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Ghosh S, Bhatti GK, Sharma PK, Kandimalla R, Mastana SS, Bhatti JS. Potential of Nano-Engineered Stem Cells in the Treatment of Multiple Sclerosis: A Comprehensive Review. Cell Mol Neurobiol 2023; 44:6. [PMID: 38104307 PMCID: PMC11397842 DOI: 10.1007/s10571-023-01434-5] [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: 06/12/2023] [Accepted: 11/06/2023] [Indexed: 12/19/2023]
Abstract
Multiple sclerosis (MS) is a chronic and degrading autoimmune disorder mainly targeting the central nervous system, leading to progressive neurodegeneration, demyelination, and axonal damage. Current treatment options for MS are limited in efficacy, generally linked to adverse side effects, and do not offer a cure. Stem cell therapies have emerged as a promising therapeutic strategy for MS, potentially promoting remyelination, exerting immunomodulatory effects and protecting against neurodegeneration. Therefore, this review article focussed on the potential of nano-engineering in stem cells as a therapeutic approach for MS, focusing on the synergistic effects of combining stem cell biology with nanotechnology to stimulate the proliferation of oligodendrocytes (OLs) from neural stem cells and OL precursor cells, by manipulating neural signalling pathways-PDGF, BMP, Wnt, Notch and their essential genes such as Sox, bHLH, Nkx. Here we discuss the pathophysiology of MS, the use of various types of stem cells in MS treatment and their mechanisms of action. In the context of nanotechnology, we present an overview of its applications in the medical and research field and discuss different methods and materials used to nano-engineer stem cells, including surface modification, biomaterials and scaffolds, and nanoparticle-based delivery systems. We further elaborate on nano-engineered stem cell techniques, such as nano script, nano-exosome hybrid, nano-topography and their potentials in MS. The article also highlights enhanced homing, engraftment, and survival of nano-engineered stem cells, targeted and controlled release of therapeutic agents, and immunomodulatory and tissue repair effects with their challenges and limitations. This visual illustration depicts the process of utilizing nano-engineering in stem cells and exosomes for the purpose of delivering more accurate and improved treatments for Multiple Sclerosis (MS). This approach targets specifically the creation of oligodendrocytes, the breakdown of which is the primary pathological factor in MS.
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Affiliation(s)
- Sushruta Ghosh
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, School of Health Sciences Central, University of Punjab, Bathinda, India
| | - Gurjit Kaur Bhatti
- Department of Medical Lab Technology, University Institute of Applied Health Sciences, Chandigarh University, Mohali, India
| | - Pushpender Kumar Sharma
- Amity Institute of Biotechnology, Amity University, Rajasthan, India
- Amity Centre for Nanobiotechnology and Nanomedicine, Amity University, Rajasthan, India
| | - Ramesh Kandimalla
- Department of Biochemistry, Kakatiya Medical College, Warangal, Telangana, India
- Department of Applied Biology, CSIR-Indian Institute of Technology, Hyderabad, India
| | - Sarabjit Singh Mastana
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK
| | - Jasvinder Singh Bhatti
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, School of Health Sciences Central, University of Punjab, Bathinda, India.
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Yu Z, Wang H, Ying B, Mei X, Zeng D, Liu S, Qu W, Pan X, Pu S, Li R, Qin Y. Mild photothermal therapy assist in promoting bone repair: Related mechanism and materials. Mater Today Bio 2023; 23:100834. [PMID: 38024841 PMCID: PMC10643361 DOI: 10.1016/j.mtbio.2023.100834] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 07/21/2023] [Accepted: 10/14/2023] [Indexed: 12/01/2023] Open
Abstract
Achieving precision treatment in bone tissue engineering (BTE) remains a challenge. Photothermal therapy (PTT), as a form of precision therapy, has been extensively investigated for its safety and efficacy. It has demonstrated significant potential in the treatment of orthopedic diseases such as bone tumors, postoperative infections and osteoarthritis. However, the high temperatures associated with PTT can lead to certain limitations and drawbacks. In recent years, researchers have explored the use of biomaterials for mild photothermal therapy (MPT), which offers a promising approach for addressing these limitations. This review provides a comprehensive overview of the mechanisms underlying MPT and presents a compilation of photothermal agents and their utilization strategies for bone tissue repair. Additionally, the paper discusses the future prospects of MPT-assisted bone tissue regeneration, aiming to provide insights and recommendations for optimizing material design in this field.
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Affiliation(s)
- Zehao Yu
- Department of Joint Surgery of Orthopaedic Center, The Second Hospital of Jilin University, Changchun, 130041, People’s Republic of China
- Jilin Provincial Key Laboratory of Orhtopeadics, Changchun, Jilin 130041 People’s Republic of China
| | - Hao Wang
- Department of Joint Surgery of Orthopaedic Center, The Second Hospital of Jilin University, Changchun, 130041, People’s Republic of China
- Jilin Provincial Key Laboratory of Orhtopeadics, Changchun, Jilin 130041 People’s Republic of China
| | - Boda Ying
- Department of Joint Surgery of Orthopaedic Center, The Second Hospital of Jilin University, Changchun, 130041, People’s Republic of China
- Jilin Provincial Key Laboratory of Orhtopeadics, Changchun, Jilin 130041 People’s Republic of China
| | - Xiaohan Mei
- National & Local Joint Engineering Laboratory for Synthesis Technology of High-Performance Polymer, College of Chemistry, Jilin University, Changchun, 130012, People’s Republic of China
| | - Dapeng Zeng
- Department of Joint Surgery of Orthopaedic Center, The Second Hospital of Jilin University, Changchun, 130041, People’s Republic of China
- Jilin Provincial Key Laboratory of Orhtopeadics, Changchun, Jilin 130041 People’s Republic of China
| | - Shibo Liu
- Department of Joint Surgery of Orthopaedic Center, The Second Hospital of Jilin University, Changchun, 130041, People’s Republic of China
- Jilin Provincial Key Laboratory of Orhtopeadics, Changchun, Jilin 130041 People’s Republic of China
| | - Wenrui Qu
- Department of Joint Surgery of Orthopaedic Center, The Second Hospital of Jilin University, Changchun, 130041, People’s Republic of China
- Jilin Provincial Key Laboratory of Orhtopeadics, Changchun, Jilin 130041 People’s Republic of China
| | - Xiangjun Pan
- Department of Joint Surgery of Orthopaedic Center, The Second Hospital of Jilin University, Changchun, 130041, People’s Republic of China
- Jilin Provincial Key Laboratory of Orhtopeadics, Changchun, Jilin 130041 People’s Republic of China
| | - Si Pu
- Department of Joint Surgery of Orthopaedic Center, The Second Hospital of Jilin University, Changchun, 130041, People’s Republic of China
- Jilin Provincial Key Laboratory of Orhtopeadics, Changchun, Jilin 130041 People’s Republic of China
| | - Ruiyan Li
- Department of Joint Surgery of Orthopaedic Center, The Second Hospital of Jilin University, Changchun, 130041, People’s Republic of China
- Jilin Provincial Key Laboratory of Orhtopeadics, Changchun, Jilin 130041 People’s Republic of China
| | - Yanguo Qin
- Department of Joint Surgery of Orthopaedic Center, The Second Hospital of Jilin University, Changchun, 130041, People’s Republic of China
- Jilin Provincial Key Laboratory of Orhtopeadics, Changchun, Jilin 130041 People’s Republic of China
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Salvermoser L, Flisikowski K, Dressel-Böhm S, Nytko KJ, Rohrer Bley C, Schnieke A, Samt AK, Thölke D, Lennartz P, Schwab M, Wang F, Bashiri Dezfouli A, Multhoff G. Elevated circulating Hsp70 levels are correlative for malignancies in different mammalian species. Cell Stress Chaperones 2023; 28:105-118. [PMID: 36399258 PMCID: PMC9877270 DOI: 10.1007/s12192-022-01311-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 10/28/2022] [Accepted: 11/07/2022] [Indexed: 11/19/2022] Open
Abstract
Circulating Hsp70 levels were determined in feline and porcine cohorts using two different ELISA systems. These comparative animal models of larger organisms often reflect diseases, and especially malignant tumors, better than conventional rodent models. It is therefore essential to investigate the biology and utility of tumor biomarkers in animals such as cats and pigs. In this study, levels of free Hsp70 in the blood of cats with spontaneously occurring tumors were detected using a commercial Hsp70 ELISA (R&D Systems). Sub-analysis of different tumor groups revealed that animals with tumors of epithelial origin presented with significantly elevated circulating Hsp70 concentrations. In addition to free Hsp70 levels measured with the R&D Systems Hsp70 ELISA, levels of exosomal Hsp70 were determined using the compHsp70 ELISA in pigs. Both ELISA systems detected significantly elevated Hsp70 levels (R&D Systems: median 24.9 ng/mL; compHsp70: median 44.2 ng/mL) in the blood of a cohort of APC1311/+ pigs diagnosed with high-grade adenoma polyps, and the R&D Systems Hsp70 ELISA detected also elevated Hsp70 levels in animals with low-grade polyps. In contrast, in flTP53R167H pigs, suffering from malignant osteosarcoma, the compHsp70 ELISA (median 674.32 ng/mL), but not the R&D Systems Hsp70 ELISA (median 4.78 ng/mL), determined significantly elevated Hsp70 concentrations, indicating that in tumor-bearing animals, the dominant form of Hsp70 is of exosomal origin. Our data suggest that both ELISA systems are suitable for detecting free circulating Hsp70 levels in pigs with high-grade adenoma, but only the compHsp70 ELISA can measure elevated, tumor-derived exosomal Hsp70 levels in tumor-bearing animals.
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Affiliation(s)
- Lukas Salvermoser
- Radiation Immuno-Oncology Group, Center for Translational Cancer Research Technische, Universität München (TranslaTUM), Technische Universität München (TUM), Klinikum Rechts Der IsarEinsteinstr 25, 81675, Munich, Germany.
- Department of Radiation Oncology, Klinikum Rechts Der Isar, Technische Universität München (TUM), Ismaningerstr 22, 81675, Munich, Germany.
- Department of Radiology, University Hospital, LMU Munich, Marchioninistr 15, 81377, Munich, Germany.
| | - Krzysztof Flisikowski
- Livestock Biotechnology, School of Live Sciences, Technische Universität München (TUM), Liesel-Beckmannstr 1, 85354, Freising, Germany
| | - Susann Dressel-Böhm
- Vetsuisse Faculty, Division of Radiation Oncology, University of Zurich, Winterthurerstr 258C, CH-8057, Zurich, Switzerland
| | - Katarzyna J Nytko
- Vetsuisse Faculty, Division of Radiation Oncology, University of Zurich, Winterthurerstr 258C, CH-8057, Zurich, Switzerland
| | - Carla Rohrer Bley
- Vetsuisse Faculty, Division of Radiation Oncology, University of Zurich, Winterthurerstr 258C, CH-8057, Zurich, Switzerland
| | - Angelika Schnieke
- Livestock Biotechnology, School of Live Sciences, Technische Universität München (TUM), Liesel-Beckmannstr 1, 85354, Freising, Germany
| | - Ann-Kathrin Samt
- Radiation Immuno-Oncology Group, Center for Translational Cancer Research Technische, Universität München (TranslaTUM), Technische Universität München (TUM), Klinikum Rechts Der IsarEinsteinstr 25, 81675, Munich, Germany
- Department of Radiation Oncology, Klinikum Rechts Der Isar, Technische Universität München (TUM), Ismaningerstr 22, 81675, Munich, Germany
| | - Dennis Thölke
- Radiation Immuno-Oncology Group, Center for Translational Cancer Research Technische, Universität München (TranslaTUM), Technische Universität München (TUM), Klinikum Rechts Der IsarEinsteinstr 25, 81675, Munich, Germany
- Department of Radiation Oncology, Klinikum Rechts Der Isar, Technische Universität München (TUM), Ismaningerstr 22, 81675, Munich, Germany
| | - Philipp Lennartz
- Radiation Immuno-Oncology Group, Center for Translational Cancer Research Technische, Universität München (TranslaTUM), Technische Universität München (TUM), Klinikum Rechts Der IsarEinsteinstr 25, 81675, Munich, Germany
- Department of Radiation Oncology, Klinikum Rechts Der Isar, Technische Universität München (TUM), Ismaningerstr 22, 81675, Munich, Germany
| | - Melissa Schwab
- Radiation Immuno-Oncology Group, Center for Translational Cancer Research Technische, Universität München (TranslaTUM), Technische Universität München (TUM), Klinikum Rechts Der IsarEinsteinstr 25, 81675, Munich, Germany
- Department of Radiation Oncology, Klinikum Rechts Der Isar, Technische Universität München (TUM), Ismaningerstr 22, 81675, Munich, Germany
| | - Fei Wang
- Radiation Immuno-Oncology Group, Center for Translational Cancer Research Technische, Universität München (TranslaTUM), Technische Universität München (TUM), Klinikum Rechts Der IsarEinsteinstr 25, 81675, Munich, Germany
- Department of Radiation Oncology, Klinikum Rechts Der Isar, Technische Universität München (TUM), Ismaningerstr 22, 81675, Munich, Germany
| | - Ali Bashiri Dezfouli
- Radiation Immuno-Oncology Group, Center for Translational Cancer Research Technische, Universität München (TranslaTUM), Technische Universität München (TUM), Klinikum Rechts Der IsarEinsteinstr 25, 81675, Munich, Germany
- Department of Radiation Oncology, Klinikum Rechts Der Isar, Technische Universität München (TUM), Ismaningerstr 22, 81675, Munich, Germany
| | - Gabriele Multhoff
- Radiation Immuno-Oncology Group, Center for Translational Cancer Research Technische, Universität München (TranslaTUM), Technische Universität München (TUM), Klinikum Rechts Der IsarEinsteinstr 25, 81675, Munich, Germany
- Department of Radiation Oncology, Klinikum Rechts Der Isar, Technische Universität München (TUM), Ismaningerstr 22, 81675, Munich, Germany
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Khan K, Caron C, Mahmoud I, Derish I, Schwertani A, Cecere R. Extracellular Vesicles as a Cell-free Therapy for Cardiac Repair: a Systematic Review and Meta-analysis of Randomized Controlled Preclinical Trials in Animal Myocardial Infarction Models. Stem Cell Rev Rep 2022; 18:1143-1167. [PMID: 35107768 DOI: 10.1007/s12015-021-10289-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/18/2021] [Indexed: 12/14/2022]
Abstract
Stem cell therapy for cardiac regeneration has been gaining traction as a possible intervention for the reduction of the burden associated with MI and heart failure. However, stem cell therapies have several shortcomings, including poor engraftment, limited improvements in cardiac function, and possible teratogenicity. Recently, extracellular vesicles (EVs) from stem cell sources have been explored as a novel therapy to regenerate the injured myocardium in several animal MI trials. In this systematic review and meta-analysis, we investigate the use of stem cell-derived EVs for cardiac repair preclinical trials in animal MI models. Cochrane Library, Medline, Embase, PubMed, Scopus and Web of Science and grey literature (Canadian Agency for Drugs, Technologies in Health, and Google Scholar) were searched through August 20, 2020 and 37 articles were included in the final analysis. The overall effect size observed in EV-treated small animals after MI for ejection fraction (EF) was 10.85 [95 %CI: 8.79, 12.90] and for fractional shortening (FS) was 7.19 [95 %CI: 5.43, 8.96] compared to control-treated animals. The most abundant stem cell source used were mesenchymal stem cells which showed robust improvements in EF and FS (MD = 11.89 [95 % CI: 9.44, 14.34] and MD = 6.96 [95 % CI: 4.97, 8.96], respectively). Significant publication bias was detected for EF and FS outcomes. This study supports the use of EVs derived from stem cells as a novel therapy for cardiac repair after MI. Further investigation in larger animal studies may be necessary before clinical trials.PROSPERO registration number: CRD42019142218.
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Affiliation(s)
- Kashif Khan
- Division of Cardiology and Cardiac Surgery, Glen Campus - The Royal Victoria Hospital, McGill University Health Centre, 1001 Decarie Blvd, Block C, C07.1284, Montreal, Quebec, Canada
| | - Christophe Caron
- Division of Cardiology and Cardiac Surgery, Glen Campus - The Royal Victoria Hospital, McGill University Health Centre, 1001 Decarie Blvd, Block C, C07.1284, Montreal, Quebec, Canada
| | - Ibtisam Mahmoud
- McConnell Resource Centre, McGill University Health Centre, Montreal, Quebec, Canada
| | - Ida Derish
- Division of Cardiology and Cardiac Surgery, Glen Campus - The Royal Victoria Hospital, McGill University Health Centre, 1001 Decarie Blvd, Block C, C07.1284, Montreal, Quebec, Canada
| | - Adel Schwertani
- Division of Cardiology and Cardiac Surgery, Glen Campus - The Royal Victoria Hospital, McGill University Health Centre, 1001 Decarie Blvd, Block C, C07.1284, Montreal, Quebec, Canada
| | - Renzo Cecere
- Division of Cardiology and Cardiac Surgery, Glen Campus - The Royal Victoria Hospital, McGill University Health Centre, 1001 Decarie Blvd, Block C, C07.1284, Montreal, Quebec, Canada.
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Linder M, Pogge von Strandmann E. The Role of Extracellular HSP70 in the Function of Tumor-Associated Immune Cells. Cancers (Basel) 2021; 13:cancers13184721. [PMID: 34572948 PMCID: PMC8466959 DOI: 10.3390/cancers13184721] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 09/08/2021] [Accepted: 09/14/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary The intracellular heat shock protein 70 (HSP70) is essential for cells to respond to stress, for instance, by refolding damaged proteins or inhibiting apoptosis. However, in cancer, HSP70 is overexpressed and can translocate to the extracellular milieu, where it emerged as an important modulator of tumor-associated immune cells. By targeting the tumor microenvironment (TME) through different mechanisms, extracellular HSP70 can trigger pro- or anti-tumorigenic responses. Therefore, understanding the pathways and their consequences is crucial for therapeutically targeting cancer and its surrounding microenvironment. In this review, we summarize current knowledge on the translocation of extracellular HSP70. We further elucidate its functions within the TME and provide an overview of potential therapeutic options. Abstract Extracellular vesicles released by tumor cells (T-EVs) are known to contain danger-associated molecular patterns (DAMPs), which are released in response to cellular stress to alert the immune system to the dangerous cell. Part of this defense mechanism is the heat shock protein 70 (HSP70), and HSP70-positive T-EVs are known to trigger anti-tumor immune responses. Moreover, extracellular HSP70 acts as an immunogen that contributes to the cross-presentation of major histocompatibility complex (MHC) class I molecules. However, the release of DAMPs, including HSP70, may also induce chronic inflammation or suppress immune cell activity, promoting tumor growth. Here, we summarize the current knowledge on soluble, membrane-bound, and EV-associated HSP70 regarding their functions in regulating tumor-associated immune cells in the tumor microenvironment. The molecular mechanisms involved in the translocation of HSP70 to the plasma membrane of tumor cells and its release via exosomes or soluble proteins are summarized. Furthermore, perspectives for immunotherapies aimed to target HSP70 and its receptors for cancer treatment are discussed and presented.
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Corrêa RR, Juncosa EM, Masereeuw R, Lindoso RS. Extracellular Vesicles as a Therapeutic Tool for Kidney Disease: Current Advances and Perspectives. Int J Mol Sci 2021; 22:ijms22115787. [PMID: 34071399 PMCID: PMC8198688 DOI: 10.3390/ijms22115787] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 05/18/2021] [Accepted: 05/18/2021] [Indexed: 12/12/2022] Open
Abstract
Extracellular vesicles (EVs) have been described as important mediators of cell communication, regulating several physiological processes, including tissue recovery and regeneration. In the kidneys, EVs derived from stem cells have been shown to support tissue recovery in diverse disease models and have been considered an interesting alternative to cell therapy. For this purpose, however, several challenges remain to be overcome, such as the requirement of a high number of EVs for human therapy and the need for optimization of techniques for their isolation and characterization. Moreover, the kidney’s complexity and the pathological process to be treated require that EVs present a heterogeneous group of molecules to be delivered. In this review, we discuss the recent advances in the use of EVs as a therapeutic tool for kidney diseases. Moreover, we give an overview of the new technologies applied to improve EVs’ efficacy, such as novel methods of EV production and isolation by means of bioreactors and microfluidics, bioengineering the EV content and the use of alternative cell sources, including kidney organoids, to support their transfer to clinical applications.
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Affiliation(s)
- Raphael Rodrigues Corrêa
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil;
| | - Estela Mancheño Juncosa
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands;
| | - Rosalinde Masereeuw
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands;
- Correspondence: (R.M.); (R.S.L.); Tel.: +31-30-253-3529 (R.M.); Tel.: +55-21-3938-6520 (R.S.L.)
| | - Rafael Soares Lindoso
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil;
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands;
- National Institute of Science and Technology for Regenerative Medicine-REGENERA, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
- Correspondence: (R.M.); (R.S.L.); Tel.: +31-30-253-3529 (R.M.); Tel.: +55-21-3938-6520 (R.S.L.)
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Fang L, Li J, Papakonstantinou E, Karakioulaki M, Sun Q, Schumann D, Tamm M, Stolz D, Roth M. Secreted heat shock proteins control airway remodeling: Evidence from bronchial thermoplasty. J Allergy Clin Immunol 2021; 148:1249-1261.e8. [PMID: 33675818 DOI: 10.1016/j.jaci.2021.02.022] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 02/09/2021] [Accepted: 02/11/2021] [Indexed: 10/22/2022]
Abstract
BACKGROUND Increased airway smooth muscle mass is a key pathology in asthma. Bronchial thermoplasty is a treatment for severe asthma based on selective heating of the airways that aims to reduce the mass of airway smooth muscle cells (ASMCs), and thereby bronchoconstriction. However, short heat exposure is insufficient to explain the long-lasting effect, and heat shock proteins (HSPs) have been suggested to play a role. OBJECTIVE We sought to determine the role of HSP70 and HSP90 in the control of airway wall remodeling by bronchial thermoplasty. METHODS Bronchoalveolar lavage fluid and endobronchial biopsies of 20 patients with severe asthma were obtained before and after thermoplasty. Isolated epithelial cells and ASMCs were exposed to 65oC for 10 seconds, mimicking thermoplasty. Proteins were determined by immunohistochemistry, Western blotting, immunofluorescence, and ELISA; proliferation by cell counts and antigen Ki67 (MKI67) expression. RESULTS Thermoplasty significantly increased the expression of HSP70 and HSP90 in the epithelium and bronchoalveolar lavage fluid. In ASMCs, thermoplasty reduced both HSPs. These cell-type-specific effects were detectable even 1 month after thermoplasty in tissue sections. In epithelial cells, ex vivo exposure to heat (65oC, 10 seconds) increased the expression and secretion of HSP70 and HSP90. In addition, epithelial cell proliferation was upregulated by heat or treatment with human recombinant HSP70 or HSP90. In ASMCs, heat exposure or exogenous HSPs reduced proliferation and differentiation. In both cell types, HSP70 and HSP90 activated the signaling cascade of serine/threonine-protein kinase →mammalian target of rapamycin→ribosomal protein S6 kinase 1 and CCAAT/enhancer binding protein-β→protein arginine methyltransferase 1→ mitochondria activity. CONCLUSIONS Epithelial cell-derived HSP70 and HSP90 improve the function of epithelial cells, but block ASMC remodeling.
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Affiliation(s)
- Lei Fang
- Pulmonary Cell Research & Clinic of Respiratory Medicine, Department of Biomedicine, University of Basel & University Hospital of Basel, Basel, Switzerland
| | - Junling Li
- Pulmonary Cell Research & Clinic of Respiratory Medicine, Department of Biomedicine, University of Basel & University Hospital of Basel, Basel, Switzerland; The affiliated Dongguan Shilong People's Hospital of Southern Medical University, Guangdong, China
| | - Eleni Papakonstantinou
- Pulmonary Cell Research & Clinic of Respiratory Medicine, Department of Biomedicine, University of Basel & University Hospital of Basel, Basel, Switzerland
| | - Meropi Karakioulaki
- Pulmonary Cell Research & Clinic of Respiratory Medicine, Department of Biomedicine, University of Basel & University Hospital of Basel, Basel, Switzerland
| | - Qingzhu Sun
- College of Animal Science and Technology, Northwest A & F University, Yangling, Shaanxi, China
| | - Desiree Schumann
- Pulmonary Cell Research & Clinic of Respiratory Medicine, Department of Biomedicine, University of Basel & University Hospital of Basel, Basel, Switzerland
| | - Michael Tamm
- Pulmonary Cell Research & Clinic of Respiratory Medicine, Department of Biomedicine, University of Basel & University Hospital of Basel, Basel, Switzerland
| | - Daiana Stolz
- Pulmonary Cell Research & Clinic of Respiratory Medicine, Department of Biomedicine, University of Basel & University Hospital of Basel, Basel, Switzerland
| | - Michael Roth
- Pulmonary Cell Research & Clinic of Respiratory Medicine, Department of Biomedicine, University of Basel & University Hospital of Basel, Basel, Switzerland.
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Alessio N, Siniscalco D, Peluso G, Galderisi U. New Frontiers in Stem Cell Research and Translational Approaches. BIOLOGY 2020; 9:11. [PMID: 31947909 PMCID: PMC7168217 DOI: 10.3390/biology9010011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 12/30/2019] [Accepted: 01/02/2020] [Indexed: 12/17/2022]
Abstract
Stem cell biology represents a challenging research area with a huge potential translational approach. This review focuses on the most recent findings on stem cell basics and clinics in several fields of research, as final outcome of the 10th conference held by Stem Cell Research Italy (SCR Italy) in Naples, Italy in June 2019. Current state-of-the-art and novel findings on stem cell research are discussed, bringing together basic and applied research with the newest insights in stem cell therapy.
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Affiliation(s)
- Nicola Alessio
- Department of Experimental Medicine, Division of Molecular Biology, Biotechnology and Histology. University of Campania “Luigi Vanvitelli”, via S. Maria di Costantinopoli 16, 80138 Naples, Italy; (N.A.); (U.G.)
| | - Dario Siniscalco
- Department of Experimental Medicine, Division of Molecular Biology, Biotechnology and Histology. University of Campania “Luigi Vanvitelli”, via S. Maria di Costantinopoli 16, 80138 Naples, Italy; (N.A.); (U.G.)
| | - Gianfranco Peluso
- Research Institute on Terrestrial Ecosystems (IRET), National Research Council of Italy, (CNR), via P. Castellino 111, 80131 Naples, Italy;
| | - Umberto Galderisi
- Department of Experimental Medicine, Division of Molecular Biology, Biotechnology and Histology. University of Campania “Luigi Vanvitelli”, via S. Maria di Costantinopoli 16, 80138 Naples, Italy; (N.A.); (U.G.)
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WIN55,212-2-Induced Expression of Mir-29b1 Favours the Suppression of Osteosarcoma Cell Migration in a SPARC-Independent Manner. Int J Mol Sci 2019; 20:ijms20205235. [PMID: 31652569 PMCID: PMC6834304 DOI: 10.3390/ijms20205235] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 10/09/2019] [Accepted: 10/18/2019] [Indexed: 12/23/2022] Open
Abstract
WIN55,212-2 (WIN) is a synthetic agonist of cannabinoid receptors that displays promising antitumour properties. The aim of this study is to demonstrate that WIN is able to block the migratory ability of osteosarcoma cells and characterize the mechanisms involved. Using wound healing assay and zymography, we showed that WIN affects cell migration and reduces the activity of the metalloproteases MMP2 and MMP9. This effect seemed to be independent of secreted protein acidic and rich in cysteine (SPARC), a matricellular protein involved in tissue remodeling and extracellular matrix deposition. SPARC release was indeed prevented by WIN, and SPARC silencing by RNA interference did not influence the effect of the cannabinoid on cell migration. WIN also increased the release of extracellular vesicles and dramatically upregulated miR-29b1, a key miRNA that modulates cell proliferation and migration. Interestingly, reduced cell migration was observed in stably miR-29b1-transfected cells, similarly to WIN-treated cells. Finally, we show the absence of SPARC in the extracellular vesicles released by osteosarcoma cells and no changes in SPARC level in miR-29b1 overexpressing cells. Overall, these findings suggest that WIN markedly affects cell migration, dependently on miR-29b1 and independently of SPARC, and can thus be considered as a potential innovative therapeutic agent in the treatment of osteosarcoma.
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Yang HJ, Hu R, Sun H, Bo Chen, Li X, Chen JB. 4-HNE induces proinflammatory cytokines of human retinal pigment epithelial cells by promoting extracellular efflux of HSP70. Exp Eye Res 2019; 188:107792. [PMID: 31499034 DOI: 10.1016/j.exer.2019.107792] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 08/09/2019] [Accepted: 09/05/2019] [Indexed: 12/14/2022]
Abstract
Oxidative stress and subsequent chronic inflammation result in dysfunction of the retinal pigment epithelium (RPE) and represent therapeutic targets in the context of age-related macular degeneration (AMD). However, molecular mechanisms that linked oxidative stress and inflammation still unclear. As an important byproduct of oxidative stress, 4-hydroxynonenal (4-HNE) induces apoptosis and lysosome dysregulation of RPE cells. In the present study, we evaluated cytokines production of RPE cells induced by 4-HNE by using cytokine array and confirmed that 4-HNE induced IL-6, IL-1β and TNF-α production in a concentration dependent manner. Specifically, 4-HNE also induced IL-10 and TGF-β production in low concentration. Molecular analysis revealed that intracellular HSP70 inhibited 4-HNE-induced production of pro-inflammatory cytokines, and 4-HNE exerted proinflammatory effects in RPE cells by enhancing extracellular release of HSP70, as efflux inhibitor Methyl-β-cyclodextrin (MBC) treatment significantly blocked the release of HSP70 and decreased IL-6 production of RPE cells induced by 4-HNE. Meanwhile, HSP70 inducer arimoclomol increased intracellular HSP70 production, but showed no influence on its extracellular level, also performed anti-inflammatory effects in 4-HNE-stimulated RPE cells. Whereas the anti-inflammatory effects of paeoniflorin, an HSP70 inducer simultaneously promoted its extracellular efflux, was lower than arimoclomol. In addition, we further confirmed that MBC exhibited synergetic effect with both paeoniflorin and arimoclomol to inhibit the production of proinflammatory cytokines induced by 4-HNE. Taken together, these results indicate that HSP70 plays a vital role in regulating inflammation of RPE cells induced by oxidative stress and might be a potential novel target for clinical treatment of AMD.
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Affiliation(s)
- Hua-Jing Yang
- Department of Ophthalomology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Rui Hu
- Department of Eugenic Genetics Laboratory, Wuhan Medical and Health Center for Women and Children, Huazhong University of Science and Technology, Wuhan, 430016, China
| | - Hong Sun
- Department of Eugenic Genetics Laboratory, Wuhan Medical and Health Center for Women and Children, Huazhong University of Science and Technology, Wuhan, 430016, China
| | - Bo Chen
- Department of Ophthalomology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xia Li
- Ophthalmic Center, The Central Hospital of Enshi Autonomous Prefecture, Enshi Clinical College of Wuhan University, Enshi, Hubei, 445000, China.
| | - Jian-Bin Chen
- Department of Ophthalomology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China.
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11
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Miller DJ, Fort PE. Heat Shock Proteins Regulatory Role in Neurodevelopment. Front Neurosci 2018; 12:821. [PMID: 30483047 PMCID: PMC6244093 DOI: 10.3389/fnins.2018.00821] [Citation(s) in RCA: 108] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Accepted: 10/22/2018] [Indexed: 01/20/2023] Open
Abstract
Heat shock proteins (Hsps) are a large family of molecular chaperones that are well-known for their roles in protein maturation, re-folding and degradation. While some Hsps are constitutively expressed in certain regions, others are rapidly upregulated in the presence of stressful stimuli. Numerous stressors, including hyperthermia and hypoxia, can induce the expression of Hsps, which, in turn, interact with client proteins and co-chaperones to regulate cell growth and survival. Such interactions must be tightly regulated, especially at critical points during embryonic and postnatal development. Hsps exhibit specific patterns of expression consistent with a spatio-temporally regulated role in neurodevelopment. There is also growing evidence that Hsps may promote or inhibit neurodevelopment through specific pathways regulating cell differentiation, neurite outgrowth, cell migration, or angiogenesis. This review will examine the regulatory role that these individual chaperones may play in neurodevelopment, and will focus specifically on the signaling pathways involved in the maturation of neuronal and glial cells as well as the underlying vascular network.
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Affiliation(s)
- David J Miller
- Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, United States.,Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, United States
| | - Patrice E Fort
- Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, United States.,Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, United States
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Extracellular Vesicles and Matrix Remodeling Enzymes: The Emerging Roles in Extracellular Matrix Remodeling, Progression of Diseases and Tissue Repair. Cells 2018; 7:cells7100167. [PMID: 30322133 PMCID: PMC6210724 DOI: 10.3390/cells7100167] [Citation(s) in RCA: 127] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Revised: 09/17/2018] [Accepted: 10/12/2018] [Indexed: 12/21/2022] Open
Abstract
Extracellular vesicles (EVs) are membrane enclosed micro- and nano-sized vesicles that are secreted from almost every species, ranging from prokaryotes to eukaryotes, and from almost every cell type studied so far. EVs contain repertoire of bioactive molecules such as proteins (including enzymes and transcriptional factors), lipids, carbohydrates and nucleic acids including DNA, coding and non-coding RNAs. The secreted EVs are taken up by neighboring cells where they release their content in recipient cells, or can sail through body fluids to reach distant organs. Since EVs transport bioactive cargo between cells, they have emerged as novel mediators of extra- and intercellular activities in local microenvironment and inter-organ communications distantly. Herein, we review the activities of EV-associated matrix-remodeling enzymes such as matrix metalloproteinases, heparanases, hyaluronidases, aggrecanases, and their regulators such as extracellular matrix metalloproteinase inducers and tissue inhibitors of metalloproteinases as novel means of matrix remodeling in physiological and pathological conditions. We discuss how such EVs act as novel mediators of extracellular matrix degradation to prepare a permissive environment for various pathological conditions such as cancer, cardiovascular diseases, arthritis and metabolic diseases. Additionally, the roles of EV-mediated matrix remodeling in tissue repair and their potential applications as organ therapies have been reviewed. Collectively, this knowledge could benefit the development of new approaches for tissue engineering.
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Labusca L, Herea DD, Mashayekhi K. Stem cells as delivery vehicles for regenerative medicine-challenges and perspectives. World J Stem Cells 2018. [PMID: 29849930 DOI: : 10.4252/wjsc.v10.i5.43] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The use of stem cells as carriers for therapeutic agents is an appealing modality for targeting tissues or organs of interest. Combined delivery of cells together with various information molecules as therapeutic agents has the potential to enhance, modulate or even initiate local or systemic repair processes, increasing stem cell efficiency for regenerative medicine applications. Stem-cell-mediated delivery of genes, proteins or small molecules takes advantage of the innate capability of stem cells to migrate and home to injury sites. As the native migratory properties are affected by in vitro expansion, the existent methods for enhancing stem cell targeting capabilities (modified culture methods, genetic modification, cell surface engineering) are described. The role of various nanoparticles in equipping stem cells with therapeutic small molecules is revised together with their class-specific advantages and shortcomings. Modalities to circumvent common challenges when designing a stem-cell-mediated targeted delivery system are described as well as future prospects in using this approach for regenerative medicine applications.
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Affiliation(s)
- Luminita Labusca
- Orthopedics and Traumatology Clinic, Emergency County Hospital Saint Spiridon Iasi Romania, Iasi 700000, Romania
| | - Dumitru Daniel Herea
- Stem Cell Laboratory, National Institute of Research and Development for Technical Physics (NIRDTP), Iasi 700349, Romania
| | - Kaveh Mashayekhi
- Systems Bioinformatics and Modelling SBIM, Frankfurt 45367, Germany
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Labusca L, Herea DD, Mashayekhi K. Stem cells as delivery vehicles for regenerative medicine-challenges and perspectives. World J Stem Cells 2018; 10:43-56. [PMID: 29849930 PMCID: PMC5973910 DOI: 10.4252/wjsc.v10.i5.43] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 04/26/2018] [Accepted: 05/09/2018] [Indexed: 02/06/2023] Open
Abstract
The use of stem cells as carriers for therapeutic agents is an appealing modality for targeting tissues or organs of interest. Combined delivery of cells together with various information molecules as therapeutic agents has the potential to enhance, modulate or even initiate local or systemic repair processes, increasing stem cell efficiency for regenerative medicine applications. Stem-cell-mediated delivery of genes, proteins or small molecules takes advantage of the innate capability of stem cells to migrate and home to injury sites. As the native migratory properties are affected by in vitro expansion, the existent methods for enhancing stem cell targeting capabilities (modified culture methods, genetic modification, cell surface engineering) are described. The role of various nanoparticles in equipping stem cells with therapeutic small molecules is revised together with their class-specific advantages and shortcomings. Modalities to circumvent common challenges when designing a stem-cell-mediated targeted delivery system are described as well as future prospects in using this approach for regenerative medicine applications.
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Affiliation(s)
- Luminita Labusca
- Orthopedics and Traumatology Clinic, Emergency County Hospital Saint Spiridon Iasi Romania, Iasi 700000, Romania
| | - Dumitru Daniel Herea
- Stem Cell Laboratory, National Institute of Research and Development for Technical Physics (NIRDTP), Iasi 700349, Romania
| | - Kaveh Mashayekhi
- Systems Bioinformatics and Modelling SBIM, Frankfurt 45367, Germany
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15
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Extracellular vesicles – biogenesis, composition, function, uptake and therapeutic applications. Biologia (Bratisl) 2018. [DOI: 10.2478/s11756-018-0047-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Oxidative stress preconditioning of mouse perivascular myogenic progenitors selects a subpopulation of cells with a distinct survival advantage in vitro and in vivo. Cell Death Dis 2018; 9:1. [PMID: 29298988 PMCID: PMC5849040 DOI: 10.1038/s41419-017-0012-9] [Citation(s) in RCA: 233] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Revised: 08/07/2017] [Accepted: 09/18/2017] [Indexed: 01/01/2023]
Abstract
Cell engraftment, survival and integration during transplantation procedures represent the crux of cell-based therapies. Thus, there have been many studies focused on improving cell viability upon implantation. We used severe oxidative stress to select for a mouse mesoangioblast subpopulation in vitro and found that this subpopulation retained self-renewal and myogenic differentiation capacities while notably enhancing cell survival, proliferation and migration relative to unselected cells. Additionally, this subpopulation of cells presented different resistance and recovery properties upon oxidative stress treatment, demonstrating select advantages over parental mesoangioblasts in our experimental analysis. Specifically, the cells were resistant to oxidative environments, demonstrating survival, continuous self-renewal and improved migration capability. The primary outcome of the selected cells was determined in in vivo experiments in which immunocompromised dystrophic mice were injected intramuscularly in the tibialis anterior with selected or non-selected mesoangioblasts. Resistant mesoangioblasts exhibited markedly enhanced survival and integration into the host skeletal muscle, accounting for a more than 70% increase in engraftment compared with that of the unselected mesoangioblast cell population and leading to remarkable muscle recovery. Thus, the positive effects of sorting on mesoangioblast cell behaviour in vitro and in vivo suggest that a selection step involving oxidative stress preconditioning may provide a novel methodology to select for resistant cells for use in regenerative tissue applications to prevent high mortality rates upon transplantation.
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Yin Y, Li X, He XT, Wu RX, Sun HH, Chen FM. Leveraging Stem Cell Homing for Therapeutic Regeneration. J Dent Res 2017; 96:601-609. [PMID: 28414563 DOI: 10.1177/0022034517706070] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Resident stem cell pools in many tissues/organs are responsible not only for tissue maintenance during physiologic turnover but also for the process of wound repair following injury. With inspiration from stem cell trafficking within the body under physiologic and pathologic conditions, recent advances have been made toward inducing stem cell mobilization and directing patients' own cells to sites of interest for treating a broad spectrum of diseases. An evolving body of work corroborates that delivering guidance cues can mobilize stem cells from the bone marrow and drive these cells toward a specific region. In addition, the transplantation of cell-friendly biomaterials incorporating certain biomolecules has led to the regeneration of lost/damaged tissue without the need for delivering cellular materials manipulated ex vivo. Recently, cell homing has resulted in remarkable biological discoveries in the laboratory as well as great curative successes in preclinical scenarios. Here, we review the biological evidence underlying in vivo cell mobilization and homing with the aim of leveraging endogenous reparative cells for therapeutic applications. Considering both the promise and the obstacles of this approach, we discuss how matrix components of the in vivo milieu can be modified to promote the native regenerative process and inspire future tissue-engineering design.
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Affiliation(s)
- Y Yin
- 1 State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, Department of Periodontology, School of Stomatology, Fourth Military Medical University, Xi'an, China
| | - X Li
- 1 State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, Department of Periodontology, School of Stomatology, Fourth Military Medical University, Xi'an, China
| | - X T He
- 1 State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, Department of Periodontology, School of Stomatology, Fourth Military Medical University, Xi'an, China
| | - R X Wu
- 1 State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, Department of Periodontology, School of Stomatology, Fourth Military Medical University, Xi'an, China
| | - H H Sun
- 1 State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, Department of Periodontology, School of Stomatology, Fourth Military Medical University, Xi'an, China
| | - F M Chen
- 1 State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, Department of Periodontology, School of Stomatology, Fourth Military Medical University, Xi'an, China
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