|
1
|
Wölfel EM, Fernandez-Guerra P, Nørgård MØ, Jeromdesella S, Kjær PK, Elkjær AS, Kassem M, Figeac F. Senescence of skeletal stem cells and their contribution to age-related bone loss. Mech Ageing Dev 2024; 221:111976. [PMID: 39111640 DOI: 10.1016/j.mad.2024.111976] [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: 05/31/2024] [Revised: 07/30/2024] [Accepted: 08/03/2024] [Indexed: 08/18/2024]
Abstract
Human aging is linked to bone loss, resulting in bone fragility and an increased risk of fractures. This is primarily due to an age-related decline in the function of bone-forming osteoblastic cells and accelerated cellular senescence within the bone microenvironment. Here, we provide a detailed discussion of the hypothesis that age-related defective bone formation is caused by senescence of skeletal stem cells, as they are the main source of bone forming osteoblastic cells and influence the composition of bone microenvironment. Furthermore, this review discusses potential strategies to target cellular senescence as an emerging approach to treat age-related bone loss.
Collapse
Affiliation(s)
- Eva M Wölfel
- Molecular Endocrinology Unit, KMEB, Department of Endocrinology, Odense University Hospital, Winsløws Vej 4, Odense C 5000, Denmark.
| | - Paula Fernandez-Guerra
- Molecular Endocrinology Unit, KMEB, Department of Endocrinology, Odense University Hospital, Winsløws Vej 4, Odense C 5000, Denmark.
| | - Mikkel Ørnfeldt Nørgård
- Molecular Endocrinology Unit, KMEB, Department of Endocrinology, Odense University Hospital, Winsløws Vej 4, Odense C 5000, Denmark.
| | - Shakespeare Jeromdesella
- Molecular Endocrinology Unit, KMEB, Department of Endocrinology, Odense University Hospital, Winsløws Vej 4, Odense C 5000, Denmark.
| | - Pernille Kirkegaard Kjær
- Molecular Endocrinology Unit, KMEB, Department of Endocrinology, Odense University Hospital, Winsløws Vej 4, Odense C 5000, Denmark.
| | - Anna Sofie Elkjær
- Molecular Endocrinology Unit, KMEB, Department of Endocrinology, Odense University Hospital, Winsløws Vej 4, Odense C 5000, Denmark.
| | - Moustapha Kassem
- Molecular Endocrinology Unit, KMEB, Department of Endocrinology, Odense University Hospital, Winsløws Vej 4, Odense C 5000, Denmark; Institute of Cellular and Molecular Medicine (ICMM), Panum Institute, University of Copenhagen, 3B Blegdamsvej, Copenhagen N 2200, Denmark.
| | - Florence Figeac
- Molecular Endocrinology Unit, KMEB, Department of Endocrinology, Odense University Hospital, Winsløws Vej 4, Odense C 5000, Denmark.
| |
Collapse
|
|
2
|
Zhao H, Zhao H, Ji S. A Mesenchymal stem cell Aging Framework, from Mechanisms to Strategies. Stem Cell Rev Rep 2024; 20:1420-1440. [PMID: 38727878 DOI: 10.1007/s12015-024-10732-4] [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] [Accepted: 05/02/2024] [Indexed: 08/13/2024]
Abstract
Mesenchymal stem cells (MSCs) are extensively researched for therapeutic applications in tissue engineering and show significant potential for clinical use. Intrinsic or extrinsic factors causing senescence may lead to reduced proliferation, aberrant differentiation, weakened immunoregulation, and increased inflammation, ultimately limiting the potential of MSCs. It is crucial to comprehend the molecular pathways and internal processes responsible for the decline in MSC function due to senescence in order to devise innovative approaches for rejuvenating senescent MSCs and enhancing MSC treatment. We investigate the main molecular processes involved in senescence, aiming to provide a thorough understanding of senescence-related issues in MSCs. Additionally, we analyze the most recent advancements in cutting-edge approaches to combat MSC senescence based on current research. We are curious whether the aging process of stem cells results in a permanent "memory" and if cellular reprogramming may potentially revert the aging epigenome to a more youthful state.
Collapse
Affiliation(s)
- Hongqing Zhao
- Nanbu County People's Hospital, Nanchong City, 637300, Sichuan Province, China
- Jinzhou Medical University, No.82 Songpo Road, Guta District, Jinzhou, 121001, Liaoning Province, China
| | - Houming Zhao
- Graduate School of PLA Medical College, Chinese PLA General Hospital, Beijing, 100083, China
| | - Shuaifei Ji
- Graduate School of PLA Medical College, Chinese PLA General Hospital, Beijing, 100083, China.
| |
Collapse
|
|
3
|
Mistry JJ, Young KA, Colom Díaz PA, Maestre IF, Levine RL, Trowbridge JJ. Mesenchymal Stromal Cell Senescence Induced by Dnmt3a -Mutant Hematopoietic Cells is a Targetable Mechanism Driving Clonal Hematopoiesis and Initiation of Hematologic Malignancy. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.28.587254. [PMID: 38585779 PMCID: PMC10996614 DOI: 10.1101/2024.03.28.587254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2024]
Abstract
Clonal hematopoiesis (CH) can predispose to blood cancers due to enhanced fitness of mutant hematopoietic stem and progenitor cells (HSPCs), but the mechanisms driving this progression are not understood. We hypothesized that malignant progression is related to microenvironment-remodelling properties of CH-mutant HSPCs. Single-cell transcriptomic profiling of the bone marrow microenvironment in Dnmt3a R878H/+ mice revealed signatures of cellular senescence in mesenchymal stromal cells (MSCs). Dnmt3a R878H/+ HSPCs caused MSCs to upregulate the senescence markers SA-β-gal, BCL-2, BCL-xL, Cdkn1a (p21) and Cdkn2a (p16), ex vivo and in vivo . This effect was cell contact-independent and can be replicated by IL-6 or TNFα, which are produced by Dnmt3a R878H/+ HSPCs. Depletion of senescent MSCs in vivo reduced the fitness of Dnmt3a R878H/+ hematopoietic cells and the progression of CH to myeloid neoplasms using a sequentially inducible Dnmt3a ; Npm1 -mutant model. Thus, Dnmt3a -mutant HSPCs reprogram their microenvironment via senescence induction, creating a self-reinforcing niche favoring fitness and malignant progression. Statement of Significance Mesenchymal stromal cell senescence induced by Dnmt3a -mutant hematopoietic stem and progenitor cells drives clonal hematopoiesis and initiation of hematologic malignancy.
Collapse
|
|
4
|
Ibragimova M, Kussainova A, Aripova A, Bersimbaev R, Bulgakova O. The Molecular Mechanisms in Senescent Cells Induced by Natural Aging and Ionizing Radiation. Cells 2024; 13:550. [PMID: 38534394 PMCID: PMC10969416 DOI: 10.3390/cells13060550] [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: 02/20/2024] [Revised: 03/17/2024] [Accepted: 03/19/2024] [Indexed: 03/28/2024] Open
Abstract
This review discusses the relationship between cellular senescence and radiation exposure. Given the wide range of ionizing radiation sources encountered by people in professional and medical spheres, as well as the influence of natural background radiation, the question of the effect of radiation on biological processes, particularly on aging processes, remains highly relevant. The parallel relationship between natural and radiation-induced cellular senescence reveals the common aspects underlying these processes. Based on recent scientific data, the key points of the effects of ionizing radiation on cellular processes associated with aging, such as genome instability, mitochondrial dysfunction, altered expression of miRNAs, epigenetic profile, and manifestation of the senescence-associated secretory phenotype (SASP), are discussed. Unraveling the molecular mechanisms of cellular senescence can make a valuable contribution to the understanding of the molecular genetic basis of age-associated diseases in the context of environmental exposure.
Collapse
Affiliation(s)
- Milana Ibragimova
- Department of General Biology and Genomics, Institute of Cell Biology and Biotechnology, L.N. Gumilyov Eurasian National University, Astana 010008, Kazakhstan; (M.I.); (A.K.); (A.A.); (R.B.)
| | - Assiya Kussainova
- Department of General Biology and Genomics, Institute of Cell Biology and Biotechnology, L.N. Gumilyov Eurasian National University, Astana 010008, Kazakhstan; (M.I.); (A.K.); (A.A.); (R.B.)
- Department of Health Sciences, University of Genova, Via Pastore 1, 16132 Genoa, Italy
| | - Akmaral Aripova
- Department of General Biology and Genomics, Institute of Cell Biology and Biotechnology, L.N. Gumilyov Eurasian National University, Astana 010008, Kazakhstan; (M.I.); (A.K.); (A.A.); (R.B.)
| | - Rakhmetkazhi Bersimbaev
- Department of General Biology and Genomics, Institute of Cell Biology and Biotechnology, L.N. Gumilyov Eurasian National University, Astana 010008, Kazakhstan; (M.I.); (A.K.); (A.A.); (R.B.)
| | - Olga Bulgakova
- Department of General Biology and Genomics, Institute of Cell Biology and Biotechnology, L.N. Gumilyov Eurasian National University, Astana 010008, Kazakhstan; (M.I.); (A.K.); (A.A.); (R.B.)
| |
Collapse
|
|
5
|
Noguchi M, Ihara T, Suzuki K, Yokoya A. Temporal Dynamic Regulation of Autophagy and Senescence Induction in Response to Radiation Exposure. Radiat Res 2023; 200:538-547. [PMID: 37902247 DOI: 10.1667/rade-23-00173.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 10/14/2023] [Indexed: 10/31/2023]
Abstract
Autophagy and senescence are closely related cellular responses to genotoxic stress, and play significant roles in the execution of cellular responses to radiation exposure. However, little is known about their interplay in the fate-decision of cells receiving lethal doses of radiation. Here, we report that autophagy precedes the establishment of premature senescence in normal human fibroblasts exposed to lethal doses of radiation. Activation of the p53-dependent DNA damage response caused sustained dephosphorylation of RB proteins and consequent cell cycle arrest, concurrently with Ulk1 dephosphorylation at Ser638 by PPM1D, which promoted autophagy induction 1-2 days after irradiation. In addition, mitochondrial fragmentation became obvious 1-2 days after irradiation, and autophagy was further enhanced. However, Ulk1 levels decreased significantly after 2 days, resulting in lower LC3-II levels. An autophagic flux assay using chloroquine (CQ) also revealed that the flux in irradiated cells gradually decreased over 30 days. In contrast, lysosomal augmentation started at 1 day, became significantly upregulated after 5 days, and continued for over 30 days. After a rapid decrease in autophagy, p16 expression increased and senescence was established, but autophagic activity remained reduced. These results demonstrated that X-ray irradiation triggered two processes, autophagy and senescence, with the former being temporary and regulated by DNA damage response and mitophagy, and the latter being sustained and regulated by persistent cell cycle arrest. The interplay between autophagy and senescence seems to be essential for the proper implementation of the cellular response to radiation exposure.
Collapse
Affiliation(s)
- Miho Noguchi
- Institute for Quantum Life Science, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba-shi, Chiba 263-8555, Japan
| | - Tomokazu Ihara
- Institute for Quantum Life Science, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba-shi, Chiba 263-8555, Japan
- Graduate School of Science and Engineering, Ibaraki University, 2-1-1, Bunkyo, Mito-shi, Ibaraki 310-8512, Japan
| | - Keiji Suzuki
- Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki-shi, Nagasaki 852-8523, Japan
| | - Akinari Yokoya
- Institute for Quantum Life Science, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba-shi, Chiba 263-8555, Japan
- Graduate School of Science and Engineering, Ibaraki University, 2-1-1, Bunkyo, Mito-shi, Ibaraki 310-8512, Japan
| |
Collapse
|
|
6
|
Afifi MM, Crncec A, Cornwell JA, Cataisson C, Paul D, Ghorab LM, Hernandez MO, Wong M, Kedei N, Cappell SD. Irreversible cell cycle exit associated with senescence is mediated by constitutive MYC degradation. Cell Rep 2023; 42:113079. [PMID: 37656618 PMCID: PMC10591853 DOI: 10.1016/j.celrep.2023.113079] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 07/21/2023] [Accepted: 08/21/2023] [Indexed: 09/03/2023] Open
Abstract
Cells can irreversibly exit the cell cycle and become senescent to safeguard against uncontrolled proliferation. While the p53-p21 and p16-Rb pathways are thought to mediate senescence, they also mediate reversible cell cycle arrest (quiescence), raising the question of whether senescence is actually reversible or whether alternative mechanisms underly the irreversibility associated with senescence. Here, we show that senescence is irreversible and that commitment to and maintenance of senescence are mediated by irreversible MYC degradation. Senescent cells start dividing when a non-degradable MYC mutant is expressed, and quiescent cells convert to senescence when MYC is knocked down. In early oral carcinogenesis, epithelial cells exhibit MYC loss and become senescent as a safeguard against malignant transformation. Later stages of oral premalignant lesions exhibit elevated MYC levels and cellular dysplasia. Thus, irreversible cell cycle exit associated with senescence is mediated by constitutive MYC degradation, but bypassing this degradation may allow tumor cells to escape during cancer initiation.
Collapse
Affiliation(s)
- Marwa M Afifi
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Adrijana Crncec
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - James A Cornwell
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Christophe Cataisson
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Debasish Paul
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Laila M Ghorab
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Maria O Hernandez
- Collaborative Protein Technology Resource, Office of Science and Technology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Madeline Wong
- Collaborative Protein Technology Resource, Office of Science and Technology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Noemi Kedei
- Collaborative Protein Technology Resource, Office of Science and Technology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Steven D Cappell
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
| |
Collapse
|
|
7
|
Zhang W, Wang T, Xue Y, Zhan B, Lai Z, Huang W, Peng X, Zhou Y. Research progress of extracellular vesicles and exosomes derived from mesenchymal stem cells in the treatment of oxidative stress-related diseases. Front Immunol 2023; 14:1238789. [PMID: 37646039 PMCID: PMC10461809 DOI: 10.3389/fimmu.2023.1238789] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 07/24/2023] [Indexed: 09/01/2023] Open
Abstract
There is growing evidence that mesenchymal stem cell-derived extracellular vesicles and exosomes can significantly improve the curative effect of oxidative stress-related diseases. Mesenchymal stem cell extracellular vesicles and exosomes (MSC-EVs and MSC-Exos) are rich in bioactive molecules and have many biological regulatory functions. In this review, we describe how MSC-EVs and MSC-Exos reduce the related markers of oxidative stress and inflammation in various systemic diseases, and the molecular mechanism of MSC-EVs and MSC-Exos in treating apoptosis and vascular injury induced by oxidative stress. The results of a large number of experimental studies have shown that both local and systemic administration can effectively inhibit the oxidative stress response in diseases and promote the survival and regeneration of damaged parenchymal cells. The mRNA and miRNAs in MSC-EVs and MSC-Exos are the most important bioactive molecules in disease treatment, which can inhibit the apoptosis, necrosis and oxidative stress of lung, heart, kidney, liver, bone, skin and other cells, and promote their survive and regenerate.
Collapse
Affiliation(s)
- Wenwen Zhang
- The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan, Guangdong, China
- Department of Pathophysiology, Guangdong Medical University, Dongguan, Guangdong, China
| | - Tingyu Wang
- The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan, Guangdong, China
- Department of Pathophysiology, Guangdong Medical University, Dongguan, Guangdong, China
| | - Yuanye Xue
- The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan, Guangdong, China
- Department of Pathophysiology, Guangdong Medical University, Dongguan, Guangdong, China
| | - Bingbing Zhan
- School of Pharmaceutical Sciences, Guangdong Medical University, Dongguan, China
| | - Zengjie Lai
- The Second Clinical Medical College of Guangdong Medical University, Dongguan, China
| | - Wenjie Huang
- School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Xinsheng Peng
- Biomedical Innovation Center, Guangdong Medical University, Dongguan, China
- Institute of Marine Medicine, Guangdong Medical University, Zhanjiang, China
| | - Yanfang Zhou
- The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan, Guangdong, China
- Department of Pathophysiology, Guangdong Medical University, Dongguan, Guangdong, China
| |
Collapse
|
|
8
|
Lee SS, Vũ TT, Weiss AS, Yeo GC. Stress-induced senescence in mesenchymal stem cells: Triggers, hallmarks, and current rejuvenation approaches. Eur J Cell Biol 2023; 102:151331. [PMID: 37311287 DOI: 10.1016/j.ejcb.2023.151331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 06/04/2023] [Accepted: 06/05/2023] [Indexed: 06/15/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have emerged as promising cell-based therapies in the treatment of degenerative and inflammatory conditions. However, despite accumulating evidence of the breadth of MSC functional potency, their broad clinical translation is hampered by inconsistencies in therapeutic efficacy, which is at least partly due to the phenotypic and functional heterogeneity of MSC populations as they progress towards senescence in vitro. MSC senescence, a natural response to aging and stress, gives rise to altered cellular responses and functional decline. This review describes the key regenerative properties of MSCs; summarises the main triggers, mechanisms, and consequences of MSC senescence; and discusses current cellular and extracellular strategies to delay the onset or progression of senescence, or to rejuvenate biological functions lost to senescence.
Collapse
Affiliation(s)
- Sunny Shinchen Lee
- Charles Perkins Centre, The University of Sydney, NSW 2006, Australia; School of Life and Environmental Sciences, The University of Sydney, NSW 2006, Australia
| | - Thu Thuy Vũ
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Viet Nam
| | - Anthony S Weiss
- Charles Perkins Centre, The University of Sydney, NSW 2006, Australia; School of Life and Environmental Sciences, The University of Sydney, NSW 2006, Australia; Sydney Nano Institute, The University of Sydney, NSW 2006, Australia
| | - Giselle C Yeo
- Charles Perkins Centre, The University of Sydney, NSW 2006, Australia; School of Life and Environmental Sciences, The University of Sydney, NSW 2006, Australia.
| |
Collapse
|
|
9
|
Alessio N, Acar MB, Squillaro T, Aprile D, Ayaz‐Güner Ş, Di Bernardo G, Peluso G, Özcan S, Galderisi U. Progression of irradiated mesenchymal stromal cells from early to late senescence: Changes in SASP composition and anti-tumour properties. Cell Prolif 2023; 56:e13401. [PMID: 36949664 PMCID: PMC10280137 DOI: 10.1111/cpr.v56.6 10.1111/cpr.13401] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 12/29/2022] [Accepted: 12/30/2022] [Indexed: 09/30/2023] Open
Abstract
Genotoxic injuries converge on senescence-executive program that promotes production of a senescence-specific secretome (SASP). The study of SASP is particularly intriguing, since through it a senescence process, triggered in a few cells, can spread to many other cells and produce either beneficial or negative consequences for health. We analysed the SASP of quiescent mesenchymal stromal cells (MSCs) following stress induced premature senescence (SIPS) by ionizing radiation exposure. We performed a proteome analysis of SASP content obtained from early and late senescent cells. The bioinformatics studies evidenced that early and late SASPs, besides some common ontologies and signalling pathways, contain specific factors. In spite of these differences, we evidenced that SASPs can block in vitro proliferation of cancer cells and promote senescence/apoptosis. It is possible to imagine that SASP always contains core components that have an anti-tumour activity, the progression from early to late senescence enriches the SASP of factors that may promote SASP tumorigenic activity only by interacting and instructing cells of the immune system. Our results on Caco-2 cancer cells incubated with late SASP in presence of peripheral white blood cells strongly support this hypothesis. We evidenced that quiescent MSCs following SIPS produced SASP that, while progressively changed its composition, preserved the capacity to block cancer growth by inducing senescence and/or apoptosis only in an autonomous manner.
Collapse
Affiliation(s)
- Nicola Alessio
- Department of Experimental MedicineLuigi Vanvitelli Campania UniversityNaplesItaly
| | | | - Tiziana Squillaro
- Department of Experimental MedicineLuigi Vanvitelli Campania UniversityNaplesItaly
| | - Domenico Aprile
- Department of Experimental MedicineLuigi Vanvitelli Campania UniversityNaplesItaly
| | - Şerife Ayaz‐Güner
- Department of Molecular Biology and Genetics, Faculty of Life and Natural ScienceAbdullah Gül UniversityKayseriTurkey
- Department of Molecular Biology and GeneticsIzmir Institute of TechnologyIzmirTurkey
| | - Giovanni Di Bernardo
- Department of Experimental MedicineLuigi Vanvitelli Campania UniversityNaplesItaly
- The Interuniversity Consortium “Istituto Nazionale Biostrutture e Biosistemi” (INBB – Biostructures and Biosystems National Institute)RomeItaly
| | | | - Servet Özcan
- Genome and Stem Cell Center (GENKÖK) Erciyes UniversityKayseriTurkey
- Department of Biology, Faculty of ScienceErciyes UniversityKayseriTurkey
| | - Umberto Galderisi
- Department of Experimental MedicineLuigi Vanvitelli Campania UniversityNaplesItaly
- Genome and Stem Cell Center (GENKÖK) Erciyes UniversityKayseriTurkey
- Department of Molecular Biology and GeneticsIzmir Institute of TechnologyIzmirTurkey
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for BiotechnologyTemple UniversityPhiladelphiaPennsylvaniaUSA
| |
Collapse
|
|
10
|
Alessio N, Acar MB, Squillaro T, Aprile D, Ayaz‐Güner Ş, Di Bernardo G, Peluso G, Özcan S, Galderisi U. Progression of irradiated mesenchymal stromal cells from early to late senescence: Changes in SASP composition and anti-tumour properties. Cell Prolif 2023; 56:e13401. [PMID: 36949664 PMCID: PMC10280137 DOI: 10.1111/cpr.v56.6+10.1111/cpr.13401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 12/29/2022] [Accepted: 12/30/2022] [Indexed: 01/20/2024] Open
Abstract
Genotoxic injuries converge on senescence-executive program that promotes production of a senescence-specific secretome (SASP). The study of SASP is particularly intriguing, since through it a senescence process, triggered in a few cells, can spread to many other cells and produce either beneficial or negative consequences for health. We analysed the SASP of quiescent mesenchymal stromal cells (MSCs) following stress induced premature senescence (SIPS) by ionizing radiation exposure. We performed a proteome analysis of SASP content obtained from early and late senescent cells. The bioinformatics studies evidenced that early and late SASPs, besides some common ontologies and signalling pathways, contain specific factors. In spite of these differences, we evidenced that SASPs can block in vitro proliferation of cancer cells and promote senescence/apoptosis. It is possible to imagine that SASP always contains core components that have an anti-tumour activity, the progression from early to late senescence enriches the SASP of factors that may promote SASP tumorigenic activity only by interacting and instructing cells of the immune system. Our results on Caco-2 cancer cells incubated with late SASP in presence of peripheral white blood cells strongly support this hypothesis. We evidenced that quiescent MSCs following SIPS produced SASP that, while progressively changed its composition, preserved the capacity to block cancer growth by inducing senescence and/or apoptosis only in an autonomous manner.
Collapse
Affiliation(s)
- Nicola Alessio
- Department of Experimental MedicineLuigi Vanvitelli Campania UniversityNaplesItaly
| | | | - Tiziana Squillaro
- Department of Experimental MedicineLuigi Vanvitelli Campania UniversityNaplesItaly
| | - Domenico Aprile
- Department of Experimental MedicineLuigi Vanvitelli Campania UniversityNaplesItaly
| | - Şerife Ayaz‐Güner
- Department of Molecular Biology and Genetics, Faculty of Life and Natural ScienceAbdullah Gül UniversityKayseriTurkey
- Department of Molecular Biology and GeneticsIzmir Institute of TechnologyIzmirTurkey
| | - Giovanni Di Bernardo
- Department of Experimental MedicineLuigi Vanvitelli Campania UniversityNaplesItaly
- The Interuniversity Consortium “Istituto Nazionale Biostrutture e Biosistemi” (INBB – Biostructures and Biosystems National Institute)RomeItaly
| | | | - Servet Özcan
- Genome and Stem Cell Center (GENKÖK) Erciyes UniversityKayseriTurkey
- Department of Biology, Faculty of ScienceErciyes UniversityKayseriTurkey
| | - Umberto Galderisi
- Department of Experimental MedicineLuigi Vanvitelli Campania UniversityNaplesItaly
- Genome and Stem Cell Center (GENKÖK) Erciyes UniversityKayseriTurkey
- Department of Molecular Biology and GeneticsIzmir Institute of TechnologyIzmirTurkey
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for BiotechnologyTemple UniversityPhiladelphiaPennsylvaniaUSA
| |
Collapse
|
|
11
|
Alessio N, Acar MB, Squillaro T, Aprile D, Ayaz‐Güner Ş, Di Bernardo G, Peluso G, Özcan S, Galderisi U. Progression of irradiated mesenchymal stromal cells from early to late senescence: Changes in SASP composition and anti-tumour properties. Cell Prolif 2023; 56:e13401. [PMID: 36949664 PMCID: PMC10280137 DOI: 10.1111/cpr.13401] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 12/29/2022] [Accepted: 12/30/2022] [Indexed: 03/24/2023] Open
Abstract
Genotoxic injuries converge on senescence-executive program that promotes production of a senescence-specific secretome (SASP). The study of SASP is particularly intriguing, since through it a senescence process, triggered in a few cells, can spread to many other cells and produce either beneficial or negative consequences for health. We analysed the SASP of quiescent mesenchymal stromal cells (MSCs) following stress induced premature senescence (SIPS) by ionizing radiation exposure. We performed a proteome analysis of SASP content obtained from early and late senescent cells. The bioinformatics studies evidenced that early and late SASPs, besides some common ontologies and signalling pathways, contain specific factors. In spite of these differences, we evidenced that SASPs can block in vitro proliferation of cancer cells and promote senescence/apoptosis. It is possible to imagine that SASP always contains core components that have an anti-tumour activity, the progression from early to late senescence enriches the SASP of factors that may promote SASP tumorigenic activity only by interacting and instructing cells of the immune system. Our results on Caco-2 cancer cells incubated with late SASP in presence of peripheral white blood cells strongly support this hypothesis. We evidenced that quiescent MSCs following SIPS produced SASP that, while progressively changed its composition, preserved the capacity to block cancer growth by inducing senescence and/or apoptosis only in an autonomous manner.
Collapse
Affiliation(s)
- Nicola Alessio
- Department of Experimental MedicineLuigi Vanvitelli Campania UniversityNaplesItaly
| | | | - Tiziana Squillaro
- Department of Experimental MedicineLuigi Vanvitelli Campania UniversityNaplesItaly
| | - Domenico Aprile
- Department of Experimental MedicineLuigi Vanvitelli Campania UniversityNaplesItaly
| | - Şerife Ayaz‐Güner
- Department of Molecular Biology and Genetics, Faculty of Life and Natural ScienceAbdullah Gül UniversityKayseriTurkey
- Department of Molecular Biology and GeneticsIzmir Institute of TechnologyIzmirTurkey
| | - Giovanni Di Bernardo
- Department of Experimental MedicineLuigi Vanvitelli Campania UniversityNaplesItaly
- The Interuniversity Consortium “Istituto Nazionale Biostrutture e Biosistemi” (INBB – Biostructures and Biosystems National Institute)RomeItaly
| | | | - Servet Özcan
- Genome and Stem Cell Center (GENKÖK) Erciyes UniversityKayseriTurkey
- Department of Biology, Faculty of ScienceErciyes UniversityKayseriTurkey
| | - Umberto Galderisi
- Department of Experimental MedicineLuigi Vanvitelli Campania UniversityNaplesItaly
- Genome and Stem Cell Center (GENKÖK) Erciyes UniversityKayseriTurkey
- Department of Molecular Biology and GeneticsIzmir Institute of TechnologyIzmirTurkey
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for BiotechnologyTemple UniversityPhiladelphiaPennsylvaniaUSA
| |
Collapse
|
|
12
|
Weber L, Lee BS, Imboden S, Hsieh CJ, Lin NY. Phenotyping senescent mesenchymal stromal cells using AI image translation. CURRENT RESEARCH IN BIOTECHNOLOGY 2023; 5:100120. [PMID: 38045568 PMCID: PMC10691861 DOI: 10.1016/j.crbiot.2023.100120] [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] [Indexed: 02/04/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) offer promising potential in biomedical research, clinical therapeutics, and immunomodulatory therapies due to their ease of isolation and multipotent, immunoprivileged, and immunosuppersive properties. Extensive efforts have focused on optimizing the cell isolation and culture methods to generate scalable, therapeutically-relevant MSCs for clinical applications. However, MSC-based therapies are often hindered by cell heterogeneity and inconsistency of therapeutic function caused, in part, by MSC senescence. As such, noninvasive and molecular-based MSC characterizations play an essential role in assuring the consistency of MSC functions. Here, we demonstrated that AI image translation algorithms can effectively predict immunofluorescence images of MSC senescence markers from phase contrast images. We showed that the expression level of senescence markers including senescence-associated beta-galactosidase (SABG), p16, p21, and p38 are accurately predicted by deep-learning models for Doxorubicin-induced MSC senescence, irradiation-induced MSC senescence, and replicative MSC senescence. Our AI model distinguished the non-senescent and senescent MSC populations and simultaneously captured the cell-to-cell variability within a population. Our microscopy-based phenotyping platform can be integrated with cell culture routines making it an easily accessible tool for MSC engineering and manufacturing.
Collapse
Affiliation(s)
- Leya Weber
- Department of Mechanical and Aerospace Engineering, University of California, Los Angeles 90095, CA, United States
| | - Brandon S. Lee
- Department of Bioengineering, University of California, Los Angeles 90095, CA, United States
| | - Sara Imboden
- Department of Mechanical and Aerospace Engineering, University of California, Los Angeles 90095, CA, United States
| | - Cho-Jui Hsieh
- Department of Computer Science, University of California, Los Angeles 90095, CA, United States
| | - Neil Y.C. Lin
- Department of Mechanical and Aerospace Engineering, University of California, Los Angeles 90095, CA, United States
- Department of Bioengineering, University of California, Los Angeles 90095, CA, United States
- California NanoSystems Institute, University of California, Los Angeles 90095, CA, United States
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles 90095, CA, United States
- Institute for Quantitative and Computational Biosciences, University of California, Los Angeles 90095, CA, United States
- Broad Stem Cell Center, University of California, Los Angeles 90095, CA, United States
| |
Collapse
|
|
13
|
Slaven JE, Wilkerson M, Soltis AR, Rittase WB, Bradfield DT, Bylicky M, Cary L, Tsioplaya A, Bouten R, Dalgard C, Day RM. Transcriptomic Profiling and Pathway Analysis of Mesenchymal Stem Cells Following Low Dose-Rate Radiation Exposure. Antioxidants (Basel) 2023; 12:antiox12020241. [PMID: 36829800 PMCID: PMC9951969 DOI: 10.3390/antiox12020241] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/17/2023] [Accepted: 01/19/2023] [Indexed: 01/26/2023] Open
Abstract
Low dose-rate radiation exposure can occur in medical imaging, as background from environmental or industrial radiation, and is a hazard of space travel. In contrast with high dose-rate radiation exposure that can induce acute life-threatening syndromes, chronic low-dose radiation is associated with Chronic Radiation Syndrome (CRS), which can alter environmental sensitivity. Secondary effects of chronic low dose-rate radiation exposure include circulatory, digestive, cardiovascular, and neurological diseases, as well as cancer. Here, we investigated 1-2 Gy, 0.66 cGy/h, 60Co radiation effects on primary human mesenchymal stem cells (hMSC). There was no significant induction of apoptosis or DNA damage, and cells continued to proliferate. Gene ontology (GO) analysis of transcriptome changes revealed alterations in pathways related to cellular metabolism (cholesterol, fatty acid, and glucose metabolism), extracellular matrix modification and cell adhesion/migration, and regulation of vasoconstriction and inflammation. Interestingly, there was increased hypoxia signaling and increased activation of pathways regulated by iron deficiency, but Nrf2 and related genes were reduced. The data were validated in hMSC and human lung microvascular endothelial cells using targeted qPCR and Western blotting. Notably absent in the GO analysis were alteration pathways for DNA damage response, cell cycle inhibition, senescence, and pro-inflammatory response that we previously observed for high dose-rate radiation exposure. Our findings suggest that cellular gene transcription response to low dose-rate ionizing radiation is fundamentally different compared to high-dose-rate exposure. We hypothesize that cellular response to hypoxia and iron deficiency are driving processes, upstream of the other pathway regulation.
Collapse
Affiliation(s)
- John E. Slaven
- Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814, USA
| | - Matthew Wilkerson
- Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20817, USA
| | - Anthony R. Soltis
- Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20817, USA
| | - W. Bradley Rittase
- Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814, USA
| | - Dmitry T. Bradfield
- Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814, USA
| | - Michelle Bylicky
- Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814, USA
| | - Lynnette Cary
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
| | - Alena Tsioplaya
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
| | - Roxane Bouten
- Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814, USA
| | - Clifton Dalgard
- The American Genome Center, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
- Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
| | - Regina M. Day
- Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814, USA
- Correspondence: ; Tel.: +1-301-295-3236; Fax: +1-301-295-3220
| |
Collapse
|
|
14
|
Li Z, Li D, Su H, Xue H, Tan G, Xu Z. Autophagy: An important target for natural products in the treatment of bone metabolic diseases. Front Pharmacol 2022; 13:999017. [PMID: 36467069 PMCID: PMC9716086 DOI: 10.3389/fphar.2022.999017] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 11/08/2022] [Indexed: 12/28/2024] Open
Abstract
Bone homeostasis depends on a precise dynamic balance between bone resorption and bone formation, involving a series of complex and highly regulated steps. Any imbalance in this process can cause disturbances in bone metabolism and lead to the development of many associated bone diseases. Autophagy, one of the fundamental pathways for the degradation and recycling of proteins and organelles, is a fundamental process that regulates cellular and organismal homeostasis. Importantly, basic levels of autophagy are present in all types of bone-associated cells. Due to the cyclic nature of autophagy and the ongoing bone metabolism processes, autophagy is considered a new participant in bone maintenance. Novel therapeutic targets have emerged as a result of new mechanisms, and bone metabolism can be controlled by interfering with autophagy by focusing on certain regulatory molecules in autophagy. In parallel, several studies have reported that various natural products exhibit a good potential to mediate autophagy for the treatment of metabolic bone diseases. Therefore, we briefly described the process of autophagy, emphasizing its function in different cell types involved in bone development and metabolism (including bone marrow mesenchymal stem cells, osteoblasts, osteocytes, chondrocytes, and osteoclasts), and also summarized research advances in natural product-mediated autophagy for the treatment of metabolic bone disease caused by dysfunction of these cells (including osteoporosis, rheumatoid joints, osteoarthritis, fracture nonunion/delayed union). The objective of the study was to identify the function that autophagy serves in metabolic bone disease and the effects, potential, and challenges of natural products for the treatment of these diseases by targeting autophagy.
Collapse
Affiliation(s)
- Zhichao Li
- First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Dandan Li
- College of Integrated Traditional Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Hui Su
- First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Haipeng Xue
- Department of Orthopedics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Guoqing Tan
- Department of Orthopedics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Zhanwang Xu
- Department of Orthopedics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| |
Collapse
|
|
15
|
Najahi H, Alessio N, Squillaro T, Conti GO, Ferrante M, Di Bernardo G, Galderisi U, Messaoudi I, Minucci S, Banni M. Environmental microplastics (EMPs) exposure alter the differentiation potential of mesenchymal stromal cells. ENVIRONMENTAL RESEARCH 2022; 214:114088. [PMID: 35973457 DOI: 10.1016/j.envres.2022.114088] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 08/05/2022] [Accepted: 08/06/2022] [Indexed: 06/15/2023]
Abstract
Humans are exposed to environmental microplastic (MPs) that can be frequent in surrounding environment. The mesenchymal stromal cells are a heterogeneous population, which contain fibroblasts and stromal cells, progenitor cells and stem cells. They are part of the stromal component of most tissue and organs in our organisms. Any injury to their functions may impair tissue renewal and homeostasis. We evaluated the effects of different size MPs that could be present in water bottles on human bone marrow mesenchymal stromal cells (BMMSCs) and adipose mesenchymal stromal cells (AMSCs). MPs of polyethylene terephthalate (MPs-PET) (<1 μm and <2.6 μm) were tested in this study. PET treatments induced a reduction in proliferating cells (around 30%) associated either with the onset of senescence or increase in apoptosis. The AMSCs and BMMSCs exposed to PET showed an alteration of differentiation potential. AMSCs remained in an early stage of adipocyte differentiation as shown by high levels of mRNA for Peroxisome Proliferator Activated Receptor Gamma (PPARG) (7.51 vs 1.00) and reduction in Lipoprotein Lipase (LPL) mRNA levels (0.5 vs 1.0). A loss of differentiation capacity was also observed for the osteocyte phenotype in BMMSCs. In particular, we observed a reduction in Bone Gamma-Carboxy glutamate Protein (BGLAP) (0.4 for PET1 and 0.6 for PET2.6 vs 0.1 CTRL) and reduction in Osteopontin (SPP1) (0.3 for PET 1 and 0.64 for PET 2.6 vs 0.1 CTRL). This pioneering mesenchymal cell response study demonstrated that environmental microplastic could be bioavailable for cell uptake and may further lead to irreversible diseases.
Collapse
Affiliation(s)
- Hana Najahi
- Laboratory of Agrobiodiversity and Ecotoxicology LR21AGR02, Sousse University, Chott-Mariem, 4042, Sousse, Tunisia; Higher Institute of Biotechnology, Monastir University, Tunisia
| | - Nicola Alessio
- Department of Experimental Medicine, "Luigi Vanvitelli" Campania University, 81038, Napoli, Italy
| | - Tiziana Squillaro
- Department of Experimental Medicine, "Luigi Vanvitelli" Campania University, 81038, Napoli, Italy
| | - Gea Oliveri Conti
- Environmental and Food Hygiene Laboratory (LIAA), Department of Medical, Surgical Sciences and Advanced Technologies G. F. Ingrassia, Catania University, Via Santa Sofia 87, 95123, Catania, Italy
| | - Margherita Ferrante
- Environmental and Food Hygiene Laboratory (LIAA), Department of Medical, Surgical Sciences and Advanced Technologies G. F. Ingrassia, Catania University, Via Santa Sofia 87, 95123, Catania, Italy
| | - Giovanni Di Bernardo
- Department of Experimental Medicine, "Luigi Vanvitelli" Campania University, 81038, Napoli, Italy
| | - Umberto Galderisi
- Department of Experimental Medicine, "Luigi Vanvitelli" Campania University, 81038, Napoli, Italy
| | - Imed Messaoudi
- Higher Institute of Biotechnology, Monastir University, Tunisia
| | - Sergio Minucci
- Department of Experimental Medicine, "Luigi Vanvitelli" Campania University, 81038, Napoli, Italy
| | - Mohamed Banni
- Laboratory of Agrobiodiversity and Ecotoxicology LR21AGR02, Sousse University, Chott-Mariem, 4042, Sousse, Tunisia; Higher Institute of Biotechnology, Monastir University, Tunisia.
| |
Collapse
|
|
16
|
Peci F, Dekker L, Pagliaro A, van Boxtel R, Nierkens S, Belderbos M. The cellular composition and function of the bone marrow niche after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 2022; 57:1357-1364. [PMID: 35690693 PMCID: PMC9187885 DOI: 10.1038/s41409-022-01728-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 04/29/2022] [Accepted: 05/26/2022] [Indexed: 11/09/2022]
Abstract
Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative therapy for patients with a variety of malignant and non-malignant diseases. Despite its life-saving potential, HCT is associated with significant morbidity and mortality. Reciprocal interactions between hematopoietic stem cells (HSCs) and their surrounding bone marrow (BM) niche regulate HSC function during homeostatic hematopoiesis as well as regeneration. However, current pre-HCT conditioning regimens, which consist of high-dose chemotherapy and/or irradiation, cause substantial short- and long-term toxicity to the BM niche. This damage may negatively affect HSC function, impair hematopoietic regeneration after HCT and predispose to HCT-related morbidity and mortality. In this review, we summarize current knowledge on the cellular composition of the human BM niche after HCT. We describe how pre-HCT conditioning affects the cell types in the niche, including endothelial cells, mesenchymal stromal cells, osteoblasts, adipocytes, and neurons. Finally, we discuss therapeutic strategies to prevent or repair conditioning-induced niche damage, which may promote hematopoietic recovery and improve HCT outcome.
Collapse
Affiliation(s)
- Flavia Peci
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Oncode Institute, Utrecht, The Netherlands
| | - Linde Dekker
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Anna Pagliaro
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Ruben van Boxtel
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Oncode Institute, Utrecht, The Netherlands
| | - Stefan Nierkens
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Mirjam Belderbos
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
| |
Collapse
|
|
17
|
Farhadi S, Bahreyni-Toossi MT, Zafari-Ghadim N, Khademi S, Sadat-Darbandi M, Azimian H. DNA double-strand break repair and adaptive responses of low-dose radiation in normal and tumor lung cell lines. MUTATION RESEARCH. GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2022; 881:503528. [PMID: 36031334 DOI: 10.1016/j.mrgentox.2022.503528] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 07/19/2022] [Accepted: 07/20/2022] [Indexed: 06/15/2023]
Abstract
The adaptive response (AR), which can be induced by low-dose ionizing radiation (LD), may influence the therapeutic ratio of cancer treatment. We investigated the AR and the DNA double-strand break (DSB) repair pathway in human lung tumor cells and normal cells. We measured viability and proliferation of normal lung cells (MRC-5) and lung cancer cells (QU-DB) using the MTT and colony formation assays. Flow cytometric analysis of γ-H2AX was used to measure DNA-DSBs induction, repair, and residual damages. AR was seen in the normal cells but not in the cancer cells. Our findings suggest that LD stimulates DSB repair and that this may contribute to distinctive AR in normal vs. cancer cells.
Collapse
Affiliation(s)
- Sonia Farhadi
- Department of Medical Physics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | | | - Navid Zafari-Ghadim
- Department of Medical Physics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Sara Khademi
- Department of Radiology Technology, School of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Mahdi Sadat-Darbandi
- Department of Medical Physics, Reza Radiotherapy and Oncology Center, Mashhad, Iran.
| | - Hosein Azimian
- Medical Physics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| |
Collapse
|
|
18
|
Gresham RC, Kumar D, Copp J, Lee MA, Leach JK. Characterization of Induction and Targeting of Senescent Mesenchymal Stromal Cells. Tissue Eng Part C Methods 2022; 28:239-249. [PMID: 35438548 PMCID: PMC9247679 DOI: 10.1089/ten.tec.2022.0048] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) from older donors have limited potential for bone tissue formation compared with cells from younger donors, and cellular senescence has been postulated as an underlying cause. There is a critical need for methods to induce premature senescence to study this phenomenon efficiently and reproducibly. However, the field lacks consensus on the appropriate method to induce and characterize senescence. Moreover, we have a limited understanding of the effects of commonly used induction methods on senescent phenotype. To address this significant challenge, we assessed the effect of replicative, hydrogen peroxide, etoposide, and irradiation-induced senescence on human MSCs using a battery of senescent cell characteristics. All methods arrested proliferation and resulted in increased cell spreading compared with low passage controls. Etoposide and irradiation increased expression of senescence-related genes in MSCs at early time points, proinflammatory cytokine secretion, DNA damage, and production of senescence-associated β-galactosidase. We then evaluated the effect of fisetin, a flavonoid and candidate senolytic agent, to clear senescent cells and promote osteogenic differentiation of MSCs entrapped in gelatin methacryloyl (GelMA) hydrogels in vitro. When studying a mixture of nonsenescent and senescent MSCs, we did not observe decreases in senescent markers or increases in osteogenesis with fisetin treatment. However, the application of the same treatment toward a heterogeneous population of human bone marrow-derived cells entrapped in GelMA decreased senescent markers and increased osteogenesis after 14 days in culture. These results identify best practices for inducing prematurely senescent MSCs and motivate the need for further study of fisetin as a senolytic agent. Impact Statement The accumulation of senescent cells within the body has detrimental effects on tissue homeostasis. To study the role of senescent cells on tissue repair and regeneration, there is a need for effective means to induce premature cell senescence. Herein, we characterized the influence of common stressors to induce premature senescence in human mesenchymal stromal cells (MSCs). Irradiation of MSCs resulted in a phenotype most similar to quiescent, high-passage cells. These studies establish key biomarkers for evaluation when studying senescent cells in vitro.
Collapse
Affiliation(s)
- Robert C.H. Gresham
- Department of Orthopedic Surgery, School of Medicine, University of California Davis Health, Sacramento, California, USA
| | - Devanshi Kumar
- Department of Biomedical Engineering, University of California, Davis, Davis, California, USA
| | - Jonathan Copp
- Department of Orthopedic Surgery, School of Medicine, University of California Davis Health, Sacramento, California, USA.,Department of Orthopedic Trauma Surgery, Forrest General Hospital, Hattiesburg, Mississippi, USA
| | - Mark A. Lee
- Department of Orthopedic Surgery, School of Medicine, University of California Davis Health, Sacramento, California, USA
| | - J. Kent Leach
- Department of Orthopedic Surgery, School of Medicine, University of California Davis Health, Sacramento, California, USA.,Department of Biomedical Engineering, University of California, Davis, Davis, California, USA.,Address correspondence to: J. Kent Leach, PhD, Department of Orthopaedic Surgery, School of Medicine, University of California, Davis Health, 4800 Y Street, Suite 3600, Sacramento, CA 95817, USA
| |
Collapse
|
|
19
|
Xue J, Du R, Ling S, Song J, Yuan X, Liu C, Sun W, Li Y, Zhong G, Wang Y, Yuan G, Jin X, Liu Z, Zhao D, Li Y, Xing W, Fan Y, Liu Z, Pan J, Zhen Z, Zhao Y, Yang Q, Li J, Chang YZ, Li Y. Osteoblast Derived Exosomes Alleviate Radiation- Induced Hematopoietic Injury. Front Bioeng Biotechnol 2022; 10:850303. [PMID: 35528209 PMCID: PMC9070646 DOI: 10.3389/fbioe.2022.850303] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 03/30/2022] [Indexed: 12/29/2022] Open
Abstract
As hematopoietic stem cells can differentiate into all hematopoietic lineages, mitigating the damage to hematopoietic stem cells is important for recovery from overdose radiation injury. Cells in bone marrow microenvironment are essential for hematopoietic stem cells maintenance and protection, and many of the paracrine mediators have been discovered in shaping hematopoietic function. Several recent reports support exosomes as effective regulators of hematopoietic stem cells, but the role of osteoblast derived exosomes in hematopoietic stem cells protection is less understood. Here, we investigated that osteoblast derived exosomes could alleviate radiation damage to hematopoietic stem cells. We show that intravenous injection of osteoblast derived exosomes promoted WBC, lymphocyte, monocyte and hematopoietic stem cells recovery after irradiation significantly. By sequencing osteoblast derived exosomes derived miRNAs and verified in vitro, we identified miR-21 is involved in hematopoietic stem cells protection via targeting PDCD4. Collectively, our data demonstrate that osteoblast derived exosomes derived miR-21 is a resultful regulator to radio-protection of hematopoietic stem cells and provide a new strategy for reducing radiation induced hematopoietic injury.
Collapse
Affiliation(s)
- Jianqi Xue
- Laboratory of Molecular Iron Metabolism, Key Laboratory of Molecular and Cellular Biology of Ministry of Education, College of Life Science, Hebei Normal University, Shijiazhuang, China.,State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Ruikai Du
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Shukuan Ling
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Jinping Song
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Xinxin Yuan
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Caizhi Liu
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Weijia Sun
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Yuheng Li
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Guohui Zhong
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Yinbo Wang
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Guodong Yuan
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Xiaoyan Jin
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Zizhong Liu
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Dingsheng Zhao
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Youyou Li
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Wenjuan Xing
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Yuanyuan Fan
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Zifan Liu
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Junjie Pan
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Zhen Zhen
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Yunzhang Zhao
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Qinna Yang
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Jianwei Li
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Yan-Zhong Chang
- Laboratory of Molecular Iron Metabolism, Key Laboratory of Molecular and Cellular Biology of Ministry of Education, College of Life Science, Hebei Normal University, Shijiazhuang, China
| | - Yingxian Li
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| |
Collapse
|
|
20
|
Kumar K, Datta K, Fornace AJ, Suman S. Total body proton and heavy-ion irradiation causes cellular senescence and promotes pro-osteoclastogenic activity in mouse bone marrow. Heliyon 2022; 8:e08691. [PMID: 35028468 PMCID: PMC8741516 DOI: 10.1016/j.heliyon.2021.e08691] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 12/01/2021] [Accepted: 12/27/2021] [Indexed: 12/12/2022] Open
Abstract
Low-LET photon radiation-induced persistent alterations in bone marrow (BM) cells are well documented in total-body irradiated (TBI) rodents and also among radiotherapy patients. However, the late effects of protons and high-LET heavy-ion radiation on BM cells and its implications in osteoclastogenesis are not fully understood. Therefore, C57BL6/J female mice (8 weeks; n = 10/group) were irradiated to sham, and 1 Gy of the proton (0.22 keV/μm), or high-LET 56Fe-ions (148 keV/μm) and at 60 d post-exposure, mice were sacrificed and femur sections were obtained for histological, cellular and molecular analysis. Cell proliferation (PCNA), cell death (active caspase-3), senescence (p16), osteoclast (RANK), osteoblast (OPG), osteoblast progenitor (c-Kit), and osteoclastogenesis-associated secretory factors (like RANKL) were assessed using immunostaining. While no change in cell proliferation and apoptosis between control and irradiated groups was noted, the number of BM megakaryocytes was significantly reduced in irradiated mice at 60 d post-exposure. A remarkable increase in p16 positive cells indicated a persistent increase in cell senescence, whereas increased RANKL/OPG ratio, reductions in the number of osteoblast progenitor cells, and osteocalcin provided clear evidence that exposure to both proton and 56Fe-ions promotes pro-osteoclastogenic activity in BM. Among irradiated groups, 56Fe-induced alterations in the BM cellularity and osteoclastogenesis were significantly greater than the protons that demonstrated a radiation quality-dependent effect. This study has implications in understanding the role of IR-induced late changes in the BM cells and its involvement in bone degeneration among deep-space astronauts, and also in patients undergoing proton or heavy-ion radiotherapy.
Collapse
Affiliation(s)
- Kamendra Kumar
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Kamal Datta
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Albert J. Fornace
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Shubhankar Suman
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
- Corresponding author.
| |
Collapse
|
|
21
|
Effect of Low-Dose Ionizing Radiation on the Expression of Mitochondria-Related Genes in Human Mesenchymal Stem Cells. Int J Mol Sci 2021; 23:ijms23010261. [PMID: 35008689 PMCID: PMC8745621 DOI: 10.3390/ijms23010261] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/22/2021] [Accepted: 12/24/2021] [Indexed: 12/16/2022] Open
Abstract
The concept of hormesis describes a phenomenon of adaptive response to low-dose ionizing radiation (LDIR). Similarly, the concept of mitohormesis states that the adaptive program in mitochondria is activated in response to minor stress effects. The mechanisms of hormesis effects are not clear, but it is assumed that they can be mediated by reactive oxygen species. Here, we studied effects of LDIR on mitochondria in mesenchymal stem cells. We have found that X-ray radiation at a dose of 10 cGy as well as oxidized fragments of cell-free DNA (cfDNA) at a concentration of 50 ng/mL resulted in an increased expression of a large number of genes regulating the function of the mitochondrial respiratory chain complexes in human mesenchymal stem cells (MSC). Several genes remained upregulated within hours after the exposure. Both X-ray radiation and oxidized cfDNA resulted in upregulation of FIS1 and MFN1 genes, which regulated fusion and fission of mitochondria, within 3-24 h after the exposure. Three hours after the exposure, the number of copies of mitochondrial DNA in cells had increased. These findings support the hypothesis that assumes oxidized cell-free DNA as a mediator of MSC response to low doses of radiation.
Collapse
|
|
22
|
Hermann RM, Trillmann A, Becker JN, Kaltenborn A, Nitsche M, Ruettermann M. Prospective Evaluation of Low-Dose External Beam Radiotherapy (LD-EBRT) for Painful Trapeziometacarpal Osteoarthritis (Rhizarthrosis) on Pain, Function, and Quality of Life to Calculate the Required Number of Patients for a Prospective Randomized Study. Med Sci (Basel) 2021; 9:medsci9040066. [PMID: 34842775 PMCID: PMC8628986 DOI: 10.3390/medsci9040066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 10/20/2021] [Accepted: 10/25/2021] [Indexed: 11/30/2022] Open
Abstract
Background: Retrospective studies have described the effectiveness of low-dose radiotherapy (LD-EBRT) in painful arthrosis of small finger joints, but two recent prospective studies have yielded ambiguous results. To generate accurate data for the planning of a trial, we conducted a prospective, monocentric, observational study to describe the effects of LD-EBRT as precisely as possible. Methods: Twenty-five consecutive patients with symptomatic trapeziometacarpal (TMC) arthrosis were irradiated with 6 × 0.5 Gy. Before, 3, and 12 months after LD-EBRT, we assessed subjective endpoints (modified “von-Pannewitz score”, 10-point visual analogue scale (VAS), “patient-rated wrist evaluation” (PRWE)), and objective measurements (“active range of motion” (AROM), Kapandji index, grip strength, pinch grip). Results: At 3/12 months, 80%/57% reported partial and 4%/18% complete remission according to the “von-Pannewitz” score. VAS “overall pain” significantly decreased from a median of seven (IQR 4) at baseline to three (IQR 6; p = 0.046) and to two (IQR 2; p = 0.013). Similar results were obtained for VAS “pain during exercise”, VAS “pain during daytime”, and VAS “function”. “PRWE overall score” was reduced from 0.5 at baseline (SD 0.19) to 0.36 (SD 0.24, p = 0.05) and to 0.27 (SD 0.18, p = 0.0009). We found no improvements of the objective endpoints (AROM, Kapandji, grip strength) except for flexion, which increased from 64° (SD 12°) at baseline to 73° (SD 9.7°, p = 0.046) at 12 months. Conclusions: We recommend the PRWE score as a useful endpoint for further studies for this indication. To prove a 15% superiority over sham irradiation, we calculated that 750 patients need to be prospectively randomized.
Collapse
Affiliation(s)
- Robert Michael Hermann
- Center for Radiotherapy and Radiooncology Bremen and Westerstede, 26655 Westerstede, Germany;
- Department of Radiotherapy and Special Oncology, Hannover Medical School, 49511 Hannover, Germany;
- Correspondence:
| | - Annika Trillmann
- Department of Anaesthesia, Federal Armed Forces Hospital Westerstede, 26655 Westerstede, Germany;
| | - Jan-Niklas Becker
- Department of Radiotherapy and Special Oncology, Hannover Medical School, 49511 Hannover, Germany;
| | - Alexander Kaltenborn
- Department of Trauma and Orthopaedic Surgery, Section for Plastic, Reconstructive and Hand Surgery, Federal Armed Forces Hospital Westerstede, 26655 Westerstede, Germany; (A.K.); (M.R.)
| | - Mirko Nitsche
- Center for Radiotherapy and Radiooncology Bremen and Westerstede, 26655 Westerstede, Germany;
- Radiotherapy, Karl-Lennert-Krebscentrum, Universität Kiel, 24105 Kiel, Germany
| | - Mike Ruettermann
- Department of Trauma and Orthopaedic Surgery, Section for Plastic, Reconstructive and Hand Surgery, Federal Armed Forces Hospital Westerstede, 26655 Westerstede, Germany; (A.K.); (M.R.)
- HPC-Institute for Hand and Plastic Surgery, 26122 Oldenburg, Germany
- University Medical Center Groningen, Department of Plastic Surgery, University of Groningen, 9713 Groningen, The Netherlands
| |
Collapse
|
|
23
|
Schuster M, Tewary G, Bao X, Subedi P, Hauck SM, Olsen AK, Eide DM, Trott KR, Götz S, Atkinson MJ, Rosemann M. In vitro cellular and proteome assays identify Wnt pathway and CDKN2A-regulated senescence affected in mesenchymal stem cells from mice after a chronic LD gamma irradiation in utero. RADIATION AND ENVIRONMENTAL BIOPHYSICS 2021; 60:397-410. [PMID: 34287697 PMCID: PMC8310520 DOI: 10.1007/s00411-021-00925-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 07/07/2021] [Indexed: 06/13/2023]
Abstract
Reliable data on the effects of chronic prenatal exposure to low dose (LD) of ionizing radiation in humans are missing. There are concerns about adverse long-term effects that may persist throughout postnatal life of the offspring. Due to their slow cell cycle kinetics and life-long residence time in the organism, mesenchymal stem cells (MSCs) are more susceptible to low level genotoxic stress caused by extrinsic multiple LD events. The aim of this study was to investigate the effect of chronic, prenatal LD gamma irradiation to the biology of MSCs later in life. C3H mice were exposed in utero to chronic prenatal irradiation of 10 mGy/day over a period of 3 weeks. Two years later, MSCs were isolated from the bone marrow and analyzed in vitro for their radiosensitivity, for cellular senescence and for DNA double-strand break recognition after a second acute gamma-irradiation. In addition to these cellular assays, changes in protein expression were measured using HPLC-MS/MS and dysregulated molecular signaling pathways identified using bioinformatics. We observed radiation-induced proteomic changes in MSCs from the offspring of in utero irradiated mice (leading to ~ 9.4% of all detected proteins being either up- or downregulated) as compared to non-irradiated controls. The proteomic changes map to regulation pathways involved in the extracellular matrix, the response to oxidative stress, and the Wnt signaling pathway. In addition, chronic prenatal LD irradiation lead to an increased rate of in vitro radiation-induced senescence later in life and to an increased number of residual DNA double-strand breaks after 4 Gy irradiation, indicating a remarkable interaction of in vivo radiation in combination with a second acute dose of in vitro radiation. This study provides the first insight into a molecular mechanism of persistent MSC damage response by ionizing radiation exposure during prenatal time and will help to predict therapeutic safety and efficacy with respect to a clinical application of stem cells.
Collapse
Affiliation(s)
- Martina Schuster
- Institute of Radiation Biology, Helmholtz Zentrum München GmbH, German Research Center for Environmental Health GmbH (HMGU), Ingolstaedter Landstraße 1, 85764, Neuherberg, Germany
| | - Gargi Tewary
- Institute of Radiation Biology, Helmholtz Zentrum München GmbH, German Research Center for Environmental Health GmbH (HMGU), Ingolstaedter Landstraße 1, 85764, Neuherberg, Germany
| | - Xuanwen Bao
- Institute of Radiation Biology, Helmholtz Zentrum München GmbH, German Research Center for Environmental Health GmbH (HMGU), Ingolstaedter Landstraße 1, 85764, Neuherberg, Germany
| | - Prabal Subedi
- Institute of Radiation Biology, Helmholtz Zentrum München GmbH, German Research Center for Environmental Health GmbH (HMGU), Ingolstaedter Landstraße 1, 85764, Neuherberg, Germany
| | - Stefanie M Hauck
- Research Unit Protein Science, Helmholtz Zentrum München GmbH, German Research Center for Environmental Health GmbH (HMGU), 80939, Munich, Germany
| | - Ann Karin Olsen
- Department of Molecular Biology/Domain for Infection Control and Environmental Health, Norwegian Institute of Public Health, Lovisenberggt. 8, 0456, Oslo, Norway
| | - Dag Markus Eide
- Department of Molecular Biology/Domain for Infection Control and Environmental Health, Norwegian Institute of Public Health, Lovisenberggt. 8, 0456, Oslo, Norway
| | - Klaus Rüdiger Trott
- Chair of Radiation Biology, Technical University Munich (TUM), 80333, Munich, Germany
| | - Sebastian Götz
- Institute of Radiation Biology, Helmholtz Zentrum München GmbH, German Research Center for Environmental Health GmbH (HMGU), Ingolstaedter Landstraße 1, 85764, Neuherberg, Germany
| | - Michael J Atkinson
- Institute of Radiation Biology, Helmholtz Zentrum München GmbH, German Research Center for Environmental Health GmbH (HMGU), Ingolstaedter Landstraße 1, 85764, Neuherberg, Germany
- Chair of Radiation Biology, Technical University Munich (TUM), 80333, Munich, Germany
| | - Michael Rosemann
- Institute of Radiation Biology, Helmholtz Zentrum München GmbH, German Research Center for Environmental Health GmbH (HMGU), Ingolstaedter Landstraße 1, 85764, Neuherberg, Germany.
- Medical Graduate School, Technical University Munich (TUM), 80333, Munich, Germany.
| |
Collapse
|
|
24
|
Effects of low-dose X-ray medical diagnostics on female gonads: Insights from large animal oocytes and human ovaries as complementary models. PLoS One 2021; 16:e0253536. [PMID: 34166427 PMCID: PMC8224917 DOI: 10.1371/journal.pone.0253536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 06/08/2021] [Indexed: 11/19/2022] Open
Abstract
Diagnostic imaging has significantly grown over the last thirty years as indispensable support for diagnostic, prognostic, therapeutic and monitoring procedures of human diseases. This study explored the effects of low-dose X-ray medical diagnostics exposure on female fertility. To aim this, cumulus-oocyte complexes (COCs) recovered from the ovaries of juvenile sheep and human ovaries were used as complementary models for in vitro studies. In the sheep model, the effects of low-dose X-rays on oocyte viability and developmental competence were evaluated. In human ovaries originated from two age group (21–25 and 33–36 years old) subjects with gender dysphoria, X-rays effects on tissue morphology, follicular density and expression of apoptosis-related (NOXA, PUMA, Bcl2, Bak, γH2AX) and cell cycle-related genes (p21 and ki67) were investigated. It was noted that in sheep, the minimum dose of 10 mGy did not influence most of examined parameters at oocyte and embryo levels, whereas 50 and 100 mGy X-ray exposure reduced oocyte bioenergetic/oxidative activity but without any visible effects on oocyte and embryo development. In addition, blastocyst bioenergetic/oxidative status was reduced with all used doses. Overall data on human ovaries showed that low-dose X-rays, similarly as in sheep, did not alter any of examined parameters. However, in women belonging to the 33–36 year group, significantly reduced follicular density was observed after exposure to 50 and 100 mGy, and increased NOXA and Bax expression after exposure at 50 mGy. In conclusion, used low-doses of X-ray exposure, which resemble doses used in medical diagnostics, produce weak damaging effects on female fertility with increased susceptibility in advanced age.
Collapse
|
|
25
|
Nanduri LSY, Duddempudi PK, Yang WL, Tamarat R, Guha C. Extracellular Vesicles for the Treatment of Radiation Injuries. Front Pharmacol 2021; 12:662437. [PMID: 34084138 PMCID: PMC8167064 DOI: 10.3389/fphar.2021.662437] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 05/04/2021] [Indexed: 01/02/2023] Open
Abstract
Normal tissue injury from accidental or therapeutic exposure to high-dose radiation can cause severe acute and delayed toxicities, which result in mortality and chronic morbidity. Exposure to single high-dose radiation leads to a multi-organ failure, known as acute radiation syndrome, which is caused by radiation-induced oxidative stress and DNA damage to tissue stem cells. The radiation exposure results in acute cell loss, cell cycle arrest, senescence, and early damage to bone marrow and intestine with high mortality from sepsis. There is an urgent need for developing medical countermeasures against radiation injury for normal tissue toxicity. In this review, we discuss the potential of applying secretory extracellular vesicles derived from mesenchymal stromal/stem cells, endothelial cells, and macrophages for promoting repair and regeneration of organs after radiation injury.
Collapse
Affiliation(s)
- Lalitha Sarad Yamini Nanduri
- Department of Radiation Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, United States
| | - Phaneendra K. Duddempudi
- Department of Biochemistry, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, United States
| | - Weng-Lang Yang
- Department of Radiation Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, United States
| | - Radia Tamarat
- Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Fontenay-aux-Roses, France
| | - Chandan Guha
- Department of Radiation Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, United States
- Department of Pathology, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, United States
- Department of Urology, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, United States
- Institute for Onco-Physics, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, United States
| |
Collapse
|
|
26
|
Wei F, Neal CJ, Sakthivel TS, Seal S, Kean T, Razavi M, Coathup M. Cerium oxide nanoparticles protect against irradiation-induced cellular damage while augmenting osteogenesis. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2021; 126:112145. [PMID: 34082956 DOI: 10.1016/j.msec.2021.112145] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 04/10/2021] [Accepted: 04/26/2021] [Indexed: 01/16/2023]
Abstract
Increased bone loss and risk of fracture are two of the main challenges for cancer patients who undergo ionizing radiation (IR) therapy. This decline in bone quality is in part, caused by the excessive and sustained release of reactive oxygen species (ROS). Cerium oxide nanoparticles (CeONPs) have proven antioxidant and regenerative properties and the purpose of this study was to investigate the effect of CeONPs in reducing IR-induced functional damage in human bone marrow-derived mesenchymal stromal cells (hBMSCs). hBMSCs were supplemented with CeONPs at a concentration of either 1 or 10 μg/mL 24 h prior to exposure to a single 7 Gy irradiation dose. ROS levels, cellular proliferation, morphology, senescence, DNA damage, p53 expression and autophagy were evaluated as well as alkaline phosphatase, osteogenic protein gene expression and bone matrix deposition following osteogenic differentiation. Results showed that supplementation of CeONPs at a concentration of 1 μg/mL reduced cell senescence and significantly augmented cell autophagy (p = 0.01), osteogenesis and bone matrix deposition >2-fold (p = 0.0001) while under normal, non-irradiated culture conditions. Following irradiation, functional damage was attenuated and CeONPs at both 1 or 10 μg/mL significantly reduced ROS levels (p = 0.05 and 0.001 respectively), DNA damage by >4-fold (p < 0.05) while increasing autophagy >3.5-fold and bone matrix deposition 5-fold (p = 0.0001 in both groups). When supplemented with 10 μg/mL, p53 expression increased 3.5-fold (p < 0.05). We conclude that cellular uptake of CeONPs offered a significant, multifunctional and protective effect against IR-induced cellular damage while also augmenting osteogenic differentiation and subsequent new bone deposition. The use of CeONPs holds promise as a novel multifunctional therapeutic strategy for irradiation-induced bone loss.
Collapse
Affiliation(s)
- Fei Wei
- Biionix Cluster, Department of Internal Medicine, College of Medicine, University of Central Florida, Orlando, FL, United States
| | - Craig J Neal
- Advanced Materials Processing and Analysis Centre, Nanoscience Technology Center (NSTC), Materials Science and Engineering, College of Medicine, University of Central Florida, Orlando, FL, United States
| | - Tamil Selvan Sakthivel
- Advanced Materials Processing and Analysis Centre, Nanoscience Technology Center (NSTC), Materials Science and Engineering, College of Medicine, University of Central Florida, Orlando, FL, United States
| | - Sudipta Seal
- Advanced Materials Processing and Analysis Centre, Nanoscience Technology Center (NSTC), Materials Science and Engineering, College of Medicine, University of Central Florida, Orlando, FL, United States
| | - Thomas Kean
- Biionix Cluster, Department of Internal Medicine, College of Medicine, University of Central Florida, Orlando, FL, United States
| | - Mehdi Razavi
- Biionix Cluster, Department of Internal Medicine, College of Medicine, University of Central Florida, Orlando, FL, United States
| | - Melanie Coathup
- Biionix Cluster, Department of Internal Medicine, College of Medicine, University of Central Florida, Orlando, FL, United States.
| |
Collapse
|
|
27
|
Pignolo RJ, Law SF, Chandra A. Bone Aging, Cellular Senescence, and Osteoporosis. JBMR Plus 2021; 5:e10488. [PMID: 33869998 PMCID: PMC8046105 DOI: 10.1002/jbm4.10488] [Citation(s) in RCA: 95] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 02/17/2021] [Indexed: 12/15/2022] Open
Abstract
Changes in aging bone that lead to osteoporosis are mediated at multiple levels, including hormonal alterations, skeletal unloading, and accumulation of senescent cells. This pathological interplay is superimposed upon medical conditions, potentially bone-wasting medications, modifiable and unmodifiable personal risk factors, and genetic predisposition that accelerate bone loss with aging. In this study, the focus is on bone hemostasis and its dysregulation with aging. The major physiological changes with aging in bone and the role of cellular senescence in contributing to age-related osteoporosis are summarized. The aspects of bone aging are reviewed including remodeling deficits, uncoupling phenomena, inducers of cellular senescence related to bone aging, roles of the senescence-associated secretory phenotype, radiation-induced bone loss as a model for bone aging, and the accumulation of senescent cells in the bone microenvironment as a predominant mechanism for age-related osteoporosis. The study also addresses the rationale and potential for therapeutic interventions based on the clearance of senescent cells or suppression of the senescence-associated secretory phenotype. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
Collapse
Affiliation(s)
- Robert J Pignolo
- Department of MedicineMayo ClinicRochesterMNUSA
- Department of Physiology and Biomedical EngineeringMayo ClinicRochesterMNUSA
| | - Susan F Law
- Department of MedicineMayo ClinicRochesterMNUSA
| | - Abhishek Chandra
- Department of MedicineMayo ClinicRochesterMNUSA
- Department of Physiology and Biomedical EngineeringMayo ClinicRochesterMNUSA
| |
Collapse
|
|
28
|
Das U, Saha T, Das SK. Antioxidant Properties of Trianthema Portulacastrum and Protection Against Ionizing Radiation-Induced Liver Damage Ex vivo. Indian J Clin Biochem 2021; 37:192-198. [PMID: 35463107 PMCID: PMC8993979 DOI: 10.1007/s12291-021-00964-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 02/17/2021] [Indexed: 11/27/2022]
Abstract
Antioxidants in fruits and vegetables protect cells against radiation induced damage. Trianthema portulacastrum is used as vegetables from ancient time. The effects of T. Portulacastrum ethanolic extracts against γ-radiation induced liver tissue damage ex vivo were evaluated in this study. Antioxidant phytochemicals present in T. Portulacastrum includes flavonoids [3.3 ± 0.15 to 10 ± 0.16 mg catethin equivalent (CE)/g fresh weight (fw)], ascorbic acid (0.15 ± 0.03 to 0.21 ± 0.03 mg/g fw), glutathione s-transferase (GST) (1.57 ± 0.06 to 3.59 ± 0.05 nmole/mg fw/min), superoxide dismutase (SOD) (1.6 ± 0.03 to 1.79 ± 0.04 U/min), peroxidase (3.26 ± 0.18 to 6.38 ± 0.03 U/g fw) and catalase (0.51 ± 0.03 to 2.84 ± 0.15 mg H2O2 decomposed/g fw/min). Total phenolic content varied from 122.9 ± 8.7 to 302.8 ± 15.7 mg gallic acid equivalent/g extract, and flavonoid content varied from 316.7 ± 33.3 to 800.7 ± 28.9 CE mg/g extract. The IC50 value of Nitric oxide (NO•) scavenging activity of extracts varies from 208.7 to 387.4 µg/ ml. Pre-treatment with the T. portulacastrum extracts mitigated the 4-Gy gamma(γ) radiation-induced oxidative stress related parameters in hepatic tissue such as TBARS, catalase, nitrite, Glutathione reductase (GR), SOD and GST in dose dependent manner. The ethanolic extract of the stem from T. Portulacastrum demonstrated highest protection in comparison to leaf and whole plant extracts. This study demonstrated the hepatoprotective efficacy of T. portulacastrum extracts against γ-radiation in ex-vivo condition was possibly due to its potential antioxidant properties of phenolic and flavonoids present in extracts.
Collapse
Affiliation(s)
- Uttam Das
- Department of Biochemistry, College of Medicine and JNM Hospital, WBUHS, Kalyani, Nadia, West Bengal 741235 India
| | - Tanmay Saha
- Department of Biochemistry, College of Medicine and JNM Hospital, WBUHS, Kalyani, Nadia, West Bengal 741235 India
| | - Subir Kumar Das
- Department of Biochemistry, College of Medicine and JNM Hospital, WBUHS, Kalyani, Nadia, West Bengal 741235 India
| |
Collapse
|
|
29
|
Therapeutic Potential of Mesenchymal Stromal Cells and Extracellular Vesicles in the Treatment of Radiation Lesions-A Review. Cells 2021; 10:cells10020427. [PMID: 33670501 PMCID: PMC7922519 DOI: 10.3390/cells10020427] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 02/08/2021] [Accepted: 02/13/2021] [Indexed: 12/14/2022] Open
Abstract
Ionising radiation-induced normal tissue damage is a major concern in clinic and public health. It is the most limiting factor in radiotherapy treatment of malignant diseases. It can also cause a serious harm to populations exposed to accidental radiation exposure or nuclear warfare. With regard to the clinical use of radiation, there has been a number of modalities used in the field of radiotherapy. These includes physical modalities such modified collimators or fractionation schedules in radiotherapy. In addition, there are a number of pharmacological agents such as essential fatty acids, vasoactive drugs, enzyme inhibitors, antioxidants, and growth factors for the prevention or treatment of radiation lesions in general. However, at present, there is no standard procedure for the treatment of radiation-induced normal tissue lesions. Stem cells and their role in tissue regeneration have been known to biologists, in particular to radiobiologists, for many years. It was only recently that the potential of stem cells was studied in the treatment of radiation lesions. Stem cells, immediately after their successful isolation from a variety of animal and human tissues, demonstrated their likely application in the treatment of various diseases. This paper describes the types and origin of stem cells, their characteristics, current research, and reviews their potential in the treatment and regeneration of radiation induced normal tissue lesions. Adult stem cells, among those mesenchymal stem cells (MSCs), are the most extensively studied of stem cells. This review focuses on the effects of MSCs in the treatment of radiation lesions.
Collapse
|
|
30
|
Belmans N, Gilles L, Welkenhuysen J, Vermeesen R, Baselet B, Salmon B, Baatout S, Jacobs R, Lucas S, Lambrichts I, Moreels M. In vitro Assessment of the DNA Damage Response in Dental Mesenchymal Stromal Cells Following Low Dose X-ray Exposure. Front Public Health 2021; 9:584484. [PMID: 33692980 PMCID: PMC7939020 DOI: 10.3389/fpubh.2021.584484] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 01/13/2021] [Indexed: 12/11/2022] Open
Abstract
Stem cells contained within the dental mesenchymal stromal cell (MSC) population are crucial for tissue homeostasis. Assuring their genomic stability is therefore essential. Exposure of stem cells to ionizing radiation (IR) is potentially detrimental for normal tissue homeostasis. Although it has been established that exposure to high doses of ionizing radiation (IR) has severe adverse effects on MSCs, knowledge about the impact of low doses of IR is lacking. Here we investigated the effect of low doses of X-irradiation with medical imaging beam settings (<0.1 Gray; 900 mGray per hour), in vitro, on pediatric dental mesenchymal stromal cells containing dental pulp stem cells from deciduous teeth, dental follicle progenitor cells and stem cells from the apical papilla. DNA double strand break (DSB) formation and repair kinetics were monitored by immunocytochemistry of γH2AX and 53BP1 as well as cell cycle progression by flow cytometry and cellular senescence by senescence-associated β-galactosidase assay and ELISA. Increased DNA DSB repair foci, after exposure to low doses of X-rays, were measured as early as 30 min post-irradiation. The number of DSBs returned to baseline levels 24 h after irradiation. Cell cycle analysis revealed marginal effects of IR on cell cycle progression, although a slight G2/M phase arrest was seen in dental pulp stromal cells from deciduous teeth 72 h after irradiation. Despite this cell cycle arrest, no radiation-induced senescence was observed. In conclusion, low X-ray IR doses (< 0.1 Gray; 900 mGray per hour), were able to induce significant increases in the number of DNA DSBs repair foci, but cell cycle progression seems to be minimally affected. This highlights the need for more detailed and extensive studies on the effects of exposure to low IR doses on different mesenchymal stromal cells.
Collapse
Affiliation(s)
- Niels Belmans
- Morphology Group, Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium.,Belgian Nuclear Research Centre, Institute for Environment, Health and Safety, Radiobiology Unit, Mol, Belgium
| | - Liese Gilles
- Belgian Nuclear Research Centre, Institute for Environment, Health and Safety, Radiobiology Unit, Mol, Belgium.,Environmental Risk and Health Unit, Flemish Institute for Technological Research (VITO), Mol, Belgium
| | | | - Randy Vermeesen
- Belgian Nuclear Research Centre, Institute for Environment, Health and Safety, Radiobiology Unit, Mol, Belgium
| | - Bjorn Baselet
- Belgian Nuclear Research Centre, Institute for Environment, Health and Safety, Radiobiology Unit, Mol, Belgium
| | - Benjamin Salmon
- Université de Paris, Orofacial Pathologies, Imaging and Biotherapies UR2496 Lab, Montrouge, France.,Dental Medicine Department, AP-HP, Bretonneau hospital, Paris, France
| | - Sarah Baatout
- Belgian Nuclear Research Centre, Institute for Environment, Health and Safety, Radiobiology Unit, Mol, Belgium
| | - Reinhilde Jacobs
- Oral and Maxillofacial Surgery, Dentomaxillofacial Imaging Center, Department of Imaging and Pathology, OMFS-IMPATH Research Group, and University Hospitals, Katholieke Universiteit Leuven, Leuven, Belgium.,Department Dental Medicine, Karolinska Institutet, Huddinge, Sweden
| | - Stéphane Lucas
- Laboratory of Analysis by Nuclear Reaction (LARN/PMR), Namur Research Institute for Life Sciences, University of Namur, Namur, Belgium
| | - Ivo Lambrichts
- Belgian Nuclear Research Centre, Institute for Environment, Health and Safety, Radiobiology Unit, Mol, Belgium
| | - Marjan Moreels
- Belgian Nuclear Research Centre, Institute for Environment, Health and Safety, Radiobiology Unit, Mol, Belgium
| |
Collapse
|
|
31
|
Rothmiller S, Jäger N, Meier N, Meyer T, Neu A, Steinritz D, Thiermann H, Scherer M, Rummel C, Mangerich A, Bürkle A, Schmidt A. Chronic senescent human mesenchymal stem cells as possible contributor to the wound healing disorder after exposure to the alkylating agent sulfur mustard. Arch Toxicol 2021; 95:727-747. [PMID: 33491125 PMCID: PMC7870771 DOI: 10.1007/s00204-020-02946-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 10/28/2020] [Indexed: 12/25/2022]
Abstract
Wound healing is a complex process, and disturbance of even a single mechanism can result in chronic ulcers developing after exposure to the alkylating agent sulfur mustard (SM). A possible contributor may be SM-induced chronic senescent mesenchymal stem cells (MSCs), unable to fulfil their regenerative role, by persisting over long time periods and creating a proinflammatory microenvironment. Here we show that senescence induction in human bone marrow derived MSCs was time- and concentration-dependent, and chronic senescence could be verified 3 weeks after exposure to between 10 and 40 µM SM. Morphological changes, reduced clonogenic and migration potential, longer scratch closure times, differences in senescence, motility and DNA damage response associated genes as well as increased levels of proinflammatory cytokines were revealed. Selective removal of these cells by senolytic drugs, in which ABT-263 showed initial potential in vitro, opens the possibility for an innovative treatment strategy for chronic wounds, but also tumors and age-related diseases.
Collapse
Affiliation(s)
- Simone Rothmiller
- Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstraße 11, 80937, Munich, Germany
- Molecular Toxicology Group, Department of Biology, University of Konstanz, 78457, Konstanz, Germany
| | - Niklas Jäger
- Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstraße 11, 80937, Munich, Germany
| | - Nicole Meier
- Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstraße 11, 80937, Munich, Germany
| | - Thimo Meyer
- Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstraße 11, 80937, Munich, Germany
| | - Adrian Neu
- Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstraße 11, 80937, Munich, Germany
| | - Dirk Steinritz
- Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstraße 11, 80937, Munich, Germany
- Walther-Straub-Institute of Pharmacology and Toxicology, University of Munich, Goethestr. 33, 80336, Munich, Germany
| | - Horst Thiermann
- Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstraße 11, 80937, Munich, Germany
| | - Michael Scherer
- Department of Traumatology and Orthopedics, HELIOS Amper Clinics, Krankenhausstraße 15, 85221, Dachau, Germany
| | - Christoph Rummel
- Department of Orthopedics and Sports Medicine, Wolfart Clinic, Waldstraße 7, 82166, Gräfelfing, Germany
| | - Aswin Mangerich
- Molecular Toxicology Group, Department of Biology, University of Konstanz, 78457, Konstanz, Germany
| | - Alexander Bürkle
- Molecular Toxicology Group, Department of Biology, University of Konstanz, 78457, Konstanz, Germany
| | - Annette Schmidt
- Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstraße 11, 80937, Munich, Germany.
- Faculty of Human Sciences, Institute for Sports Sciences, Universität Der Bundeswehr München, Werner-Heisenberg-Weg 39, 85577, Neubiberg, Germany.
| |
Collapse
|
|
32
|
Iwasa M, Fujii S, Fujishiro A, Maekawa T, Andoh A, Takaori-Kondo A, Ichinohe T, Miura Y. Impact of 2 Gy γ-irradiation on the hallmark characteristics of human bone marrow-derived MSCs. Int J Hematol 2021; 113:703-711. [PMID: 33386593 DOI: 10.1007/s12185-020-03072-9] [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: 08/30/2020] [Revised: 12/14/2020] [Accepted: 12/15/2020] [Indexed: 11/24/2022]
Abstract
Two gray γ-irradiation is a widely employed basic module for total body irradiation (TBI) in allogeneic hematopoietic cell transplantation (HCT). The effects of γ-irradiation on hematopoietic and immune cells have been well investigated, but its effects on the bone marrow microenvironment (BMM) are unknown. Given the crucial contribution of mesenchymal/stromal stem cells (MSCs) in the BMM to hematopoiesis and osteogenesis, we investigated whether γ-irradiation affects the hallmark characteristics of human bone marrow-derived MSCs (BM-MSCs). Expansion of 2 Gy γ-irradiated BM-MSCs was delayed but eventually recovered. Colony formation and osteogenic, adipogenic, and chondrogenic differentiation capabilities of these cells were extensively suppressed. Irradiation of BM-MSCs did not affect the expansion of CD34 + hematopoietic stem and progenitor cells or production of CD11b + mature myeloid cells in co-cultures. However, it reduced production of CD19 + B-cells, as well as expression of CXCL12 and interleukin-7, which are essential for B-cell lymphopoiesis, in 2 Gy γ-irradiated BM-MSCs. Collectively, colony formation, osteogenic differentiation, and B-cell lymphopoiesis-supportive capabilities of γ-irradiated BM-MSCs were reduced. These effects may predispose survivors receiving HCT with TBI to defective bone formation and a perturbed humoral immune response.
Collapse
Affiliation(s)
- Masaki Iwasa
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
- Division of Gastroenterology and Hematology, Department of Medicine, Shiga University of Medical Science, Setatsukinowacho, Otsu, Shiga, 520-2192, Japan.
| | - Sumie Fujii
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
- Department of Hematology/Oncology, Kyoto University Graduate School for Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Aya Fujishiro
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
- Division of Gastroenterology and Hematology, Department of Medicine, Shiga University of Medical Science, Setatsukinowacho, Otsu, Shiga, 520-2192, Japan
| | - Taira Maekawa
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Akira Andoh
- Division of Gastroenterology and Hematology, Department of Medicine, Shiga University of Medical Science, Setatsukinowacho, Otsu, Shiga, 520-2192, Japan
| | - Akifumi Takaori-Kondo
- Department of Hematology/Oncology, Kyoto University Graduate School for Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Tatsuo Ichinohe
- Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, 734-8553, Japan
| | - Yasuo Miura
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
- Department of Hematology/Oncology, Kyoto University Graduate School for Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
- Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, 734-8553, Japan
| |
Collapse
|
|
33
|
Konkova M, Abramova M, Kalianov A, Ershova E, Dolgikh O, Umriukhin P, Izhevskaya V, Kutsev S, Veiko N, Kostyuk S. Mesenchymal Stem Cells Early Response to Low-Dose Ionizing Radiation. Front Cell Dev Biol 2021; 8:584497. [PMID: 33381502 PMCID: PMC7767887 DOI: 10.3389/fcell.2020.584497] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 11/13/2020] [Indexed: 12/13/2022] Open
Abstract
Introduction Mesenchymal stem cells (MSCs) are applied as the therapeutic agents, e.g., in the tumor radiation therapy. Purpose of the Study To evaluate the human adipose MSC early response to low-dose ionizing radiation (LDIR). Materials and Methods We investigated different LDIR (3, 10, and 50 cGy) effects on reactive oxygen species production, DNA oxidation (marker 8-oxodG), and DNA breaks (marker ɣ H2AX) in the two lines of human adipose MSC. Using reverse transcriptase-polymerase chain reaction, fluorescence-activated cell sorting, and fluorescence microscopy, we determined expression of genes involved in the oxidative stress development (NOX4), antioxidative response (NRF2), antiapoptotic and proapoptotic response (BCL2, BCL2A1, BCL2L1, BIRC2, BIRC3, and BAX1), in the development of the nuclear DNA damage response (DDR) (BRCA1, BRCA2, ATM, and P53). Cell cycle changes were investigated by genes transcription changes (CCND1, CDKN2A, and CDKN1A) and using proliferation markers KI-67 and proliferating cell nuclear antigen (PCNA). Results Fifteen to 120 min after exposure to LDIR in MSCs, transient oxidative stress and apoptosis of the most damaged cells against the background of the cell cycle arrest were induced. Simultaneously, DDR and an antiapoptotic response were found in other cells of the population. The 10-cGy dose causes the strongest and fastest DDR following cell nuclei DNA damage. The 3-cGy dose induces a less noticeable and prolonged response. The maximal low range dose, 50 cGy, causes a damaging effect on the MSCs. Conclusion Transient oxidative stress and the death of a small fraction of the damaged cells are essential components of the MSC population response to LDIR along with the development of DDR and antiapoptotic response. A scheme describing the early MSC response to LDIR is proposed.
Collapse
Affiliation(s)
- Marina Konkova
- Department of Molecular Biology, Research Centre for Medical Genetics, Moscow, Russia
| | - Margarita Abramova
- Department of Molecular Biology, Research Centre for Medical Genetics, Moscow, Russia
| | - Andrey Kalianov
- Department of Molecular Biology, Research Centre for Medical Genetics, Moscow, Russia
| | - Elizaveta Ershova
- Department of Molecular Biology, Research Centre for Medical Genetics, Moscow, Russia.,I.M. Sechenov First Moscow State Medical University, Department of Normal Physiology, Moscow, Russia
| | - Olga Dolgikh
- Department of Molecular Biology, Research Centre for Medical Genetics, Moscow, Russia
| | - Pavel Umriukhin
- Department of Molecular Biology, Research Centre for Medical Genetics, Moscow, Russia.,I.M. Sechenov First Moscow State Medical University, Department of Normal Physiology, Moscow, Russia.,P.K. Anokhin Institute of Normal Physiology, Moscow, Russia
| | - Vera Izhevskaya
- Department of Molecular Biology, Research Centre for Medical Genetics, Moscow, Russia
| | - Sergey Kutsev
- Department of Molecular Biology, Research Centre for Medical Genetics, Moscow, Russia
| | - Natalia Veiko
- Department of Molecular Biology, Research Centre for Medical Genetics, Moscow, Russia
| | - Svetlana Kostyuk
- Department of Molecular Biology, Research Centre for Medical Genetics, Moscow, Russia.,I.M. Sechenov First Moscow State Medical University, Department of Normal Physiology, Moscow, Russia
| |
Collapse
|
|
34
|
Harada S, Mabuchi Y, Kohyama J, Shimojo D, Suzuki S, Kawamura Y, Araki D, Suyama T, Kajikawa M, Akazawa C, Okano H, Matsuzaki Y. FZD5 regulates cellular senescence in human mesenchymal stem/stromal cells. Stem Cells 2020; 39:318-330. [PMID: 33338299 PMCID: PMC7986096 DOI: 10.1002/stem.3317] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 12/01/2020] [Indexed: 12/18/2022]
Abstract
Human mesenchymal stem/stromal cells (hMSCs) have garnered enormous interest as a potential resource for cell‐based therapies. However, the molecular mechanisms regulating senescence in hMSCs remain unclear. To elucidate these mechanisms, we performed gene expression profiling to compare clonal immature MSCs exhibiting multipotency with less potent MSCs. We found that the transcription factor Frizzled 5 (FZD5) is expressed specifically in immature hMSCs. The FZD5 cell surface antigen was also highly expressed in the primary MSC fraction (LNGFR+THY‐1+) and cultured MSCs. Treatment of cells with the FZD5 ligand WNT5A promoted their proliferation. Upon FZD5 knockdown, hMSCs exhibited markedly attenuated proliferation and differentiation ability. The observed increase in the levels of senescence markers suggested that FZD5 knockdown promotes cellular senescence by regulating the noncanonical Wnt pathway. Conversely, FZD5 overexpression delayed cell cycle arrest during the continued culture of hMSCs. These results indicated that the intrinsic activation of FZD5 plays an essential role in negatively regulating senescence in hMSCs and suggested that controlling FZD5 signaling offers the potential to regulate hMSC quality and improve the efficacy of cell‐replacement therapies using hMSCs.
Collapse
Affiliation(s)
- Seiko Harada
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan
| | - Yo Mabuchi
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan.,Department of Biochemistry and Biophysics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.,Department of Haematology, University of Cambridge, Cambridge, UK
| | - Jun Kohyama
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan
| | - Daisuke Shimojo
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan
| | - Sadafumi Suzuki
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan
| | - Yoshimi Kawamura
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan.,Department of Aging and Longevity Research, Faculty of Life Sciences, Kumamoto University, Kumamoto, Kumamoto, Japan
| | - Daisuke Araki
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan
| | - Takashi Suyama
- Department of Life Science, Shimane University Faculty of Medicine, Izumo, Shimane, Japan
| | | | - Chihiro Akazawa
- Department of Biochemistry and Biophysics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.,Intractable Disease Research Centre, Juntendo University School of Medicine, Tokyo, Japan
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan
| | - Yumi Matsuzaki
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan.,Department of Life Science, Shimane University Faculty of Medicine, Izumo, Shimane, Japan
| |
Collapse
|
|
35
|
Zorina TD. New Insights on the Role of the Mesenchymal-Hematopoietic Stem Cell Axis in Autologous and Allogeneic Hematopoiesis. Stem Cells Dev 2020; 30:2-16. [PMID: 33231142 DOI: 10.1089/scd.2020.0148] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Cytoreductive protocols are integral both as conditioning regimens for bone marrow (BM) transplantation and as part of therapies for malignancies, but their associated comorbidities represent a long-standing clinical problem. In particular, they cause myeloablation that debilitates the physiological role of mesenchymal stem and precursor cells (MSPCs) in sustaining hematopoiesis. This review addresses the damaging impact of cytoreductive regimens on MSPCs. In addition, it discusses prospects for alleviating the resulting iatrogenic comorbidities. New insights into the structural and functional dynamics of hematopoietic stem cell (HSC) niches reveal the existence of "empty" niches and the ability of the donor-derived healthy HSCs to outcompete the defective HSCs in occupying these niches. These findings support the notion that conditioning regimens, conventionally used to ablate the recipient hematopoiesis to create space for engraftment of the donor-derived HSCs, may not be a necessity for allogeneic BM transplantation. In addition, the capacity of the MSPCs to cross-talk with HSCs, despite major histocompatibility complex disparity, and suppress graft versus host disease indicates the possibility for development of a conditioning-free, MSPCs-enhanced protocol for BM transplantation. The clinical advantage of supplementing cytoreductive protocols with MSPCs to improve autologous hematopoiesis reconstitution and alleviate cytopenia associated with chemo and radiation therapies for cancer is also discussed.
Collapse
Affiliation(s)
- Tatiana D Zorina
- Department of Medical Laboratory Science and Biotechnology, Jefferson College of Health Professions, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| |
Collapse
|
|
36
|
Effects of p-Cresol on Senescence, Survival, Inflammation, and Odontoblast Differentiation in Canine Dental Pulp Stem Cells. Int J Mol Sci 2020; 21:ijms21186931. [PMID: 32967298 PMCID: PMC7555360 DOI: 10.3390/ijms21186931] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 09/09/2020] [Accepted: 09/15/2020] [Indexed: 12/12/2022] Open
Abstract
Aging, defined by a decrease in the physical and functional integrity of the tissues, leads to age-associated degenerative diseases. There is a relation between aged dental pulp and the senescence of dental pulp stem cells (DPSCs). Therefore, it is important to investigate the molecular processes underlying the senescence of DPSCs to elucidate the dental pulp aging mechanisms. p-Cresol (PC), a uremic toxin, is strongly related to cellular senescence. Here, age-related phenotypic changes including senescence, apoptosis, inflammation, and declining odontoblast differentiation in PC-treated canine DPSCs were investigated. Under the PC condition, cellular senescence was induced by decreased proliferation capacity and increased cell size, senescence-associated β-galactosidase (SA-β-gal) activity, and senescence markers p21, IL-1β, IL-8, and p53. Exposure to PC could stimulate inflammation by the increased expression of IL-6 and cause the distraction of the cell cycle by the increased level of Bax protein and decreased Bcl-2. The levels of odontoblast differentiation markers, dentin sialophosphoprotein (DSPP), dentin matrix protein 1, and osterix, were decreased. Consistent with those findings, the alizarin red staining, alkaline phosphatase, and DSPP protein level were decreased during the odontoblast differentiation process. Taken together, these findings indicate that PC could induce cellular senescence in DPSCs, which may demonstrate the changes in aging dental pulp.
Collapse
|
|
37
|
banimohamad-shotorbani B, Kahroba H, Sadeghzadeh H, Wilson DM, Maadi H, Samadi N, Hejazi MS, Farajpour H, Onari BN, Sadeghi MR. DNA damage repair response in mesenchymal stromal cells: From cellular senescence and aging to apoptosis and differentiation ability. Ageing Res Rev 2020; 62:101125. [PMID: 32683038 DOI: 10.1016/j.arr.2020.101125] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Revised: 07/04/2020] [Accepted: 07/10/2020] [Indexed: 12/12/2022]
Abstract
Mesenchymal stromal cells (MSCs) are heterogeneous and contain several populations, including stem cells. MSCs' secretome has the ability to induce proliferation, differentiation, chemo-attraction, anti-apoptosis, and immunomodulation activities in stem cells. Moreover, these cells recognize tissue damage caused by drugs, radiation (e.g., Ultraviolet, infra-red) and oxidative stress, and respond in two ways: either MSCs differentiate into particular cell lineages to preserve tissue homeostasis, or they release a regenerative secretome to activate tissue repairing mechanisms. The maintenance of MSCs in quiescence can increase the incidence and accumulation of various forms of genomic modifications, particularly upon environmental insults. Thus, dysregulated DNA repair pathways can predispose MSCs to senescence or apoptosis, reducing their stemness and self-renewal properties. For instance, DNA damage can impair telomere replication, activating DNA damage checkpoints to maintain MSC function. In this review, we aim to summarize the role of DNA damage and associated repair responses in MSC senescence, differentiation and programmed cell death.
Collapse
|
|
38
|
Li X, Xu J, Dai B, Wang X, Guo Q, Qin L. Targeting autophagy in osteoporosis: From pathophysiology to potential therapy. Ageing Res Rev 2020; 62:101098. [PMID: 32535273 DOI: 10.1016/j.arr.2020.101098] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 05/26/2020] [Accepted: 06/03/2020] [Indexed: 12/19/2022]
Abstract
Osteoporosis is a highly prevalent disorder characterized by the loss of bone mass and microarchitecture deterioration of bone tissue, attributed to various factors, including menopause (primary), aging (primary) and adverse effects of relevant medications (secondary). In recent decades, knowledge regarding the etiological mechanisms underpinning osteoporosis emphasizes that bone cellular homeostasis, including the maintenance of cell functions, differentiation, and the response to stress, is tightly regulated by autophagy, which is a cell survival mechanism for eliminating and recycling damaged proteins and organelles. With the important roles in the maintenance of cellular homeostasis and organ function, autophagy has emerged as a potential target for the prevention and treatment of osteoporosis. In this review, we update and discuss the pathophysiology of autophagy in normal bone cell life cycle and metabolism. Then, the alternations of autophagy in primary and secondary osteoporosis, and the accompanied pathological process are discussed. Finally, we discuss current strategies, limitations, and challenges involved in targeting relevant pathways and propose strategies by which such hurdles may be circumvented in the future for their translation into clinical validations and applications for the prevention and treatment of osteoporosis.
Collapse
|
|
39
|
Chen XD, Tan JL, Feng Y, Huang LJ, Zhang M, Cheng B. Autophagy in fate determination of mesenchymal stem cells and bone remodeling. World J Stem Cells 2020; 12:776-786. [PMID: 32952858 PMCID: PMC7477662 DOI: 10.4252/wjsc.v12.i8.776] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 05/17/2020] [Accepted: 06/20/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have been widely exploited as promising candidates in clinical settings for bone repair and regeneration in view of their self-renewal capacity and multipotentiality. However, little is known about the mechanisms underlying their fate determination, which would illustrate their effectiveness in regenerative medicine. Recent evidence has shed light on a fundamental biological role of autophagy in the maintenance of the regenerative capability of MSCs and bone homeostasis. Autophagy has been implicated in provoking an immediately available cytoprotective mechanism in MSCs against stress, while dysfunction of autophagy impairs the function of MSCs, leading to imbalances of bone remodeling and a wide range of aging and degenerative bone diseases. This review aims to summarize the up-to-date knowledge about the effects of autophagy on MSC fate determination and its role as a stress adaptation response. Meanwhile, we highlight autophagy as a dynamic process and a double-edged sword to account for some discrepancies in the current research. We also discuss the contribution of autophagy to the regulation of bone cells and bone remodeling and emphasize its potential involvement in bone disease.
Collapse
Affiliation(s)
- Xiao-Dan Chen
- Hospital of Stomatology, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Stomatology; Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510055, Guangdong Province, China
| | - Jia-Li Tan
- Hospital of Stomatology, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Stomatology; Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510055, Guangdong Province, China
| | - Yi Feng
- Hospital of Stomatology, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Stomatology; Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510055, Guangdong Province, China
| | - Li-Jia Huang
- Hospital of Stomatology, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Stomatology; Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510055, Guangdong Province, China
| | - Mei Zhang
- Hospital of Stomatology, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Stomatology; Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510055, Guangdong Province, China
| | - Bin Cheng
- Hospital of Stomatology, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Stomatology; Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510055, Guangdong Province, China
| |
Collapse
|
|
40
|
Yang KL, Khoo BY, Ong MT, Yoong ICK, Sreeramanan S. In vitro anti-breast cancer studies of LED red light therapy through autophagy. Breast Cancer 2020; 28:60-66. [PMID: 32654094 DOI: 10.1007/s12282-020-01128-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 06/22/2020] [Indexed: 11/29/2022]
Abstract
LED red light has been reported to have many health benefits. The present study was conducted to characterise anti-proliferation properties of four LED red light wavelengths (615, 630, 660 and 730 nm) against non-triple negative (MCF-7) and triple negative (MDA-MB-231) breast cancer-origin cell lines. It has been shown by MTT assay that at 24 h post-exposure time point, only LED red light with wavelength 660 nm possessed anti-proliferative effects against both cell lines with 40% reduction of cell viability. The morphology of LED 660 nm irradiated cells was found flatten with enlarged cell size, typical characteristic of cell senescent. Indications of autophagy activities following the irradiation have been provided by acridine orange staining, showing high presence of acidic vesicle organelles (AVOs). In addition, high LC3-II/LC3-I to LC3 ratio has been observed qualitatively in Western blot analysis indicating an increase number of autophagosomes formation in LED 660 nm irradiated cells compared to control cells. Electron dense bodies observed in these cells under TEM micrographs provided additional support to the above observations, leading to the conclusion that LED 660 nm irradiation promoted anti-proliferative activities through autophagy in breast cancer-origin cells. These findings have suggested that LED 660 nm might be developed and be employed as an alternative cancer treatment method in future.
Collapse
Affiliation(s)
- Kok Lee Yang
- School of Biological Sciences, Universiti Sains Malaysia, Minden Heights, 11800 USM, Pulau Pinang, Malaysia
| | - Boon Yin Khoo
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Minden Heights, 11800 USM, Pulau Pinang, Malaysia
| | - Ming Thong Ong
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Minden Heights, 11800 USM, Pulau Pinang, Malaysia
| | - Ivan Chew Ken Yoong
- Osram Oopto Semiconductor Sdn. Bhd., Bayan Lepas Free Industrial Zone Phase 1, 11900, Bayan Lepas, Penang, Malaysia
| | - Subramaniam Sreeramanan
- School of Biological Sciences, Universiti Sains Malaysia, Minden Heights, 11800 USM, Pulau Pinang, Malaysia. .,Centre for Chemical Biology, Universiti Sains Malaysia, Bayan Lepas, Penang, Malaysia.
| |
Collapse
|
|
41
|
Bao X, Wang J, Zhou G, Aszodi A, Schönitzer V, Scherthan H, Atkinson MJ, Rosemann M. Extended in vitro culture of primary human mesenchymal stem cells downregulates Brca1-related genes and impairs DNA double-strand break recognition. FEBS Open Bio 2020; 10:1238-1250. [PMID: 32333827 PMCID: PMC7327915 DOI: 10.1002/2211-5463.12867] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 04/15/2020] [Accepted: 04/22/2020] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are multilineage adult stem cells with considerable potential for cell‐based regenerative therapies. In vitro expansion changes their epigenetic and cellular properties, with a poorly understood impact on DNA damage response (DDR) and genome stability. We report here results of a transcriptome‐based pathway analysis of in vitro‐expanded human bone marrow‐derived mesenchymal stem cell (hBM‐MSCs), supplemented with cellular assays focusing on DNA double‐strand break (DSB) repair. Gene pathways affected by in vitro aging were mapped using gene ontology, KEGG, and GSEA, and were found to involve DNA repair, homologous recombination (HR), cell cycle control, and chromosomal replication. Assays for the recognition (γ‐H2AX + 53BP1 foci) and repair (pBRCA1 + γ‐H2AX foci) of X‐ray‐induced DNA DSBs in hBM‐MSCs show that over a period of 8 weeks of in vitro aging (i.e., about 10 doubling times), cells exhibit a reduced DDR and a higher fraction of residual DNA damage. Furthermore, a distinct subpopulation of cells with impaired DNA DSB recognition was observed. Several genes that participate in DNA repair by HR (e.g., Rad51, Rad54, BRCA1) show a 2.3‐ to fourfold reduction of their mRNA expression by qRT‐PCR. We conclude that the in vitro expansion of hMSCs can lead to aging‐related impairment of the recognition and repair of DNA breaks.
Collapse
Affiliation(s)
- Xuanwen Bao
- Institute of Radiation Biology, Helmholtz Center Munich - German Research Center for Environmental Health, Neuherberg, Germany.,Medical Graduate School, Technical University of Munich, Germany
| | - Jing Wang
- Institute of Radiation Biology, Helmholtz Center Munich - German Research Center for Environmental Health, Neuherberg, Germany.,Medical Graduate School, Technical University of Munich, Germany
| | - Guangming Zhou
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, China
| | - Attila Aszodi
- Laboratory of Experimental Surgery and Regenerative Medicine, Clinic for General, Trauma and Reconstructive Surgery, Ludwig-Maximilians-University, Munich, Germany
| | - Veronika Schönitzer
- Laboratory of Experimental Surgery and Regenerative Medicine, Clinic for General, Trauma and Reconstructive Surgery, Ludwig-Maximilians-University, Munich, Germany
| | - Harry Scherthan
- Bundeswehr Institute of Radiobiology, Affiliated to the University of Ulm, Munich, Germany
| | - Michael J Atkinson
- Institute of Radiation Biology, Helmholtz Center Munich - German Research Center for Environmental Health, Neuherberg, Germany.,Radiation Biology, Technical University of Munich, Germany
| | - Michael Rosemann
- Institute of Radiation Biology, Helmholtz Center Munich - German Research Center for Environmental Health, Neuherberg, Germany.,Medical Graduate School, Technical University of Munich, Germany
| |
Collapse
|
|
42
|
Chong LW, Tsai CL, Yang KC, Liao CC, Hsu YC. Targeting protein palmitoylation decreases palmitate‑induced sphere formation of human liver cancer cells. Mol Med Rep 2020; 22:939-947. [PMID: 32468006 PMCID: PMC7339714 DOI: 10.3892/mmr.2020.11172] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 04/15/2020] [Indexed: 01/22/2023] Open
Abstract
Although non-alcoholic fatty liver disease (NAFLD) is considered a benign disorder, hepatic steatosis has been proposed to be involved in the tumorigenesis of liver cancer. However, the underlying mechanism for carcinogenesis in fatty liver diseases remains unclear. Cancer stem cells (CSCs) have been hypothesized to serve a key role in tumorigenesis. Tumor formation begins with a subset of heterogeneous cells that share properties with stem cells, such as self-renewal and undifferentiated properties. Our previous study reported that the saturated fatty acid palmitate (PA) significantly enhanced the CSC properties of the HepG2 human liver cancer cell line; however, its underlying mechanisms are unknown. In the present study, a proteomic approach was used to investigate the palmitoylation of proteins in HepG2 CSCs. CSC behavior was induced in HepG2 cells via 200 µM PA. Proteomic analysis was performed to identify post-transcriptional modifications of proteins in HepG2 CSCs in response to PA treatment. The present study identified proteins modified by palmitoylation in HepG2 CSC spheres formed following PA treatment. It was therefore hypothesized that palmitoylation may be crucial for CSC sphere formation. Furthermore, the present study demonstrated that two palmitoylation inhibitors, tunicamycin (5, 10 and 25 µg/ml) and 2-bromohexadecanoic acid (25, 50 and 150 µM), significantly decreased CSC sphere formation without affecting cell viability. An association was identified between sphere formation capacity and tumor-initiating capacity of CSCs. The results of the present study demonstrated that protein palmitoylation may influence the PA-induced CSC tumor-initiating capacity, and that the inhibition of palmitoylation may be a suitable chemopreventive strategy for treating patients with NAFLD.
Collapse
Affiliation(s)
- Lee-Won Chong
- Division of Hepatology and Gastroenterology, Department of Internal Medicine, Shin Kong Wu Ho Su Memorial Hospital, Taipei, Taiwan, R.O.C
| | - Chia-Ling Tsai
- Institute of Biomedical Sciences, Mackay Medical College, New Taipei City, Taipei, Taiwan, R.O.C
| | - Kou-Ching Yang
- Division of Hepatology and Gastroenterology, Department of Internal Medicine, Shin Kong Wu Ho Su Memorial Hospital, Taipei, Taiwan, R.O.C
| | - Chen-Chung Liao
- Proteomics Research Center, National Yang‑Ming University, Taipei, Taiwan, R.O.C
| | - Yi-Chao Hsu
- Institute of Biomedical Sciences, Mackay Medical College, New Taipei City, Taipei, Taiwan, R.O.C
| |
Collapse
|
|
43
|
Piper M, Mueller AC, Karam SD. The interplay between cancer associated fibroblasts and immune cells in the context of radiation therapy. Mol Carcinog 2020; 59:754-765. [PMID: 32363633 DOI: 10.1002/mc.23205] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 03/25/2020] [Accepted: 03/25/2020] [Indexed: 02/06/2023]
Abstract
Fibroblasts are a key component of the tumor microenvironment (TME) that can serve as a scaffold for tumor cell migration and augment the tumor's ability to withstand harsh conditions. When activated by external or endogenous stimuli, normal fibroblasts become cancer associated fibroblasts (CAFs), a heterogeneous group of stromal cells in the tumor that are phenotypically and epigenetically different from normal fibroblasts. Dynamic crosstalk between cancer cells, immune cells, and CAFs through chemokines and surface signaling makes the TME conducive to tumor growth. When activated, CAFs promote tumorigenesis and metastasis through several phenomena including regulation of tumor immunity, metabolic reprogramming of the TME, extracellular matrix remodeling and contraction, and induction of therapeutic resistance. Ionizing radiation (radiation theraphy [RT]) is a potent immunological stimulant that has been shown to increase cytotoxic Teff infiltration and IFN-I stimulated genes. RT, however, is unable to overcome the infiltration and activation of immunosuppressive cells which can contribute to tumor progression. Another paradox of RT is that, while very effective at killing cancer cells, it can contribute to the formation of CAFs. This review examines how the interplay between CAFs and immune cells during RT contributes to organ fibrosis, immunosuppression, and tumor growth. We focus on targeting mechanistic pathways of CAF formation as a potentially effective strategy not only for preventing organ fibrosis, but also in hampering tumor progression in response to RT.
Collapse
Affiliation(s)
- Miles Piper
- Department of Radiation Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Adam C Mueller
- Department of Radiation Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Sana D Karam
- Department of Radiation Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| |
Collapse
|
|
44
|
Chen Y, Tang L. Stem Cell Senescence: the Obstacle of the Treatment of Degenerative Disk Disease. Curr Stem Cell Res Ther 2020; 14:654-668. [PMID: 31490764 DOI: 10.2174/1574888x14666190906163253] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 05/05/2019] [Accepted: 06/01/2019] [Indexed: 12/14/2022]
Abstract
Intervertebral disc (IVD) has a pivotal role in the maintenance of flexible motion. IVD degeneration is one of the primary causes of low back pain and disability, which seriously influences patients' health, and increases the family and social economic burden. Recently, stem cell therapy has been proven to be more effective on IVD degeneration disease. However, stem cell senescence is the limiting factor in the IVD degeneration treatment. Senescent stem cells have a negative effect on the self-repair on IVD degeneration. In this review, we delineate that the factors such as telomerase shortening, DNA damage, oxidative stress, microenvironment and exosomes will induce stem cell aging. Recent studies tried to delay the aging of stem cells by regulating the expression of aging-related genes and proteins, changing the activity of telomerase, improving the survival microenvironment of stem cells and drug treatment. Understanding the mechanism of stem cell aging and exploring new approaches to delay or reverse stem cell aging asks for research on the repair of the degenerated disc.
Collapse
Affiliation(s)
- Ying Chen
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering Chongqing University, Chongqing 400044, China
| | - Liling Tang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering Chongqing University, Chongqing 400044, China
| |
Collapse
|
|
45
|
Dong Y, Li Y, Zhang C, Chen H, Liu L, Chen S. Effects of SW033291 on the myogenesis of muscle-derived stem cells and muscle regeneration. Stem Cell Res Ther 2020; 11:76. [PMID: 32085799 PMCID: PMC7035785 DOI: 10.1186/s13287-020-1574-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Revised: 01/17/2020] [Accepted: 01/27/2020] [Indexed: 12/15/2022] Open
Abstract
Background The unmet medical needs in repairing large muscle defects promote the development of tissue regeneration strategy. The use of bioactive molecules in combination with biomaterial scaffold has become an area of great interest. SW033291, a small-molecule inhibitor targeting 15-hydroxyprostaglandin dehydrogenase (15-PDGH) and subsequently elevating the production of prostaglandin E2 (PGE2), has been proved to accelerate the recovery and potentiate the regeneration of multiple tissues including the bone, liver, and colon. The limited understanding of the potential therapeutic effects on myogenesis motivated us to investigate the role of SW033291 in regulating muscle-derived stem cell (MDSC) myogenic differentiation and MDSC-mediated muscle regeneration. Methods The characteristics of rat MDSCs, including cell-specific markers and myogenic differentiation potential, were determined. MDSCs were incubated with SW033291 to evaluate PGE2 production and cytotoxicity. The effects of SW033291 on MDSC myogenic differentiation were assessed by quantitative real-time polymerase chain reaction (qPCR), western blot, and immunocytochemistry. The fibrin gel containing MDSCs and SW033291 was used for muscle regeneration in a tibialis anterior muscle defect model. Results Our data demonstrated that MDSCs were well-tolerated to SW033291 and treatment with SW033291 significantly promoted the production of PGE2 by MDSCs. In vitro analysis showed that SW033291 enhanced the myogenic differentiation and myotube formation by upregulating a series of myogenic markers. Additionally, the activation of PI3K/Akt pathway was involved in the mechanism underlying these promotive effects. Then, in situ casting of fibrin gel containing MDSCs and SW033291 was used to repair the tibialis anterior muscle defect; the addition of SW033291 significantly promoted myofiber formation within the defect region with mild immune response, less fibrosis, and sufficient vascularization. Conclusion SW033291 acted as a positive regulator of MDSC myogenic differentiation, and incorporating the compound with MDSCs in fibrin gel could serve as an effective method to repair large skeletal muscle defects.
Collapse
Affiliation(s)
- Yuanqiang Dong
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China
| | - Yuan Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China
| | - Chuan Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China
| | - Haibin Chen
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China
| | - Lijia Liu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China.
| | - Simeng Chen
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China.
| |
Collapse
|
|
46
|
Neri S, Borzì RM. Molecular Mechanisms Contributing to Mesenchymal Stromal Cell Aging. Biomolecules 2020; 10:E340. [PMID: 32098040 PMCID: PMC7072652 DOI: 10.3390/biom10020340] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 02/13/2020] [Accepted: 02/19/2020] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are a reservoir for tissue homeostasis and repair that age during organismal aging. Beside the fundamental in vivo role of MSCs, they have also emerged in the last years as extremely promising therapeutic agents for a wide variety of clinical conditions. MSC use frequently requires in vitro expansion, thus exposing cells to replicative senescence. Aging of MSCs (both in vivo and in vitro) can affect not only their replicative potential, but also their properties, like immunomodulation and secretory profile, thus possibly compromising their therapeutic effect. It is therefore of critical importance to unveil the underlying mechanisms of MSC senescence and to define shared methods to assess MSC aging status. The present review will focus on current scientific knowledge about MSC aging mechanisms, control and effects, including possible anti-aging treatments.
Collapse
Affiliation(s)
- Simona Neri
- IRCCS Istituto Ortopedico Rizzoli, Laboratorio di Immunoreumatologia e Rigenerazione Tissutale, 40136 Bologna, Italy;
| | | |
Collapse
|
|
47
|
Uhlig S, Wuhrer A, Berlit S, Tuschy B, Sütterlin M, Bieback K. Intraoperative radiotherapy for breast cancer treatment efficiently targets the tumor bed preventing breast adipose stromal cell outgrowth. Strahlenther Onkol 2020; 196:398-404. [PMID: 32030446 PMCID: PMC7089893 DOI: 10.1007/s00066-020-01586-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 01/16/2020] [Indexed: 01/17/2023]
Abstract
OBJECTIVES Mesenchymal stromal cells (MSC) in bone marrow have been shown to be radioresistant, which is related to pronounced DNA repair mechanisms. Intraoperative radiotherapy (IORT) during breast-conserving surgery for early breast cancer is an innovative technique applying low energy x‑ray to the tumor bed immediately after removal of the tumor. IORT is considered to reduce the risk of local tumor recurrence by directly targeting cells of the tumor bed and altering the local microenvironment. Aim of this study was to investigate whether IORT affects the outgrowth potential of breast adipose tissue-derived MSC (bASC) as part of the tumor bed. MATERIALS AND METHODS After surgical tumor resection, biopsies of the tumor bed were taken before (pre IORT) and after IORT (post IORT) and processed applying well-established protocols for ASC isolation and characterization. RESULTS In all, 95% of pre IORT tumor bed samples yielded persistently outgrowing bASC with typical ASC characteristics: fibroblastoid morphology, proliferation, adipogenic and osteogenic differentiation and ASC surface marker expression. However, none of the post IORT samples yielded persistent outgrowth of bASC. CONCLUSIONS After breast-conserving surgery, approximately 90% of local recurrences emerge in close proximity to the initial tumor bed, potentially reflecting a significant contribution of the tumor bed to relapse. Our data show that IORT, besides the proven effect on breast cancer cells, efficiently modifies the tumor environment by having an impact on tumor bed bASC. This effect on tumor bed stromal cells might contribute to reduce the risk of tumor relapse and metastases.
Collapse
Affiliation(s)
- Stefanie Uhlig
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, German Red Cross Blood Donor Services, Heidelberg University, Friedrich-Ebert Str. 107, 68167, Mannheim, Germany
- FlowCore Mannheim, Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl Str. 13-17, 68167, Mannheim, Germany
| | - Anne Wuhrer
- Department of Obstetrics and Gynecology, University Medical Center Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
| | - Sebastian Berlit
- Department of Obstetrics and Gynecology, University Medical Center Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
| | - Benjamin Tuschy
- Department of Obstetrics and Gynecology, University Medical Center Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
| | - Marc Sütterlin
- Department of Obstetrics and Gynecology, University Medical Center Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
| | - Karen Bieback
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, German Red Cross Blood Donor Services, Heidelberg University, Friedrich-Ebert Str. 107, 68167, Mannheim, Germany.
- FlowCore Mannheim, Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl Str. 13-17, 68167, Mannheim, Germany.
| |
Collapse
|
|
48
|
Ghosh D, Mejia Pena C, Quach N, Xuan B, Lee AH, Dawson MR. Senescent mesenchymal stem cells remodel extracellular matrix driving breast cancer cells to a more-invasive phenotype. J Cell Sci 2020; 133:jcs232470. [PMID: 31932504 PMCID: PMC6983709 DOI: 10.1242/jcs.232470] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 12/19/2019] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are essential for the regenerative process; however, biological aging and environmental stress can induce senescence - an irreversible state of growth arrest - that not only affects the behavior of cells but also disrupts their ability to restore tissue integrity. While abnormal tissue properties, including increased extracellular matrix stiffness, are linked with the risk of developing breast cancer, the role and contribution of senescent MSCs to the disease progression to malignancy are not well understood. Here, we investigated senescence-associated biophysical changes in MSCs and how this influences cancer cell behavior in a 3D matrix interface model. Although senescent MSCs were far less motile than pre-senescent MSCs, they induced an invasive breast cancer phenotype, characterized by increased spheroid growth and cell invasion in collagen gels. Further analysis of collagen gels using second-harmonic generation showed increased collagen density when senescent MSCs were present, suggesting that senescent MSCs actively remodel the surrounding matrix. This study provides direct evidence of the pro-malignant effects of senescent MSCs in tumors.
Collapse
Affiliation(s)
- Deepraj Ghosh
- Brown University, Department of Molecular Pharmacology, Physiology, and Biotechnology, Providence, RI 02912, USA
| | - Carolina Mejia Pena
- Brown University, Department of Molecular Biology, Cell Biology and Biochemistry, Providence, RI 02912, USA
| | - Nhat Quach
- Brown University, Department of Molecular Pharmacology, Physiology, and Biotechnology, Providence, RI 02912, USA
| | - Botai Xuan
- Brown University, Department of Molecular Pharmacology, Physiology, and Biotechnology, Providence, RI 02912, USA
| | - Amy H Lee
- Brown University, Center for Biomedical Engineering, Providence, PI 02912, USA
| | - Michelle R Dawson
- Brown University, Department of Molecular Pharmacology, Physiology, and Biotechnology, Providence, RI 02912, USA
- Brown University, Department of Molecular Biology, Cell Biology and Biochemistry, Providence, RI 02912, USA
- Brown University, Center for Biomedical Engineering, Providence, PI 02912, USA
| |
Collapse
|
|
49
|
Senile Osteoporosis: The Involvement of Differentiation and Senescence of Bone Marrow Stromal Cells. Int J Mol Sci 2020; 21:ijms21010349. [PMID: 31948061 PMCID: PMC6981793 DOI: 10.3390/ijms21010349] [Citation(s) in RCA: 159] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 12/26/2019] [Accepted: 12/31/2019] [Indexed: 12/12/2022] Open
Abstract
Senile osteoporosis has become a worldwide bone disease with the aging of the world population. It increases the risk of bone fracture and seriously affects human health. Unlike postmenopausal osteoporosis which is linked to menopause in women, senile osteoporosis is due to aging, hence, affecting both men and women. It is commonly found in people with more than their 70s. Evidence has shown that with age increase, bone marrow stromal cells (BMSCs) differentiate into more adipocytes rather than osteoblasts and undergo senescence, which leads to decreased bone formation and contributes to senile osteoporosis. Therefore, it is necessary to uncover the molecular mechanisms underlying the functional changes of BMSCs. It will benefit not only for understanding the senile osteoporosis development, but also for finding new therapies to treat senile osteoporosis. Here, we review the recent advances of the functional alterations of BMSCs and the related mechanisms during senile osteoporosis development. Moreover, the treatment of senile osteoporosis by aiming at BMSCs is introduced.
Collapse
|
|
50
|
Zhang C, Zhang J, Wu Q, Xu B, Jin G, Qiao Y, Zhao S, Yang Y, Shang J, Li X, Liu K. Sulforaphene induces apoptosis and inhibits the invasion of esophageal cancer cells through MSK2/CREB/Bcl-2 and cadherin pathway in vivo and in vitro. Cancer Cell Int 2019; 19:342. [PMID: 31889894 PMCID: PMC6921404 DOI: 10.1186/s12935-019-1061-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Accepted: 12/09/2019] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND As a novel type of isothiocyanate derived from radish seeds from cruciferous vegetables, sulforaphene (SFE, 4-methylsufinyl-3-butenyl isothiocyanate) has various important biological effects, such as anti-oxidative and anti-bacterial effects. Recently, sulforaphene has attracted increasing attention for its anti-tumor effects and its ability to suppress the development of multiple tumors through different regulatory mechanisms. However, it has not yet been widely investigated for the treatment of esophageal cancer. METHODS We observed an increased apoptosis in esophageal cancer cells on sulforaphene treatment through flow cytometry (FCM) analysis and transmission electron microscopy (TEM). Through mass spectrometry (MS) analysis, we further detected global changes in the proteomes and phosphoproteomes of esophageal cancer cells on sulforaphene treatment. The molecular mechanism of sulforaphene was verified by western blot,the effect and mechanism of SFE on esophageal cancer was further verified by patient-derived xenograft mouse model. RESULTS We identified multiple cellular processes that were changed after sulforaphene treatment by proteomics. We found that sulforaphene could repress the phosphorylation of CREB through MSK2, leading to suppression of Bcl-2 and further promoted cell apoptosis. Additionally, we confirmed that sulforaphene induces tumor cell apoptosis in mice. Interestingly, we also observed the obvious inhibition of cell migration and invasion caused by sulforaphene treatment by inhibiting the expression of cadherin, indicating the complex effects of sulforaphene on the development of esophageal cancer. CONCLUSIONS Our data demonstrated that sulforaphene induced cell apoptosis and inhibits the invasion of esophageal cancer through a mechanism involving the inhibition of the MSK2-CREB-Bcl2 and cadherin pathway. Sulforaphene could therefore serve as a promising anti-tumor drug for the treatment of esophageal cancer.
Collapse
Affiliation(s)
- Chengjuan Zhang
- Biorepository Center, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan People’s Republic of China
- Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan People’s Republic of China
| | - Junxia Zhang
- Experimental Research Center, Henan University of Chinese Medicine, Zhengzhou, Henan People’s Republic of China
| | - Qiong Wu
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan People’s Republic of China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan People’s Republic of China
| | - Benling Xu
- Department of Immunotherapy, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan People’s Republic of China
| | - Guoguo Jin
- Laboratory of Bone Tumor, Henan Luoyang Orthopedic Hospital, Zhengzhou, Henan People’s Republic of China
| | - Yan Qiao
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan People’s Republic of China
- Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan People’s Republic of China
| | - Simin Zhao
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan People’s Republic of China
- Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan People’s Republic of China
| | - Yang Yang
- Clinical Systems Biology Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan People’s Republic of China
| | - Jinwen Shang
- Biorepository Center, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan People’s Republic of China
| | - Xiaofang Li
- Shangqiu Medical College, Shangqiu, Henan People’s Republic of China
| | - Kangdong Liu
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan People’s Republic of China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan People’s Republic of China
- Department of Immunotherapy, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan People’s Republic of China
| |
Collapse
|