkordi N, Raissi-Dehkordi N, Ebrahimibagha H, Tayebi T, Moeinabadi-Bidgoli K, Hassani M, Niknejad H. Advancing chronic and acute wound healing with cold atmospheric plasma: cellular and molecular mechanisms, benefits, risks, and future directions. Front Med (Lausanne) 2025; 12:1527736. [PMID: 40093019 PMCID: PMC11907477 DOI: 10.3389/fmed.2025.1527736] [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: 11/16/2024] [Accepted: 01/23/2025] [Indexed: 03/19/2025] Open
Abstract
Chronic and acute wounds represent significant challenges in healthcare, often leading to prolonged recovery times and increased complications. While chronic wounds, such as diabetic foot ulcers and venous leg ulcers, persist due to underlying conditions and biofilm formation, acute wounds, including surgical incisions and burns, can also benefit from innovative therapeutic approaches. Cold atmospheric plasma (CAP) has emerged as a promising non-invasive therapy capable of enhancing wound healing outcomes across both wound types. This review examines the cellular and molecular mechanisms by which CAP promotes wound repair, focusing on its modulation of inflammation, stimulation of angiogenesis, facilitation of tissue remodeling, and antimicrobial effects, which can potentially be used in regenerative medicine. CAP generates reactive oxygen and nitrogen species that influence key cellular processes, accelerating tissue regeneration while reducing bacterial load and preventing biofilm formation. Clinical applications of CAP have demonstrated its efficacy in improving wound healing metrics for both chronic and acute wounds. Despite promising results, translating CAP into routine clinical practice requires addressing challenges such as standardizing treatment protocols, assessing long-term safety, and developing portable devices. Future research should prioritize optimizing CAP parameters and exploring combination therapies to maximize its therapeutic potential. Overall, CAP represents a safe, effective, and versatile modality in wound management, with the potential to significantly improve patient outcomes in both chronic and acute wound care.
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Affiliation(s)
- Nastaran Raissi-Dehkordi
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Negar Raissi-Dehkordi
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Ebrahimibagha
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Tahereh Tayebi
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kasra Moeinabadi-Bidgoli
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Hassani
- Department of Vascular and Endovascular Surgery, Taleghani General Hospital, Tehran, Iran
| | - Hassan Niknejad
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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19
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Liberale L, Tual-Chalot S, Sedej S, Ministrini S, Georgiopoulos G, Grunewald M, Bäck M, Bochaton-Piallat ML, Boon RA, Ramos GC, de Winther MPJ, Drosatos K, Evans PC, Ferguson JF, Forslund-Startceva SK, Goettsch C, Giacca M, Haendeler J, Kallikourdis M, Ketelhuth DFJ, Koenen RR, Lacolley P, Lutgens E, Maffia P, Miwa S, Monaco C, Montecucco F, Norata GD, Osto E, Richardson GD, Riksen NP, Soehnlein O, Spyridopoulos I, Van Linthout S, Vilahur G, Wentzel JJ, Andrés V, Badimon L, Benetos A, Binder CJ, Brandes RP, Crea F, Furman D, Gorbunova V, Guzik TJ, Hill JA, Lüscher TF, Mittelbrunn M, Nencioni A, Netea MG, Passos JF, Stamatelopoulos KS, Tavernarakis N, Ungvari Z, Wu JC, Kirkland JL, Camici GG, Dimmeler S, Kroemer G, Abdellatif M, Stellos K. Roadmap for alleviating the manifestations of ageing in the cardiovascular system. Nat Rev Cardiol 2025:10.1038/s41569-025-01130-5. [PMID: 39972009 DOI: 10.1038/s41569-025-01130-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/22/2025] [Indexed: 02/21/2025]
Abstract
Ageing of the cardiovascular system is associated with frailty and various life-threatening diseases. As global populations grow older, age-related conditions increasingly determine healthspan and lifespan. The circulatory system not only supplies nutrients and oxygen to all tissues of the human body and removes by-products but also builds the largest interorgan communication network, thereby serving as a gatekeeper for healthy ageing. Therefore, elucidating organ-specific and cell-specific ageing mechanisms that compromise circulatory system functions could have the potential to prevent or ameliorate age-related cardiovascular diseases. In support of this concept, emerging evidence suggests that targeting the circulatory system might restore organ function. In this Roadmap, we delve into the organ-specific and cell-specific mechanisms that underlie ageing-related changes in the cardiovascular system. We raise unanswered questions regarding the optimal design of clinical trials, in which markers of biological ageing in humans could be assessed. We provide guidance for the development of gerotherapeutics, which will rely on the technological progress of the diagnostic toolbox to measure residual risk in elderly individuals. A major challenge in the quest to discover interventions that delay age-related conditions in humans is to identify molecular switches that can delay the onset of ageing changes. To overcome this roadblock, future clinical trials need to provide evidence that gerotherapeutics directly affect one or several hallmarks of ageing in such a manner as to delay, prevent, alleviate or treat age-associated dysfunction and diseases.
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Affiliation(s)
- Luca Liberale
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino Genoa - Italian Cardiovascular Network, Genoa, Italy
| | - Simon Tual-Chalot
- Biosciences Institute, Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
| | - Simon Sedej
- Department of Cardiology, Medical University of Graz, Graz, Austria
| | - Stefano Ministrini
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
| | | | - Myriam Grunewald
- Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Magnus Bäck
- Translational Cardiology, Centre for Molecular Medicine, Department of Medicine Solna, and Department of Cardiology, Heart and Vascular Centre, Karolinska Institutet, Stockholm, Sweden
- Inserm, DCAC, Université de Lorraine, Nancy, France
| | | | - Reinier A Boon
- Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC location VUmc, Amsterdam, Netherlands
| | - Gustavo Campos Ramos
- Department of Internal Medicine I/Comprehensive Heart Failure Centre, University Hospital Würzburg, Würzburg, Germany
| | - Menno P J de Winther
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences: Atherosclerosis and Ischaemic Syndromes; Amsterdam Infection and Immunity: Inflammatory Diseases, Amsterdam UMC location AMC, Amsterdam, Netherlands
| | - Konstantinos Drosatos
- Metabolic Biology Laboratory, Cardiovascular Center, Department of Pharmacology, Physiology, and Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Paul C Evans
- William Harvey Research Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Jane F Ferguson
- Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Sofia K Forslund-Startceva
- Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Claudia Goettsch
- Department of Internal Medicine I, Division of Cardiology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Mauro Giacca
- British Heart foundation Centre of Reseach Excellence, King's College London, London, UK
| | - Judith Haendeler
- Cardiovascular Degeneration, Medical Faculty, University Hospital and Heinrich-Heine University, Düsseldorf, Germany
| | - Marinos Kallikourdis
- Adaptive Immunity Lab, IRCCS Humanitas Research Hospital, Rozzano (Milan), Italy
| | - Daniel F J Ketelhuth
- Cardiovascular and Renal Research Unit, Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Rory R Koenen
- CARIM-School for Cardiovascular Diseases, Department of Biochemistry, Maastricht University, Maastricht, Netherlands
| | | | - Esther Lutgens
- Department of Cardiovascular Medicine & Immunology, Mayo Clinic, Rochester, MN, USA
| | - Pasquale Maffia
- School of Infection & Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Satomi Miwa
- Biosciences Institute, Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK
| | - Claudia Monaco
- Kennedy Institute, NDORMS, University of Oxford, Oxford, UK
| | - Fabrizio Montecucco
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino Genoa - Italian Cardiovascular Network, Genoa, Italy
| | - Giuseppe Danilo Norata
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Elena Osto
- Division of Physiology and Pathophysiology, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Medical University of Graz, Graz, Austria
| | - Gavin D Richardson
- Biosciences Institute, Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK
| | - Niels P Riksen
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands
| | - Oliver Soehnlein
- Institute of Experimental Pathology, University of Münster, Münster, Germany
| | - Ioakim Spyridopoulos
- Translational and Clinical Research Institute, Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK
| | - Sophie Van Linthout
- BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité - Universitätmedizin Berlin, Berlin, Germany
| | - Gemma Vilahur
- Research Institute, Hospital de la Santa Creu y Sant Pau l, IIB-Sant Pau, Barcelona, Spain
| | - Jolanda J Wentzel
- Cardiology, Biomedical Engineering, Erasmus MC, Rotterdam, Netherlands
| | - Vicente Andrés
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), CIBERCV, Madrid, Spain
| | - Lina Badimon
- Cardiovascular Health and Innovation Research Foundation (FICSI) and Cardiovascular Health and Network Medicine Department, University of Vic (UVIC-UCC), Barcelona, Spain
| | - Athanase Benetos
- Department of Geriatrics, University Hospital of Nancy and Inserm DCAC, Université de Lorraine, Nancy, France
| | - Christoph J Binder
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Ralf P Brandes
- Institute for Cardiovascular Physiology, Goethe University, Frankfurt am Main, Germany
| | - Filippo Crea
- Centre of Excellence of Cardiovascular Sciences, Ospedale Isola Tiberina - Gemelli Isola, Roma, Italy
| | - David Furman
- Buck Institute for Research on Aging, Novato, CA, USA
| | - Vera Gorbunova
- Departments of Biology and Medicine, University of Rochester, Rochester, NY, USA
| | - Tomasz J Guzik
- Centre for Cardiovascular Sciences, University of Edinburgh, Edinburgh, UK
| | - Joseph A Hill
- University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Thomas F Lüscher
- Heart Division, Royal Brompton and Harefield Hospital and National Heart and Lung Institute, Imperial College, London, UK
| | - María Mittelbrunn
- Consejo Superior de Investigaciones Científicas (CSIC), Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid (UAM), Madrid, Spain
| | - Alessio Nencioni
- IRCCS Ospedale Policlinico San Martino Genoa - Italian Cardiovascular Network, Genoa, Italy
- Dipartimento di Medicina Interna e Specialità Mediche-DIMI, Università degli Studi di Genova, Genova, Italy
| | - Mihai G Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands
| | - João F Passos
- Department of Physiology and Biomedical Engineering, Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
| | - Kimon S Stamatelopoulos
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Nektarios Tavernarakis
- Medical School, University of Crete, and Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Greece
| | - Zoltan Ungvari
- Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Joseph C Wu
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - James L Kirkland
- Center for Advanced Gerotherapeutics, Division of Endocrinology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Giovanni G Camici
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
| | - Stefanie Dimmeler
- Institute for Cardiovascular Regeneration, Goethe University, Frankfurt am Main, Germany
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université Paris Cité, Sorbonne Université, Inserm, Institut Universitaire de France, Paris, France
| | | | - Konstantinos Stellos
- Department of Cardiovascular Research, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
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20
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Carver CM, Rodriguez SL, Atkinson EJ, Dosch AJ, Asmussen NC, Gomez PT, Leitschuh EA, Espindola-Netto JM, Jeganathan KB, Whaley MG, Kamenecka TM, Baker DJ, Haak AJ, LeBrasseur NK, Schafer MJ. IL-23R is a senescence-linked circulating and tissue biomarker of aging. NATURE AGING 2025; 5:291-305. [PMID: 39658621 PMCID: PMC11839461 DOI: 10.1038/s43587-024-00752-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Accepted: 10/17/2024] [Indexed: 12/12/2024]
Abstract
Cellular senescence is an aging mechanism characterized by cell cycle arrest and a senescence-associated secretory phenotype (SASP). Preclinical studies demonstrate that senolytic drugs, which target survival pathways in senescent cells, can counteract age-associated conditions that span several organs. The comparative efficacy of distinct senolytic drugs for modifying aging and senescence biomarkers in vivo has not been demonstrated. Here, we established aging- and senescence-related plasma proteins and tissue transcripts that changed in old versus young female and male mice. We investigated responsivity to acute treatment with venetoclax, navitoclax, fisetin or luteolin versus transgenic senescent cell clearance in aged p16-InkAttac mice. We discovered that age-dependent changes in plasma proteins, including IL-23R, CCL5 and CA13, were reversed by senotherapeutics, which corresponded to expression differences in tissues, particularly in the kidney. In plasma from humans across the lifespan, IL-23R increased with age. Our results reveal circulating factors as candidate mediators of senescence-associated interorgan signal transduction and translationally impactful biomarkers of systemic senescent cell burden.
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Affiliation(s)
- Chase M Carver
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
| | - Sonia L Rodriguez
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
| | - Elizabeth J Atkinson
- Department of Quantitative Health Sciences, Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, USA
| | - Andrew J Dosch
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
| | - Niels C Asmussen
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
| | - Paul T Gomez
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | - Ethan A Leitschuh
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
| | - Jair M Espindola-Netto
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
| | - Karthik B Jeganathan
- Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA
| | - Madison G Whaley
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Theodore M Kamenecka
- Department of Molecular Medicine, UF Scripps Institute, The Scripps Research Institute, Scripps Florida, Jupiter, FL, USA
| | - Darren J Baker
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
- Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | - Andrew J Haak
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Nathan K LeBrasseur
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
| | - Marissa J Schafer
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA.
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
- Department of Neurology, Mayo Clinic, Rochester, MN, USA.
- Department of Neuroscience, Mayo Clinic, Rochester, MN, USA.
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21
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Widgerow AD, Ziegler ME, Shafiq F. TriHex 2.0-Advancing Skin Health Science and the TriHex Technology. J Cosmet Dermatol 2025; 24:e16690. [PMID: 39660586 PMCID: PMC11845939 DOI: 10.1111/jocd.16690] [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: 10/14/2024] [Revised: 10/30/2024] [Accepted: 11/09/2024] [Indexed: 12/12/2024]
Abstract
BACKGROUND The original TriHex combination-Tripeptide-1 and Hexapeptide-12 (TriHex) encompasses a peptide combination selected for its ability to modulate the extracellular matrix (ECM) by progressively eliminating clumped collagen and elastin fragments and then stimulating replacement with new collagen and elastin. Incorporation of a proprietary, patent-pending Octapeptide-45 (Octa) to the TriHex original provides potential for added benefit based on the peptide's capacity to stimulate hyaluronic acid (HA) and its anticipated added benefit in wound healing. This is named TriHex 2.0 in the paper. MATERIALS AND METHODS A full-scale validation process was structured to assess Octa synergy with TriHex using an ex vivo model, assessing ECM changes histologically in relation to elastin, HA and basement membrane components. In addition, gene expression studies were undertaken, including bulk and single cell sequencing analysis to assess the particular changes that occurred by adding Octa to the TriHex. Following the gene expression analysis, a further round of ex vivo studies was conducted to assess protein expression of the defined differentially expressed genes using histological staining. RESULTS Octa synergized with TriHex as demonstrated by significantly upregulated genes (p < 0.05) affecting the ECM and basement membrane. A histological assessment using the ex vivo model demonstrated tropoelastin intensity significantly increasing with TriHex (43%) and 2.0 (42%) (p < 0.05 for both) compared to untreated explants. HA levels (CD44 intensity) significantly increased with TriHex (69%; p < 0.01), while TriHex 2.0 demonstrated HA levels 160% greater (p < 0.001) than the untreated tissue. Single cell sequencing identified a gene expression profile upregulation relating to ECM modulation and wound healing in both TriHex and 2.0, but TriHex 2.0 showed additional activities in basement membrane physiology, stem cell recruitment, and protection of fibroblasts against cellular senescence. CONCLUSION The addition of Octapeptide-45 to TriHex technology in the form of TriHex 2.0 is a significant advance to TriHex technology science. Both forms demonstrate ECM remodeling and positive wound healing, but supplementary benefits are evident including increased elastin and hyaluronic acid stimulation, added effects on the basement membrane, additional wound healing capacity in basal keratinocytes and anti-senescent effects in fibroblasts. This is helpful for pre-conditioning of the skin prior to procedures and post procedure related to additional ECM remodeling, wound healing advantages, senescent cell targeting and DEJ strengthening. Clinical studies to follow.
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Affiliation(s)
- Alan D. Widgerow
- Division Chief Research, Professor Plastic Surgery Center for Tissue EngineeringUniversity of CaliforniaIrvineCaliforniaUSA
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22
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Li Z, Wang Y, Yang Z, Pang J, Song L, Liu C, Zhang J, Dong L. Drug-induced senescence of donor dermal fibroblasts enhances revascularization and graft success in skin transplantation. Eur J Pharmacol 2025; 987:177208. [PMID: 39694176 DOI: 10.1016/j.ejphar.2024.177208] [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: 08/07/2024] [Revised: 12/12/2024] [Accepted: 12/16/2024] [Indexed: 12/20/2024]
Abstract
Full-thickness skin grafts often face challenges related to inefficient vascularization in clinical settings. Senescent cells, known for secreting various growth factors, have demonstrated excellent effects on angiogenesis. In this study, we induced senescence in a subset of fibroblasts in the donor dermis by co-administering trametinib and palbociclib before harvesting the skin grafts for transplantation. Grafts containing these senescent fibroblasts showed significant promotion of vascularization when surgically transplanted into recipient animals. This approach resulted in a 100% survival rate of the transplanted skin. Additionally, the senescent fibroblasts optimized wound healing and matrix remodeling, subsequently reducing inflammation and scar hyperplasia. Importantly, these senescent fibroblasts disappeared 14 days post-grafting, preventing excessive accumulation of senescent cells. Overall, our study indicates that inducing senescence in the donor dermis prior to transplantation is an effective strategy to enhance vascularization and increase the success rate of skin grafting.
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Affiliation(s)
- Zhenjiang Li
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210023, China
| | - Yulian Wang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210023, China
| | - Zhewei Yang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210023, China
| | - Jiayun Pang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210023, China
| | - Lin Song
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210023, China
| | - Chunyan Liu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210023, China
| | - Junfeng Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210023, China; School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong, 266003, China.
| | - Lei Dong
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210023, China; Chemistry and Biomedicine Innovative Center, Nanjing University, Nanjing, Jiangsu, 210023, China.
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23
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Yu GT, Ganier C, Allison DB, Tchkonia T, Khosla S, Kirkland JL, Lynch MD, Wyles SP. Mapping epidermal and dermal cellular senescence in human skin aging. Aging Cell 2025; 24:e14358. [PMID: 39370688 PMCID: PMC11709101 DOI: 10.1111/acel.14358] [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: 05/12/2024] [Revised: 08/27/2024] [Accepted: 09/13/2024] [Indexed: 10/08/2024] Open
Abstract
Single-cell RNA sequencing and spatial transcriptomics enable unprecedented insight into cellular and molecular pathways implicated in human skin aging and regeneration. Senescent cells are individual cells that are irreversibly cell cycle arrested and can accumulate across the human lifespan due to cell-intrinsic and -extrinsic stressors. With an atlas of single-cell RNA-sequencing and spatial transcriptomics, epidermal and dermal senescence and its effects were investigated, with a focus on melanocytes and fibroblasts. Photoaging due to ultraviolet light exposure was associated with higher burdens of senescent cells, a sign of biological aging, compared to chronological aging. A skin-specific cellular senescence gene set, termed SenSkin™, was curated and confirmed to be elevated in the context of photoaging, chronological aging, and non-replicating CDKN1A+ (p21) cells. In the epidermis, senescent melanocytes were associated with elevated melanin synthesis, suggesting haphazard pigmentation, while in the dermis, senescent reticular dermal fibroblasts were associated with decreased collagen and elastic fiber synthesis. Spatial analysis revealed the tendency for senescent cells to cluster, particularly in photoaged skin. This work proposes a strategy for characterizing age-related skin dysfunction through the lens of cellular senescence and suggests a role for senescent epidermal cells (i.e., melanocytes) and senescent dermal cells (i.e., reticular dermal fibroblasts) in age-related skin sequelae.
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Affiliation(s)
- Grace T. Yu
- Mayo Clinic Medical Scientist Training ProgramMayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic Alix School of MedicineRochesterMinnesotaUSA
| | - Clarisse Ganier
- Centre for Gene Therapy and Regenerative MedicineKing's College London, Guy's HospitalLondonUK
| | | | - Tamara Tchkonia
- Division of Endocrinology and Metabolism, Department of MedicineCenter for Gerotherapeutics, Cedars‐Sinai Medical CenterLos AngelesCaliforniaUSA
| | - Sundeep Khosla
- Division of Endocrinology, Department of MedicineMayo ClinicRochesterMinnesotaUSA
- Robert and Arlene Kogod Center on AgingMayo ClinicRochesterMinnesotaUSA
| | - James L. Kirkland
- Division of Endocrinology and Metabolism, Department of MedicineCenter for Gerotherapeutics, Cedars‐Sinai Medical CenterLos AngelesCaliforniaUSA
| | - Magnus D. Lynch
- Centre for Gene Therapy and Regenerative MedicineKing's College London, Guy's HospitalLondonUK
- St. John's Institute of DermatologyKing's College London, Guy's HospitalLondonUK
| | - Saranya P. Wyles
- Robert and Arlene Kogod Center on AgingMayo ClinicRochesterMinnesotaUSA
- Department of DermatologyMayo ClinicRochesterMinnesotaUSA
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24
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Yu Lin MO, Sampath D, Bosykh DA, Wang C, Wang X, Subramaniam T, Han W, Hong W, Chakraborty S. YAP/TAZ Drive Agrin-Matrix Metalloproteinase 12-Mediated Diabetic Skin Wound Healing. J Invest Dermatol 2025; 145:155-170.e2. [PMID: 38810954 DOI: 10.1016/j.jid.2024.05.005] [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: 09/05/2023] [Revised: 04/19/2024] [Accepted: 05/06/2024] [Indexed: 05/31/2024]
Abstract
Macroscopic loss of extracellular matrix can lead to chronic defects in skin wound healing, but supplementation of extracellular matrix holds promise for facilitating wound closure, particularly in diabetic wound healing. We recently showed that the extracellular matrix proteoglycan agrin accelerates cutaneous wound healing by improving mechanoperception of migrating keratinocytes and allowing them to respond to mechanical stresses through matrix metalloproteinase 12 (MMP12). RNA-sequencing analysis revealed that in addition to a disorganized extracellular matrix, agrin-depleted skin cells have impaired YAP/TAZ transcriptional outcomes, leading us to hypothesize that YAP/TAZ, as central mechanosensors, drive the functionality of agrin-MMP12 signaling during cutaneous wound repair. In this study, we demonstrate that agrin activates YAP/TAZ during migration of keratinocytes after wounding in vitro and in vivo. Mechanistically, YAP/TAZ sustain agrin and MMP12 protein expression during migration after wounding through positive feedback. YAP/TAZ silencing abolishes agrin-MMP12-mediated force recognition and geometrical constraints. Importantly, soluble agrin therapy accelerates wound closure in diabetic mouse models by engaging MMP12-YAP. Because patients with diabetic foot ulcers and impaired wound healing have reduced expression of agrin-MMP12 that correlates with YAP/TAZ inactivation, we propose that timely activation of YAP/TAZ by soluble agrin therapy can accentuate mechanobiological microenvironments for efficient wound healing, under normal and diabetic conditions.
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Affiliation(s)
| | | | - Dmitriy A Bosykh
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Chengchun Wang
- Institute of Molecular and Cell Biology, Singapore, Singapore
| | - Xiaomeng Wang
- Institute of Molecular and Cell Biology, Singapore, Singapore; Centre for Vision Research, Duke-NUS Medical School, Singapore, Singapore
| | - Tavintharan Subramaniam
- Clinical Research Unit, Khoo Teck Puat Hospital, Singapore, Singapore; Division of Endocrinology, Department of Medicine, Khoo Teck Puat Hospital, Singapore, Singapore
| | - Weiping Han
- Institute of Molecular and Cell Biology, Singapore, Singapore
| | - Wanjin Hong
- Institute of Molecular and Cell Biology, Singapore, Singapore.
| | - Sayan Chakraborty
- Institute of Molecular and Cell Biology, Singapore, Singapore; Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA; Program of Developmental Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.
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25
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Wang Z, Chen C, Ai J, Gao Y, Wang L, Xia S, Jia Y, Qin Y. The crosstalk between senescence, tumor, and immunity: molecular mechanism and therapeutic opportunities. MedComm (Beijing) 2025; 6:e70048. [PMID: 39811803 PMCID: PMC11731108 DOI: 10.1002/mco2.70048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Revised: 11/30/2024] [Accepted: 12/10/2024] [Indexed: 01/16/2025] Open
Abstract
Cellular senescence is characterized by a stable cell cycle arrest and a hypersecretory, proinflammatory phenotype in response to various stress stimuli. Traditionally, this state has been viewed as a tumor-suppressing mechanism that prevents the proliferation of damaged cells while activating the immune response for their clearance. However, senescence is increasingly recognized as a contributing factor to tumor progression. This dual role necessitates a careful evaluation of the beneficial and detrimental aspects of senescence within the tumor microenvironment (TME). Specifically, senescent cells display a unique senescence-associated secretory phenotype that releases a diverse array of soluble factors affecting the TME. Furthermore, the impact of senescence on tumor-immune interaction is complex and often underappreciated. Senescent immune cells create an immunosuppressive TME favoring tumor progression. In contrast, senescent tumor cells could promote a transition from immune evasion to clearance. Given these intricate dynamics, therapies targeting senescence hold promise for advancing antitumor strategies. This review aims to summarize the dual effects of senescence on tumor progression, explore its influence on tumor-immune interactions, and discuss potential therapeutic strategies, alongside challenges and future directions. Understanding how senescence regulates antitumor immunity, along with new therapeutic interventions, is essential for managing tumor cell senescence and remodeling the immune microenvironment.
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Affiliation(s)
- Zehua Wang
- Department of OncologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Chen Chen
- Department of OncologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Jiaoyu Ai
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Yaping Gao
- Department of OncologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Lei Wang
- Department of OncologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Shurui Xia
- Department of OncologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Yongxu Jia
- Department of OncologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Yanru Qin
- Department of OncologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
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26
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McHugh D, Durán I, Gil J. Senescence as a therapeutic target in cancer and age-related diseases. Nat Rev Drug Discov 2025; 24:57-71. [PMID: 39548312 DOI: 10.1038/s41573-024-01074-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/08/2024] [Indexed: 11/17/2024]
Abstract
Cellular senescence is a stress response that restrains the growth of aged, damaged or abnormal cells. Thus, senescence has a crucial role in development, tissue maintenance and cancer prevention. However, lingering senescent cells fuel chronic inflammation through the acquisition of a senescence-associated secretory phenotype (SASP), which contributes to cancer and age-related tissue dysfunction. Recent progress in understanding senescence has spurred interest in the development of approaches to target senescent cells, known as senotherapies. In this Review, we evaluate the status of various types of senotherapies, including senolytics that eliminate senescent cells, senomorphics that suppress the SASP, interventions that mitigate senescence and strategies that harness the immune system to clear senescent cells. We also summarize how these approaches can be combined with cancer therapies, and we discuss the challenges and opportunities in moving senotherapies into clinical practice. Such therapies have the potential to address root causes of age-related diseases and thus open new avenues for preventive therapies and treating multimorbidities.
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Affiliation(s)
- Domhnall McHugh
- Senescence Group, MRC Laboratory of Medical Sciences (LMS), London, UK
- Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK
| | - Imanol Durán
- Senescence Group, MRC Laboratory of Medical Sciences (LMS), London, UK
- Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK
| | - Jesús Gil
- Senescence Group, MRC Laboratory of Medical Sciences (LMS), London, UK.
- Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK.
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27
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Fu Z, Wang W, Gao Y. Understanding the impact of ER stress on lung physiology. Front Cell Dev Biol 2024; 12:1466997. [PMID: 39744015 PMCID: PMC11688383 DOI: 10.3389/fcell.2024.1466997] [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: 07/24/2024] [Accepted: 11/22/2024] [Indexed: 01/04/2025] Open
Abstract
Human lungs consist of a distinctive array of cell types, which are subjected to persistent challenges from chemical, mechanical, biological, immunological, and xenobiotic stress throughout life. The disruption of endoplasmic reticulum (ER) homeostatic function, triggered by various factors, can induce ER stress. To overcome the elevated ER stress, an adaptive mechanism known as the unfolded protein response (UPR) is activated in cells. However, persistent ER stress and maladaptive UPR can lead to defects in proteostasis at the cellular level and are typical features of the lung aging. The aging lung and associated lung diseases exhibit signs of ER stress-related disruption in cellular homeostasis. Dysfunction resulting from ER stress and maladaptive UPR can compromise various cellular and molecular processes associated with aging. Hence, comprehending the mechanisms of ER stress and UPR components implicated in aging and associated lung diseases could enable to develop appropriate therapeutic strategies for the vulnerable population.
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Affiliation(s)
- Zhiling Fu
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Wei Wang
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yuan Gao
- Department of Pulmonary and Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
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28
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Wu Z, Qu J, Liu GH. Roles of chromatin and genome instability in cellular senescence and their relevance to ageing and related diseases. Nat Rev Mol Cell Biol 2024; 25:979-1000. [PMID: 39363000 DOI: 10.1038/s41580-024-00775-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/12/2024] [Indexed: 10/05/2024]
Abstract
Ageing is a complex biological process in which a gradual decline in physiological fitness increases susceptibility to diseases such as neurodegenerative disorders and cancer. Cellular senescence, a state of irreversible cell-growth arrest accompanied by functional deterioration, has emerged as a pivotal driver of ageing. In this Review, we discuss how heterochromatin loss, telomere attrition and DNA damage contribute to cellular senescence, ageing and age-related diseases by eliciting genome instability, innate immunity and inflammation. We also discuss how emerging therapeutic strategies could restore heterochromatin stability, maintain telomere integrity and boost the DNA repair capacity, and thus counteract cellular senescence and ageing-associated pathologies. Finally, we outline current research challenges and future directions aimed at better comprehending and delaying ageing.
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Affiliation(s)
- Zeming Wu
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Jing Qu
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.
- University of Chinese Academy of Sciences, Beijing, China.
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
- Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
- Aging Biomarker Consortium, Beijing, China.
| | - Guang-Hui Liu
- Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.
- University of Chinese Academy of Sciences, Beijing, China.
- Aging Biomarker Consortium, Beijing, China.
- Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital, Capital Medical University, Beijing, China.
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29
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Hudson HR, Riessland M, Orr ME. Defining and characterizing neuronal senescence, 'neurescence', as G X arrested cells. Trends Neurosci 2024; 47:971-984. [PMID: 39389805 DOI: 10.1016/j.tins.2024.09.006] [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: 05/21/2024] [Revised: 08/16/2024] [Accepted: 09/18/2024] [Indexed: 10/12/2024]
Abstract
Cellular senescence is a cell state characterized by resistance to apoptosis and stable cell cycle arrest. Senescence was first observed in mitotic cells in vitro. Recent evidence from in vivo studies and human tissue indicates that postmitotic cells, including neurons, may also become senescent. The quiescent cell state of neurons and inconsistent descriptions of neuronal senescence across studies, however, have caused confusion in this burgeoning field. We summarize evidence demonstrating that exit from G0 quiescence may protect neurons against apoptosis and predispose them toward senescence. Additionally, we propose the term 'neurescent' for senescent neurons and introduce the cell state, GX, to describe cell cycle arrest achieved by passing through G0 quiescence. Criteria are provided to identify neurescent cells, distinguish them from G0 quiescent neurons, and compare neurescent phenotypes with classic replicative senescence.
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Affiliation(s)
- Hannah R Hudson
- Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Department of Internal Medicine Section on Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Markus Riessland
- Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, NY, USA; Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY, USA
| | - Miranda E Orr
- Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Department of Internal Medicine Section on Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Salisbury VA Medical Center, Salisbury, NC, USA.
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30
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Yang F, Shu R, Dai W, Li B, Liu C, Yang H, Johnson HM, Yu S, Bai D, Yang W, Deng Y. H 2Se-evolving bio-heterojunctions promote cutaneous regeneration in infected wounds by inhibiting excessive cellular senescence. Biomaterials 2024; 311:122659. [PMID: 38861831 DOI: 10.1016/j.biomaterials.2024.122659] [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: 01/25/2024] [Revised: 06/04/2024] [Accepted: 06/06/2024] [Indexed: 06/13/2024]
Abstract
Pathogenic infection leads to excessive senescent cell accumulation and stagnation of wound healing. To address these issues, we devise and develop a hydrogen selenide (H2Se)-evolving bio-heterojunction (bio-HJ) composed of graphene oxide (GO) and FeSe2 to deracinate bacterial infection, suppress cellular senescence and remedy recalcitrant infected wounds. Excited by near-infrared (NIR) laser, the bio-HJ exerts desired photothermal and photodynamic effects, resulting in rapid disinfection. The crafted bio-HJ could also evolve gaseous H2Se to inhibit cellular senescence and dampen inflammation. Mechanism studies reveal the anti-senescence effects of H2Se-evolving bio-HJ are mediated by selenium pathway and glutathione peroxidase 1 (GPX1). More critically, in vivo experiments authenticate that the H2Se-evolving bio-HJ could inhibit cellular senescence and potentiate wound regeneration in rats. As envisioned, our work not only furnishes the novel gasotransmitter-delivering bio-HJ for chronic infected wounds, but also gets insight into the development of anti-senescence biomaterials.
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Affiliation(s)
- Fan Yang
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, College of Biomedical Engineering, School of Chemical Engineering, Sichuan University, Chengdu, China; Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Rui Shu
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, College of Biomedical Engineering, School of Chemical Engineering, Sichuan University, Chengdu, China; Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Wenyu Dai
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, College of Biomedical Engineering, School of Chemical Engineering, Sichuan University, Chengdu, China; Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Bin Li
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, College of Biomedical Engineering, School of Chemical Engineering, Sichuan University, Chengdu, China; Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Chuang Liu
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, College of Biomedical Engineering, School of Chemical Engineering, Sichuan University, Chengdu, China
| | - Hang Yang
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, College of Biomedical Engineering, School of Chemical Engineering, Sichuan University, Chengdu, China
| | - Hannah M Johnson
- Department of Chemistry, Washington State University, Washington, USA
| | - Sheng Yu
- Department of Chemistry, Washington State University, Washington, USA
| | - Ding Bai
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, College of Biomedical Engineering, School of Chemical Engineering, Sichuan University, Chengdu, China; Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Weizhong Yang
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, College of Biomedical Engineering, School of Chemical Engineering, Sichuan University, Chengdu, China.
| | - Yi Deng
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, College of Biomedical Engineering, School of Chemical Engineering, Sichuan University, Chengdu, China; State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu, China; Department of Mechanical Engineering, The University of Hong Kong, Hong Kong, China.
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31
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O'Reilly S, Tsou PS, Varga J. Senescence and tissue fibrosis: opportunities for therapeutic targeting. Trends Mol Med 2024; 30:1113-1125. [PMID: 38890028 DOI: 10.1016/j.molmed.2024.05.012] [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: 04/10/2024] [Revised: 05/20/2024] [Accepted: 05/22/2024] [Indexed: 06/20/2024]
Abstract
Cellular senescence is a key hallmark of aging. It has now emerged as a key mediator in normal tissue turnover and is associated with a variety of age-related diseases, including organ-specific fibrosis and systemic sclerosis (SSc). This review discusses the recent evidence of the role of senescence in tissue fibrosis, with an emphasis on SSc, a systemic autoimmune rheumatic disease. We discuss the physiological role of these cells, their role in fibrosis, and that targeting these cells specifically could be a new therapeutic avenue in fibrotic disease. We argue that targeting senescent cells, with senolytics or senomorphs, is a viable therapeutic target in fibrotic diseases which remain largely intractable.
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Affiliation(s)
- Steven O'Reilly
- Bioscience Department, Durham University, South Road, Durham, UK.
| | - Pei-Suen Tsou
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - John Varga
- Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
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32
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Lacina L, Kolář M, Pfeiferová L, Gál P, Smetana K. Wound healing: insights into autoimmunity, ageing, and cancer ecosystems through inflammation and IL-6 modulation. Front Immunol 2024; 15:1403570. [PMID: 39676864 PMCID: PMC11638159 DOI: 10.3389/fimmu.2024.1403570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 10/30/2024] [Indexed: 12/17/2024] Open
Abstract
Wound healing represents a complex and evolutionarily conserved process across vertebrates, encompassing a series of life-rescuing events. The healing process runs in three main phases: inflammation, proliferation, and maturation/remodelling. While acute inflammation is indispensable for cleansing the wound, removing infection, and eliminating dead tissue characterised by the prevalence of neutrophils, the proliferation phase is characterised by transition into the inflammatory cell profile, shifting towards the prevalence of macrophages. The proliferation phase involves development of granulation tissue, comprising fibroblasts, activated myofibroblasts, and inflammatory and endothelial cells. Communication among these cellular components occurs through intercellular contacts, extracellular matrix secretion, as well as paracrine production of bioactive factors and proteolytic enzymes. The proliferation phase of healing is intricately regulated by inflammation, particularly interleukin-6. Prolonged inflammation results in dysregulations during the granulation tissue formation and may lead to the development of chronic wounds or hypertrophic/keloid scars. Notably, pathological processes such as autoimmune chronic inflammation, organ fibrosis, the tumour microenvironment, and impaired repair following viral infections notably share morphological and functional similarities with granulation tissue. Consequently, wound healing emerges as a prototype for understanding these diverse pathological processes. The prospect of gaining a comprehensive understanding of wound healing holds the potential to furnish fundamental insights into modulation of the intricate dialogue between cancer cells and non-cancer cells within the cancer ecosystem. This knowledge may pave the way for innovative approaches to cancer diagnostics, disease monitoring, and anticancer therapy.
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Affiliation(s)
- Lukáš Lacina
- Institute of Anatomy, First Faculty of Medicine, Charles, University, Prague, Czechia
- BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czechia
- Department Dermatovenereology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czechia
| | - Michal Kolář
- Laboratory of Genomics and Bioinformatics, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czechia
| | - Lucie Pfeiferová
- Laboratory of Genomics and Bioinformatics, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czechia
| | - Peter Gál
- Department of Pharmacology, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, Košice, Slovakia
- Department of Biomedical Research, East-Slovak Institute of Cardiovascular Diseases Inc., Košice, Slovakia
- Prague Burn Centre, Third Faculty of Medicine, Charles University and University Hospital Královské Vinohrady, Prague, Czechia
- Department of Pharmacognosy and Botany, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia
| | - Karel Smetana
- Institute of Anatomy, First Faculty of Medicine, Charles, University, Prague, Czechia
- BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czechia
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33
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Venkataraman A, Kordic I, Li J, Zhang N, Bharadwaj NS, Fang Z, Das S, Coskun AF. Decoding senescence of aging single cells at the nexus of biomaterials, microfluidics, and spatial omics. NPJ AGING 2024; 10:57. [PMID: 39592596 PMCID: PMC11599402 DOI: 10.1038/s41514-024-00178-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 11/05/2024] [Indexed: 11/28/2024]
Abstract
Aging has profound effects on the body, most notably an increase in the prevalence of several diseases. An important aging hallmark is the presence of senescent cells that no longer multiply nor die off properly. Another characteristic is an altered immune system that fails to properly self-surveil. In this multi-player aging process, cellular senescence induces a change in the secretory phenotype, known as senescence-associated secretory phenotype (SASP), of many cells with the intention of recruiting immune cells to accelerate the clearance of these damaged senescent cells. However, the SASP phenotype results in inducing secondary senescence of nearby cells, resulting in those cells becoming senescent, and improper immune activation resulting in a state of chronic inflammation, called inflammaging, in many diseases. Senescence in immune cells, termed immunosenescence, results in further dysregulation of the immune system. An interdisciplinary approach is needed to physiologically assess aging changes of the immune system at the cellular and tissue level. Thus, the intersection of biomaterials, microfluidics, and spatial omics has great potential to collectively model aging and immunosenescence. Each of these approaches mimics unique aspects of the body undergoes as a part of aging. This perspective highlights the key aspects of how biomaterials provide non-cellular cues to cell aging, microfluidics recapitulate flow-induced and multi-cellular dynamics, and spatial omics analyses dissect the coordination of several biomarkers of senescence as a function of cell interactions in distinct tissue environments. An overview of how senescence and immune dysregulation play a role in organ aging, cancer, wound healing, Alzheimer's, and osteoporosis is included. To illuminate the societal impact of aging, an increasing trend in anti-senescence and anti-aging interventions, including pharmacological interventions, medical procedures, and lifestyle changes is discussed, including further context of senescence.
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Affiliation(s)
- Abhijeet Venkataraman
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
- Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Dr NW, Atlanta, GA, 30332, USA
| | - Ivan Kordic
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - JiaXun Li
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Nicholas Zhang
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
- Interdisciplinary Bioengineering Graduate Program, Georgia Institute of Technology, Atlanta, GA, USA
| | - Nivik Sanjay Bharadwaj
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Zhou Fang
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
- Machine Learning Graduate Program, Georgia Institute of Technology, Atlanta, GA, USA
| | - Sandip Das
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Ahmet F Coskun
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
- Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Dr NW, Atlanta, GA, 30332, USA.
- Interdisciplinary Bioengineering Graduate Program, Georgia Institute of Technology, Atlanta, GA, USA.
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34
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Song I, Kim PJ, Choi YJ, Chung YS, Lee S, Baek JH, Woo KM. Exploring the Interplay Between Senescent Osteocytes and Bone Remodeling in Young Rodents. J Aging Res 2024; 2024:4213141. [PMID: 39583064 PMCID: PMC11585373 DOI: 10.1155/2024/4213141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 07/25/2024] [Accepted: 09/14/2024] [Indexed: 11/26/2024] Open
Abstract
This study identifies senescent osteocytes in the femur and tibia of young rodents and explores their role in bone remodeling. The proximity of osteoclasts to senescent osteocytes was observed, which is a new finding. Cultured osteocytes, sorted using a podoplanin antibody in FACS, exhibited osteocytic characteristics and increased senescence-related genes. Senescent osteocytes secreted cytokines associated with senescence, remodeling, and inflammation. Notably, IGF1 and MMP2 were elevated in podoplanin-positive (pdpn+) osteocytes. Migration assays demonstrated significant osteoclast precursor migration towards senescent osteocytes, further confirmed by co-culture experiments leading to osteoclast differentiation. These findings suggest that senescent osteocytes have a pivotal role in initiating bone resorption, with recruitment of osteoclast precursors during early bone remodeling stages. In conclusion, our research enhances our understanding of complicated bone remodeling mechanisms and bone homeostasis.
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Affiliation(s)
- Insun Song
- Dental Research Institute, Seoul National University, Seoul 08826, Republic of Korea
| | - Pil-Jong Kim
- School of Dentistry and Dental Research Institute, Seoul National University, Seoul 08826, Republic of Korea
| | - Yong Jun Choi
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - Yoon-Sok Chung
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon 16499, Republic of Korea
| | - Soonchul Lee
- Department of Orthopaedic Surgery, CHA Bundang Medical Center, CHA University School of Medicine, 59 Yatap-ro, Bundang-gu, Seongnam-si 13496, Republic of Korea
| | - Jeong-Hwa Baek
- Dental Research Institute, Seoul National University, Seoul 08826, Republic of Korea
- Department of Molecular Genetics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 08826, Republic of Korea
| | - Kyung Mi Woo
- Dental Research Institute, Seoul National University, Seoul 08826, Republic of Korea
- Department of Molecular Genetics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 08826, Republic of Korea
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35
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Pun R, Kumari N, Monieb RH, Wagh S, North BJ. BubR1 and SIRT2: Insights into aneuploidy, aging, and cancer. Semin Cancer Biol 2024; 106-107:201-216. [PMID: 39490401 PMCID: PMC11625622 DOI: 10.1016/j.semcancer.2024.10.005] [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: 08/09/2024] [Revised: 10/22/2024] [Accepted: 10/23/2024] [Indexed: 11/05/2024]
Abstract
Aging is a significant risk factor for cancer which is due, in part, to heightened genomic instability. Mitotic surveillance proteins such as BubR1 play a pivotal role in ensuring accurate chromosomal segregation and preventing aneuploidy. BubR1 levels have been shown to naturally decline with age and its loss is associated with various age-related pathologies. Sirtuins, a class of NAD+-dependent deacylases, are implicated in cancer and genomic instability. Among them, SIRT2 acts as an upstream regulator of BubR1, offering a critical pathway that can potentially mitigate age-related diseases, including cancer. In this review, we explore BubR1 as a key regulator of cellular processes crucial for aging-related phenotypes. We delve into the intricate mechanisms through which BubR1 influences genomic stability and cellular senescence. Moreover, we highlight the role of NAD+ and SIRT2 in modulating BubR1 expression and function, emphasizing its potential as a therapeutic target. The interaction between BubR1 and SIRT2 not only serves as a fundamental regulatory pathway in cellular homeostasis but also represents a promising avenue for developing targeted therapies against age-related diseases, particularly cancer.
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Affiliation(s)
- Renju Pun
- Biomedical Sciences Department, Creighton University School of Medicine, Omaha, NE, USA
| | - Niti Kumari
- Biomedical Sciences Department, Creighton University School of Medicine, Omaha, NE, USA
| | - Rodaina Hazem Monieb
- Biomedical Sciences Department, Creighton University School of Medicine, Omaha, NE, USA
| | - Sachin Wagh
- Biomedical Sciences Department, Creighton University School of Medicine, Omaha, NE, USA
| | - Brian J North
- Biomedical Sciences Department, Creighton University School of Medicine, Omaha, NE, USA.
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36
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Papismadov N, Levi N, Roitman L, Agrawal A, Ovadya Y, Cherqui U, Yosef R, Akiva H, Gal H, Krizhanovsky V. p21 regulates expression of ECM components and promotes pulmonary fibrosis via CDK4 and Rb. EMBO J 2024; 43:5360-5380. [PMID: 39349844 PMCID: PMC11574164 DOI: 10.1038/s44318-024-00246-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 08/05/2024] [Accepted: 09/05/2024] [Indexed: 11/20/2024] Open
Abstract
Fibrosis and accumulation of senescent cells are common tissue changes associated with aging. Here, we show that the CDK inhibitor p21 (CDKN1A), known to regulate the cell cycle and the viability of senescent cells, also controls the expression of extracellular matrix (ECM) components in senescent and proliferating cells of the fibrotic lung, in a manner dependent on CDK4 and Rb phosphorylation. p21 knockout protects mice from the induction of lung fibrosis. Moreover, inducible p21 silencing during fibrosis development alleviates disease pathology, decreasing the inflammatory response and ECM accumulation in the lung, and reducing the amount of senescent cells. Furthermore, p21 silencing limits fibrosis progression even when introduced during disease development. These findings show that one common mechanism regulates both cell cycle progression and expression of ECM components, and suggest that targeting p21 might be a new approach for treating age-related fibrotic pathologies.
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Affiliation(s)
- Nurit Papismadov
- Department of Molecular Cell Biology, The Weizmann Institute of Science, 7610001, Rehovot, Israel
| | - Naama Levi
- Department of Molecular Cell Biology, The Weizmann Institute of Science, 7610001, Rehovot, Israel
| | - Lior Roitman
- Department of Molecular Cell Biology, The Weizmann Institute of Science, 7610001, Rehovot, Israel
| | - Amit Agrawal
- Department of Molecular Cell Biology, The Weizmann Institute of Science, 7610001, Rehovot, Israel
| | - Yossi Ovadya
- Department of Molecular Cell Biology, The Weizmann Institute of Science, 7610001, Rehovot, Israel
| | - Ulysse Cherqui
- Department of Molecular Cell Biology, The Weizmann Institute of Science, 7610001, Rehovot, Israel
| | - Reut Yosef
- Department of Molecular Cell Biology, The Weizmann Institute of Science, 7610001, Rehovot, Israel
| | - Hagay Akiva
- Department of Molecular Cell Biology, The Weizmann Institute of Science, 7610001, Rehovot, Israel
| | - Hilah Gal
- Department of Molecular Cell Biology, The Weizmann Institute of Science, 7610001, Rehovot, Israel
| | - Valery Krizhanovsky
- Department of Molecular Cell Biology, The Weizmann Institute of Science, 7610001, Rehovot, Israel.
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37
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Dedic B, Westerberg L, Mosqueda Solís A, Dumont KD, Ruas JL, Thorell A, Näslund E, Spalding KL. Senescence detection using reflected light. Aging Cell 2024; 23:e14295. [PMID: 39102872 PMCID: PMC11561700 DOI: 10.1111/acel.14295] [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: 02/26/2024] [Revised: 07/10/2024] [Accepted: 07/18/2024] [Indexed: 08/07/2024] Open
Abstract
Senescence is an important cellular program occurring in development, tissue repair, cancer, and aging. Increased senescence is also associated with disease states, including obesity and Type 2 diabetes (T2D). Characterizing and quantifying senescent cells at a single cell level has been challenging and particularly difficult in large primary cells, such as human adipocytes. In this study, we present a novel approach that utilizes reflected light for accurate senescence-associated beta-galactosidase (SABG) staining measurements, which can be integrated with immunofluorescence and is compatible with primary mature adipocytes from both human and mouse, as well as with differentiated 3T3-L1 cells. This technique provides a more comprehensive classification of a cell's senescent state by incorporating multiple criteria, including robust sample-specific pH controls. By leveraging the precision of confocal microscopy to detect X-gal crystals using reflected light, we achieved superior sensitivity over traditional brightfield techniques. This strategy allows for the capture of all X-gal precipitates in SABG-stained samples, revealing diverse X-gal staining patterns and improved detection sensitivity. Additionally, we demonstrate that reflected light outperforms western blot analysis for the detection and quantification of senescence in mature human adipocytes, as it offers a more accurate representation of SABG activity. This detection strategy enables a more thorough investigation of senescent cell characteristics and specifically a deeper look at the relationship between adipocyte senescence and obesity associated disorders, such as T2D.
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Affiliation(s)
- Benjamin Dedic
- Department of Cell and Molecular BiologyKarolinska InstitutetStockholmSweden
| | - Leo Westerberg
- Department of Cell and Molecular BiologyKarolinska InstitutetStockholmSweden
| | - Andrea Mosqueda Solís
- Department of Cell and Molecular BiologyKarolinska InstitutetStockholmSweden
- Department of Biosciences and NutritionKarolinska InstitutetStockholmSweden
| | - Kyle D. Dumont
- Molecular and Cellular Exercise Physiology, Department of Physiology and PharmacologyKarolinska InstitutetStockholmSweden
| | - Jorge L. Ruas
- Molecular and Cellular Exercise Physiology, Department of Physiology and PharmacologyKarolinska InstitutetStockholmSweden
- Department of Pharmacology and Stanley and Judith Frankel Institute for Heart and Brain HealthUniversity of Michigan Medical SchoolAnn ArborMichiganUSA
| | - Anders Thorell
- Department of Clinical SciencesDanderyd Hospital, Karolinska Institutet and Department of Surgery, Ersta Hospital, Karolinska InstitutetStockholmSweden
| | - Erik Näslund
- Department of Clinical SciencesDanderyd Hospital, Karolinska InstitutetStockholmSweden
| | - Kirsty L. Spalding
- Department of Cell and Molecular BiologyKarolinska InstitutetStockholmSweden
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38
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Fischer AG, Elliott EM, Brittian KR, Garrett L, Sadri G, Aebersold J, Singhal RA, Nong Y, Leask A, Jones SP, Moore Iv JB. Matricellular protein CCN1 promotes collagen alignment and scar integrity after myocardial infarction. Matrix Biol 2024; 133:14-32. [PMID: 39098433 PMCID: PMC11476287 DOI: 10.1016/j.matbio.2024.08.001] [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: 04/13/2024] [Revised: 07/17/2024] [Accepted: 08/01/2024] [Indexed: 08/06/2024]
Abstract
BACKGROUND Members of the cellular communication network family (CCN) of matricellular proteins, like CCN1, have long been implicated in the regulation of cellular processes underlying wound healing, tissue fibrogenesis, and collagen dynamics. While many studies suggest antifibrotic actions for CCN1 in the adult heart through the promotion of myofibroblast senescence, they largely relied on exogenous supplementation strategies in in vivo models of cardiac injury where its expression is already induced-which may confound interpretation of its function in this process. The objective of this study was to interrogate the role of the endogenous protein on fibroblast function, collagen structural dynamics, and its associated impact on cardiac fibrosis after myocardial infarction (MI). METHODS/RESULTS Here, we employed CCN1 loss-of-function methodologies, including both in vitro siRNA-mediated depletion and in vivo fibroblast-specific knockout mice to assess the role of the endogenous protein on cardiac fibroblast fibrotic signaling, and its involvement in acute scar formation after MI. In vitro depletion of CCN1 reduced cardiac fibroblast senescence and proliferation. Although depletion of CCN1 decreased the expression of collagen processing and stabilization enzymes (i.e., P4HA1, PLOD1, and PLOD2), it did not inhibit myofibroblast induction or type I collagen synthesis. Alone, fibroblast-specific removal of CCN1 did not negatively impact ventricular performance or myocardial collagen content but did contribute to disorganization of collagen fibrils and increased matrix compliance. Similarly, Ccn1 ablated animals subjected to MI showed no discernible alterations in cardiac structure or function one week after permanent coronary artery ligation, but exhibited marked increases in incidence of mortality and cardiac rupture. Consistent with our findings that CCN1 depletion does not assuage myofibroblast conversion or type I collagen synthesis in vitro, Ccn1 knockout animals revealed no measurable differences in collagen scar width or mass compared to controls; however, detailed structural analyses via SHG and TEM of scar regions revealed marked alterations in their scar collagen topography-exhibiting changes in numerous macro- and micro-level collagen architectural attributes. Specifically, Ccn1 knockout mice displayed heightened ECM structural complexity in post-MI scar regions, including diminished local alignment and heightened tortuosity of collagen fibers, as well as reduced organizational coherency, packing, and size of collagen fibrils. Associated with these changes in ECM topography with the loss of CCN1 were reductions in fibroblast-matrix interactions, as evidenced by reduced fibroblast nuclear and cellular deformation in vivo and reduced focal-adhesion formation in vitro; findings that ultimately suggest CCN1's ability to influence fibroblast-led collagen alignment may in part be credited to its capacity to augment fibroblast-matrix interactions. CONCLUSIONS These findings underscore the pivotal role of endogenous CCN1 in the scar formation process occurring after MI, directing the appropriate arrangement of the extracellular matrix's collagenous components in the maturing scar-shaping the mechanical properties that support its structural stability. While this suggests an adaptive role for CCN1 in regulating collagen structural attributes crucial for supporting scar integrity post MI, the long-term protracted expression of CCN1 holds maladaptive implications, potentially diminishing collagen structural complexity and compliance in non-infarct regions.
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Affiliation(s)
- Annalara G Fischer
- Center for Cardiometabolic Science, University of Louisville School of Medicine, 580 South Preston Street, Delia Baxter Research Building, Room 304C, Louisville, KY 40202, USA
| | - Erin M Elliott
- Center for Cardiometabolic Science, University of Louisville School of Medicine, 580 South Preston Street, Delia Baxter Research Building, Room 304C, Louisville, KY 40202, USA
| | - Kenneth R Brittian
- Center for Cardiometabolic Science, University of Louisville School of Medicine, 580 South Preston Street, Delia Baxter Research Building, Room 304C, Louisville, KY 40202, USA
| | - Lauren Garrett
- Center for Cardiometabolic Science, University of Louisville School of Medicine, 580 South Preston Street, Delia Baxter Research Building, Room 304C, Louisville, KY 40202, USA
| | - Ghazal Sadri
- Center for Cardiometabolic Science, University of Louisville School of Medicine, 580 South Preston Street, Delia Baxter Research Building, Room 304C, Louisville, KY 40202, USA
| | - Julia Aebersold
- Micro/Nano Technology Center, University of Louisville, Louisville, KY, USA
| | - Richa A Singhal
- Center for Cardiometabolic Science, University of Louisville School of Medicine, 580 South Preston Street, Delia Baxter Research Building, Room 304C, Louisville, KY 40202, USA
| | - Yibing Nong
- Center for Cardiometabolic Science, University of Louisville School of Medicine, 580 South Preston Street, Delia Baxter Research Building, Room 304C, Louisville, KY 40202, USA
| | - Andrew Leask
- College of Dentistry, University of Saskatchewan, Saskatoon, SK, Canada
| | - Steven P Jones
- Center for Cardiometabolic Science, University of Louisville School of Medicine, 580 South Preston Street, Delia Baxter Research Building, Room 304C, Louisville, KY 40202, USA
| | - Joseph B Moore Iv
- Center for Cardiometabolic Science, University of Louisville School of Medicine, 580 South Preston Street, Delia Baxter Research Building, Room 304C, Louisville, KY 40202, USA.
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Tian Y, Shao S, Feng H, Zeng R, Li S, Zhang Q. Targeting senescent cells in atherosclerosis: Pathways to novel therapies. Ageing Res Rev 2024; 101:102502. [PMID: 39278272 DOI: 10.1016/j.arr.2024.102502] [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: 07/01/2024] [Revised: 08/16/2024] [Accepted: 09/08/2024] [Indexed: 09/18/2024]
Abstract
Targeting senescent cells has recently emerged as a promising strategy for treating age-related diseases, such as atherosclerosis, which significantly contributes to global cardiovascular morbidity and mortality. This review elucidates the role of senescent cells in the development of atherosclerosis, including persistently damaging DNA, inducing oxidative stress and secreting pro-inflammatory factors known as the senescence-associated secretory phenotype. Therapeutic approaches targeting senescent cells to mitigate atherosclerosis are summarized in this review, which include the development of senotherapeutics and immunotherapies. These therapies are designed to either remove these cells or suppress their deleterious effects. These emerging therapies hold potential to decelerate or even alleviate the progression of AS, paving the way for new avenues in cardiovascular research and treatment.
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Affiliation(s)
- Yuhan Tian
- College of Pharmacy, Key Laboratory of Research and Application of Ethnic Medicine Processing and Preparation on the Qinghai-Tibet Plateau, Southwest Minzu University, Chengdu 610041, China
| | - Sihang Shao
- School of Electrical and Electronic Engineering, Nanyang Technological University, Singapore
| | - Haibo Feng
- College of Animal & Veterinary Sciences, Southwest Minzu University, Chengdu 610041, China
| | - Rui Zeng
- College of Pharmacy, Key Laboratory of Research and Application of Ethnic Medicine Processing and Preparation on the Qinghai-Tibet Plateau, Southwest Minzu University, Chengdu 610041, China
| | - Shanshan Li
- College of Pharmacy, Key Laboratory of Research and Application of Ethnic Medicine Processing and Preparation on the Qinghai-Tibet Plateau, Southwest Minzu University, Chengdu 610041, China.
| | - Qixiong Zhang
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China; Department of Pharmacy, Sichuan Provincial People's Hospital East Sichuan Hospital & Dazhou First People's Hospital, Dazhou 635000, China.
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40
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Liu X, Zhang X, Li Q, Wei C, Guo X, Zhao L, Liu T, Bao Q, Dou S, Seitz B, Hua G. CYR61/CCN1: A novel mediator of redox response in corneal stromal cells of keratoconus. Exp Eye Res 2024; 248:110093. [PMID: 39277098 DOI: 10.1016/j.exer.2024.110093] [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: 07/25/2024] [Revised: 08/30/2024] [Accepted: 09/11/2024] [Indexed: 09/17/2024]
Abstract
Keratoconus (KC) is a progressive, multifactorial and ectatic corneal disorder that characterized by steepening thinning of the cornea. It was previously demonstrated that oxidative stress has a strong link with KC progression. However, the molecular mechanism underlying oxidative stress response in KC remains unclear. Hence, the present study analyzed the heterogeneity of response of corneal stromal cells (CSCs) to oxidative stress in order to further illustrate how oxidative shape the pathophysiology of KC. Single-cell transcriptomics analysis revealed that CSCs demonstrated significant higher oxidative stress score in the KC group compared to the Ctrl group. The expression of oxidative markers verified by experiments illustrated elevated oxidative stress levels and insufficient antioxidant levels in CSCs of KC. In further single-cell transcriptomics analysis, we identified CYR61 to distinguish different subgroups of CSCs responding to oxidative stress. The cornea stroma cells in KC could be differentiated into CYR61high cells and CYR61low cells. Of note, the CYR61high cells showed lower score in collagen production process and higher score in collagen catabolic process. Further experiments illustrated that CYR61 was elevated in KC and associated with collagen production.
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Affiliation(s)
- Xiaoxue Liu
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, 266000, China; Eye Hospital of Shandong First Medical University, Jinan, 250021, China; School of Ophthalmology, Shandong First Medical University, Jinan, 250000, China
| | - Xiaowen Zhang
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, 266000, China; School of Ophthalmology, Shandong First Medical University, Jinan, 250000, China
| | - Qinghua Li
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, 266000, China; Eye Hospital of Shandong First Medical University, Jinan, 250021, China; School of Ophthalmology, Shandong First Medical University, Jinan, 250000, China
| | - Chaoqun Wei
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, 266000, China; Eye Hospital of Shandong First Medical University, Jinan, 250021, China; School of Ophthalmology, Shandong First Medical University, Jinan, 250000, China
| | - Xinghan Guo
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, 266000, China; Eye Hospital of Shandong First Medical University, Jinan, 250021, China; School of Ophthalmology, Shandong First Medical University, Jinan, 250000, China
| | - Longfei Zhao
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, 266000, China; Eye Hospital of Shandong First Medical University, Jinan, 250021, China; School of Ophthalmology, Shandong First Medical University, Jinan, 250000, China
| | - Ting Liu
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, 266000, China; School of Ophthalmology, Shandong First Medical University, Jinan, 250000, China
| | - Qingdong Bao
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, 266000, China; Eye Hospital of Shandong First Medical University, Jinan, 250021, China; School of Ophthalmology, Shandong First Medical University, Jinan, 250000, China
| | - Shengqian Dou
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, 266000, China; School of Ophthalmology, Shandong First Medical University, Jinan, 250000, China.
| | - Berthold Seitz
- Department of Ophthalmology, Saarland University Medical Center (UKS), Homburg, Saar, Germany
| | - Gao Hua
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, 266000, China; Eye Hospital of Shandong First Medical University, Jinan, 250021, China; School of Ophthalmology, Shandong First Medical University, Jinan, 250000, China; School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.
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O’Reilly S, Markiewicz E, Idowu OC. Aging, senescence, and cutaneous wound healing-a complex relationship. Front Immunol 2024; 15:1429716. [PMID: 39483466 PMCID: PMC11524853 DOI: 10.3389/fimmu.2024.1429716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 09/19/2024] [Indexed: 11/03/2024] Open
Abstract
Cutaneous wound healing is a complex multi-step process that is highly controlled, ensuring efficient repair to damaged tissue and restoring tissue architecture. Multiple cell types play a critical role in wound healing, and perturbations in this can lead to non-healing wounds or scarring and fibrosis. Thus, the process is tightly regulated and controlled. Cellular senescence is defined as irreversible cell cycle arrest and is associated with various phenotypic changes and metabolic alterations and coupled to a secretory program. Its role in wound healing, at least in the acute setting, appears to help promote appropriate mechanisms leading to the complete restoration of tissue architecture. Opposing this is the role of senescence in chronic wounds where it can lead to either chronic non-healing wounds or fibrosis. Given the two opposing outcomes of wound healing in either acute or chronic settings, this has led to disparate views on the role of senescence in wound healing. This review aims to consolidate knowledge on the role of senescence and aging in wound healing, examining the nuances of the roles in the acute or chronic settings, and attempts to evaluate the modulation of this to promote efficient wound healing.
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Affiliation(s)
- Steven O’Reilly
- Hexislab Limited, The Catalyst, Newcastle Upon Tyne, United Kingdom
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42
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Kim SH, Lee B, Lee SM, Kim Y. Restoring social deficits in IRSp53-deleted mice: chemogenetic inhibition of ventral dentate gyrus Emx1-expressing cells. Transl Psychiatry 2024; 14:425. [PMID: 39375329 PMCID: PMC11458854 DOI: 10.1038/s41398-024-03104-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 09/18/2024] [Accepted: 09/20/2024] [Indexed: 10/09/2024] Open
Abstract
IRSp53 is a synaptic scaffold protein reported to be involved in schizophrenia, autism spectrum disorders, and social deficits in knockout mice. Identifying critical brain regions and cells related to IRSp53 deletion is expected to be of great help in the treatment of psychiatric problems. In this study, we performed chemogenetic inhibition within the ventral dentate gyrus (vDG) of mice with IRSp53 deletion in Emx1-expressing cells (Emx1-Cre;IRSp53 flox/flox). We observed the recovery of social deficits after chemogenetic inhibition within vDG of Emx1-Cre;IRSp53 flox/flox mice. Additionally, chemogenetic activation induced social deficits in Emx1-Cre mice. CRHR1 expression increased in the hippocampus of Emx1-Cre;IRSp53 flox/flox mice, and CRHR1 was reduced by chemogenetic inhibition. Htd2, Ccn1, and Atp61l were decreased in bulk RNA sequencing, and Eya1 and Ecrg4 were decreased in single-cell RNA sequencing of the hippocampus in Emx1-Cre;IRSp53 flox/flox mice compared to control mice. This study determined that the vDG is a critical brain region for social deficits caused by IRSp53 deletion. Social deficits in Emx1-Cre;IRSp53 flox/flox mice were recovered through chemogenetic inhibition, providing clues for new treatment methods for psychiatric disorders accompanied by social deficits.
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Affiliation(s)
- Su Hyun Kim
- Mental Health Research Institute, National Center for Mental Health, Seoul, South Korea
| | - Bomee Lee
- Mental Health Research Institute, National Center for Mental Health, Seoul, South Korea
| | - Seong Mi Lee
- Mental Health Research Institute, National Center for Mental Health, Seoul, South Korea
| | - Yangsik Kim
- Department of Psychiatry, Inha University Hospital, College of Medicine, Inha University, Incheon, South Korea.
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43
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Constantinou SM, Bennett DC. Cell Senescence and the Genetics of Melanoma Development. Genes Chromosomes Cancer 2024; 63:e23273. [PMID: 39422311 DOI: 10.1002/gcc.23273] [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: 08/22/2024] [Accepted: 08/26/2024] [Indexed: 10/19/2024] Open
Abstract
Cutaneous malignant melanoma is an aggressive skin cancer with an approximate lifetime risk of 1 in 38 in the UK. While exposure to ultraviolet radiation is a key environmental risk factor for melanoma, up to ~10% of patients report a family history of melanoma, and ~1% have a strong family history. The understanding of causal mutations in melanoma has been critical to the development of novel targeted therapies that have contributed to improved outcomes for late-stage patients. Here, we review current knowledge of the genes affected by familial melanoma mutations and their partial overlap with driver genes commonly mutated in sporadic melanoma development. One theme linking a set of susceptibility loci/genes is the regulation of skin pigmentation and suntanning. The largest functional set of susceptibility variants, typically with high penetrance, includes CDKN2A, RB1, and telomerase reverse transcriptase (TERT) mutations, associated with attenuation of cell senescence. We discuss the mechanisms of action of these gene sets in the biology and progression of nevi and melanoma.
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Affiliation(s)
- Sophie M Constantinou
- Molecular & Cellular Sciences Research Section, City St George's, University of London, London, UK
| | - Dorothy C Bennett
- Molecular & Cellular Sciences Research Section, City St George's, University of London, London, UK
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44
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Elwakiel A, Gupta D, Rana R, Manoharan J, Al-Dabet MM, Ambreen S, Fatima S, Zimmermann S, Mathew A, Li Z, Singh K, Gupta A, Pal S, Sulaj A, Kopf S, Schwab C, Baber R, Geffers R, Götze T, Alo B, Lamers C, Kluge P, Kuenze G, Kohli S, Renné T, Shahzad K, Isermann B. Factor XII signaling via uPAR-integrin β1 axis promotes tubular senescence in diabetic kidney disease. Nat Commun 2024; 15:7963. [PMID: 39261453 PMCID: PMC11390906 DOI: 10.1038/s41467-024-52214-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 08/30/2024] [Indexed: 09/13/2024] Open
Abstract
Coagulation factor XII (FXII) conveys various functions as an active protease that promotes thrombosis and inflammation, and as a zymogen via surface receptors like urokinase-type plasminogen activator receptor (uPAR). While plasma levels of FXII are increased in diabetes mellitus and diabetic kidney disease (DKD), a pathogenic role of FXII in DKD remains unknown. Here we show that FXII is locally expressed in kidney tubular cells and that urinary FXII correlates with kidney dysfunction in DKD patients. F12-deficient mice (F12-/-) are protected from hyperglycemia-induced kidney injury. Mechanistically, FXII interacts with uPAR on tubular cells promoting integrin β1-dependent signaling. This signaling axis induces oxidative stress, persistent DNA damage and senescence. Blocking uPAR or integrin β1 ameliorates FXII-induced tubular cell injury. Our findings demonstrate that FXII-uPAR-integrin β1 signaling on tubular cells drives senescence. These findings imply previously undescribed diagnostic and therapeutic approaches to detect or treat DKD and possibly other senescence-associated diseases.
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Affiliation(s)
- Ahmed Elwakiel
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany.
| | - Dheerendra Gupta
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany
| | - Rajiv Rana
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany
| | - Jayakumar Manoharan
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany
| | - Moh'd Mohanad Al-Dabet
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany
- Department of Medical Laboratory Sciences, School of Science, University of Jordan, Amman, Jordan
| | - Saira Ambreen
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany
| | - Sameen Fatima
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany
| | - Silke Zimmermann
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany
| | - Akash Mathew
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany
| | - Zhiyang Li
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany
| | - Kunal Singh
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany
| | - Anubhuti Gupta
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany
| | - Surinder Pal
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany
| | - Alba Sulaj
- Internal Medicine I and Clinical Chemistry, German Diabetes Center (DZD), University of Heidelberg, Heidelberg, Germany
| | - Stefan Kopf
- Internal Medicine I and Clinical Chemistry, German Diabetes Center (DZD), University of Heidelberg, Heidelberg, Germany
| | - Constantin Schwab
- Institute of pathology, University of Heidelberg, Heidelberg, Germany
| | - Ronny Baber
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany
- Leipzig Medical Biobank, Leipzig University, Leipzig, Germany
| | - Robert Geffers
- Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Tom Götze
- Institute for Drug Discovery, Faculty of Medicine, Leipzig University, Leipzig, Germany
| | - Bekas Alo
- Institute for Drug Discovery, Faculty of Medicine, Leipzig University, Leipzig, Germany
| | - Christina Lamers
- Institute for Drug Discovery, Faculty of Medicine, Leipzig University, Leipzig, Germany
| | - Paul Kluge
- Institute for Drug Discovery, Faculty of Medicine, Leipzig University, Leipzig, Germany
| | - Georg Kuenze
- Institute for Drug Discovery, Faculty of Medicine, Leipzig University, Leipzig, Germany
- Center for Scalable Data Analytics and Artificial Intelligence, Leipzig University, Leipzig, Germany
| | - Shrey Kohli
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany
| | - Thomas Renné
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Center for Thrombosis and Hemostasis (CTH), Johannes Gutenberg University Medical Center, Mainz, Germany
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Khurrum Shahzad
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany
- National Centre of Excellence in Molecular Biology, University of the Punjab, 87-West Canal Bank Road, Lahore, Pakistan
| | - Berend Isermann
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany.
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Calubag MF, Robbins PD, Lamming DW. A nutrigeroscience approach: Dietary macronutrients and cellular senescence. Cell Metab 2024; 36:1914-1944. [PMID: 39178854 PMCID: PMC11386599 DOI: 10.1016/j.cmet.2024.07.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 07/09/2024] [Accepted: 07/31/2024] [Indexed: 08/26/2024]
Abstract
Cellular senescence, a process in which a cell exits the cell cycle in response to stressors, is one of the hallmarks of aging. Senescence and the senescence-associated secretory phenotype (SASP)-a heterogeneous set of secreted factors that disrupt tissue homeostasis and promote the accumulation of senescent cells-reprogram metabolism and can lead to metabolic dysfunction. Dietary interventions have long been studied as methods to combat age-associated metabolic dysfunction, promote health, and increase lifespan. A growing body of literature suggests that senescence is responsive to diet, both to calories and specific dietary macronutrients, and that the metabolic benefits of dietary interventions may arise in part through reducing senescence. Here, we review what is currently known about dietary macronutrients' effect on senescence and the SASP, the nutrient-responsive molecular mechanisms that may mediate these effects, and the potential for these findings to inform the development of a nutrigeroscience approach to healthy aging.
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Affiliation(s)
- Mariah F Calubag
- Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Graduate Program in Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Paul D Robbins
- Institute On the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, 6-155 Jackson Hall, 321 Church Street, SE, Minneapolis, MN 55455, USA
| | - Dudley W Lamming
- Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Graduate Program in Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, WI 53705, USA.
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Eun K, Kim AY, Ryu S. Matricellular proteins in immunometabolism and tissue homeostasis. BMB Rep 2024; 57:400-416. [PMID: 38919018 PMCID: PMC11444987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 10/11/2023] [Accepted: 04/25/2024] [Indexed: 06/27/2024] Open
Abstract
Matricellular proteins are integral non-structural components of the extracellular matrix. They serve as essential modulators of immunometabolism and tissue homeostasis, playing critical roles in physiological and pathological conditions. These extracellular matrix proteins including thrombospondins, osteopontin, tenascins, the secreted protein acidic and rich in cysteine (SPARC) family, the Cyr61, CTGF, NOV (CCN) family, and fibulins have multi-faceted functions in regulating immune cell functions, metabolic pathways, and tissue homeostasis. They are involved in immune-metabolic regulation and influence processes such as insulin signaling, adipogenesis, lipid metabolism, and immune cell function, playing significant roles in metabolic disorders such as obesity and diabetes. Furthermore, their modulation of tissue homeostasis processes including cellular adhesion, differentiation, migration, repair, and regeneration is instrumental for maintaining tissue integrity and function. The importance of these proteins in maintaining physiological equilibrium is underscored by the fact that alterations in their expression or function often coincide with disease manifestation. This review contributes to our growing understanding of these proteins, their mechanisms, and their potential therapeutic applications. [BMB Reports 2024; 57(9): 400-416].
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Affiliation(s)
- Kyoungjun Eun
- Department of Pharmacology, College of Medicine, Hallym University, Chuncheon 24252, Korea
- Department of Biochemistry, Chung-Ang University College of Medicine, Seoul 06974, Korea
| | - Ah Young Kim
- Department of Pharmacology, College of Medicine, Hallym University, Chuncheon 24252, Korea
- Department of Biochemistry, Chung-Ang University College of Medicine, Seoul 06974, Korea
| | - Seungjin Ryu
- Department of Pharmacology, College of Medicine, Hallym University, Chuncheon 24252, Korea
- Institute of Natural Medicine, College of Medicine, Hallym Unviersity, Chuncheon 24252, Korea
- Department of Biochemistry, Chung-Ang University College of Medicine, Seoul 06974, Korea
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47
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Yu GT, Gomez PT, Prata LG, Lehman JS, Tchkonia T, Kirkland JL, Meves A, Wyles SP. Clinicopathological and cellular senescence biomarkers in chronic stalled wounds. Int J Dermatol 2024; 63:1227-1235. [PMID: 38351588 PMCID: PMC11323232 DOI: 10.1111/ijd.17072] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 01/15/2024] [Accepted: 01/19/2024] [Indexed: 08/16/2024]
Abstract
BACKGROUND Chronic wounds have been associated with an elevated burden of cellular senescence, a state of essentially irreversible cell cycle arrest, resistance to apoptosis, and a secretory phenotype. However, whether senescent cells contribute to wound chronicity in humans remains unclear. The objective of this article is to assess the role of clinicopathological characteristics and cellular senescence in the time-to-healing of chronic wounds. METHODS A cohort of 79 patients with chronic wounds was evaluated in a single-center academic practice from February 1, 2005, to February 28, 2015, and followed for up to 36 months. Clinical characteristics and wound biopsies were obtained at baseline, and time-to-healing was assessed. Wound biopsies were analyzed histologically for pathological characteristics and molecularly for markers of cellular senescence. In addition, biopsy slides were stained for p16INK4a expression. RESULTS No clinical or pathological characteristics were found to have significant associations with time-to-healing. A Cox proportional hazard ratio model revealed increased CDKN1A (p21CIP1/WAF1) expression to predict longer time-to-healing, and a model adjusted for gender and epidermal hyperplasia revealed increased CDKN1A expression and decreased PAPPA expression to predict longer time-to-healing. Increased p16INK4a staining was observed in diabetic wounds compared to non-diabetic wounds, and the same association was observed in the context of high dermal fibrosis. CONCLUSIONS The findings of this pilot study suggest that senescent cells contribute to wound chronicity in humans, especially in diabetic wounds.
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Affiliation(s)
- Grace Tianen Yu
- Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic Alix School of Medicine, and Mayo Clinic Medical Scientist Training Program, Rochester, MN
| | - Paul T. Gomez
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN
| | - Larissa G. Prata
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN
| | - Julia Scott Lehman
- Department of Dermatology, Mayo Clinic, Rochester, MN
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Tamar Tchkonia
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN
| | - James L. Kirkland
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN
- Division of General Internal Medicine, Department of Medicine, Mayo Clinic, Rochester, MN
| | | | - Saranya P. Wyles
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN
- Department of Dermatology, Mayo Clinic, Rochester, MN
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48
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Muthamil S, Kim HY, Jang HJ, Lyu JH, Shin UC, Go Y, Park SH, Lee HG, Park JH. Biomarkers of Cellular Senescence and Aging: Current State-of-the-Art, Challenges and Future Perspectives. Adv Biol (Weinh) 2024; 8:e2400079. [PMID: 38935557 DOI: 10.1002/adbi.202400079] [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: 02/13/2024] [Revised: 05/29/2024] [Indexed: 06/29/2024]
Abstract
Population aging has increased the global prevalence of aging-related diseases, including cancer, sarcopenia, neurological disease, arthritis, and heart disease. Understanding aging, a fundamental biological process, has led to breakthroughs in several fields. Cellular senescence, evinced by flattened cell bodies, vacuole formation, and cytoplasmic granules, ubiquitously plays crucial roles in tissue remodeling, embryogenesis, and wound repair as well as in cancer therapy and aging. The lack of universal biomarkers for detecting and quantifying senescent cells, in vitro and in vivo, constitutes a major limitation. The applications and limitations of major senescence biomarkers, including senescence-associated β-galactosidase staining, telomere shortening, cell-cycle arrest, DNA methylation, and senescence-associated secreted phenotypes are discussed. Furthermore, explore senotherapeutic approaches for aging-associated diseases and cancer. In addition to the conventional biomarkers, this review highlighted the in vitro, in vivo, and disease models used for aging studies. Further, technologies from the current decade including multi-omics and computational methods used in the fields of senescence and aging are also discussed in this review. Understanding aging-associated biological processes by using cellular senescence biomarkers can enable therapeutic innovation and interventions to improve the quality of life of older adults.
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Affiliation(s)
- Subramanian Muthamil
- Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Jeollanam-do, Naju, 58245, Republic of Korea
| | - Hyun-Yong Kim
- Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Jeollanam-do, Naju, 58245, Republic of Korea
| | - Hyun-Jun Jang
- Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Jeollanam-do, Naju, 58245, Republic of Korea
| | - Ji-Hyo Lyu
- Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Jeollanam-do, Naju, 58245, Republic of Korea
| | - Ung Cheol Shin
- Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Jeollanam-do, Naju, 58245, Republic of Korea
| | - Younghoon Go
- Korean Medicine (KM)-application Center, Korea Institute of Oriental Medicine, Daegu, 41062, Republic of Korea
| | - Seong-Hoon Park
- Genetic and Epigenetic Toxicology Research Group, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea
| | - Hee Gu Lee
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea
| | - Jun Hong Park
- Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Jeollanam-do, Naju, 58245, Republic of Korea
- Korean Convergence Medicine Major, University of Science & Technology (UST), KIOM Campus, Daejeon, 34054, Republic of Korea
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49
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Feng H, Li J, Wang H, Wei Z, Feng S. Senescence- and Immunity-Related Changes in the Central Nervous System: A Comprehensive Review. Aging Dis 2024:AD.2024.0755. [PMID: 39325939 DOI: 10.14336/ad.2024.0755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 08/26/2024] [Indexed: 09/28/2024] Open
Abstract
Senescence is a cellular state characterized by an irreversible halt in the cell cycle, accompanied by alterations in cell morphology, function, and secretion. Senescent cells release a plethora of inflammatory and growth factors, extracellular matrix proteins, and other bioactive substances, collectively known as the senescence-associated secretory phenotype (SASP). These excreted substances serve as crucial mediators of senescent tissues, while the secretion of SASP by senescent neurons and glial cells in the central nervous system modulates the activity of immune cells. Senescent immune cells also influence the physiological activities of various cells in the central nervous system. Further, the interaction between cellular senescence and immune regulation collectively affects the physiological and pathological processes of the central nervous system. Herein, we explore the role of senescence in the physiological and pathological processes underlying embryonic development, aging, degeneration, and injury of the central nervous system, through the immune response. Further, we elucidate the role of senescence in the physiological and pathological processes of the central nervous system, proposing a new theoretical foundation for treating central nervous system diseases.
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Affiliation(s)
- Haiwen Feng
- Tianjin Key Laboratory of Spine and Spinal Cord, International Science and Technology Cooperation Base of Spinal Cord Injury, Department of Orthopedics, International Chinese Musculoskeletal Research Society Collaborating Center for Spinal Cord Injury, Tianjin Medical University General Hospital, Tianjin 300070, China
| | - Junjin Li
- Tianjin Key Laboratory of Spine and Spinal Cord, International Science and Technology Cooperation Base of Spinal Cord Injury, Department of Orthopedics, International Chinese Musculoskeletal Research Society Collaborating Center for Spinal Cord Injury, Tianjin Medical University General Hospital, Tianjin 300070, China
| | - Hongda Wang
- Tianjin Key Laboratory of Spine and Spinal Cord, International Science and Technology Cooperation Base of Spinal Cord Injury, Department of Orthopedics, International Chinese Musculoskeletal Research Society Collaborating Center for Spinal Cord Injury, Tianjin Medical University General Hospital, Tianjin 300070, China
| | - Zhijian Wei
- Orthopedic Research Center of Shandong University and Department of Orthopedics, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
| | - Shiqing Feng
- Tianjin Key Laboratory of Spine and Spinal Cord, International Science and Technology Cooperation Base of Spinal Cord Injury, Department of Orthopedics, International Chinese Musculoskeletal Research Society Collaborating Center for Spinal Cord Injury, Tianjin Medical University General Hospital, Tianjin 300070, China
- Orthopedic Research Center of Shandong University and Department of Orthopedics, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
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50
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Samarawickrama PN, Zhang G, Zhu E, Dong X, Nisar A, Zhu H, Ma Y, Zhou Z, Yang H, Gui L, Cao M, Li W, Chang Y, Zi M, Cui H, Duan Z, Zhang X, Li W, He Y. Clearance of senescent cells enhances skin wound healing in type 2 diabetic mice. Theranostics 2024; 14:5429-5442. [PMID: 39310100 PMCID: PMC11413796 DOI: 10.7150/thno.100991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 08/16/2024] [Indexed: 09/25/2024] Open
Abstract
Background: Diabetic foot ulcers (DFUs) pose a substantial healthcare challenge due to their high rates of morbidity, recurrence, disability, and mortality. Current DFU therapeutics continue to grapple with multiple limitations. Senescent cells (SnCs) have been found to have a beneficial effect on acute wound healing, however, their roles in chronic wounds, such as DFU, remain unclear. Methods and results: We collected skin, fat, and muscle samples from clinical patients with DFU and lower limb fractures. RNA-sequencing combined with qPCR analyses on these samples demonstrate a significant accumulation of SnCs at DFU, as indicated by higher senescence markers (e.g., p16 and p21) and a senescence-associated secretory phenotype (SASP). We constructed a type 2 diabetic model of db/db mice, fed with a high-fat diet (Db-HFD), which were wounded using a 6 mm punch to the dorsal skin. HFD slightly affected wound healing in wild-type (WT) mice, but high glucose significantly delayed wound healing in the Db-HFD mice. We injected the mice with a previously developed fluorescent probe (XZ1208), which allows the detection of SnCs in vivo, and observed a strong senescence signal at the wound site of the Db-HFD mice. Contrary to the beneficial effects of SnCs in acute wound healing, our results demonstrated that clearance of SnCs using the senolytic compound ABT263 significantly accelerated wound healing in Db-HFD mice. Conclusion: Collectively, these findings suggest that SnCs critically accumulate at wound sites, delaying the healing process in DFUs. Thus, targeting SnCs with senolytic therapy represents a promising approach for DFU treatment, potentially improving the quality of life for patients with DFUs.
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Affiliation(s)
- Priyadarshani Nadeeshika Samarawickrama
- Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China
- Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Guiqin Zhang
- Department of Endocrinology, the Second Affiliated Hospital of Dali University (the Third People's Hospital of Yunnan Province), Kunming, Yunnan 650011, China
| | - Enfang Zhu
- Department of Endocrinology, the Second Affiliated Hospital of Dali University (the Third People's Hospital of Yunnan Province), Kunming, Yunnan 650011, China
| | - Xin Dong
- Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China
- Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China
| | - Ayesha Nisar
- Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China
- Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Hong Zhu
- Department of Endocrinology, the Second Affiliated Hospital of Dali University (the Third People's Hospital of Yunnan Province), Kunming, Yunnan 650011, China
| | - Yuan Ma
- Department of Orthopedics, the Third People's Hospital of Yunnan Province, Kunming, Yunnan 650011, China
| | - Zheyan Zhou
- Department of Pathology, the Third People's Hospital of Yunnan Province, Kunming, Yunnan 650011, China
| | - Honglin Yang
- Department of Orthopedics, the Third People's Hospital of Yunnan Province, Kunming, Yunnan 650011, China
| | - Li Gui
- Department of Endocrinology, the Second Affiliated Hospital of Dali University (the Third People's Hospital of Yunnan Province), Kunming, Yunnan 650011, China
| | - Mei Cao
- Department of Endocrinology, the Second Affiliated Hospital of Dali University (the Third People's Hospital of Yunnan Province), Kunming, Yunnan 650011, China
| | - Wei Li
- Department of Endocrinology, the Second Affiliated Hospital of Dali University (the Third People's Hospital of Yunnan Province), Kunming, Yunnan 650011, China
| | - Yu Chang
- Department of Endocrinology, the Second Affiliated Hospital of Dali University (the Third People's Hospital of Yunnan Province), Kunming, Yunnan 650011, China
| | - Meiting Zi
- Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China
- Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China
| | - Haoling Cui
- Department of Endocrinology, the Second Affiliated Hospital of Dali University (the Third People's Hospital of Yunnan Province), Kunming, Yunnan 650011, China
| | - Zhongping Duan
- Department of Endocrinology, the Second Affiliated Hospital of Dali University (the Third People's Hospital of Yunnan Province), Kunming, Yunnan 650011, China
| | - Xuan Zhang
- Drug Discovery & Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Wen Li
- Department of Endocrinology, the Second Affiliated Hospital of Dali University (the Third People's Hospital of Yunnan Province), Kunming, Yunnan 650011, China
| | - Yonghan He
- Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China
- Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China
- University of Chinese Academy of Sciences, Beijing 100049, China
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