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1
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Qu Y, Liang W, Yu M, Wang C, Luo M, Zhong L, Li Z, Wang F. MYO1F in neutrophils is required for the response to immune checkpoint blockade therapy. J Exp Med 2025; 222:e20241957. [PMID: 40202509 PMCID: PMC11980683 DOI: 10.1084/jem.20241957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 01/29/2025] [Accepted: 02/21/2025] [Indexed: 04/10/2025] Open
Abstract
Tumor-associated neutrophils (TANs) represent a significant barrier to the effectiveness of immune checkpoint blockade (ICB) therapy. A comprehensive understanding of TANs' regulatory mechanisms is therefore essential for predicting ICB efficacy and improving immunotherapy strategies. Our study reveals that MYO1F is selectively downregulated in neutrophils within both human cancers and murine tumor models, showing a negative correlation with ICB response. Mechanistically, MYO1F normally inhibits neutrophil immunosuppression and proliferation by restraining STAT3 activity. However, during tumorigenesis, tumor-derived TGF-β1 disrupts the binding of SPI1 to intron 8 of Myo1f via DNA methylation, thereby suppressing Myo1f transcription. The resultant decrease in MYO1F reprograms neutrophils into an immunosuppressive state through the STAT3-dependent signaling pathways. This immunosuppressive state further contributes to tumor microenvironment (TME) remodeling by inducing CTL exhaustion. These findings establish MYO1F as a critical regulator within TANs, highlighting its significant role in modulating ICB therapy efficacy.
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Affiliation(s)
- Yingying Qu
- Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Children’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Center for Microbiota and Immunological Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenhua Liang
- Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Children’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mingzhu Yu
- Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Children’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chenhui Wang
- The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Min Luo
- Institute of Pediatrics of Children’s Hospital of Fudan University, The Shanghai Key Laboratory of Medical Epigenetics, The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Lin Zhong
- Department of Liver Surgery and Organ Transplantation Center, Shenzhen Third People’s Hospital, Second Affiliated Hospital, Southern University of Science and Technology, Shenzhen, China
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhigang Li
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Feng Wang
- Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Children’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Bakht SM, Pardo A, Gomez‐Florit M, Caballero D, Kundu SC, Reis RL, Domingues RMA, Gomes ME. Human Tendon-on-Chip: Unveiling the Effect of Core Compartment-T Cell Spatiotemporal Crosstalk at the Onset of Tendon Inflammation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2401170. [PMID: 39258510 PMCID: PMC11538684 DOI: 10.1002/advs.202401170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 06/27/2024] [Indexed: 09/12/2024]
Abstract
The lack of representative in vitro models recapitulating human tendon (patho)physiology is among the major factors hindering consistent progress in the knowledge-based development of adequate therapies for tendinopathy.Here, an organotypic 3D tendon-on-chip model is designed that allows studying the spatiotemporal dynamics of its cellular and molecular mechanisms.Combining the synergistic effects of a bioactive hydrogel matrix with the biophysical cues of magnetic microfibers directly aligned on the microfluidic chip, it is possible to recreate the anisotropic architecture, cell patterns, and phenotype of tendon intrinsic (core) compartment. When incorporated with vascular-like vessels emulating the interface between its intrinsic-extrinsic compartments, crosstalk with endothelial cells are found to drive stromal tenocytes toward a reparative profile. This platform is further used to study adaptive immune cell responses at the onset of tissue inflammation, focusing on interactions between tendon compartment tenocytes and circulating T cells.The proinflammatory signature resulting from this intra/inter-cellular communication induces the recruitment of T cells into the inflamed core compartment and confirms the involvement of this cellular crosstalk in positive feedback loops leading to the amplification of tendon inflammation.Overall, the developed 3D tendon-on-chip provides a powerful new tool enabling mechanistic studies on the pathogenesis of tendinopathy as well as for assessing new therapies.
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Affiliation(s)
- Syeda M. Bakht
- 3B's Research Group I3Bs – Research Institute on BiomaterialsBiodegradables and Biomimetics University of Minho Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine AvePark – Parque de Ciência e Tecnologia Zona Industrial da Gandra BarcoGuimarães4805‐017Portugal
- ICVS/3B's – PT Government Associate Laboratory Braga/GuimarãesPortugal
| | - Alberto Pardo
- 3B's Research Group I3Bs – Research Institute on BiomaterialsBiodegradables and Biomimetics University of Minho Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine AvePark – Parque de Ciência e Tecnologia Zona Industrial da Gandra BarcoGuimarães4805‐017Portugal
- ICVS/3B's – PT Government Associate Laboratory Braga/GuimarãesPortugal
- Colloids and Polymers Physics GroupParticle Physics DepartmentMaterials Institute (iMATUS)and Health Research Institute (IDIS)University of Santiago de CompostelaSantiago de Compostela15782Spain
| | | | - David Caballero
- 3B's Research Group I3Bs – Research Institute on BiomaterialsBiodegradables and Biomimetics University of Minho Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine AvePark – Parque de Ciência e Tecnologia Zona Industrial da Gandra BarcoGuimarães4805‐017Portugal
- ICVS/3B's – PT Government Associate Laboratory Braga/GuimarãesPortugal
| | - Subhas C. Kundu
- 3B's Research Group I3Bs – Research Institute on BiomaterialsBiodegradables and Biomimetics University of Minho Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine AvePark – Parque de Ciência e Tecnologia Zona Industrial da Gandra BarcoGuimarães4805‐017Portugal
- ICVS/3B's – PT Government Associate Laboratory Braga/GuimarãesPortugal
| | - Rui L. Reis
- 3B's Research Group I3Bs – Research Institute on BiomaterialsBiodegradables and Biomimetics University of Minho Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine AvePark – Parque de Ciência e Tecnologia Zona Industrial da Gandra BarcoGuimarães4805‐017Portugal
- ICVS/3B's – PT Government Associate Laboratory Braga/GuimarãesPortugal
| | - Rui M. A. Domingues
- 3B's Research Group I3Bs – Research Institute on BiomaterialsBiodegradables and Biomimetics University of Minho Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine AvePark – Parque de Ciência e Tecnologia Zona Industrial da Gandra BarcoGuimarães4805‐017Portugal
- ICVS/3B's – PT Government Associate Laboratory Braga/GuimarãesPortugal
| | - Manuela E. Gomes
- 3B's Research Group I3Bs – Research Institute on BiomaterialsBiodegradables and Biomimetics University of Minho Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine AvePark – Parque de Ciência e Tecnologia Zona Industrial da Gandra BarcoGuimarães4805‐017Portugal
- ICVS/3B's – PT Government Associate Laboratory Braga/GuimarãesPortugal
- School of Medicine and Biomedical Sciences (ICBAS), Unit for Multidisciplinary Research in Biomedicine (UMIB)University of PortoRua Jorge Viterbo Ferreira 228Porto4050‐313 PortoPortugal
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Lv S, Zhu G, Li Q, Zhang J, Tang L. Predicting in vivo therapeutic efficacy of CelTrac1000-labeled hair follicle epidermal neural crest stem cells in models of repairing rat facial nerve defects via second near-infrared fluorescence imaging. Life Sci 2024; 352:122869. [PMID: 38950644 DOI: 10.1016/j.lfs.2024.122869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 06/07/2024] [Accepted: 06/23/2024] [Indexed: 07/03/2024]
Abstract
AIMS To detect the therapeutic efficacy of CelTrac1000-labeled hair follicle epidermal neural crest stem cells (EPI-NCSCs) on repairing facial nerve defects by second near-infrared (NIR-II) fluorescence imaging. MATERIALS AND METHODS Firstly, CelTrac1000-labeled EPI-NCSCs were microinjected into the acellular nerve allografts (ANAs) to bridge a 10-mm-long gap in the buccal branch of facial nerve in adult rats. Then, Celtrac1000-labeled EPI-NCSCs were detected by NIR-II fluorescence imaging system to visualize the behavior of the transplanted cells in vivo. Additionally, the effect of the transplanted EPI-NCSCs on repairing facial nerve defect was examined. KEY FINDINGS Through 14 weeks of dynamic observation, the transplanted EPI-NCSCs survived in the ANAs in vivo after surgery. Meanwhile, the region of the NIR-II fluorescence signals was gradually limited to be consistent with the direction of the regenerative nerve segment. Furthermore, the results of functional and morphological analysis showed that the transplanted EPI-NCSCs could promote the recovery of facial paralysis and neural regeneration after injury. SIGNIFICANCE Our research provides a novel way to track the transplanted cells in preclinical studies of cell therapy for facial paralysis, and demonstrates the therapeutic potential of EPI-NCSCs combined with ANAs in bridging rat facial nerve defects.
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Affiliation(s)
- Shangrui Lv
- Department of Otorhinolaryngology-Head and Neck Surgery, Nanjing Medical University Affiliated Wuxi No 2 People's Hospital, Wuxi, 214002, Jiangsu, China
| | - Guochen Zhu
- Department of Otorhinolaryngology-Head and Neck Surgery, Nanjing Medical University Affiliated Wuxi No 2 People's Hospital, Wuxi, 214002, Jiangsu, China; Department of Otorhinolaryngology-Head and Neck Surgery, Jiangnan University Medical Center, Wuxi, 214002, Jiangsu, China; Department of Otorhinolaryngology-Head and Neck Surgery, Nantong University Affiliated Wuxi Clinical College, Wuxi, 214002, Jiangsu, China.
| | - Qianwen Li
- Department of Otorhinolaryngology-Head and Neck Surgery, Nanjing Medical University Affiliated Wuxi No 2 People's Hospital, Wuxi, 214002, Jiangsu, China
| | - Jing Zhang
- Department of Otorhinolaryngology-Head and Neck Surgery, Nantong University Affiliated Wuxi Clinical College, Wuxi, 214002, Jiangsu, China
| | - Li Tang
- Department of Otorhinolaryngology-Head and Neck Surgery, Nanjing Medical University Affiliated Wuxi No 2 People's Hospital, Wuxi, 214002, Jiangsu, China
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4
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Mishra A, Kumar R, Harilal S, Nigam M, Datta D, Singh S. Emerging Landscape of In Vitro Models for Assessing Rheumatoid Arthritis Management. ACS Pharmacol Transl Sci 2024; 7:2280-2305. [PMID: 39144547 PMCID: PMC11320735 DOI: 10.1021/acsptsci.4c00260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 06/23/2024] [Accepted: 06/24/2024] [Indexed: 08/16/2024]
Abstract
Rheumatoid arthritis (RA) is a complex condition that is influenced by various causes, including immunological, genetic, and environmental factors. Several studies using animal models have documented immune system dysfunction and described the clinical characteristics of the disease. These studies have provided valuable insights into the pathogenesis of inflammatory arthritis and the identification of new targets for treatment. Nevertheless, none of these animal models successfully replicated all the characteristics of RA. Additionally, numerous experimental medications, which were developed based on our enhanced comprehension of the immune system's function in RA, have shown potential in animal research but ultimately proved ineffective during different stages of clinical trials. There have been several novel therapy alternatives, which do not achieve a consistently outstanding therapeutic outcome in all patients. This underscores the importance of employing the progress in in vitro models, particularly 3D models like tissue explants, and diverse multicomponent approaches such as coculture strategies, synovial membrane, articular cartilage, and subchondral bone models that accurately replicate the structural characteristics of RA pathophysiology. These methods are crucial for the advancement of potential therapeutic strategies. This review discusses the latest advancements in in vitro models and their potential to greatly impact research on managing RA.
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Affiliation(s)
- Abhay
Prakash Mishra
- Department
of Pharmacology, University of Free State, Bloemfontein 9301, South Africa
- Department
of Pharmaceutical Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Rajesh Kumar
- Faculty
of Pharmaceutical Sciences, Kerala University
of Health Sciences, Kerala 680596, India
| | - Seetha Harilal
- Faculty
of Pharmaceutical Sciences, Kerala University
of Health Sciences, Kerala 680596, India
| | - Manisha Nigam
- Department
of Biochemistry, Hemvati Nandan Bahuguna
Garhwal University, Srinagar
Garhwal, Uttarakhand 246174, India
| | - Deepanjan Datta
- Department
of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Sudarshan Singh
- Office of
Research Administration, Chiang Mai University, Chiang Mai 50200, Thailand
- Faculty of
Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand
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Casadei M, Miguel B, Rubione J, Fiore E, Mengelle D, Guerri-Guttenberg RA, Montaner A, Villar MJ, Constandil-Córdova L, Romero-Sandoval AE, Brumovsky PR. Mesenchymal Stem Cell Engagement Modulates Neuroma Microenviroment in Rats and Humans and Prevents Postamputation Pain. THE JOURNAL OF PAIN 2024; 25:104508. [PMID: 38484854 PMCID: PMC11283994 DOI: 10.1016/j.jpain.2024.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 03/05/2024] [Accepted: 03/06/2024] [Indexed: 04/11/2024]
Abstract
Postamputation pain is currently managed unsatisfactorily with neuron-targeted pharmacological and interventional therapies. Non-neuronal pain mechanisms have emerged as crucial factors in the development and persistence of postamputation pain. Consequently, these mechanisms offer exciting prospects as innovative therapeutic targets. We examined the hypothesis that engaging mesenchymal stem cells (MSCs) would foster local neuroimmune interactions, leading to a potential reduction in postamputation pain. We utilized an ex vivo neuroma model from a phantom limb pain patient to uncover that the oligodeoxynucleotide IMT504 engaged human primary MSCs to promote an anti-inflammatory microenvironment. Reverse translation experiments recapitulated these effects. Thus, in an in vivo rat model, IMT504 exhibited strong efficacy in preventing autotomy (self-mutilation) behaviors. This effect was linked to a substantial accumulation of MSCs in the neuroma and associated dorsal root ganglia and the establishment of an anti-inflammatory phenotype in these compartments. Centrally, this intervention reduced glial reactivity in the dorsal horn spinal cord, demonstrating diminished nociceptive activity. Accordingly, the exogenous systemic administration of MSCs phenocopied the behavioral effects of IMT504. Our findings underscore the mechanistic relevance of MSCs and the translational therapeutic potential of IMT504 to engage non-neuronal cells for the prevention of postamputation pain. PERSPECTIVE: The present study suggests that IMT504-dependent recruitment of endogenous MSCs within severely injured nerves may prevent post-amputation pain by modifying the inflammatory scenario at relevant sites in the pain pathway. Reinforcing data in rat and human tissues supports the potential therapeutic value of IMT504 in patients suffering postamputation pain.
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Affiliation(s)
- Mailín Casadei
- Instituto de Investigaciones en Medicina Traslacional, CONICET-Universidad Austral, Buenos Aires, Argentina, B1629AHJ
| | - Bernardo Miguel
- Instituto de Investigaciones en Medicina Traslacional, CONICET-Universidad Austral, Buenos Aires, Argentina, B1629AHJ
| | - Julia Rubione
- Instituto de Investigaciones en Medicina Traslacional, CONICET-Universidad Austral, Buenos Aires, Argentina, B1629AHJ
| | - Esteban Fiore
- Instituto de Investigaciones en Medicina Traslacional, CONICET-Universidad Austral, Buenos Aires, Argentina, B1629AHJ
| | - Diego Mengelle
- Hospital Universitario Austral, Universidad Austral, Buenos Aires, Argentina, B1629AHJ
| | | | - Alejandro Montaner
- Instituto de Ciencia y Tecnología “César Milstein”, CONICET-Fundación Pablo Cassará, Buenos Aires, Argentina, C1440FFX
| | - Marcelo J. Villar
- Instituto de Investigaciones en Medicina Traslacional, CONICET-Universidad Austral, Buenos Aires, Argentina, B1629AHJ
| | | | | | - Pablo R. Brumovsky
- Instituto de Investigaciones en Medicina Traslacional, CONICET-Universidad Austral, Buenos Aires, Argentina, B1629AHJ
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Zaripova LN, Midgley A, Christmas SE, Beresford MW, Pain C, Baildam EM, Oldershaw RA. Mesenchymal Stem Cells in the Pathogenesis and Therapy of Autoimmune and Autoinflammatory Diseases. Int J Mol Sci 2023; 24:16040. [PMID: 38003230 PMCID: PMC10671211 DOI: 10.3390/ijms242216040] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 10/27/2023] [Accepted: 10/31/2023] [Indexed: 11/26/2023] Open
Abstract
Mesenchymal stem cells (MSCs) modulate immune responses and maintain self-tolerance. Their trophic activities and regenerative properties make them potential immunosuppressants for treating autoimmune and autoinflammatory diseases. MSCs are drawn to sites of injury and inflammation where they can both reduce inflammation and contribute to tissue regeneration. An increased understanding of the role of MSCs in the development and progression of autoimmune disorders has revealed that MSCs are passive targets in the inflammatory process, becoming impaired by it and exhibiting loss of immunomodulatory activity. MSCs have been considered as potential novel cell therapies for severe autoimmune and autoinflammatory diseases, which at present have only disease modifying rather than curative treatment options. MSCs are emerging as potential therapies for severe autoimmune and autoinflammatory diseases. Clinical application of MSCs in rare cases of severe disease in which other existing treatment modalities have failed, have demonstrated potential use in treating multiple diseases, including rheumatoid arthritis, systemic lupus erythematosus, myocardial infarction, liver cirrhosis, spinal cord injury, multiple sclerosis, and COVID-19 pneumonia. This review explores the biological mechanisms behind the role of MSCs in autoimmune and autoinflammatory diseases. It also covers their immunomodulatory capabilities, potential therapeutic applications, and the challenges and risks associated with MSC therapy.
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Affiliation(s)
- Lina N. Zaripova
- Institute of Fundamental and Applied Medicine, National Scientific Medical Center, 42 Abylai Khan Avenue, Astana 010000, Kazakhstan;
- Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of Liverpool, William Henry Duncan Building, 6 West Derby Street, Liverpool L7 8TX, UK
| | - Angela Midgley
- Department of Women and Children’s Health, Institute of Life Course and Medical Sciences, University of Liverpool, Institute in the Park, Alder Hey Children’s NHS Foundation Trust, Liverpool L14 5AB, UK; (A.M.); (M.W.B.); (C.P.)
| | - Stephen E. Christmas
- Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, Faculty of Health and Life Sciences, University of Liverpool, The Ronald Ross Building, 8 West Derby Street, Liverpool L69 7BE, UK;
| | - Michael W. Beresford
- Department of Women and Children’s Health, Institute of Life Course and Medical Sciences, University of Liverpool, Institute in the Park, Alder Hey Children’s NHS Foundation Trust, Liverpool L14 5AB, UK; (A.M.); (M.W.B.); (C.P.)
- Department of Paediatric Rheumatology, Alder Hey Children’s NHS Foundation Trust, East Prescott Road, Liverpool L14 5AB, UK
| | - Clare Pain
- Department of Women and Children’s Health, Institute of Life Course and Medical Sciences, University of Liverpool, Institute in the Park, Alder Hey Children’s NHS Foundation Trust, Liverpool L14 5AB, UK; (A.M.); (M.W.B.); (C.P.)
- Department of Paediatric Rheumatology, Alder Hey Children’s NHS Foundation Trust, East Prescott Road, Liverpool L14 5AB, UK
| | - Eileen M. Baildam
- Department of Paediatric Rheumatology, The Alexandra Hospital, Mill Lane, Cheadle SK8 2PX, UK;
| | - Rachel A. Oldershaw
- Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of Liverpool, William Henry Duncan Building, 6 West Derby Street, Liverpool L7 8TX, UK
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7
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Chiu YH, Liang YH, Hwang JJ, Wang HS. IL-1β stimulated human umbilical cord mesenchymal stem cells ameliorate rheumatoid arthritis via inducing apoptosis of fibroblast-like synoviocytes. Sci Rep 2023; 13:15344. [PMID: 37714911 PMCID: PMC10504325 DOI: 10.1038/s41598-023-42585-1] [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: 03/07/2023] [Accepted: 09/12/2023] [Indexed: 09/17/2023] Open
Abstract
Rheumatoid arthritis (RA) is characterized by synovial proliferation and lymphocyte accumulation leading to progressive damage of the periarticular bone and the articular cartilage. The hyperplasia of the synovial intima lining mainly consists of fibroblast-like synoviocytes-rheumatoid arthritis (HFLS-RA) which exhibit apoptosis-resistance, hyper-proliferation, and high invasiveness. The therapeutic efficacy of mesenchymal stem cells (MSCs) treatment in RA has been shown to be due to its immuno-regulatory ability. However, the exact factors and mechanisms involved in MSCs treatment in RA remain unclear. In this study, TRAIL receptor-Death receptor 4 (DR4), DR5, and LFA-1 ligand-intercellular adhesion molecule-1 (ICAM-1) were upregulated in IL-1β-stimulated HFLS-RA. We demonstrated that the total cell number of IL-1β-stimulated hUCMSCs adhering to IL-1β-stimulated HFLA-RA increased via LFA-1/ICAM-1 interaction. Direct co-culture of IL-1β-stimulated hUCMSCs with IL-1β-stimulated HFLS-RA increased the apoptosis of HFLS-RA. RA symptoms in the CIA mouse model improved after administration of IL-1β-stimulated hUCMSCs. In conclusion, IL-1β-stimulated hUCMSCs adhering to HFLS-RA occurred via LFA-1/ICAM-1 interaction, apoptosis of HFLS-RA was induced via TRAIL/DR4, DR5 contact, and RA symptoms and inflammation were significantly improved in a CIA mouse model. The results of this study suggest that IL-1β-stimulated hUCMSCs have therapeutic potential in RA treatment.
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Affiliation(s)
- Yun-Hsuan Chiu
- Institute of Anatomy and Cell Biology, School of Medicine, National Yang Ming Chiao Tung University, Peitou, Taipei, 112, Taiwan, ROC
| | - Ya-Han Liang
- Institute of Anatomy and Cell Biology, School of Medicine, National Yang Ming Chiao Tung University, Peitou, Taipei, 112, Taiwan, ROC
| | - Jeng-Jong Hwang
- Department of Medical Imaging, Chung Shan Medical University Hospital affiliated with Medical Imaging and Radiological Sciences, Chung Shan Medical University, Taichung, 402, Taiwan, ROC
| | - Hwai-Shi Wang
- Institute of Anatomy and Cell Biology, School of Medicine, National Yang Ming Chiao Tung University, Peitou, Taipei, 112, Taiwan, ROC.
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8
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Yu S, Yu S, Liu H, Liao N, Liu X. Enhancing mesenchymal stem cell survival and homing capability to improve cell engraftment efficacy for liver diseases. Stem Cell Res Ther 2023; 14:235. [PMID: 37667383 PMCID: PMC10478247 DOI: 10.1186/s13287-023-03476-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 08/25/2023] [Indexed: 09/06/2023] Open
Abstract
Although mesenchymal stem cell (MSC) transplantation provides an alternative strategy for end-stage liver disease (ESLD), further widespread application of MSC therapy is limited owing to low cell engraftment efficiency. Improving cell engraftment efficiency plays a critical role in enhancing MSC therapy for liver diseases. In this review, we summarize the current status and challenges of MSC transplantation for ESLD. We also outline the complicated cell-homing process and highlight how low cell engraftment efficiency is closely related to huge differences in extracellular conditions involved in MSC homing journeys ranging from constant, controlled conditions in vitro to variable and challenging conditions in vivo. Improving cell survival and homing capabilities enhances MSC engraftment efficacy. Therefore, we summarize the current strategies, including hypoxic priming, drug pretreatment, gene modification, and cytokine pretreatment, as well as splenectomy and local irradiation, used to improve MSC survival and homing capability, and enhance cell engraftment and therapeutic efficiency of MSC therapy. We hope that this review will provide new insights into enhancing the efficiency of MSC engraftment in liver diseases.
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Affiliation(s)
- Shaoxiong Yu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People's Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, People's Republic of China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025, People's Republic of China
| | - Saihua Yu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People's Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, People's Republic of China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025, People's Republic of China
| | - Haiyan Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People's Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, People's Republic of China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025, People's Republic of China
| | - Naishun Liao
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People's Republic of China.
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, People's Republic of China.
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025, People's Republic of China.
| | - Xiaolong Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People's Republic of China.
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, People's Republic of China.
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025, People's Republic of China.
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9
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Diamond T, Lau M, Morrissette J, Chu N, Behrens EM. CXCL9 inhibition does not ameliorate disease in murine models of both primary and secondary hemophagocytic lymphohistiocytosis. Sci Rep 2023; 13:12298. [PMID: 37516815 PMCID: PMC10387083 DOI: 10.1038/s41598-023-39601-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Accepted: 07/27/2023] [Indexed: 07/31/2023] Open
Abstract
Hemophagocytic Lymphohistiocytosis (HLH) is a group of disorders culminating in systemic inflammation and multi-organ failure with high incidence of hepatic dysfunction. Overproduction of IFN-γ is the main immunopathological driver in this disorder. Monokine induced by IFN-γ (CXCL9) serves as a biomarker for disease activity and response to treatment in this disorder. However, very little is understood about the actual functional role of CXCL9 in pathogenesis in HLH. In the current study, we sought to determine the role of CXCL9 in pathogenesis in murine models of both Familial HLH (prf1-/-) and Toll Like Receptor (TLR) 9 repeated stimulation induced Macrophage Activation Syndrome (MAS), a form of secondary HLH. FHL and MAS were induced in both CXCL9 genetically deficient mice (cxcl9-/-) and controls as well as using AMG487, a pharmacological antagonist of the CXCL9 receptor, CXCR3. Results showed that CXCL9 genetic deficiency did not improve disease parameters or hepatitis in both models. Consistent with genetic ablation of CXCL9, inhibition of its receptor, CXCR3, by AMG487 did not show any significant effects in the FHL model. Taken together, inhibition of CXCL9-CXCR3 interaction does not ameliorate HLH physiology in general, or hepatitis as a classical target organ of disease.
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Affiliation(s)
- Tamir Diamond
- Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
- Department of Pediatrics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
| | - Michelle Lau
- Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Jeremy Morrissette
- Department of Immunology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | - Niansheng Chu
- Division of Rheumatology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Edward M Behrens
- Department of Pediatrics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Division of Rheumatology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
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10
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Li X, Li X, Yang J, Lin J, Zhu Y, Xu X, Cui W. Living and Injectable Porous Hydrogel Microsphere with Paracrine Activity for Cartilage Regeneration. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2207211. [PMID: 36651038 DOI: 10.1002/smll.202207211] [Citation(s) in RCA: 55] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 12/31/2022] [Indexed: 06/17/2023]
Abstract
Paracrine is an important mechanism in mesenchymal stem cells (MSCs) that promotes tissue regeneration. However, anoikis is attributed to unsuitable adhesion microenvironment hindered this paracrine effect. In this study, a living and injectable porous hydrogel microsphere with long-term paracrine activity is constructed via the freeze-drying microfluidic technology and the incorporation of platelet-derived growth factor-BB (PDGF-BB) and exogenous MSCs. Benefiting from the porous structure and superior mechanical property of methacrylate gelatin (GelMA) hydrogel microspheres (GMs), exogenous stem cells are able to adhere and proliferate on GMs, thereby facilitating cell-to-extracellular matrix (ECM) and cell-to-cell interactions and enhancing paracrine effect. Furthermore, the sustained release of PDGF-BB can recruit endogenous MSCs to prolong the paracrine activity of the living GMs. In vitro and in vivo experiments validated that the living GMs exhibit superior secretion properties and anti-inflammatory efficacy and can attenuate osteoarthritis (OA) progression by favoring the adherent microenvironment and utilizing the synergistic effect of exogenous and endogenous MSCs. Overall, a living injectable porous hydrogel microsphere that can enhance the paracrine activity of stem cells is fabricated and anticipated to hold the potential of future clinical translation in OA and other diseases.
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Affiliation(s)
- Xingchen Li
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, P. R. China
| | - Xiaoxiao Li
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, P. R. China
| | - Jielai Yang
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, P. R. China
| | - Jiawei Lin
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, P. R. China
| | - Yuan Zhu
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, P. R. China
| | - Xiangyang Xu
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, P. R. China
| | - Wenguo Cui
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, P. R. China
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11
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Honokiol inhibits interleukin-induced angiogenesis in the NSCLC microenvironment through the NF-κB signaling pathway. Chem Biol Interact 2023; 370:110295. [PMID: 36470525 DOI: 10.1016/j.cbi.2022.110295] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 11/13/2022] [Accepted: 11/28/2022] [Indexed: 12/04/2022]
Abstract
Tumor angiogenesis, which may be affected by microenvironmental inflammation and promotes tumor development and metastasis, is one of the key reasons contributing to increased mortality. The goal of this study is to investigate how lignin analogs, specifically honokiol (HNK), block angiogenesis induced by the inflammatory milieu of lung cancer. The human lung cancer cell lines A549 and H460 were treated with HNK. Interleukin-1 was employed to mimic an inflammatory tumor microenvironment. Findings demonstrated that HNK drastically decreased the cell viability of A549 and H460 cells. In A549 and H460 cells, HNK also reduced the production of vascular endothelial growth factor (VEGF), the most important marker of tumor angiogenesis. Signal pathway studies revealed that HNK blocked the NF-κB signaling pathway. This effect, in turn, prevented the expression of VEGF by inhibiting the NF-κB signaling pathway. Human umbilical vein endothelial cells (HUVECs) from A549-conditioned medium cultures were subjected to HNK treatment, which decreased tubulogenesis, horizontal and vertical migration, and cell proliferation in HUVECs. Overall, HNK inhibited the NF-κB pathway. This effect resulted in the downregulation of VEGF, thus reducing the viability and angiogenesis of human lung cancer cell lines. In A549 cell xenografts, HNK decreased VEGF expression, tumor angiogenesis, and tumor development. Our research shows that HNK is a potential antiangiogenic molecule for the treatment of lung cancer.
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12
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Cervera L, González-Fernández C, Cano D, Esteban MÁ, Mercado L, Chaves-Pozo E, Cuesta A. Immunity elicited by AMP-encoding plasmids fails to increase the protection of European sea bass against nodavirus. FISH & SHELLFISH IMMUNOLOGY 2023; 132:108507. [PMID: 36581252 DOI: 10.1016/j.fsi.2022.108507] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 12/20/2022] [Accepted: 12/22/2022] [Indexed: 06/17/2023]
Abstract
Antimicrobial peptides (AMPs) are a potent arm of the innate immune system that can directly kill pathogens and induce immunomodulation. In the marine aquaculture, European sea bass (Dicentrarchus labrax L.) is one of the most prosperous species but is highly susceptible to nodavirus (NNV), which produces high rates of mortality in larvae and juvenile stages. Thus, we aimed to evaluate whether AMPs exert immunomodulatory and/or NNV-preventive actions in sea bass. To do this, plasmids encoding the sea bass AMPs dicentracin (pDIC), beta-defensin (pDB1), hepcidin (pHAMP2) or NK-lysin (pNKL) were generated and intramuscularly injected into sea bass juveniles to evaluate their immunomodulatory and anti-NNV roles. Sea bass muscle transcribes the AMPs and produces an increase in their circulating levels, along with an increase of the antibacterial activity. Immune-related gene analysis revealed a great activation of the inflammatory response and the recruitment of neutrophilic granulocytes at the site of injection. However, AMP-encoding plasmids, namely pHAMP2, negatively affected to NNV disease by increasing fish mortality. In conclusion, plasmids encoding AMPs show immunostimulatory effects on European sea bass but do not improve the resistance to NNV.
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Affiliation(s)
- Laura Cervera
- Immunobiology for Aquaculture Group, Department of Cell Biology and Histology, Faculty of Biology, Regional Campus of International Excellence "Campus Mare Nostrum", University of Murcia, 30100, Murcia, Spain
| | - Carmen González-Fernández
- Immunobiology for Aquaculture Group, Department of Cell Biology and Histology, Faculty of Biology, Regional Campus of International Excellence "Campus Mare Nostrum", University of Murcia, 30100, Murcia, Spain
| | - Daniela Cano
- Immunobiology for Aquaculture Group, Department of Cell Biology and Histology, Faculty of Biology, Regional Campus of International Excellence "Campus Mare Nostrum", University of Murcia, 30100, Murcia, Spain
| | - M Ángeles Esteban
- Immunobiology for Aquaculture Group, Department of Cell Biology and Histology, Faculty of Biology, Regional Campus of International Excellence "Campus Mare Nostrum", University of Murcia, 30100, Murcia, Spain
| | - Luis Mercado
- Grupo de Marcadores Inmunológicos, Laboratorio de Genética e Inmunología Molecular, Instituto de Biología, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile
| | - Elena Chaves-Pozo
- Oceanographic Centre of Murcia, Spanish Institute of Oceanography, Spanish National Research Council (IEO-CSIC), Carretera de la Azohía s/n, Puerto de Mazarrón, 30860, Murcia, Spain
| | - Alberto Cuesta
- Immunobiology for Aquaculture Group, Department of Cell Biology and Histology, Faculty of Biology, Regional Campus of International Excellence "Campus Mare Nostrum", University of Murcia, 30100, Murcia, Spain.
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13
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Ling L, Hou J, Wang Y, Shu H, Huang Y. Effects of Low-Intensity Pulsed Ultrasound on the Migration and Homing of Human Amnion-Derived Mesenchymal Stem Cells to Ovaries in Rats With Premature Ovarian Insufficiency. Cell Transplant 2022; 31:9636897221129171. [PMID: 36282038 PMCID: PMC9608022 DOI: 10.1177/09636897221129171] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Premature ovarian insufficiency (POI) can cause multiple sequelae and is currently incurable. Mesenchymal stem cell (MSC) transplantation might provide an effective treatment method for POI. However, the clinical application of systemic MSC transplantation is limited by the low efficiency of cell homing to target tissue in vivo, including systemic MSC transplantation for POI treatment. Thus, exploration of methods to promote MSC homing is necessary. This study was to investigate the effects of low-intensity pulsed ultrasound (LIPUS) on the migration and homing of transplanted human amnion–derived MSCs (hAD-MSCs) to ovaries in rats with chemotherapy-induced POI. For LIPUS treatment, hAD-MSCs were exposed to LIPUS or sham irradiation. Chemokine receptor expressions in hAD-MSCs were detected by polymerase chain reaction (PCR), Western blot, and immunofluorescence assays. hAD-MSC migration was detected by wound healing and transwell migration assays. Cyclophosphamide-induced POI rat models were established to evaluate the effects of LIPUS on the homing of systemically transplanted hAD-MSCs to chemotherapy-induced POI ovaries in vivo. We found that hAD-MSCs expressed chemokine receptors. The LIPUS promoted the expression of chemokine receptors, especially CXCR4, in hAD-MSCs. SDF-1 induced hAD-MSC migration. The LIPUS promoted hAD-MSC migration induced by SDF-1 through SDF-1/CXCR4 axis. SDF-1 levels significantly increased in ovaries induced by chemotherapy in POI rats. Pretreating hAD-MSCs with LIPUS increased the number of hAD-MSCs homing to ovaries in rats with chemotherapy-induced POI to some extent. However, the difference was not significant. Both hAD-MSC and LIPUS-pretreated hAD-MSC transplantation reduced ovarian injuries and improved ovarian function in rats with chemotherapy-induced POI. CXCR4 antagonist significantly reduced the number of hAD-MSCs- and LIPUS-pretreated hAD-MSCs homing to POI ovaries, and further reduced their efficacy in POI treatment. According to these findings, pretreating MSCs with LIPUS before transplantation might provide a novel, convenient, and safe technique to explore for improving the homing of systemically transplanted MSCs to target tissue.
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Affiliation(s)
- Li Ling
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China,Li Ling, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, No. 74, Linjiang Road, Chongqing 400010, China.
| | - Jiying Hou
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yan Wang
- State Key Laboratory of Ultrasound Engineering in Medicine Co-founded by Chongqing and the Ministry of Science and Technology, Chongqing Key Laboratory of Biomedical Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, China
| | - Han Shu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yubin Huang
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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14
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Shi MY, Liu L, Yang FY. Strategies to improve the effect of mesenchymal stem cell therapy on inflammatory bowel disease. World J Stem Cells 2022; 14:684-699. [PMID: 36188115 PMCID: PMC9516464 DOI: 10.4252/wjsc.v14.i9.684] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 07/07/2022] [Accepted: 09/07/2022] [Indexed: 02/07/2023] Open
Abstract
Inflammatory bowel disease (IBD) includes Crohn’s disease and ulcerative colitis and is an idiopathic, chronic inflammatory disease of the colonic mucosa. The occurrence of IBD, causes irreversible damage to the colon and increases the risk of carcinoma. The routine clinical treatment of IBD includes drug treatment, endoscopic treatment and surgery. The vast majority of patients are treated with drugs and biological agents, but the complete cure of IBD is difficult. Mesenchymal stem cells (MSCs) have become a new type of cell therapy for the treatment of IBD due to their immunomodulatory and nutritional functions, which have been confirmed in many clinical trials. This review discusses some potential mechanisms of MSCs in the treatment of IBD, summarizes the experimental results, and provides new insights to enhance the therapeutic effects of MSCs in future applications.
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Affiliation(s)
- Meng-Yue Shi
- School of Medicine, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Lian Liu
- Department of Pharmacology, Medical School of Yangtze University, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Fu-Yuan Yang
- Health Science Center, Yangtze University, Jingzhou 434020, Hubei Province, China
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15
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Lari S, Hiyari S, de Araújo Silva DN, de Brito Bezerra B, Ishii M, Monajemzadeh S, Cui ZK, Tetradis S, Lee M, Pirih FQ. Local delivery of a CXCR3 antagonist decreases the progression of bone resorption induced by LPS injection in a murine model. Clin Oral Investig 2022; 26:5163-5169. [PMID: 35462591 PMCID: PMC9710470 DOI: 10.1007/s00784-022-04484-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Accepted: 04/05/2022] [Indexed: 02/03/2023]
Abstract
OBJECTIVES This experimental study was carried out to investigate the effects of locally delivered nanoparticles (AMG-487 NP) containing a CXCR3 antagonist in inhibiting the progression of LPS-induced inflammation, osteoclastic activity, and bone resorption on a murine model. MATERIALS AND METHODS Thirty, 7-week-old C57BL/6 J male mice were used. Inflammatory bone loss was induced by Porphyromonas gingivalis-lipopolysaccharide (P.g.-LPS) injections between the first and second maxillary molars, bilaterally, twice a week for 6 weeks (n = 20). AMG-487 NP were incorporated into a liposome carrier and locally delivered on sites where P.g.-LPS was injected. Control mice (n = 10) were injected with vehicle only. Experimental groups included (1) control, (2) LPS, and (3) LPS + NP. At the end of 1 and 6 weeks, mice were euthanized, maxillae harvested, fixed, and stored for further analysis. RESULTS Volumetric bone loss analysis revealed, at 1 week, an increase in bone loss in the LPS group (47.9%) compared to control (27.4%) and LPS + NP (27.8%) groups. H&E staining demonstrated reduced inflammatory infiltrate in the LPS + NP group compared to LPS group. At 6 weeks, volumetric bone loss increased in all groups; however, treatment with the CXCR3 antagonist (LPS + NP) significantly reduced bone loss compared to the LPS group. CXCR3 antagonist treatment significantly reduced osteoclast numbers when compared to LPS group at 1 and 6 weeks. CONCLUSIONS This study showed that local delivery of a CXCR antagonist, via nanoparticles, in a bone resorption model, induced by LPS injection, was effective in reducing inflammation, osteoclast numbers, and bone loss. CLINICAL RELEVANCE CXCR3 blockade can be regarded as a novel target for therapeutic intervention of bone loss. It can be a safe and convenient method for periodontitis treatment or prevention applicable in clinical practice.
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Affiliation(s)
- Soma Lari
- School of Dentistry, Section of Periodontics, University of California, Los Angeles, Los Angeles, Los Angeles, CA, USA
| | - Sarah Hiyari
- School of Dentistry, Section of Periodontics, University of California, Los Angeles, Los Angeles, Los Angeles, CA, USA
| | - Davi Neto de Araújo Silva
- School of Dentistry, Section of Periodontics, University of California, Los Angeles, Los Angeles, Los Angeles, CA, USA
- Dentistry Department, Rio Grande do Norte Federal University, Natal, RN, Brazil
| | - Beatriz de Brito Bezerra
- School of Dentistry, Section of Periodontics, University of California, Los Angeles, Los Angeles, Los Angeles, CA, USA
| | - Makiko Ishii
- Division of Periodontology, Department of Oral Biology and Tissue Engineering, Meikai University School of Dentistry, Urayasu, Japan
| | - Sepehr Monajemzadeh
- School of Dentistry, Section of Periodontics, University of California, Los Angeles, Los Angeles, Los Angeles, CA, USA
| | - Zhong-Kai Cui
- Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Sotirios Tetradis
- School of Dentistry, Section of Oral Radiology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Min Lee
- School of Dentistry, Section of Biomaterials Science, University of California, Los Angeles, Los Angeles, CA, USA
| | - Flavia Q Pirih
- School of Dentistry, Section of Periodontics, University of California, Los Angeles, Los Angeles, Los Angeles, CA, USA.
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16
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Chen K, Gao H, Yao Y. Prospects of cell chemotactic factors in bone and cartilage tissue engineering. Expert Opin Biol Ther 2022; 22:883-893. [PMID: 35668707 DOI: 10.1080/14712598.2022.2087471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
- Ke Chen
- Department of Joint Surgery, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
- Guangdong Key Laboratory of Orthopedic Technology and Implant Materials
| | - Hui Gao
- Department of Joint Surgery, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
- Guangdong Key Laboratory of Orthopedic Technology and Implant Materials
| | - Yongchang Yao
- Department of Joint Surgery, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
- Guangdong Key Laboratory of Orthopedic Technology and Implant Materials
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17
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Intracerebroventricular Administration of Human Umbilical Cord Blood—Derived Mesenchymal Stem Cells Induces Transient Inflammation in a Transgenic Mouse Model and Patients with Alzheimer’s Disease. Biomedicines 2022; 10:biomedicines10030563. [PMID: 35327365 PMCID: PMC8945031 DOI: 10.3390/biomedicines10030563] [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: 01/17/2022] [Revised: 02/22/2022] [Accepted: 02/26/2022] [Indexed: 11/17/2022] Open
Abstract
Previously we conducted a Phase I/IIa clinical trial in nine patients with mild to moderate Alzheimer’s disease (AD). Unexpectedly, all patients who were given injections of human-umbilical cord-blood-derived mesenchymal stem cells (hUCB-MSCs) developed fever which subsided after 24 h. Several possible causes of transient fever include bacterial infection, inflammatory reaction from the cell culture media composition, or the cells themselves. To delineate these causes, first we compared the levels of several cytokines in the cerebrospinal fluid (CSF) of AD patients who received saline (placebo) or hUCB-MSC injections, respectively. Compared to the placebo group, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and c-reactive protein (CRP) levels were increased in the hUCB-MSC group. Negative bacterial culture results of the CSF samples and the fact that the same hUCB-MSC administration procedure was used for both the placebo and hUCB-MSC groups ruled out the bacterial infection hypothesis. However, it was not yet clear as to whether the transplanted cells or the composition of the cell culture media generated the transient fever. Therefore, we carried out intracerebroventricular (ICV) injections of hUCB-MSCs in a 5xFAD mouse model of AD. Interestingly, we discovered that pro-inflammatory cytokine levels were higher in the hUCB-MSC group. Taken together, our data suggest that the cause of transient inflammatory response observed from both the clinical trial and mouse study was due to the transplanted hUCB-MSCs.
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18
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Zeynaloo E, Stone LD, Dikici E, Ricordi C, Deo SK, Bachas LG, Daunert S, Lanzoni G. Delivery of therapeutic agents and cells to pancreatic islets: Towards a new era in the treatment of diabetes. Mol Aspects Med 2022; 83:101063. [PMID: 34961627 PMCID: PMC11328325 DOI: 10.1016/j.mam.2021.101063] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 12/09/2021] [Accepted: 12/13/2021] [Indexed: 02/07/2023]
Abstract
Pancreatic islet cells, and in particular insulin-producing beta cells, are centrally involved in the pathogenesis of diabetes mellitus. These cells are of paramount importance for the endocrine control of glycemia and glucose metabolism. In Type 1 Diabetes, islet beta cells are lost due to an autoimmune attack. In Type 2 Diabetes, beta cells become dysfunctional and insufficient to counterbalance insulin resistance in peripheral tissues. Therapeutic agents have been developed to support the function of islet cells, as well as to inhibit deleterious immune responses and inflammation. Most of these agents have undesired effects due to systemic administration and off-target effects. Typically, only a small fraction of therapeutic agent reaches the desired niche in the pancreas. Because islets and their beta cells are scattered throughout the pancreas, access to the niche is limited. Targeted delivery to pancreatic islets could dramatically improve the therapeutic effect, lower the dose requirements, and lower the side effects of agents administered systemically. Targeted delivery is especially relevant for those therapeutics for which the manufacturing is difficult and costly, such as cells, exosomes, and microvesicles. Along with therapeutic agents, imaging reagents intended to quantify the beta cell mass could benefit from targeted delivery. Several methods have been developed to improve the delivery of agents to pancreatic islets. Intra-arterial administration in the pancreatic artery is a promising surgical approach, but it has inherent risks. Targeted delivery strategies have been developed based on ligands for cell surface molecules specific to islet cells or inflamed vascular endothelial cells. Delivery methods range from nanocarriers and vectors to deliver pharmacological agents to viral and non-viral vectors for the delivery of genetic constructs. Several strategies demonstrated enhanced therapeutic effects in diabetes with lower amounts of therapeutic agents and lower off-target side effects. Microvesicles, exosomes, polymer-based vectors, and nanocarriers are gaining popularity for targeted delivery. Notably, liposomes, lipid-assisted nanocarriers, and cationic polymers can be bioengineered to be immune-evasive, and their advantages to transport cargos into target cells make them appealing for pancreatic islet-targeted delivery. Viral vectors have become prominent tools for targeted gene delivery. In this review, we discuss the latest strategies for targeted delivery of therapeutic agents and imaging reagents to pancreatic islet cells.
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Affiliation(s)
- Elnaz Zeynaloo
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Chemistry, University of Miami, FL, USA.
| | - Logan D Stone
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
| | - Emre Dikici
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA; Dr. John T. Macdonald Foundation Biomedical Nanotechnology Institute - BioNIUM at University of Miami, Miami, FL, USA
| | - Camillo Ricordi
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Sapna K Deo
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA; Dr. John T. Macdonald Foundation Biomedical Nanotechnology Institute - BioNIUM at University of Miami, Miami, FL, USA
| | - Leonidas G Bachas
- Department of Chemistry, University of Miami, FL, USA; Dr. John T. Macdonald Foundation Biomedical Nanotechnology Institute - BioNIUM at University of Miami, Miami, FL, USA
| | - Sylvia Daunert
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA; Dr. John T. Macdonald Foundation Biomedical Nanotechnology Institute - BioNIUM at University of Miami, Miami, FL, USA; Clinical and Translational Science Institute, University of Miami, Miami, FL, USA
| | - Giacomo Lanzoni
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA; Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA; Dr. John T. Macdonald Foundation Biomedical Nanotechnology Institute - BioNIUM at University of Miami, Miami, FL, USA.
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19
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Li Y, Dong J, Zhou Y, Ye X, Cai Z, Zhang X, Shen L, Zhang M, Zhang W, Cai J. Therapeutic effects of CXCL9-overexpressing human umbilical cord mesenchymal stem cells on liver fibrosis in rats. Biochem Biophys Res Commun 2021; 584:87-94. [PMID: 34775285 DOI: 10.1016/j.bbrc.2021.10.078] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 10/29/2021] [Accepted: 10/30/2021] [Indexed: 12/18/2022]
Abstract
Umbilical cord mesenchymal stem cells (UC-MSCs) transplantation has become a promising treatment for liver fibrosis. However, UC-MSCs have limited anti-fibrosis ability, and their homing ability of UC-MSCs to the injured liver seems to be poor. In our study, we aimed to determine if the CXCL9-overexpressing UC-MSCs could have synergistic anti-fibrosis effects and whether it can promote the homing ability of UC-MSCs. Overexpression of CXCL9 in UC-MSCs (CXCL9-UC-MSCs) was attained by transfecting the lenti-CXCL9-mCherry to naive UC-MSCs. The therapeutic effect of transducted CXCL9-UC-MSCs on both repairing of hepatic fibrosis and target homing were evaluated by comparing with the control of UC-MSCs transfected with empty lenti-mCherry vector. The results revealed that the liver function of CXCL9-UC-MSCs treated group was significantly improved when compared with that of control UC-MSCs (P < 0.05), and the histopathology indicated an obvious decrease of the collagen fiber content and significant disappearing of pseudo-lobules with basically normal morphology of hepatic lobules. Furthermore, liver frozen sections confirmed that CXCL9-UC-MSCs have significantly stronger chemotaxis and stable persistence in the injured liver tissues. In summary, overexpression of CXCL9 could improve the efficacy of UC-MSCs therapy for liver fibrosis repairing on account of an enhanced ability of UC-MSCs in homing to and staying in the injured sites of liver fibrosis in rat models.
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Affiliation(s)
- Yang Li
- Department of Surgery, Hebei Medical University, Shijiazhuang, Hebei, China; Department of Oncology & Immunotherapy, Hebei General Hospital, Shijiazhuang, Hebei, China; Department of Surgery, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Jiantao Dong
- Department of Surgery, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Ye Zhou
- Department of Surgery, Hebei Medical University, Shijiazhuang, Hebei, China; Department of Oncology & Immunotherapy, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Xueshuai Ye
- Department of Surgery, Hebei Medical University, Shijiazhuang, Hebei, China; Hebei Technical-Innovation Center of Cellular Therapy, Hebei HOFOY Biotech Corporation Ltd., Shijiazhuang, Hebei, China
| | - Ziqi Cai
- Hebei Technical-Innovation Center of Cellular Therapy, Hebei HOFOY Biotech Corporation Ltd., Shijiazhuang, Hebei, China
| | - Xueqian Zhang
- Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Li Shen
- Hebei Technical-Innovation Center of Cellular Therapy, Hebei HOFOY Biotech Corporation Ltd., Shijiazhuang, Hebei, China
| | - Mengya Zhang
- Hebei Technical-Innovation Center of Cellular Therapy, Hebei HOFOY Biotech Corporation Ltd., Shijiazhuang, Hebei, China
| | - Wanxing Zhang
- Department of Surgery, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Jianhui Cai
- Department of Surgery, Hebei Medical University, Shijiazhuang, Hebei, China; Department of Oncology & Immunotherapy, Hebei General Hospital, Shijiazhuang, Hebei, China; Department of Surgery, Hebei General Hospital, Shijiazhuang, Hebei, China; Hebei Technical-Innovation Center of Cellular Therapy, Hebei HOFOY Biotech Corporation Ltd., Shijiazhuang, Hebei, China.
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20
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Ballesteros OR, Brooks PT, Haastrup EK, Fischer-Nielsen A, Munthe-Fog L, Svalgaard JD. Adipose-Derived Stromal/Stem Cell Culture: Effects of Different Concentrations of Human Platelet Lysate in Media. Cells Tissues Organs 2021; 209:257-265. [PMID: 33752213 DOI: 10.1159/000513604] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 12/06/2020] [Indexed: 11/19/2022] Open
Abstract
Adipose-derived stromal/stem cells (ASCs) are being tested as a possible treatment for a wide range of diseases to exploit the immunomodulatory and regenerative potential demonstrated in vitro. Pooled human platelet lysate (pHPL) has replaced fetal bovine serum (FBS) as the preferred growth supplement because of its xeno-free origin and improved cell proliferation. Much has been done toward reducing the concentration of pHPL required when expanding ASCs. However, little is known on how increasing the concentration of pHPL affects ASC potency, which could lead to changes with possible beneficial applications. This study investigated the effect of 5, 10, or 20% pHPL in culture media on ASC proliferation and phenotypic marker expression, including chemokine receptors CXCR2, CXCR3, CXCR4, and VLA-4. Adipogenic and osteogenic properties, as well as immunosuppressive properties, including the ability to induce indoleamine-pyrrole 2,3-dioxygenase 1 (IDO1) and suppress T cell proliferation, were also examined. We observed a significant increase in cell yield (approximately 2-fold) and a corresponding reduction in population doubling time and cell volume when doubling the concentration of pHPL in the growth media. ASCs maintained expression of phenotypic surface markers CD73, CD90, and CD105 and were negative for CD45 and CD31. The ability to induce IDO1 and suppress T cell proliferation was observed as well. Adipogenesis and osteogenesis, however, seem to be increased at higher concentrations of pHPL (20% > 10% > 5%), while expression of chemokine receptors CXCR2 and CXCR3 was lower. In conclusion, increasing the pHPL concentration to 20% could be used to optimize culture conditions when producing cells for clinical treatments and may even be used to enhance beneficial ASC properties depending on the desired therapeutic effect.
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Affiliation(s)
- Olga R Ballesteros
- Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Patrick T Brooks
- Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Eva K Haastrup
- Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Anne Fischer-Nielsen
- Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Lea Munthe-Fog
- Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Jesper D Svalgaard
- Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark,
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21
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Jauković A, Kukolj T, Obradović H, Okić-Đorđević I, Mojsilović S, Bugarski D. Inflammatory niche: Mesenchymal stromal cell priming by soluble mediators. World J Stem Cells 2020; 12:922-937. [PMID: 33033555 PMCID: PMC7524701 DOI: 10.4252/wjsc.v12.i9.922] [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: 04/14/2020] [Revised: 05/13/2020] [Accepted: 09/02/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stromal/stem cells (MSCs) are adult stem cells of stromal origin that possess self-renewal capacity and the ability to differentiate into multiple mesodermal cell lineages. They play a critical role in tissue homeostasis and wound healing, as well as in regulating the inflammatory microenvironment through interactions with immune cells. Hence, MSCs have garnered great attention as promising candidates for tissue regeneration and cell therapy. Because the inflammatory niche plays a key role in triggering the reparative and immunomodulatory functions of MSCs, priming of MSCs with bioactive molecules has been proposed as a way to foster the therapeutic potential of these cells. In this paper, we review how soluble mediators of the inflammatory niche (cytokines and alarmins) influence the regenerative and immunomodulatory capacity of MSCs, highlighting the major advantages and concerns regarding the therapeutic potential of these inflammatory primed MSCs. The data summarized in this review may provide a significant starting point for future research on priming MSCs and establishing standardized methods for the application of preconditioned MSCs in cell therapy.
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Affiliation(s)
- Aleksandra Jauković
- Laboratory for Experimental Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Belgrade 11129, Serbia
| | - Tamara Kukolj
- Laboratory for Experimental Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Belgrade 11129, Serbia
| | - Hristina Obradović
- Laboratory for Experimental Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Belgrade 11129, Serbia
| | - Ivana Okić-Đorđević
- Laboratory for Experimental Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Belgrade 11129, Serbia
| | - Slavko Mojsilović
- Laboratory for Experimental Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Belgrade 11129, Serbia
| | - Diana Bugarski
- Laboratory for Experimental Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Belgrade 11129, Serbia
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22
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Liesveld JL, Sharma N, Aljitawi OS. Stem cell homing: From physiology to therapeutics. Stem Cells 2020; 38:1241-1253. [PMID: 32526037 DOI: 10.1002/stem.3242] [Citation(s) in RCA: 142] [Impact Index Per Article: 28.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 05/20/2020] [Accepted: 05/24/2020] [Indexed: 12/13/2022]
Abstract
Stem cell homing is a multistep endogenous physiologic process that is also used by exogenously administered hematopoietic stem and progenitor cells (HSPCs). This multistep process involves cell migration and is essential for hematopoietic stem cell transplantation. The process can be manipulated to enhance ultimate engraftment potential, and understanding stem cell homing is also important to the understanding of stem cell mobilization. Homing is also of potential importance in the recruitment of marrow mesenchymal stem and stromal cells (MSCs) to sites of injury and regeneration. This process is less understood but assumes importance when these cells are used for repair purposes. In this review, the process of HSPC and MSC homing is examined, as are methods to enhance this process.
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Affiliation(s)
- Jane L Liesveld
- James P. Wilmot Cancer Institute, Department of Medicine, University of Rochester, Rochester, New York, USA
| | - Naman Sharma
- James P. Wilmot Cancer Institute, Department of Medicine, University of Rochester, Rochester, New York, USA
| | - Omar S Aljitawi
- James P. Wilmot Cancer Institute, Department of Medicine, University of Rochester, Rochester, New York, USA
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23
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Qin C, Liu H, Tang B, Cao M, Yu Z, Liu B, Liu W, Dong Y, Ren H. In Vitro Immunological Effects of CXCR3 Inhibitor AMG487 on Dendritic Cells. Arch Immunol Ther Exp (Warsz) 2020; 68:11. [PMID: 32239302 DOI: 10.1007/s00005-020-00577-3] [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: 07/10/2019] [Accepted: 03/17/2020] [Indexed: 11/28/2022]
Abstract
AMG 487 is the targeted blocker of chemokine receptor CXCR3 and improves inflammatory symptoms by blocking the inflammatory cycle. Here we investigated whether AMG 487 affects dendritic cell (DC) biology and function. The expression of co-stimulatory markers on DCs was reduced, indicating the semi-mature state of DC when AMG 487 was added throughout the in vitro differentiation period. Additionally, when added solely during the final lipopolysaccharide-induced activation step, AMG 487 inhibited DC activation, as demonstrated by a decreased expression of activation markers. AMG487 also promoted the expression of PD-L2 and impaired the ability to induce antigen-specific T cell responses. Our results demonstrated that AMG 487 significantly affects DC maturity in vitro and function leading to impaired T cell activation, inducing DCs to have characteristics similar to tolerogenic DCs. AMG 487 may directly play an immunomodulatory role during DC development and functional shaping.
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Affiliation(s)
- Chenchen Qin
- Department of Hematology, Peking University First Hospital, 8 Xishiku Street, Xicheng District, Beijing, 100034, China
| | - Huihui Liu
- Department of Hematology, Peking University First Hospital, 8 Xishiku Street, Xicheng District, Beijing, 100034, China
| | - Bo Tang
- Department of Hematology, Peking University First Hospital, 8 Xishiku Street, Xicheng District, Beijing, 100034, China
| | - Min Cao
- Department of Hematology, Peking University First Hospital, 8 Xishiku Street, Xicheng District, Beijing, 100034, China
| | - Zhengyu Yu
- Department of Hematology, Peking University First Hospital, 8 Xishiku Street, Xicheng District, Beijing, 100034, China
| | - Beichen Liu
- Department of Hematology, Peking University First Hospital, 8 Xishiku Street, Xicheng District, Beijing, 100034, China
| | - Wei Liu
- Department of Hematology, Peking University First Hospital, 8 Xishiku Street, Xicheng District, Beijing, 100034, China
| | - Yujun Dong
- Department of Hematology, Peking University First Hospital, 8 Xishiku Street, Xicheng District, Beijing, 100034, China
| | - Hanyun Ren
- Department of Hematology, Peking University First Hospital, 8 Xishiku Street, Xicheng District, Beijing, 100034, China.
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24
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Lymphatic Endothelial Cell Progenitors in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1234:87-105. [PMID: 32040857 DOI: 10.1007/978-3-030-37184-5_7] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Tumor lymphatics play a key role in cancer progression as they are solely responsible for transporting malignant cells to regional lymph nodes (LNs), a process that precedes and promotes systemic lethal spread. It is broadly accepted that tumor lymphatic sprouting is induced mainly by soluble factors derived from tumor-associated macrophages (TAMs) and malignant cells. However, emerging evidence strongly suggests that a subset of TAMs, myeloid-lymphatic endothelial cell progenitors (M-LECP), also contribute to the expansion of lymphatics through both secretion of paracrine factors and a self-autonomous mode. M-LECP are derived from bone marrow (BM) precursors of the monocyte-macrophage lineage and characterized by unique co-expression of markers identifying lymphatic endothelial cells (LEC), stem cells, M2-type macrophages, and myeloid-derived immunosuppressive cells. This review describes current evidence for the origin of M-LECP in the bone marrow, their recruitment tumors and intratumoral trafficking, similarities to other TAM subsets, and mechanisms promoting tumor lymphatics. We also describe M-LECP integration into preexisting lymphatic vessels and discuss potential mechanisms and significance of this event. We conclude that improved mechanistic understanding of M-LECP functions within the tumor environment may lead to new therapeutic approaches to suppress tumor lymphangiogenesis and metastasis to lymph nodes.
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25
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Interleukin-1 β Enhances Umbilical Cord Mesenchymal Stem Cell Adhesion Ability on Human Umbilical Vein Endothelial Cells via LFA-1/ICAM-1 Interaction. Stem Cells Int 2019; 2019:7267142. [PMID: 31949440 PMCID: PMC6948307 DOI: 10.1155/2019/7267142] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 11/13/2019] [Accepted: 11/19/2019] [Indexed: 12/13/2022] Open
Abstract
The migration of administered mesenchymal stem cells (MSCs) to sites of injury via the bloodstream has been demonstrated. However, the underlying mechanisms of umbilical cord MSC adhesion to endothelial cells during transendothelial migration are still unclear. In this study, our data showed that IL-1β induced LFA-1 expression on MSCs and ICAM-1 expression on HUVECs. We then pretreated MSCs with protein synthesis inhibitor cycloheximide. The results showed that IL-1β induced LFA-1 expression on the surface of MSCs via the protein synthesis pathway. Through the p38 MAPK signaling pathway inhibitor SB 203580, we found that IL-1β induces the expression of LFA-1 through p38 MAPK signaling and enhances ICAM-1 expression in HUVECs. In addition, IL-1β-induced MSC adhesion to HUVECs was found to be inhibited by IL-1RA and the LFA-1 inhibitor lovastatin. These results indicate that IL-1β promotes the cell adhesion of MSCs to HUVECs through LFA-1/ICAM-1 interaction. We address the evidence that the cell adhesion mechanism of IL-1β promotes MSC adhesion to HUVECs. The implications of these findings could enhance the therapeutic potential of MSCs.
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26
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Szydlak R, Majka M, Lekka M, Kot M, Laidler P. AFM-based Analysis of Wharton's Jelly Mesenchymal Stem Cells. Int J Mol Sci 2019; 20:E4351. [PMID: 31491893 PMCID: PMC6769989 DOI: 10.3390/ijms20184351] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 09/01/2019] [Accepted: 09/02/2019] [Indexed: 12/16/2022] Open
Abstract
Wharton's jelly mesenchymal stem cells (WJ-MSCs) are multipotent stem cells that can be used in regenerative medicine. However, to reach the high therapeutic efficacy of WJ-MSCs, it is necessary to obtain a large amount of MSCs, which requires their extensive in vitro culturing. Numerous studies have shown that in vitro expansion of MSCs can lead to changes in cell behavior; cells lose their ability to proliferate, differentiate and migrate. One of the important measures of cells' migration potential is their elasticity, determined by atomic force microscopy (AFM) and quantified by Young's modulus. This work describes the elasticity of WJ-MSCs during in vitro cultivation. To identify the properties that enable transmigration, the deformability of WJ-MSCs that were able to migrate across the endothelial monolayer or Matrigel was analyzed by AFM. We showed that WJ-MSCs displayed differences in deformability during in vitro cultivation. This phenomenon seems to be strongly correlated with the organization of F-actin and reflects the changes characteristic for stem cell maturation. Furthermore, the results confirm the relationship between the deformability of WJ-MSCs and their migration potential and suggest the use of Young's modulus as one of the measures of competency of MSCs with respect to their possible use in therapy.
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Affiliation(s)
- Renata Szydlak
- Chair of Medical Biochemistry, Faculty of Medicine, Jagiellonian University Medical College, Kopernika 7, 31-034 Krakow, Poland.
| | - Marcin Majka
- Department of Transplantation, Institute of Pediatrics, Jagiellonian University Medical College, Wielicka 265, 30-663 Kraków, Poland.
| | - Małgorzata Lekka
- Institute of Nuclear Physics, Polish Academy of Sciences, Radzikowskiego 152, 31-342 Kraków, Poland.
| | - Marta Kot
- Department of Transplantation, Institute of Pediatrics, Jagiellonian University Medical College, Wielicka 265, 30-663 Kraków, Poland.
| | - Piotr Laidler
- Chair of Medical Biochemistry, Faculty of Medicine, Jagiellonian University Medical College, Kopernika 7, 31-034 Krakow, Poland.
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27
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Chen HY, Xie HY, Liu XX, Li LF, Bai YR, Gao JX. Splenic irradiation combined with tumor irradiation promotes T cell infiltration in the tumor microenvironment and helps in tumor control. Biochem Biophys Res Commun 2019; 510:156-162. [DOI: 10.1016/j.bbrc.2019.01.071] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Accepted: 01/15/2019] [Indexed: 12/25/2022]
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