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Feng Y, Tang M, Li H, Yao S, Li B. Mouse mesenchymal stem cell-derived exosomal miR-205-5p modulates LPS-induced macrophage polarization and alleviates lung injury by regulating the USP7/FOXM1 axis. Drug Deliv Transl Res 2025:10.1007/s13346-025-01813-z. [PMID: 40000557 DOI: 10.1007/s13346-025-01813-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/10/2025] [Indexed: 02/27/2025]
Abstract
Exosomal microRNAs produced from mesenchymal stem cells (MSCs) are crucial in the management of acute lung injury (ALI). In this work, mMSCs separated from bone marrow were used to extract exosomes (MSC-Exos). MSC-Exos treatment attenuated pathological changes and scores, and edema in ALI mice. Also, MSC-Exos administration modulated the concentrations of inflammatory factors as well as the macrophage polarization both in vivo and in vitro. Upregulation of miR-205-5p in MSC-Exos regulated the macrophage polarization and the contents of inflammatory factors in animal and cell models. MiR-205-5p targeted USP7, and negatively modulated the expression of USP7. USP7 interacted with FOXM1, and reduced the ubiquitination degradation of FOXM1. MSC-derived exosomal miR-205-5p modulated ubiquitination of FOXM1 by targeting USP7. The ameliorative effect of MSC-Exos on the macrophage polarization and the inflammatory factors release was reversed with the overexpression of USP7 in animal and cell models. Collectively, MSC-derived exosomal miR-205-5p regulated lipopolysaccharide (LPS)-induced macrophage polarization and alleviated lung injury by the USP7/FOXM1 axis, which developed a potential target for the treatment of ALI.
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Affiliation(s)
- Yinglu Feng
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation, Huazhong University of Science and Technology), Ministry of Education, Wuhan, China
| | - Min Tang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation, Huazhong University of Science and Technology), Ministry of Education, Wuhan, China
| | - Haopeng Li
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation, Huazhong University of Science and Technology), Ministry of Education, Wuhan, China
| | - Shanglong Yao
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Key Laboratory of Anesthesiology and Resuscitation, Huazhong University of Science and Technology), Ministry of Education, Wuhan, China.
| | - Bo Li
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Key Laboratory of Anesthesiology and Resuscitation, Huazhong University of Science and Technology), Ministry of Education, Wuhan, China.
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Hazrati A, Mirarefin SMJ, Malekpour K, Rahimi A, Khosrojerdi A, Rasouli A, Akrami S, Soudi S. Mesenchymal stem cell application in pulmonary disease treatment with emphasis on their interaction with lung-resident immune cells. Front Immunol 2024; 15:1469696. [PMID: 39582867 PMCID: PMC11581898 DOI: 10.3389/fimmu.2024.1469696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 10/01/2024] [Indexed: 11/26/2024] Open
Abstract
Due to the vital importance of the lungs, lung-related diseases and their control are very important. Severe inflammatory responses mediated by immune cells were among the leading causes of lung tissue pathology and damage during the COVID-19 pandemic. In addition, uncontrolled immune cell responses can lead to lung tissue damage in other infectious and non-infectious diseases. It is essential to control immune responses in a way that leads to homeostasis. Immunosuppressive drugs only suppress inflammatory responses and do not affect the homeostasis of reactions. The therapeutic application of mesenchymal stem cells (MSCs), in addition to restoring immune homeostasis, can promote the regeneration of lung tissue through the production of growth factors and differentiation into lung-related cells. However, the communication between MSCs and immune cells after treatment of pulmonary diseases is essential, and investigating this can help develop a clinical perspective. Different studies in the clinical phase showed that MSCs can reverse fibrosis, increase regeneration, promote airway remodeling, and reduce damage to lung tissue. The proliferation and differentiation potential of MSCs is one of the mechanisms of their therapeutic effects. Furthermore, they can secrete exosomes that affect the function of lung cells and immune cells and change their function. Another important mechanism is that MSCs reduce harmful inflammatory responses through communication with innate and adaptive immune cells, which leads to a shift of the immune system toward regulatory and hemostatic responses.
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Affiliation(s)
- Ali Hazrati
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Kosar Malekpour
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Arezou Rahimi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Arezou Khosrojerdi
- Infectious Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Ashkan Rasouli
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Susan Akrami
- Department of Microbiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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Jia L, Li N, van Unen V, Zwaginga JJ, Braun J, Hiemstra PS, Koning F, Khedoe PPSJ, Stolk J. Pulmonary and Systemic Immune Profiles Following Lung Volume Reduction Surgery and Allogeneic Mesenchymal Stromal Cell Treatment in Emphysema. Cells 2024; 13:1636. [PMID: 39404398 PMCID: PMC11476308 DOI: 10.3390/cells13191636] [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: 08/12/2024] [Revised: 09/19/2024] [Accepted: 09/20/2024] [Indexed: 10/19/2024] Open
Abstract
Emphysema in patients with chronic obstructive pulmonary disease (COPD) is characterized by progressive inflammation. Preclinical studies suggest that lung volume reduction surgery (LVRS) and mesenchymal stromal cell (MSC) treatment dampen inflammation. We investigated the effects of bone marrow-derived MSC (BM-MSC) and LVRS on circulating and pulmonary immune cell profiles in emphysema patients using mass cytometry. Blood and resected lung tissue were collected at the first LVRS (L1). Following 6-10 weeks of recovery, patients received a placebo or intravenous administration of 2 × 106 cells/kg bodyweight BM-MSC (n = 5 and n = 9, resp.) in week 3 and 4 before the second LVRS (L2), where blood and lung tissue were collected. Irrespective of BM-MSC or placebo treatment, proportions of circulating lymphocytes including central memory CD4 regulatory, effector memory CD8 and γδ T cells were higher, whereas myeloid cell percentages were lower in L2 compared to L1. In resected lung tissue, proportions of Treg (p = 0.0067) and anti-inflammatory CD163- macrophages (p = 0.0001) were increased in L2 compared to L1, while proportions of pro-inflammatory CD163+ macrophages were decreased (p = 0.0004). There were no effects of BM-MSC treatment on immune profiles in emphysema patients. However, we observed alterations in the circulating and pulmonary immune cells upon LVRS, suggesting the induction of anti-inflammatory responses potentially needed for repair processes.
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Affiliation(s)
- Li Jia
- Department of Immunology, Leiden University Medical Center (LUMC), 2333 Leiden, The Netherlands; (L.J.)
- Department of Pulmonology, PulmoScience Lab, Leiden University Medical Center (LUMC), 2333 Leiden, The Netherlands (J.S.)
| | - Na Li
- Department of Immunology, Leiden University Medical Center (LUMC), 2333 Leiden, The Netherlands; (L.J.)
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory of Zoonosis Research of the Ministry of Education, Institute of Zoonosis and College of Veterinary Medicine, Jilin University, Changchun 130012, China
| | - Vincent van Unen
- Department of Immunology, Leiden University Medical Center (LUMC), 2333 Leiden, The Netherlands; (L.J.)
| | - Jaap-Jan Zwaginga
- Department of Hematology, Leiden University Medical Center, 2333 Leiden, The Netherlands
| | - Jerry Braun
- Department of Cardiothoracic Surgery, Leiden University Medical Center, 2333 Leiden, The Netherlands
| | - Pieter S. Hiemstra
- Department of Pulmonology, PulmoScience Lab, Leiden University Medical Center (LUMC), 2333 Leiden, The Netherlands (J.S.)
| | - Frits Koning
- Department of Immunology, Leiden University Medical Center (LUMC), 2333 Leiden, The Netherlands; (L.J.)
| | - P. Padmini S. J. Khedoe
- Department of Pulmonology, PulmoScience Lab, Leiden University Medical Center (LUMC), 2333 Leiden, The Netherlands (J.S.)
| | - Jan Stolk
- Department of Pulmonology, PulmoScience Lab, Leiden University Medical Center (LUMC), 2333 Leiden, The Netherlands (J.S.)
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Lai S, Guo Z. Stem cell therapies for chronic obstructive pulmonary disease: mesenchymal stem cells as a promising treatment option. Stem Cell Res Ther 2024; 15:312. [PMID: 39300523 DOI: 10.1186/s13287-024-03940-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Accepted: 09/16/2024] [Indexed: 09/22/2024] Open
Abstract
Chronic obstructive pulmonary disease(COPD) is an inflammatory disease characterized by the progressive and irreversible structural and functional damage of lung tissue. Although COPD is a significant global disease burden, the available treatments only ameliorate the symptoms, but cannot reverse lung damage. Researchers in regenerative medicine have examined the use of stem cell transplantation for treatment of COPD and other diseases because these cells have the potential for unlimited self-renewal and the ability to undergo directed differentiation. Stem cells are typically classified as embryonic stem cells, induced pluripotent stem cells, and adult stem cells (which includes mesenchymal stem cells [MSCs]), each with its own advantages and disadvantages regarding applications in regenerative medicine. Although the heterogeneity and susceptibility to senescence of MSCs make them require careful consideration for clinical applications. However, the low tumourigenicity and minimal ethical concerns of MSCs make them appear to be excellent candidates. This review summarizes the characteristics of various stem cell types and describes their therapeutic potential in the treatment of COPD, with a particular emphasis on MSCs. We aim to facilitate subsequent in-depth research and preclinical applications of MSCs by providing a comprehensive overview.
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Affiliation(s)
- Sumei Lai
- Stem Cell Laboratory, Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China.
| | - Zhifeng Guo
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
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Eryüksel E, Tunca Z, Mercancı Z, Kılıç SS, Kocakaya D, Akdeniz E, Öztop NE, Çetin E, Akkoç T. Stem cell treatment reduces T cell apoptosis in COPD patients with chronic bronchitis but not with emphysema. Tissue Cell 2024; 89:102452. [PMID: 38986345 DOI: 10.1016/j.tice.2024.102452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 06/03/2024] [Accepted: 06/17/2024] [Indexed: 07/12/2024]
Abstract
BACKGROUND Chronic obstructive pulmonary disease (COPD) is a prevalent and preventable condition. Mesenchymal stem cell (MSC) therapy is being explored to aid in the regeneration of lung cells and airway structure, aiming to restore lung function. AIM To examine varied responses of MSCs when cultured with peripheral blood mononuclear cells (PBMCs) from different COPD phenotypes, patients were grouped into ACOS, emphysema, and chronic bronchitis categories. METHODS PBMCs from these groups and controls were co-cultured with MSCs derived from dental follicles, revealing differing rates of apoptosis among COPD phenotypes compared to controls. RESULTS While the chronic bronchitis group exhibited the least lymphocyte viability (p<0.01), introducing MSCs notably enhanced viability across all phenotypes except emphysema, with the chronic bronchitis group showing the most improvement (p<0.05). CONCLUSION Stem cell therapy might reduce peripheral lymphocyte apoptosis in COPD, with varying responses based on phenotype, necessitating further research to understand mechanisms and optimize tailored therapies for each COPD subtype.
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Affiliation(s)
- Emel Eryüksel
- Pulmonary and Critical Care, Faculty of Medicine, Marmara University, Turkey.
| | - Zeynep Tunca
- Department of Immunology, Faculty of Medicine, Marmara University, Turkey; Department of Pediatric Allergy-Immunology, Faculty of Medicine, Marmara University, Turkey
| | - Zeynep Mercancı
- Pulmonary and Critical Care, Faculty of Medicine, Marmara University, Turkey
| | - Sabriye Senem Kılıç
- Department of Immunology, Faculty of Medicine, Marmara University, Turkey; Department of Pediatric Allergy-Immunology, Faculty of Medicine, Marmara University, Turkey
| | - Derya Kocakaya
- Pulmonary and Critical Care, Faculty of Medicine, Marmara University, Turkey
| | - Esra Akdeniz
- Department of Medical Education, Faculty of Medicine, Marmara University, Turkey
| | - Nur Ecem Öztop
- Department of Immunology, Faculty of Medicine, Marmara University, Turkey
| | - Esin Çetin
- Department of Immunology, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Tunç Akkoç
- Department of Immunology, Faculty of Medicine, Marmara University, Turkey; Department of Pediatric Allergy-Immunology, Faculty of Medicine, Marmara University, Turkey
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Hanna M, Elnassag SS, Mohamed DH, Elbaset MA, Shaker O, Khowailed EA, Gouda SAA. Melatonin and mesenchymal stem cells co-administration alleviates chronic obstructive pulmonary disease via modulation of angiogenesis at the vascular-alveolar unit. Pflugers Arch 2024; 476:1155-1168. [PMID: 38740599 PMCID: PMC11166745 DOI: 10.1007/s00424-024-02968-3] [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: 11/29/2023] [Revised: 03/31/2024] [Accepted: 04/25/2024] [Indexed: 05/16/2024]
Abstract
Chronic obstructive pulmonary disease (COPD) is considered a severe disease mitigating lung physiological functions with high mortality outcomes, insufficient therapy, and pathophysiology pathways which is still not fully understood. Mesenchymal stem cells (MSCs) derived from bone marrow play an important role in improving the function of organs suffering inflammation, oxidative stress, and immune reaction. It might also play a role in regenerative medicine, but that is still questionable. Additionally, Melatonin with its known antioxidative and anti-inflammatory impact is attracting attention nowadays as a useful treatment. We hypothesized that Melatonin may augment the effect of MSCs at the level of angiogenesis in COPD. In our study, the COPD model was established using cigarette smoking and lipopolysaccharide. The COPD rats were divided into four groups: COPD group, Melatonin-treated group, MSC-treated group, and combined treated group (Melatonin-MSCs). We found that COPD was accompanied by deterioration of pulmonary function tests in response to expiratory parameter affection more than inspiratory ones. This was associated with increased Hypoxia inducible factor-1α expression and vascular endothelial growth factor level. Consequently, there was increased CD31 expression indicating increased angiogenesis with massive enlargement of airspaces and thinning of alveolar septa with decreased mean radial alveolar count, in addition to, inflammatory cell infiltration and disruption of the bronchiolar epithelial wall with loss of cilia and blood vessel wall thickening. These findings were improved significantly when Melatonin and bone marrow-derived MSCs were used as a combined treatment proving the hypothesized target that Melatonin might augment MSCs aiming at vascular changes.
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Affiliation(s)
- Mira Hanna
- Department of Medical Physiology, Faculty of Medicine, Kasr Al-Ainy, Cairo University, El-Maniel 11451, Cairo, Egypt.
| | - Sabreen Sayed Elnassag
- Department of Medical Physiology, Faculty of Medicine, Kasr Al-Ainy, Cairo University, El-Maniel 11451, Cairo, Egypt
| | - Dina Hisham Mohamed
- Department of Histology, Faculty of Medicine, Cairo University, El-Maniel 11451, Cairo, Egypt
| | - Marawan Abd Elbaset
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
| | - Olfat Shaker
- Department of Biochemistry, Faculty of Medicine, Kasr Al-Ainy, Cairo University, El-Maniel 11451, Cairo, Egypt
| | - Effat A Khowailed
- Department of Medical Physiology, Faculty of Medicine, Kasr Al-Ainy, Cairo University, El-Maniel 11451, Cairo, Egypt
| | - Sarah Ali Abdelhameed Gouda
- Department of Medical Physiology, Faculty of Medicine, Kasr Al-Ainy, Cairo University, El-Maniel 11451, Cairo, Egypt
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Yu H, Zhu G, Wang D, Huang X, Han F. PI3K/AKT/FOXO3a Pathway Induces Muscle Atrophy by Ubiquitin-Proteasome System and Autophagy System in COPD Rat Model. Cell Biochem Biophys 2024; 82:805-815. [PMID: 38386223 DOI: 10.1007/s12013-024-01232-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Accepted: 02/08/2024] [Indexed: 02/23/2024]
Abstract
Muscle atrophy is a common extrapulmonary co-morbidity affecting about 20% of patients with COPD. However, the mechanism of muscle atrophy in COPD remains unclear. This study investigated the role of the ubiquitin-proteasome system (UPS) and the autophagy system in COPD muscle atrophy and its mechanism. A COPD rat model was established to evaluate the in vitro effects of the UPS and the autophagy system in muscle atrophy. In addition, the role of the UPS, autophagy systems, and the expressions of the PI3K/AKT/FOXO3a pathway were studied in the CSE-induced L6 myoblast cells. Furthermore, we evaluated the effect of FOXO3a in the CSE-induced L6 myoblast cells using siRNA-FOXO3a. The results showed that the expression of ubiquitin-related proteins and autophagy-related proteins were significantly increased in the COPD rat model and CSE-induced L6 myoblast cells. At the same time, there was a concurrent decrease in the phosphorylation protein expression of PI3K and AKT, but the transcriptional activity of FOXO3a was increased in CSE-induced L6 myoblast cells. And siRNA-FOXO3a significantly decreased the expression level of the UPS and the autophagy system in CSE-induced L6 myoblast cells. These results suggest that PI3K/AKT/FOXO3a participates in COPD muscle atrophy by regulating the UPS and the autophagy systems.
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Affiliation(s)
- Haiyang Yu
- Department of Respiratory Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guiyin Zhu
- Department of Respiratory Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dongmei Wang
- Department of Respiratory Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xuan Huang
- Department of Respiratory Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fengfeng Han
- Department of Respiratory Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Yuan D, Bao Y, El-Hashash A. Mesenchymal stromal cell-based therapy in lung diseases; from research to clinic. AMERICAN JOURNAL OF STEM CELLS 2024; 13:37-58. [PMID: 38765802 PMCID: PMC11101986 DOI: 10.62347/jawm2040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Accepted: 03/02/2024] [Indexed: 05/22/2024]
Abstract
Recent studies demonstrated that mesenchymal stem cells (MSCs) are important for the cell-based therapy of diseased or injured lung due to their immunomodulatory and regenerative properties as well as limited side effects in experimental animal models. Preclinical studies have shown that MSCs have also a remarkable effect on the immune cells, which play major roles in the pathogenesis of multiple lung diseases, by modulating their activity, proliferation, and functions. In addition, MSCs can inhibit both the infiltrated immune cells and detrimental immune responses in the lung and can be used in treating lung diseases caused by a virus infection such as Tuberculosis and SARS-COV-2. Moreover, MSCs are a source for alveolar epithelial cells such as type 2 (AT2) cells. These MSC-derived functional AT2-like cells can be used to treat and diminish serious lung disorders, including acute lung injury, asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis in animal models. As an alternative MSC-based therapy, extracellular vesicles that are derived from MSC-derived can be employed in regenerative medicine. Herein, we discussed the key research findings from recent clinical and preclinical studies on the functions of MSCs in treating some common and well-studied lung diseases. We also discussed the mechanisms underlying MSC-based therapy of well-studied lung diseases, and the recent employment of MSCs in both the attenuation of lung injury/inflammation and promotion of the regeneration of lung alveolar cells after injury. Finally, we described the role of MSC-based therapy in treating major pulmonary diseases such as pneumonia, COPD, asthma, and idiopathic pulmonary fibrosis (IPF).
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Affiliation(s)
- Dailin Yuan
- Zhejiang UniversityHangzhou 310058, Zhejiang, PR China
| | - Yufei Bao
- School of Biomedical Engineering, University of SydneyDarlington, NSW 2008, Australia
| | - Ahmed El-Hashash
- Texas A&M University, 3258 TAMU, College StationTX 77843-3258, USA
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Li XH, Huang P, Cheng HP, Zhou Y, Feng DD, Yue SJ, Han Y, Luo ZQ. NMDAR activation attenuates the protective effect of BM-MSCs on bleomycin-induced ALI via the COX-2/PGE 2 pathway. Heliyon 2024; 10:e23723. [PMID: 38205313 PMCID: PMC10776937 DOI: 10.1016/j.heliyon.2023.e23723] [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: 02/01/2023] [Revised: 12/10/2023] [Accepted: 12/12/2023] [Indexed: 01/12/2024] Open
Abstract
N-methyl-d-aspartate (NMDA) receptor (NMDAR) activation mediates glutamate (Glu) toxicity and involves bleomycin (BLM)-induced acute lung injury (ALI). We have reported that bone marrow-derived mesenchymal stem cells (BM-MSCs) are NMDAR-regulated target cells, and NMDAR activation inhibits the protective effect of BM-MSCs on BLM-induced pulmonary fibrosis, but its effect on ALI remains unknown. Here, we found that Glu release was significantly elevated in plasma of mice at d 7 after intratracheally injected with BLM. BM-MSCs were pretreated with NMDA (the selective agonist of NMDAR) and transplanted into the recipient mice after the BLM challenge. BM-MSCs administration significantly alleviated the pathological changes, inflammatory response, myeloperoxidase activity, and malondialdehyde content in the damaged lungs, but NMDA-pretreated BM-MSCs did not ameliorate BLM-induced lung injury in vivo. Moreover, NMDA down-regulated prostaglandin E2 (PGE2) secretion and cyclooxygenase (COX)-2 expression instead of COX-1 expression in BM-MSCs in vitro. We also found that NMDAR1 expression was increased and COX-2 expression was decreased, but COX-1 expression was not changed in primary BM-MSCs of BLM-induced ALI mice. Further, the cultured supernatants of lipopolysaccharide (LPS)-pretreated RAW264.7 macrophages were collected to detect inflammatory factors after co-culture with NMDA-pretreated BM-MSCs. The co-culture experiments showed that NMDA precondition inhibited the anti-inflammatory effect of BM-MSCs on LPS-induced macrophage inflammation, and PGE2 could partially alleviate this inhibition. Our findings suggest that NMDAR activation attenuated the protective effect of BM-MSCs on BLM-induced ALI in vivo. NMDAR activation inhibited COX-2 expression and PGE2 secretion in BM-MSCs and weakened the anti-inflammatory effect of BM-MSCs on LPS-induced macrophage inflammation in vitro. In conclusion, NMDAR activation attenuates the protective effect of BM-MSCs on BLM-induced ALI via the COX-2/PGE2 pathway. Keywords: Acute Lung Injury, BM-MSCs, NMDA receptor, COX-1/2, PGE2.
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Affiliation(s)
- Xiao-Hong Li
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, 410078, China
| | - Pu Huang
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, 410078, China
- Health Management Center, Changsha Central Hospital Affiliated to Nanhua University, Changsha, 410018, China
| | - Hai-Peng Cheng
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, 410078, China
| | - Yan Zhou
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, 410078, China
| | - Dan-Dan Feng
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, 410078, China
| | - Shao-Jie Yue
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yang Han
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, 410078, China
| | - Zi-Qiang Luo
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, 410078, China
- Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, 410078, China
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Xu H, Nie X, Deng W, Zhou H, Huang D, Wang Z. Bone marrow mesenchymal stem cells-derived exosomes ameliorate LPS-induced acute lung injury by miR-223-regulated alveolar macrophage M2 polarization. J Biochem Mol Toxicol 2024; 38:e23568. [PMID: 37899695 DOI: 10.1002/jbt.23568] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 09/15/2023] [Accepted: 10/12/2023] [Indexed: 10/31/2023]
Abstract
Numerous studies have shown that the M2 polarization of alveolar macrophages (AM) plays a protective role in acute lung injury (ALI). Mesenchymal stem cells (MSCs) secreted exosomes have been reported to be involved in inflammatory diseases by the effects of polarized M1/M2 macrophage populations. However, whether bone marrow mesenchymal stem cells (BMMSCs) derived exosomes could protect from ALI and its mechanisms are still unclear. Here, we explored the role of exosomes from BMMSC in rat AM polarization and the lipopolysaccharide- (LPS-) induced ALI rat model. Furthermore, the levels of exosomal miR-223 in BMMSCs were measured by RT-qPCR. Additionally, miR-223 mimics and its inhibitors were used to verify the vital role of miR-223 of BMMSCs-derived exosomes in the polarization of M2 macrophages. The results showed that BMMSCs-derived exosomes were taken up by the AM. Exosomes derived from BMMSCs promoted M2 polarization of AM in vitro. BMMSCs exosomes effectively mitigated pathological injuries, lung edema, and the inflammation of rats from LPS-induced ALI, accompanied by an increase of M2 polarization of AM in lung tissue. Interestingly, we also found that miR-223 was enriched in BMMSCs-derived exosomes, and overexpression of miR-223 in BMMSCs-derived exosomes promoted M2 polarization of AM while depressing miR-223 showed opposite effects in AM. The present study demonstrated that BMMSCs-derived exosomes triggered alveolar M2 polarization to improve inflammation by transferring miR-223, which may provide new therapeutic strategies in ALI.
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Affiliation(s)
- Hui Xu
- Department of Emergency, Jiangxi Provincial People's Hospital (The First Affiliated Hospital of Nanchang Medical College), Nanchang, China
| | - Xiangbi Nie
- Department of Emergency, Jiangxi Provincial People's Hospital (The First Affiliated Hospital of Nanchang Medical College), Nanchang, China
| | - Wu Deng
- Department of Emergency, Jiangxi Provincial People's Hospital (The First Affiliated Hospital of Nanchang Medical College), Nanchang, China
| | - Han Zhou
- Department of Emergency, Jiangxi Provincial People's Hospital (The First Affiliated Hospital of Nanchang Medical College), Nanchang, China
| | - Dan Huang
- Department of Emergency, Jiangxi Provincial People's Hospital (The First Affiliated Hospital of Nanchang Medical College), Nanchang, China
| | - Zenggeng Wang
- Department of Emergency, Jiangxi Provincial People's Hospital (The First Affiliated Hospital of Nanchang Medical College), Nanchang, China
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Liao W, Li X, Tang X. Human Umbilical Cord Mesenchymal Stem Cells Alleviate Chronic Salpingitis by Modulating Macrophage-Associated Inflammatory Factors. Curr Stem Cell Res Ther 2024; 19:1442-1448. [PMID: 38173206 DOI: 10.2174/011574888x261128231108043931] [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: 06/11/2023] [Revised: 09/24/2023] [Accepted: 10/04/2023] [Indexed: 01/05/2024]
Abstract
INTRODUCTION Mesenchymal stem cells (MSCs) have been widely studied because of their established anti-inflammatory properties. During chronic salpingitis (CS), infiltrated macrophages have vital roles in inflammation and tissue remodeling. METHODS We employed the type of MSCs, human umbilical cord (huc) MSCs in an experimental CS model and therapeutic efficacy was assessed. hucMSCs exerted this therapeutic effect by regulating macrophage function. To verify the regulatory effects of hucMSCs on the macrophage, macrophage line RAW264.7 markers were analyzed under LPS stimulation with or without co-culturing with hucMSCs for 12h and 24h. In addition, flow cytometry analysis was applied to reveal the interaction of co-culture. For animal studies, CS was induced by the MoPn strain Chlamydia trachomatis (CT), hucMSCs were intravaginally injected in the CS, and we analyzed the infiltrated macrophage by immunofluorescence. RESULTS We found the markers IL-10 was markedly increased and IL-1β, caspase-1 was notably downregulated after co-culturing with hucMSCs by RT-PCR. hucMSCs promote macrophage line RAW264.7 apoptosis. We also found that hucMSCs treatment can alleviate CS by decreasing the mRNA expression of IL-1β, caspase-1 and MCP-1 in the tubal tissue by RT-PCR and decreasing the protein expression of IL-1β, caspase-1 and TGF-β by western blotting. CONCLUSION These results suggest that macrophage function may be related to the immune-modulating characteristics of hucMSCs that contribute to CS.
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Affiliation(s)
- Wenjuan Liao
- Department of Obstetrics and Gynecology, Third Affiliated Hospital of Sun Yat-Sen University, 600, Tianhe Road, Tianhe District, Guangzhou, 510630, Guangdong, China
| | - Xiaomao Li
- Department of Obstetrics and Gynecology, Third Affiliated Hospital of Sun Yat-Sen University, 600, Tianhe Road, Tianhe District, Guangzhou, 510630, Guangdong, China
| | - Xinrang Tang
- Department of Obstetrics and Gynecology, Third Affiliated Hospital of Sun Yat-Sen University, 600, Tianhe Road, Tianhe District, Guangzhou, 510630, Guangdong, China
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12
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Ahmadi A, Ahrari S, Salimian J, Salehi Z, Karimi M, Emamvirdizadeh A, Jamalkandi SA, Ghanei M. p38 MAPK signaling in chronic obstructive pulmonary disease pathogenesis and inhibitor therapeutics. Cell Commun Signal 2023; 21:314. [PMID: 37919729 PMCID: PMC10623820 DOI: 10.1186/s12964-023-01337-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 09/27/2023] [Indexed: 11/04/2023] Open
Abstract
BACKGROUND Chronic obstructive pulmonary disease (COPD) is characterized by persistent respiratory symptoms and airflow limitation due to airway and/or alveolar remodeling. Although the abnormalities are primarily prompted by chronic exposure to inhaled irritants, maladjusted and self-reinforcing immune responses are significant contributors to the development and progression of the disease. The p38 isoforms are regarded as pivotal hub proteins that regulate immune and inflammatory responses in both healthy and disease states. As a result, their inhibition has been the subject of numerous recent studies exploring their therapeutic potential in COPD. MAIN BODY We performed a systematic search based on the PRISMA guidelines to find relevant studies about P38 signaling in COPD patients. We searched the PubMed and Google Scholar databases and used "P38" AND "COPD" Mesh Terms. We applied the following inclusion criteria: (1) human, animal, ex vivo and in vitro studies; (2) original research articles; (3) published in English; and (4) focused on P38 signaling in COPD pathogenesis, progression, or treatment. We screened the titles and abstracts of the retrieved studies and assessed the full texts of the eligible studies for quality and relevance. We extracted the following data from each study: authors, year, country, sample size, study design, cell type, intervention, outcome, and main findings. We classified the studies according to the role of different cells and treatments in P38 signaling in COPD. CONCLUSION While targeting p38 MAPK has demonstrated some therapeutic potential in COPD, its efficacy is limited. Nevertheless, combining p38 MAPK inhibitors with other anti-inflammatory steroids appears to be a promising treatment choice. Clinical trials testing various p38 MAPK inhibitors have produced mixed results, with some showing improvement in lung function and reduction in exacerbations in COPD patients. Despite these mixed results, research on p38 MAPK inhibitors is still a major area of study to develop new and more effective therapies for COPD. As our understanding of COPD evolves, we may gain a better understanding of how to utilize p38 MAPK inhibitors to treat this disease. Video Abstract.
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Affiliation(s)
- Ali Ahmadi
- Molecular Biology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Sajjad Ahrari
- Department of Biochemistry and Molecular Medicine, Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, QC, Canada
| | - Jafar Salimian
- Applied Virology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Zahra Salehi
- Hematology-Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehrdad Karimi
- Department of Traditional Medicine, School of Persian Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Emamvirdizadeh
- Department of Molecular Genetics, Faculty of Bio Sciences, Tehran North Branch, Islamic Azad University, Tehran, Iran
| | - Sadegh Azimzadeh Jamalkandi
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Mostafa Ghanei
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Hu T, Pang N, Li Z, Xu D, Jing J, Li F, Ding J, Wang J, Jiang M. The Activation of M1 Macrophages is Associated with the JNK-m6A-p38 Axis in Chronic Obstructive Pulmonary Disease. Int J Chron Obstruct Pulmon Dis 2023; 18:2195-2206. [PMID: 37822331 PMCID: PMC10564081 DOI: 10.2147/copd.s420471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 09/29/2023] [Indexed: 10/13/2023] Open
Abstract
Background Excessive activation of M1 macrophages affects the chronic inflammatory response of the airways and leads to the development of chronic obstructive pulmonary disease (COPD). Therefore, it needs to be closely monitored and investigated. MAPK signaling pathway is involved in the activation of M1 macrophages, and N6-methyladenosine (m6A) is involved in the pathogenesis of COPD. However, it is unknown whether activation of the MAPK signaling pathway is mediated by m6A in M1 macrophages in COPD. Methods The GEO data were analyzed using bioinformatics techniques to assess the differences between COPD and healthy individuals in the levels of M1 macrophages, their secreted cytokines, and m6A regulators. The MAPK signaling pathway was significantly enriched in the list of differentially regulated genes between COPD and healthy individuals. We further analyzed the correlation between M1 macrophages, m6A, and the MAPK signaling pathway. Next, blood samples from COPD and healthy individuals were collected and analyzed by using flow cytometry, ELISA, and RT-PCR. Western blotting was performed using CSE-induced THP-1 cells. COPD and healthy mice were used for Me-RIP sequencing and flow cytometry experiments. Validation of the results of the above bioinformatics analysis by molecular biology experiments and sequencing techniques. Results We found that GEO data and blood specimens from COPD patients showed increased M1 macrophages, higher levels of IL-6 and TNF-α, and higher mRNA expression of key mediators of the MAPK signaling pathway (p38, ERK, and JNK). Western blotting showed increased expression of p38, ERK, and JNK in the CSE group. In contrast, the expression of m6A regulators was low. Also, M1 macrophages in COPD mice were hyperactivated and had reduced m6A modifications of p38, ERK, and JNK compared with control. Conclusion m6A may be involved in M1 macrophage hyperactivation by regulating the MAPK signaling pathway, thereby influencing the development of COPD.
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Affiliation(s)
- Tingting Hu
- Xinjiang Laboratory of Respiratory Disease Research, Traditional Chinese Medicine Hospital Affiliated to Xinjiang Medical University, Urumqi, 830000, People’s Republic of China
| | - Nannan Pang
- CAS Key Laboratory of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, 215163, People’s Republic of China
| | - Zheng Li
- Xinjiang Laboratory of Respiratory Disease Research, Traditional Chinese Medicine Hospital Affiliated to Xinjiang Medical University, Urumqi, 830000, People’s Republic of China
| | - Dan Xu
- Xinjiang Laboratory of Respiratory Disease Research, Traditional Chinese Medicine Hospital Affiliated to Xinjiang Medical University, Urumqi, 830000, People’s Republic of China
| | - Jing Jing
- Xinjiang Laboratory of Respiratory Disease Research, Traditional Chinese Medicine Hospital Affiliated to Xinjiang Medical University, Urumqi, 830000, People’s Republic of China
| | - Fengsen Li
- Xinjiang Laboratory of Respiratory Disease Research, Traditional Chinese Medicine Hospital Affiliated to Xinjiang Medical University, Urumqi, 830000, People’s Republic of China
| | - Jianbing Ding
- Department of Immunology, College of Basic Medicine, Xinjiang Medical University, Urumqi, 830000, People’s Republic of China
| | - Jing Wang
- Xinjiang Laboratory of Respiratory Disease Research, Traditional Chinese Medicine Hospital Affiliated to Xinjiang Medical University, Urumqi, 830000, People’s Republic of China
| | - Min Jiang
- Xinjiang Laboratory of Respiratory Disease Research, Traditional Chinese Medicine Hospital Affiliated to Xinjiang Medical University, Urumqi, 830000, People’s Republic of China
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Guarnier LP, Moro LG, Lívero FADR, de Faria CA, Azevedo MF, Roma BP, Albuquerque ER, Malagutti-Ferreira MJ, Rodrigues AGD, da Silva AA, Sekiya EJ, Ribeiro-Paes JT. Regenerative and translational medicine in COPD: hype and hope. Eur Respir Rev 2023; 32:220223. [PMID: 37495247 PMCID: PMC10369169 DOI: 10.1183/16000617.0223-2022] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 05/23/2023] [Indexed: 07/28/2023] Open
Abstract
COPD is a common, preventable and usually progressive disease associated with an enhanced chronic inflammatory response in the airways and lung, generally caused by exposure to noxious particles and gases. It is a treatable disease characterised by persistent respiratory symptoms and airflow limitation due to abnormalities in the airways and/or alveoli. COPD is currently the third leading cause of death worldwide, representing a serious public health problem and a high social and economic burden. Despite significant advances, effective clinical treatments have not yet been achieved. In this scenario, cell-based therapies have emerged as potentially promising therapeutic approaches. However, there are only a few published studies of cell-based therapies in human patients with COPD and a small number of ongoing clinical trials registered on clinicaltrials.gov Despite the advances and interesting results, numerous doubts and questions remain about efficacy, mechanisms of action, culture conditions, doses, timing, route of administration and conditions related to homing and engraftment of the infused cells. This article presents the state of the art of cell-based therapy in COPD. Clinical trials that have already been completed and with published results are discussed in detail. We also discuss the questions that remain unanswered about cell-based regenerative and translational medicine for COPD.
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Affiliation(s)
- Lucas Pires Guarnier
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, Brazil
- Laboratory of Genetics and Cell Therapy - GenTe Cel, Department of Biotechnology, São Paulo State University (UNESP), Assis, Brazil
| | - Lincoln Gozzi Moro
- Laboratory of Genetics and Cell Therapy - GenTe Cel, Department of Biotechnology, São Paulo State University (UNESP), Assis, Brazil
- Biomedical Sciences Institute, Butantan Institute, Technological Research Institute, University of São Paulo (USP), São Paulo, Brazil
| | | | | | - Mauricio Fogaça Azevedo
- Laboratory of Genetics and Cell Therapy - GenTe Cel, Department of Biotechnology, São Paulo State University (UNESP), Assis, Brazil
| | - Beatriz Pizoni Roma
- Laboratory of Genetics and Cell Therapy - GenTe Cel, Department of Biotechnology, São Paulo State University (UNESP), Assis, Brazil
| | | | - Maria José Malagutti-Ferreira
- Laboratory of Genetics and Cell Therapy - GenTe Cel, Department of Biotechnology, São Paulo State University (UNESP), Assis, Brazil
| | | | - Adelson Alves da Silva
- São Lucas Research and Education Institute (IEP - São Lucas), TechLife, São Paulo, Brazil
| | - Eliseo Joji Sekiya
- São Lucas Research and Education Institute (IEP - São Lucas), TechLife, São Paulo, Brazil
| | - João Tadeu Ribeiro-Paes
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, Brazil
- Laboratory of Genetics and Cell Therapy - GenTe Cel, Department of Biotechnology, São Paulo State University (UNESP), Assis, Brazil
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Martínez-Zarco BA, Jiménez-García MG, Tirado R, Ambrosio J, Hernández-Mendoza L. [Mesenchymal stem cells: Therapeutic option in ARDS, COPD, and COVID-19 patients]. REVISTA ALERGIA MÉXICO 2023; 70:89-101. [PMID: 37566772 DOI: 10.29262/ram.v70i1.1149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 03/30/2023] [Indexed: 08/13/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD) and COVID-19 have as a common characteristic the inflammatory lesion of the lung epithelium. The therapeutic options are associated with opportunistic infections, a hyperglycemic state, and adrenal involvement. Therefore, the search for new treatment strategies that reduce inflammation, and promote re-epithelialization of damaged tissue is very important. This work describes the relevant pathophysiological characteristics of these diseases and evaluates recent findings on the immunomodulatory, anti-inflammatory and regenerative effect of mesenchymal stem cells (MSC) and their therapeutic use. In Pubmed we selected the most relevant studies on the subject, published between 2003 and 2022 following the PRISMA guide. We conclude that MSCs are an important therapeutic option for regenerative treatment in COPD, ARDS, and COVID-19, because of their ability to differentiate into type II pneumocytes and maintain the size and function of lung tissue by replacing dead or damaged cells.
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Affiliation(s)
| | | | - Rocío Tirado
- Doctor en Ciencias Biomédicas, Departamento de Microbiología y Parasitología.Universidad Nacional Autónoma de México, Facultad de Medicina, Laboratorio de Biología del Citoesqueleto y Virología, Ciudad de México
| | - Javier Ambrosio
- Doctor en Ciencias Biomédicas, Departamento de Microbiología y Parasitología.Universidad Nacional Autónoma de México, Facultad de Medicina, Laboratorio de Biología del Citoesqueleto y Virología, Ciudad de México
| | - Lilian Hernández-Mendoza
- Doctor en Ciencias Biomédicas, Departamento de Microbiología y Parasitología.Universidad Nacional Autónoma de México, Facultad de Medicina, Laboratorio de Biología del Citoesqueleto y Virología, Ciudad de México.
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16
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Li J, Huang Y, Sun H, Yang L. Mechanism of mesenchymal stem cells and exosomes in the treatment of age-related diseases. Front Immunol 2023; 14:1181308. [PMID: 37275920 PMCID: PMC10232739 DOI: 10.3389/fimmu.2023.1181308] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 05/08/2023] [Indexed: 06/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs) from multiple tissues have the capability of multidirectional differentiation and self-renewal. Many reports indicated that MSCs exert curative effects on a variety of age-related diseases through regeneration and repair of aging cells and organs. However, as research has progressed, it has become clear that it is the MSCs derived exosomes (MSC-Exos) that may have a real role to play, and that they can be modified to achieve better therapeutic results, making them even more advantageous than MSCs for treating disease. This review generalizes the biological characteristics of MSCs and exosomes and their mechanisms in treating age-related diseases, for example, MSCs and their exosomes can treat age-related diseases through mechanisms such as oxidative stress (OS), Wnt/β-catenin signaling pathway, mitogen-activated protein kinases (MAPK) signaling pathway, and so on. In addition, current in vivo and in vitro trials are described, and ongoing clinical trials are discussed, as well as the prospects and challenges for the future use of exosomes in disease treatment. This review will provide references for using exosomes to treat age-related diseases.
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Affiliation(s)
- Jia Li
- Departments of Geriatrics, The First Hospital of China Medical University, Shenyang, China
| | - Yuling Huang
- Departments of Geriatrics, The First Hospital of China Medical University, Shenyang, China
| | - Haiyan Sun
- Department of Endodontics, School of Stomatology, China Medical University, Shenyang, China
| | - Lina Yang
- Departments of Geriatrics, The First Hospital of China Medical University, Shenyang, China
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17
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Xu H, Pan G, Wang J. Repairing Mechanisms for Distal Airway Injuries and Related Targeted Therapeutics for Chronic Lung Diseases. Cell Transplant 2023; 32:9636897231196489. [PMID: 37698245 PMCID: PMC10498699 DOI: 10.1177/09636897231196489] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 08/04/2023] [Accepted: 08/07/2023] [Indexed: 09/13/2023] Open
Abstract
Chronic lung diseases, such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), involve progressive and irreversible destruction and pathogenic remodeling of airways and have become the leading health care burden worldwide. Pulmonary tissue has extensive capacities to launch injury-responsive repairing programs (IRRPs) to replace the damaged or dead cells upon acute lung injuries. However, the IRRPs are frequently compromised in chronic lung diseases. In this review, we aim to provide an overview of somatic stem cell subpopulations within distal airway epithelium and the underlying mechanisms mediating their self-renewal and trans-differentiation under both physiological and pathological circumstances. We also compared the differences between humans and mice on distal airway structure and stem cell composition. At last, we reviewed the current status and future directions for the development of targeted therapeutics on defective distal airway regeneration and repairment in chronic lung diseases.
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Affiliation(s)
- Huahua Xu
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Guangzhou Laboratory, Guangzhou International Bio Island, Guangzhou, China
| | - Guihong Pan
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Jun Wang
- Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
- The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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18
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Gao X, Liu Z, Wang Z. Dental Pulp Stem Cells Ameliorate Elastase-Induced Pulmonary Emphysema by Regulating Inflammation and Oxidative Stress. J Inflamm Res 2023; 16:1497-1508. [PMID: 37064754 PMCID: PMC10094477 DOI: 10.2147/jir.s402794] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 03/17/2023] [Indexed: 04/18/2023] Open
Abstract
Background Dental pulp stem cells (DPSCs) are considered excellent candidates for stem cell-based tissue regeneration. In this study, we aimed to evaluate the therapeutic effect of DPSCs in a mouse chronic obstructive pulmonary disease (COPD) model and to explore whether DPSCs reduce lung inflammation and oxidative stress by regulating the nuclear factor erythroid-2 related factor-2 (Nrf2) signaling pathway. Methods DPSCs were isolated from dental pulp tissue by the tissue block method. Emphysema of C57BL/6 mice was induced by endotracheal administration of porcine pancreatic elastase (PPE). Then, the DPSCs were injected into the lungs through the trachea, and after 3 weeks of stem cell treatment, various efficacy tests were performed. The AniRes2005 animal lung function analytic system was used to detect lung function. Hematoxylin-eosin staining (H&E) and Victoria blue staining was used to assess emphysema severity. The animal tissues were detected by Western blot, RT‒qPCR, ELISA and oxidative stress related detection. Results In experimental COPD models, DPSCs transplantation improved lung function, body weight, and emphysema-like changes better than bone marrow mesenchyml stem cells (BM-MSCs). Compared with the COPD group, the levels of IL-1β, TNF-α and IL-6 in lung tissue and bronchoalveolar lavage fluid (BALF) were decreased after transplantation of DPSCs. DPSCs may be associated with lower malondialdehyde (MDA) levels, and higher catalase (CAT) and glutathione (GSH) levels. Western blot results showed that the expression of Nrf2 and its downstream factors increased after transplantation of DPSCs. Conclusion The current study showed that DPSCs had good performance in the treatment of a mouse COPD model and could be a promising option for stem cell therapy. DPSCs may play antioxidant and anti-inflammatory roles in COPD by activating the Nrf2 signaling pathway.
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Affiliation(s)
- Xiaoli Gao
- Department of Stomatology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, People’s Republic of China
| | - Zhiqiang Liu
- Department of Stomatology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, People’s Republic of China
| | - Zuomin Wang
- Department of Stomatology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, People’s Republic of China
- Correspondence: Zuomin Wang; Zhiqiang Liu, Department of Stomatology, Beijing Chao-Yang Hospital, Capital Medical University, 8 Gongti South Road, Chaoyang District, Beijing, 100020, People’s Republic of China, Tel +86 10 85231492, Email ;
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19
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Chellappan DK, Paudel KR, Tan NW, Cheong KS, Khoo SSQ, Seow SM, Chellian J, Candasamy M, Patel VK, Arora P, Singh PK, Singh SK, Gupta G, Oliver BG, Hansbro PM, Dua K. Targeting the mitochondria in chronic respiratory diseases. Mitochondrion 2022; 67:15-37. [PMID: 36176212 DOI: 10.1016/j.mito.2022.09.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 08/28/2022] [Accepted: 09/14/2022] [Indexed: 12/24/2022]
Abstract
Mitochondria are one of the basic essential components for eukaryotic life survival. It is also the source of respiratory ATP. Recently published studies have demonstrated that mitochondria may have more roles to play aside from energy production. There is an increasing body of evidence which suggest that mitochondrial activities involved in normal and pathological states contribute to significant impact to the lung airway morphology and epithelial function in respiratory diseases such as asthma, COPD, and lung cancer. This review summarizes the pathophysiological pathways involved in asthma, COPD, lung cancer and highlights potential treatment strategies that target the malfunctioning mitochondria in such ailments. Mitochondria are responsive to environmental stimuli such as infection, tobacco smoke, and inflammation, which are essential in the pathogenesis of respiratory diseases. They may affect mitochondrial shape, protein production and ultimately cause dysfunction. The impairment of mitochondrial function has downstream impact on the cytosolic components, calcium control, response towards oxidative stress, regulation of genes and proteins and metabolic activities. Several novel compounds and alternative medicines that target mitochondria in asthma and chronic lung diseases have been discussed here. Moreover, mitochondrial enzymes or proteins that may serve as excellent therapeutic targets in COPD are also covered. The role of mitochondria in respiratory diseases is gaining much attention and mitochondria-based treatment strategies and personalized medicine targeting the mitochondria may materialize in the near future. Nevertheless, more in-depth studies are urgently needed to validate the advantages and efficacy of drugs that affect mitochondria in pathological states.
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Affiliation(s)
- Dinesh Kumar Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia.
| | - Keshav Raj Paudel
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, NSW 2007, Australia
| | - Nian Wan Tan
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Ka Seng Cheong
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Samantha Sert Qi Khoo
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Su Min Seow
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Jestin Chellian
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Mayuren Candasamy
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Vyoma K Patel
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia; Australian Research Centre in Complementary and Integrative Medicine, Faculty of Health, University of Technology Sydney, Ultimo, NSW 2007, Australia; Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia
| | - Poonam Arora
- Department of Pharmacognosy and Phytochemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India; Department of Pharmacognosy and Phytochemistry, SGT College of Pharmacy, SGT University, Gurugram, Haryana, India
| | - Pankaj Kumar Singh
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana 500037, India
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi G.T Road, Phagwara, Punjab, India; Australian Research Centre in Complementary and Integrative Medicine, Faculty of Health, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Gaurav Gupta
- School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, Jaipur, India; Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India; Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Brian G Oliver
- School of Life Sciences, University of Technology Sydney, Sydney, NSW, 2007, Australia; Woolcock Institute of Medical Research, University of Sydney, Sydney, NSW, Australia
| | - Philip M Hansbro
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, NSW 2007, Australia.
| | - Kamal Dua
- Australian Research Centre in Complementary and Integrative Medicine, Faculty of Health, University of Technology Sydney, Ultimo, NSW 2007, Australia; Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia.
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20
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Combined Therapy Using Human Corneal Stromal Stem Cells and Quiescent Keratocytes to Prevent Corneal Scarring after Injury. Int J Mol Sci 2022; 23:ijms23136980. [PMID: 35805991 PMCID: PMC9267074 DOI: 10.3390/ijms23136980] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 06/18/2022] [Accepted: 06/21/2022] [Indexed: 02/04/2023] Open
Abstract
Corneal blindness due to scarring is conventionally treated by corneal transplantation, but the shortage of donor materials has been a major issue affecting the global success of treatment. Pre-clinical and clinical studies have shown that cell-based therapies using either corneal stromal stem cells (CSSC) or corneal stromal keratocytes (CSK) suppress corneal scarring at lower levels. Further treatments or strategies are required to improve the treatment efficacy. This study examined a combined cell-based treatment using CSSC and CSK in a mouse model of anterior stromal injury. We hypothesize that the immuno-regulatory nature of CSSC is effective to control tissue inflammation and delay the onset of fibrosis, and a subsequent intrastromal CSK treatment deposited collagens and stromal specific proteoglycans to recover a native stromal matrix. Using optimized cell doses, our results showed that the effect of CSSC treatment for suppressing corneal opacities was augmented by an additional intrastromal CSK injection, resulting in better corneal clarity. These in vivo effects were substantiated by a further downregulated expression of stromal fibrosis genes and the restoration of stromal fibrillar organization and regularity. Hence, a combined treatment of CSSC and CSK could achieve a higher clinical efficacy and restore corneal transparency, when compared to a single CSSC treatment.
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Abbaszadeh H, Ghorbani F, Abbaspour-Aghdam S, Kamrani A, Valizadeh H, Nadiri M, Sadeghi A, Shamsasenjan K, Jadidi-Niaragh F, Roshangar L, Ahmadi M. Chronic obstructive pulmonary disease and asthma: mesenchymal stem cells and their extracellular vesicles as potential therapeutic tools. Stem Cell Res Ther 2022; 13:262. [PMID: 35725505 PMCID: PMC9208161 DOI: 10.1186/s13287-022-02938-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 05/31/2022] [Indexed: 12/15/2022] Open
Abstract
Chronic lung diseases, such as chronic obstructive pulmonary disease (COPD) and asthma, are one of the most frequent causes of morbidity and mortality in the global. COPD is characterized by progressive loss of lung function through inflammation, apoptosis, and oxidative stress caused by chronic exposure to harmful environmental pollutants. Airway inflammation and epithelial remodeling are also two main characteristics of asthma. In spite of extensive efforts from researchers, there is still a great need for novel therapeutic approaches for treatment of these conditions. Accumulating evidence suggests the potential role of mesenchymal stem cells (MSCs) in treatment of many lung injuries due to their beneficial features including immunomodulation and tissue regeneration. Besides, the therapeutic advantages of MSCs are chiefly related to their paracrine functions such as releasing extracellular vesicles (EVs). EVs comprising exosomes and microvesicles are heterogeneous bilayer membrane structures loaded with various lipids, nucleic acids and proteins. Due to their lower immunogenicity, tumorigenicity, and easier management, EVs have appeared as favorable alternatives to stem cell therapies. Therefore, in this review, we provided an overview on the current understanding of the importance of MSCs and MSC-derived EVs from different sources reported in preclinical and clinical COPD and asthmatic models.
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Affiliation(s)
- Hossein Abbaszadeh
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farzaneh Ghorbani
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Amin Kamrani
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamed Valizadeh
- Tuberculosis and Lung Disease Research Center of Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Nadiri
- Tuberculosis and Lung Disease Research Center of Tabriz University of Medical Sciences, Tabriz, Iran
| | - Armin Sadeghi
- Tuberculosis and Lung Disease Research Center of Tabriz University of Medical Sciences, Tabriz, Iran
| | - Karim Shamsasenjan
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Leila Roshangar
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Majid Ahmadi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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22
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Mesenchymal Stem Cells Attenuate Acute Lung Injury in Mice Partly by Suppressing Alveolar Macrophage Activation in a PGE2-Dependent Manner. Inflammation 2022; 45:2000-2015. [PMID: 35699823 DOI: 10.1007/s10753-022-01670-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 01/26/2022] [Accepted: 04/08/2022] [Indexed: 11/05/2022]
Abstract
Mesenchymal stem cells (MSCs) have been demonstrated to attenuate acute lung injury (ALI). We also found that they can suppress the activation of alveolar macrophages (AMs), which can partly account for their therapeutic effects. MSCs do not inherently own immunosuppressive effects, when co-cultured with inflammatory immune cells, MSCs can be activated by inflammatory cytokines and meanwhile exert immunosuppressive effects. In order to further research, RNA sequencing (RNA-seq) of MSCs cultured before and after co-culturing with activated macrophages was performed. The data suggested a total of 5268 differentially expressed genes (DEGs) along the process. We used the data of 2754 upregulated DEGs to develop a signaling network of genes and the transcription factors targeting them in order to predict the altered functions of MSCs after exposure to inflammatory stimuli. This constructed network revealed some critical target genes and potential roles of MSCs under inflammatory conditions. According to the network, Ptgs2 was assumed to be an important gene participating in the immunosuppressive effects of MSCs. We also identified significant increases in the expression of COX2 protein and the secretion of PGE2 from MSCs. The use of the COX2 inhibitor NS-398 restrained the secretion of PGE2 and reversed the suppression of macrophage activation by MSCs in vitro. In addition, a selective antagonist of PGE2 binding receptor (EP4 receptor), GW627368X, also reversed the inhibitory effects of MSCs on AMs and the protective effects in ALI mouse. In summary, the therapeutic effects of MSCs on ALI partly occur through suppressing AM activation via PGE2 binding to EP4 receptor.
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23
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Calzetta L, Aiello M, Frizzelli A, Camardelli F, Cazzola M, Rogliani P, Chetta A. Stem Cell-Based Regenerative Therapy and Derived Products in COPD: A Systematic Review and Meta-Analysis. Cells 2022; 11:cells11111797. [PMID: 35681492 PMCID: PMC9180461 DOI: 10.3390/cells11111797] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 05/25/2022] [Accepted: 05/27/2022] [Indexed: 11/25/2022] Open
Abstract
COPD is an incurable disorder, characterized by a progressive alveolar tissue destruction and defective mechanisms of repair and defense leading to emphysema. Currently, treatment for COPD is exclusively symptomatic; therefore, stem cell-based therapies represent a promising therapeutic approach to regenerate damaged structures of the respiratory system and restore lung function. The aim of this study was to provide a quantitative synthesis of the efficacy profile of stem cell-based regenerative therapies and derived products in COPD patients. A systematic review and meta-analysis was performed according to PRISMA-P. Data from 371 COPD patients were extracted from 11 studies. Active treatments elicited a strong tendency towards significance in FEV1 improvement (+71 mL 95% CI -2−145; p = 0.056) and significantly increased 6MWT (52 m 95% CI 18−87; p < 0.05) vs. baseline or control. Active treatments did not reduce the risk of hospitalization due to acute exacerbations (RR 0.77 95% CI 0.40−1.49; p > 0.05). This study suggests that stem cell-based regenerative therapies and derived products may be effective to treat COPD patients, but the current evidence comes from small clinical trials. Large and well-designed randomized controlled trials are needed to really quantify the beneficial impact of stem cell-based regenerative therapy and derived products in COPD.
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Affiliation(s)
- Luigino Calzetta
- Respiratory Disease and Lung Function Unit, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (M.A.); (A.F.); (A.C.)
- Correspondence:
| | - Marina Aiello
- Respiratory Disease and Lung Function Unit, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (M.A.); (A.F.); (A.C.)
| | - Annalisa Frizzelli
- Respiratory Disease and Lung Function Unit, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (M.A.); (A.F.); (A.C.)
| | - Francesca Camardelli
- Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy; (F.C.); (M.C.); (P.R.)
| | - Mario Cazzola
- Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy; (F.C.); (M.C.); (P.R.)
| | - Paola Rogliani
- Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy; (F.C.); (M.C.); (P.R.)
| | - Alfredo Chetta
- Respiratory Disease and Lung Function Unit, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (M.A.); (A.F.); (A.C.)
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24
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Cheng Y, Gu W, Zhang G, Guo X. Notch1 activation of Jagged1 contributes to differentiation of mesenchymal stem cells into endothelial cells under cigarette smoke extract exposure. BMC Pulm Med 2022; 22:139. [PMID: 35410206 PMCID: PMC9004089 DOI: 10.1186/s12890-022-01913-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 03/23/2022] [Indexed: 11/30/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) have shown therapeutic potential for engraftment to, differentiation into, endothelial cells (ECs). However, low-efficiency yields hinder their use as ECs for therapeutic vascularization. Methods The Notch1 signaling pathway is key to optimal pulmonary development. Recent evidence has shown that this pathway participated in angiogenesis. Herein, we found that in MSCs, Jagged1 was a target for Notch 1, resulting in a positive feedback loop that propagated a wave of ECs differentiation. Results In vitro, Jagged1 was found to be activated by Notch1 in MSCs, resulting in the RBP-Jκ-dependent expression of Jagged1 mRNA, a response that was blocked by Notch1 inhibition. Notch1 promoted the formation of cord-like structures on Matrigel. However, cigarette smoke extract inhibited this process, compared to that in control groups. Moreover, Notch1-overexpressing cells upregulated the expressing of HIF-1α gene. The HIF-1α was an angiogenic factor that clustered with Notch1, underscoring the critical role of Notch1 pathway in vessel assembly. Interestingly, this was abrogated by incubation with Notch1 shRNA. Conclusions Notch signaling pathway promotes differentiation of MSCs in to ECs. It also regulates angiogenesis and transcription of specific markers on ECs. These results provide a mechanism that regulates differentiation of MSCs into ECs phenotypes. Supplementary Information The online version contains supplementary material available at 10.1186/s12890-022-01913-3.
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Affiliation(s)
- Yi Cheng
- Department of Respiratory Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 KongJiang Road, Shanghai, 200092, China
| | - Wen Gu
- Department of Respiratory Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 KongJiang Road, Shanghai, 200092, China
| | - Guorui Zhang
- Department of Respiratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xuejun Guo
- Department of Respiratory Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 KongJiang Road, Shanghai, 200092, China.
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25
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Jin QH, Kim HK, Na JY, Jin C, Seon JK. Anti-inflammatory effects of mesenchymal stem cell-conditioned media inhibited macrophages activation in vitro. Sci Rep 2022; 12:4754. [PMID: 35306509 PMCID: PMC8934344 DOI: 10.1038/s41598-022-08398-4] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 02/24/2022] [Indexed: 12/31/2022] Open
Abstract
The immunomodulatory effects of mesenchymal stem cells (MSCs) on macrophages have been reported, however, the underlying mechanism remains unknown. Therefore, this study aimed to investigate the anti-inflammatory effects of MSCs on lipopolysaccharide (LPS)-stimulated macrophages and the subsequent downregulation of their inflammatory mediators. Macrophages were treated with conditioned media from MSCs, without a subsequent change of MSCs responding to the inflammation state. This study also evaluated whether the interleukin (IL) 4 stimulation of MSCs can improve their anti-inflammatory effects. Results demonstrated that the MSC-conditioned medium (MSC-CM) stimulated with IL4 significantly inhibited inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression of LPS-activated macrophages. MSC-CM treatment inhibited the mRNA transcription of the cytokines IL1β and IL6, the chemokines C–C motif ligand (CCL) 2, CCL3, CCL4, and CCL5, and the chemokine receptors CCR2 and CCR5, in LPS-stimulated macrophages. As revealed through western blot and immunofluorescence analyses, the phosphorylation of p38, JNK, and ERK MAPKs, as well as phosphorylation of NF-κB in stimulated macrophages, were also inhibited by the MSC-CM. Further, more potent anti-inflammatory effects were observed with the IL4-stimulated cells, compared with those observed with the non-stimulated cells. The MSC-CM demonstrated a potent anti-inflammatory effect on LPS-activated macrophages, while the IL4 stimulation improved this effect. These findings indicate that MSCs could exert anti-inflammatory effects on macrophages, and may be considered as a therapeutic agent in inflammation treatment.
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26
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Mesenchymal stem cell-based treatments for COVID-19: status and future perspectives for clinical applications. Cell Mol Life Sci 2022; 79:142. [PMID: 35187617 PMCID: PMC8858603 DOI: 10.1007/s00018-021-04096-y] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 11/17/2021] [Accepted: 12/13/2021] [Indexed: 01/08/2023]
Abstract
As a result of cross-species transmission in December 2019, the coronavirus disease 2019 (COVID-19) became a serious endangerment to human health and the causal agent of a global pandemic. Although the number of infected people has decreased due to effective management, novel methods to treat critical COVID-19 patients are still urgently required. This review describes the origins, pathogenesis, and clinical features of COVID-19 and the potential uses of mesenchymal stem cells (MSCs) in therapeutic treatments for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients. MSCs have previously been shown to have positive effects in the treatment of lung diseases, such as acute lung injury, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, lung cancer, asthma, and chronic obstructive pulmonary disease. MSC mechanisms of action involve differentiation potentials, immune regulation, secretion of anti-inflammatory factors, migration and homing, anti-apoptotic properties, antiviral effects, and extracellular vesicles. Currently, 74 clinical trials are investigating the use of MSCs (predominately from the umbilical cord, bone marrow, and adipose tissue) to treat COVID-19. Although most of these trials are still in their early stages, the preliminary data are promising. However, long-term safety evaluations are still lacking, and large-scale and controlled trials are required for more conclusive judgments regarding MSC-based therapies. The main challenges and prospective directions for the use of MSCs in clinical applications are discussed herein. In summary, while the clinical use of MSCs to treat COVID-19 is still in the preliminary stages of investigation, promising results indicate that they could potentially be utilized in future treatments.
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27
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Squassoni SD, Sekiya EJ, Fiss E, Lapa MS, Cayetano DDS, Nascimento F, Alves A, Machado NC, Escaramboni B, Lívero FADR, Malagutti-Ferreira MJ, Soares MR, Dos Santos Figueiredo FW, Kramer BKN, Zago PMJJ, Ribeiro-Paes JT. Autologous Infusion of Bone Marrow and Mesenchymal Stromal Cells in Patients with Chronic Obstructive Pulmonary Disease: Phase I Randomized Clinical Trial. Int J Chron Obstruct Pulmon Dis 2022; 16:3561-3574. [PMID: 35002228 PMCID: PMC8733220 DOI: 10.2147/copd.s332613] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Accepted: 12/06/2021] [Indexed: 12/23/2022] Open
Abstract
Background and Objectives Chronic obstructive pulmonary disease (COPD) is characterized by the destruction of alveolar walls, chronic inflammation and persistent respiratory symptoms. There is no curative clinical treatment for COPD. In this context, cell-based therapy is a promising therapeutic alternative for COPD. Thus, in this open, controlled and randomized Phase I Clinical Trial, we aimed to assess the safety of the infusion of autologous bone marrow mononuclear cells (BMMC), adipose-derived mesenchymal stromal cells (ADSC) and, especially, the safety of concomitant infusion (co-infusion) of BMMC and ADSC as a new therapeutic alternative for COPD. The rationale for co-infusion of BMMC and ADSC is based on the hypothesis of an additive or synergistic therapeutic effect resulting from this association. Methods To achieve the proposed objectives, twenty patients with moderate-to-severe COPD were randomly divided into four groups: control group - patients receiving conventional treatment; BMMC group - patients receiving only BMMC; ADSC group - patients receiving only ADSC, and co-infusion group - patients receiving the concomitant infusion of BMMC and ADSC. Patients were assessed for pulmonary function, biochemical profile, and quality of life over a 12 months follow-up. Results No adverse events were detected immediately after the infusion of BMMC, ADSC or co-infusion. In the 12-month follow-up, no causal relationship was established between adverse events and cell therapy procedures. Regarding the efficacy, the BMMC group showed an increase in forced expiratory volume (FEV1) and diffusing capacity for carbon monoxide (DLCO). Co-infusion group showed a DLCO, and gas exchange improvement and a better quality of life. Conclusion The results obtained allow us to conclude that cell-based therapy with co-infusion of BMMC and ADSC is a safe procedure and a promising therapeutic for COPD. However, additional studies with a greater number of patients are needed before randomized and controlled Phase III clinical trials can be implemented.
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Affiliation(s)
| | - Eliseo Joji Sekiya
- São Lucas Research and Education Institute (IEP-Sao Lucas), TechLife, São Paulo, SP, Brazil
| | - Elie Fiss
- ABC Medical School, São Paulo, SP, Brazil.,Hospital Alemão Oswaldo Cruz, São Paulo, SP, Brazil
| | | | | | - Flávia Nascimento
- São Lucas Research and Education Institute (IEP-Sao Lucas), TechLife, São Paulo, SP, Brazil
| | - Adelson Alves
- São Lucas Research and Education Institute (IEP-Sao Lucas), TechLife, São Paulo, SP, Brazil
| | | | | | | | | | - Murilo Racy Soares
- Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, SP, Brazil
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28
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Shaw TD, Krasnodembskaya AD, Schroeder GN, Zumla A, Maeurer M, O’Kane CM. Mesenchymal Stromal Cells: an Antimicrobial and Host-Directed Therapy for Complex Infectious Diseases. Clin Microbiol Rev 2021; 34:e0006421. [PMID: 34612662 PMCID: PMC8510528 DOI: 10.1128/cmr.00064-21] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
There is an urgent need for new antimicrobial strategies for treating complex infections and emerging pathogens. Human mesenchymal stromal cells (MSCs) are adult multipotent cells with antimicrobial properties, mediated through direct bactericidal activity and modulation of host innate and adaptive immune cells. More than 30 in vivo studies have reported on the use of human MSCs for the treatment of infectious diseases, with many more studies of animal MSCs in same-species models of infection. MSCs demonstrate potent antimicrobial effects against the major classes of human pathogens (bacteria, viruses, fungi, and parasites) across a wide range of infection models. Mechanistic studies have yielded important insight into their immunomodulatory and bactericidal activity, which can be enhanced through various forms of preconditioning. MSCs are being investigated in over 80 clinical trials for difficult-to-treat infectious diseases, including sepsis and pulmonary, intra-abdominal, cutaneous, and viral infections. Completed trials consistently report MSCs to be safe and well tolerated, with signals of efficacy against some infectious diseases. Although significant obstacles must be overcome to produce a standardized, affordable, clinical-grade cell therapy, these studies suggest that MSCs may have particular potential as an adjunct therapy in complex or resistant infections.
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Affiliation(s)
- Timothy D. Shaw
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast, United Kingdom
| | - Anna D. Krasnodembskaya
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast, United Kingdom
| | - Gunnar N. Schroeder
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast, United Kingdom
| | - Alimuddin Zumla
- Center for Clinical Microbiology, Division of Infection and Immunity, University College London, NIHR Biomedical Research Centre, UCL Hospitals NHS Foundation Trust, London, United Kingdom
| | - Markus Maeurer
- Immunosurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal
- Department of Oncology and Haematology, Krankenhaus Nordwest, Frankfurt, Germany
| | - Cecilia M. O’Kane
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast, United Kingdom
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29
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Caldeira DDAF, Weiss DJ, Rocco PRM, Silva PL, Cruz FF. Mitochondria in Focus: From Function to Therapeutic Strategies in Chronic Lung Diseases. Front Immunol 2021; 12:782074. [PMID: 34887870 PMCID: PMC8649841 DOI: 10.3389/fimmu.2021.782074] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 10/29/2021] [Indexed: 01/14/2023] Open
Abstract
Mitochondria are essential organelles for cell metabolism, growth, and function. Mitochondria in lung cells have important roles in regulating surfactant production, mucociliary function, mucus secretion, senescence, immunologic defense, and regeneration. Disruption in mitochondrial physiology can be the central point in several pathophysiologic pathways of chronic lung diseases such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and asthma. In this review, we summarize how mitochondria morphology, dynamics, redox signaling, mitophagy, and interaction with the endoplasmic reticulum are involved in chronic lung diseases and highlight strategies focused on mitochondrial therapy (mito-therapy) that could be tested as a potential therapeutic target for lung diseases.
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Affiliation(s)
- Dayene de Assis Fernandes Caldeira
- Laboratory of Pulmonary Investigation, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Daniel J Weiss
- Department of Medicine, College of Medicine, University of Vermont, Burlington, VT, United States
| | - Patricia Rieken Macêdo Rocco
- Laboratory of Pulmonary Investigation, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.,National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil.,Rio de Janeiro Innovation Network in Nanosystems for Health-NanoSAÚDE/FAPERJ, Rio de Janeiro, Brazil
| | - Pedro Leme Silva
- Laboratory of Pulmonary Investigation, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.,National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil.,Rio de Janeiro Innovation Network in Nanosystems for Health-NanoSAÚDE/FAPERJ, Rio de Janeiro, Brazil
| | - Fernanda Ferreira Cruz
- Laboratory of Pulmonary Investigation, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.,National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil.,Rio de Janeiro Innovation Network in Nanosystems for Health-NanoSAÚDE/FAPERJ, Rio de Janeiro, Brazil
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30
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Nasri A, Foisset F, Ahmed E, Lahmar Z, Vachier I, Jorgensen C, Assou S, Bourdin A, De Vos J. Roles of Mesenchymal Cells in the Lung: From Lung Development to Chronic Obstructive Pulmonary Disease. Cells 2021; 10:3467. [PMID: 34943975 PMCID: PMC8700565 DOI: 10.3390/cells10123467] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 12/02/2021] [Accepted: 12/07/2021] [Indexed: 12/28/2022] Open
Abstract
Mesenchymal cells are an essential cell type because of their role in tissue support, their multilineage differentiation capacities and their potential clinical applications. They play a crucial role during lung development by interacting with airway epithelium, and also during lung regeneration and remodeling after injury. However, much less is known about their function in lung disease. In this review, we discuss the origins of mesenchymal cells during lung development, their crosstalk with the epithelium, and their role in lung diseases, particularly in chronic obstructive pulmonary disease.
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Affiliation(s)
- Amel Nasri
- Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM, Centre Hospitalier Universitaire de Montpellier, 34000 Montpellier, France; (A.N.); (F.F.); (C.J.); (S.A.)
| | - Florent Foisset
- Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM, Centre Hospitalier Universitaire de Montpellier, 34000 Montpellier, France; (A.N.); (F.F.); (C.J.); (S.A.)
| | - Engi Ahmed
- Department of Respiratory Diseases, Université de Montpellier, INSERM, Centre Hospitalier Universitaire de Montpellier, 34090 Montpellier, France; (E.A.); (Z.L.); (I.V.); (A.B.)
- PhyMedExp, Université de Montpellier, INSERM, Centre Hospitalier Universitaire de Montpellier, 34295 Montpellier, France
| | - Zakaria Lahmar
- Department of Respiratory Diseases, Université de Montpellier, INSERM, Centre Hospitalier Universitaire de Montpellier, 34090 Montpellier, France; (E.A.); (Z.L.); (I.V.); (A.B.)
- PhyMedExp, Université de Montpellier, INSERM, Centre Hospitalier Universitaire de Montpellier, 34295 Montpellier, France
| | - Isabelle Vachier
- Department of Respiratory Diseases, Université de Montpellier, INSERM, Centre Hospitalier Universitaire de Montpellier, 34090 Montpellier, France; (E.A.); (Z.L.); (I.V.); (A.B.)
| | - Christian Jorgensen
- Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM, Centre Hospitalier Universitaire de Montpellier, 34000 Montpellier, France; (A.N.); (F.F.); (C.J.); (S.A.)
| | - Said Assou
- Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM, Centre Hospitalier Universitaire de Montpellier, 34000 Montpellier, France; (A.N.); (F.F.); (C.J.); (S.A.)
| | - Arnaud Bourdin
- Department of Respiratory Diseases, Université de Montpellier, INSERM, Centre Hospitalier Universitaire de Montpellier, 34090 Montpellier, France; (E.A.); (Z.L.); (I.V.); (A.B.)
- PhyMedExp, Université de Montpellier, INSERM, Centre Hospitalier Universitaire de Montpellier, 34295 Montpellier, France
| | - John De Vos
- Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM, Centre Hospitalier Universitaire de Montpellier, 34000 Montpellier, France; (A.N.); (F.F.); (C.J.); (S.A.)
- Department of Cell and Tissue Engineering, Université de Montpellier, Centre Hospitalier Universitaire de Montpellier, 34000 Montpellier, France
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31
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Li Y, Fu C, Liu L, Liu Y, Li F. mTOR and ERK1/2 signaling participate in the process of acetate regulating lipid metabolism and HSL expression. Anim Biosci 2021; 35:1444-1453. [PMID: 34727637 PMCID: PMC9449403 DOI: 10.5713/ab.21.0341] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 10/01/2021] [Indexed: 11/27/2022] Open
Abstract
Objective Acetate plays an important role in host lipid metabolism. However, the network of acetate-regulated lipid metabolism remains unclear. Previous studies show that mitogen-activated protein kinases (MAPKs) and mechanistic target of rapamycin (mTOR) play a crucial role in lipid metabolism. We hypothesize that acetate could affect MAPKs and/or mTOR signaling and then regulate lipid metabolism. The present study investigated whether any cross talk occurs among MAPKs, mTOR and acetate in regulating lipid metabolism. Methods The ceramide C6 (an extracellular signaling-regulated kinases 1 and 2 [ERK1/2] activator) and MHY1485 (a mTOR activator) were used to treat rabbit adipose-derived stem cells (ADSCs) with or without acetate, respectively. Results It indicated that acetate (9 mM) treatment for 48 h decreased the lipid deposition in rabbit ADSCs. Acetate treatment decreased significantly phosphorylated protein levels of ERK1/2 and mTOR but significantly increased mRNA level of hormone-sensitive lipase (HSL). Acetate treatment did not significantly alter the phosphorylated protein level of p38 MAPK and c-Jun aminoterminal kinase (JNK). Activation of ERK1/2 and mTOR by respective addition in media with ceramide C6 and MHY1485 significantly attenuated decreased lipid deposition and increased HSL expression caused by acetate. Conclusion Our results suggest that ERK1/2 and mTOR signaling pathways are associated with acetate regulated HSL gene expression and lipid deposition.
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Affiliation(s)
- Yujuan Li
- Department of Animal Science, Shandong Agricultural University, Taian, Shandong 271018, China
| | - Chunyan Fu
- Department of Animal Science, Shandong Agricultural University, Taian, Shandong 271018, China.,Poultry Institute, Shandong Academy of Agricultural Science, Jinan, Shandong 250023, China
| | - Lei Liu
- Department of Animal Science, Shandong Agricultural University, Taian, Shandong 271018, China
| | - Yongxu Liu
- Qingdao Kangda Food Co., LTD., Qingdao, Shandong 266555, China
| | - Fuchang Li
- Department of Animal Science, Shandong Agricultural University, Taian, Shandong 271018, China
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Wang M, Zhou T, Zhang Z, Liu H, Zheng Z, Xie H. Current therapeutic strategies for respiratory diseases using mesenchymal stem cells. MedComm (Beijing) 2021; 2:351-380. [PMID: 34766151 PMCID: PMC8554668 DOI: 10.1002/mco2.74] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 03/15/2021] [Accepted: 03/18/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stromal/stem cells (MSCs) have a great potential to proliferate, undergo multi-directional differentiation, and exert immunoregulatory effects. There is already much enthusiasm for their therapeutic potentials for respiratory inflammatory diseases. Although the mechanism of MSCs-based therapy has been well explored, only a few articles have summarized the key advances in this field. We hereby provide a review over the latest progresses made on the MSCs-based therapies for four types of inflammatory respiratory diseases, including idiopathic pulmonary fibrosis, acute respiratory distress syndrome, chronic obstructive pulmonary disease, and asthma, and the uncovery of their underlying mechanisms from the perspective of biological characteristics and functions. Furthermore, we have also discussed the advantages and disadvantages of the MSCs-based therapies and prospects for their optimization.
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Affiliation(s)
- Ming‐yao Wang
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Ting‐yue Zhou
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Zhi‐dong Zhang
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Hao‐yang Liu
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Zhi‐yao Zheng
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Hui‐qi Xie
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
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Zhang Y, Li Y, Fu X, Wang P, Wang Q, Meng W, Wang T, Yang J, Chai R. The Detrimental and Beneficial Functions of Macrophages After Cochlear Injury. Front Cell Dev Biol 2021; 9:631904. [PMID: 34458249 PMCID: PMC8385413 DOI: 10.3389/fcell.2021.631904] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Accepted: 07/14/2021] [Indexed: 12/20/2022] Open
Abstract
Macrophages are the main intrinsic immune cells in the cochlea; they can be activated and play a complicated role after cochlear injury. Many studies have shown that the number of macrophages and their morphological characteristics within the major cochlear partitions undergo significant changes under various pathological conditions including acoustic trauma, ototoxic drug treatment, age-related cochlear degeneration, selective hair cell (HC) and spiral ganglion neuron (SGN) elimination, and surgery. However, the exact role of these macrophages after cochlear injury is still unclear. Regulating the migration and activity of macrophages may be a therapeutic approach to reduce the risk or magnitude of trauma-induced hearing loss, and this review highlights the role of macrophages on the peripheral auditory structures of the cochlea and elucidate the mechanisms of macrophage injury and the strategies to reduce the injury by regulating macrophage.
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Affiliation(s)
- Yuan Zhang
- MOE Key Laboratory for Developmental Genes and Human Disease, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, School of Life Sciences and Technology, Southeast University, Nanjing, China.,Department of Otolaryngology Head and Neck, Nanjing Tongren Hospital, School of Medicine, Southeast University, Nanjing, China.,Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Yiyuan Li
- MOE Key Laboratory for Developmental Genes and Human Disease, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, School of Life Sciences and Technology, Southeast University, Nanjing, China
| | - Xiaolong Fu
- MOE Key Laboratory for Developmental Genes and Human Disease, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, School of Life Sciences and Technology, Southeast University, Nanjing, China
| | - Pengjun Wang
- Department of Otorhinolaryngology, Affiliated Sixth People's Hospital of Shanghai Jiao Tong University, Shanghai, China
| | - Qin Wang
- Department of Otolaryngology-Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Wei Meng
- Department of Otolaryngology Head and Neck, Nanjing Tongren Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Tian Wang
- Department of Otolaryngology-Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Jianming Yang
- Department of Otorhinolaryngology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Renjie Chai
- MOE Key Laboratory for Developmental Genes and Human Disease, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, School of Life Sciences and Technology, Southeast University, Nanjing, China.,Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
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34
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Abdul Halim NSS, Yahaya BH, Lian J. Therapeutic Potential of Adipose-Derived Stem Cells in the Treatment of Pulmonary Diseases. Curr Stem Cell Res Ther 2021; 17:103-112. [PMID: 34387168 DOI: 10.2174/1574888x16666210812145202] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 05/07/2021] [Accepted: 05/25/2021] [Indexed: 11/22/2022]
Abstract
Stem cells derived from adipose tissues (ADSCs) have emerged as an ideal candidate for various models of respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome. ADSCs have qualities that may make them better suited for treating inflammatory lung diseases than other MSCs. ADSCs show a lower senescence ratio, higher proliferative capacity and stability in terms of their genetic and morphology during long-term culture over bone marrow-derived mesenchymal stem cells (BMMSCs). With advanced research techniques, the advantageous effects of ADSCs seem limited to their ability to engraft, differentiate, and be related to their secretion of trophic factors. These trophic factors regulate the therapeutic and regenerative outcomes in various lung inflammatory diseases. Taken together, these particular qualities of ADSCs make them significantly relevant for clinical applications. This article discusses a recent advance of ADSCs biology and their translational application emphasizing their anti-inflammatory, immunomodulatory and regenerative properties particularly on lung inflammatory diseases. Besides, the relevant advancements made in the field, the regulatory aspects, and other challenges and obstacles will be highlighted.
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Affiliation(s)
- Nur Shuhaidatul Sarmiza Abdul Halim
- Lung Stem Cell and Gene Therapy Group, Regenerative Medicine Cluster, Advanced Medical and Dental Institute (IPPT), SAINS@BERTAM, Universiti Sains Malaysia, 13200 Kepala Batas, Penang . Malaysia
| | - Badrul Hisham Yahaya
- Lung Stem Cell and Gene Therapy Group, Regenerative Medicine Cluster, Advanced Medical and Dental Institute (IPPT), SAINS@BERTAM, Universiti Sains Malaysia, 13200 Kepala Batas, Penang . Malaysia
| | - Jie Lian
- Lung Stem Cell and Gene Therapy Group, Regenerative Medicine Cluster, Advanced Medical and Dental Institute (IPPT), SAINS@BERTAM, Universiti Sains Malaysia, 13200 Kepala Batas, Penang . Malaysia
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35
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Chen YT, Miao K, Zhou L, Xiong WN. Stem cell therapy for chronic obstructive pulmonary disease. Chin Med J (Engl) 2021; 134:1535-1545. [PMID: 34250959 PMCID: PMC8280064 DOI: 10.1097/cm9.0000000000001596] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Indexed: 12/25/2022] Open
Abstract
ABSTRACT Chronic obstructive pulmonary disease (COPD), characterized by persistent and not fully reversible airflow restrictions, is currently one of the most widespread chronic lung diseases in the world. The most common symptoms of COPD are cough, expectoration, and exertional dyspnea. Although various strategies have been developed during the last few decades, current medical treatment for COPD only focuses on the relief of symptoms, and the reversal of lung function deterioration and improvement in patient's quality of life are very limited. Consequently, development of novel effective therapeutic strategies for COPD is urgently needed. Stem cells were known to differentiate into a variety of cell types and used to regenerate lung parenchyma and airway structures. Stem cell therapy is a promising therapeutic strategy that has the potential to restore the lung function and improve the quality of life in patients with COPD. This review summarizes the current state of knowledge regarding the clinical research on the treatment of COPD with mesenchymal stem cells (MSCs) and aims to update the understanding of the role of MSCs in COPD treatment, which may be helpful for developing effective therapeutic strategies in clinical settings.
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Affiliation(s)
- Yun-Tian Chen
- Department of Pulmonary and Critical Care Medicine, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China
| | - Kang Miao
- Department of Pulmonary and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Key Cite of National Clinical Research Center for Respiratory Disease, Wuhan Clinical Medical Research Center for Chronic Airway Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Linfu Zhou
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Wei-Ning Xiong
- Department of Pulmonary and Critical Care Medicine, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China
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36
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Weiss DJ, Segal K, Casaburi R, Hayes J, Tashkin D. Effect of mesenchymal stromal cell infusions on lung function in COPD patients with high CRP levels. Respir Res 2021; 22:142. [PMID: 33964910 PMCID: PMC8106850 DOI: 10.1186/s12931-021-01734-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 04/26/2021] [Indexed: 12/13/2022] Open
Abstract
Background We previously reported a Phase 1/2 randomized placebo-controlled trial of systemic administration of bone marrow-derived allogeneic MSCs (remestemcel-L) in COPD. While safety profile was good, no functional efficacy was observed. However, in view of growing recognition of effects of inflammatory environments on MSC actions we conducted a post-hoc analysis with stratification by baseline levels of a circulating inflammatory marker, C-reactive protein (CRP) to determine the effects of MSC administration in COPD patients with varying circulating CRP levels. Methods Time course of lung function, exercise performance, patient reported responses, and exacerbation frequency following four monthly infusions of remestemcel-L vs. placebo were re-assessed in subgroups based on baseline circulating CRP levels. Results In COPD patients with baseline CRP ≥ 4 mg/L, compared to COPD patients receiving placebo (N = 17), those treated with remestemcel-L (N = 12), demonstrated significant improvements from baseline in forced expiratory volume in one second, forced vital capacity, and six minute walk distance at 120 days with treatment differences evident as early as 10 days after the first infusion. Significant although smaller benefits were also detected in those with CRP levels ≥ 2 or ≥ 3 mg/L. These improvements persisted variably over the 2-year observational period. No significant benefits were observed in patient reported responses or number of COPD exacerbations between treatment groups. Conclusion In an inflammatory environment, defined by elevated circulating CRP, remestemcel-L administration yielded at least transient meaningful pulmonary and functional improvements. These findings warrant further investigation of potential MSC-based therapies in COPD and other inflammatory pulmonary diseases. Trial registration: Clinicaltrials.gov NCT00683722.
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Affiliation(s)
- Daniel J Weiss
- University of Vermont College of Medicine, 226 Health Science Research Facility, Burlington, VT, 05405, USA.
| | | | - Richard Casaburi
- Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | | | - Donald Tashkin
- UCLA David Geffen School of Medicine, Los Angeles, CA, USA
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37
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Glassberg MK, Csete I, Simonet E, Elliot SJ. Stem Cell Therapy for COPD: Hope and Exploitation. Chest 2021; 160:1271-1281. [PMID: 33894254 DOI: 10.1016/j.chest.2021.04.020] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 04/05/2021] [Accepted: 04/11/2021] [Indexed: 12/21/2022] Open
Abstract
COPD is a chronic inflammatory and destructive disease characterized by progressive decline in lung function that can accelerate with aging. Preclinical studies suggest that mesenchymal stem cells (MSCs) may provide a therapeutic option for this incurable disease because of their antiinflammatory, reparative, and immunomodulatory properties. To date, clinical trials using MSCs demonstrate safety in patients with COPD. However, because of the notable absence of large, multicenter randomized trials, no efficacy or evidence exists to support the possibility that MSCs can restore lung function in patients with COPD. Unfortunately, the investigational status of cell-based interventions for lung diseases has not hindered the propagation of commercial businesses, exploitation of the public, and explosion of medical tourism to promote unproven and potentially harmful cell-based interventions for COPD in the United States and worldwide. Patients with COPD constitute the largest group of patients with lung disease flocking to these unregulated clinics. This review highlights the numerous questions and concerns that remain before the establishment of cell-based interventions as safe and efficacious treatments for patients with COPD.
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Affiliation(s)
- Marilyn K Glassberg
- Division of Pulmonary, Critical Care, and Sleep, Department of Medicine, University of Arizona College of Medicine, Phoenix, AZ.
| | | | | | - Sharon J Elliot
- Division of Pulmonary, Critical Care, and Sleep, Department of Medicine, University of Arizona College of Medicine, Phoenix, AZ; University of Miami Miller School of Medicine, Miami, FL
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38
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Karnati S, Seimetz M, Kleefeldt F, Sonawane A, Madhusudhan T, Bachhuka A, Kosanovic D, Weissmann N, Krüger K, Ergün S. Chronic Obstructive Pulmonary Disease and the Cardiovascular System: Vascular Repair and Regeneration as a Therapeutic Target. Front Cardiovasc Med 2021; 8:649512. [PMID: 33912600 PMCID: PMC8072123 DOI: 10.3389/fcvm.2021.649512] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 03/08/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide and encompasses chronic bronchitis and emphysema. It has been shown that vascular wall remodeling and pulmonary hypertension (PH) can occur not only in patients with COPD but also in smokers with normal lung function, suggesting a causal role for vascular alterations in the development of emphysema. Mechanistically, abnormalities in the vasculature, such as inflammation, endothelial dysfunction, imbalances in cellular apoptosis/proliferation, and increased oxidative/nitrosative stress promote development of PH, cor pulmonale, and most probably pulmonary emphysema. Hypoxemia in the pulmonary chamber modulates the activation of key transcription factors and signaling cascades, which propagates inflammation and infiltration of neutrophils, resulting in vascular remodeling. Endothelial progenitor cells have angiogenesis capabilities, resulting in transdifferentiation of the smooth muscle cells via aberrant activation of several cytokines, growth factors, and chemokines. The vascular endothelium influences the balance between vaso-constriction and -dilation in the heart. Targeting key players affecting the vasculature might help in the development of new treatment strategies for both PH and COPD. The present review aims to summarize current knowledge about vascular alterations and production of reactive oxygen species in COPD. The present review emphasizes on the importance of the vasculature for the usually parenchyma-focused view of the pathobiology of COPD.
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Affiliation(s)
- Srikanth Karnati
- Institute of Anatomy and Cell Biology, Julius-Maximilians-University Würzburg, Würzburg, Germany
| | - Michael Seimetz
- Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Florian Kleefeldt
- Institute of Anatomy and Cell Biology, Julius-Maximilians-University Würzburg, Würzburg, Germany
| | - Avinash Sonawane
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, India
| | - Thati Madhusudhan
- Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany
| | - Akash Bachhuka
- UniSA Science, Technology, Engineering and Mathematics, University of South Australia, Mawson Lakes Campus, Adelaide, SA, Australia
| | - Djuro Kosanovic
- Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.,Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Norbert Weissmann
- Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Karsten Krüger
- Department of Exercise Physiology and Sports Therapy, University of Giessen, Giessen, Germany
| | - Süleyman Ergün
- Institute of Anatomy and Cell Biology, Julius-Maximilians-University Würzburg, Würzburg, Germany
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39
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Deng Y, Li L, Zhu JH, Li PP, Deng YX, Luo HH, Yang YY, He BC, Su Y. COX-2 promotes the osteogenic potential of BMP9 through TGF-β1/p38 signaling in mesenchymal stem cells. Aging (Albany NY) 2021; 13:11336-11351. [PMID: 33833129 PMCID: PMC8109063 DOI: 10.18632/aging.202825] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 01/21/2021] [Indexed: 12/14/2022]
Abstract
This study investigated the effects of transforming growth factor-β1 (TGF-β1) and cyclooxygenase-2 (COX-2) on bone morphogenetic protein 9 (BMP9) in mesenchymal stem cells (MSCs). We found that BMP9 increased mRNA levels of TGF-β1 and COX-2 in C3H10T1/2 cells. BMP9-induced osteogenic markers were enhanced by TGF-β1 and reduced by TGF-βRI-specific inhibitor LY364947. BMP9 increased level of p-Smad2/3, which were either enhanced or reduced by COX-2 and its inhibitor NS398. BMP9-induced osteogenic markers were decreased by NS398 and it was partially reversed by TGF-β1. COX-2 increased BMP9-induced osteogenic marker levels, which almost abolished by LY364947. BMP9-induced bone formation was enhanced by TGF-β1 but reduced by silencing TGF-β1 or COX-2. BMP9’s osteogenic ability was inhibited by silencing COX-2 but partially reversed by TGF-β1. TGF-β1 and COX-2 enhanced activation of p38 signaling, which was induced by BMP9 and reduced by LY364947. The ability of TGF-β1 to increase the BMP9-induced osteogenic markers was reduced by p38-specific inhibitor, while BMP9-induced TGF-β1 expression was reduced by NS398, but enhanced by COX-2. Furthermore, CREB interacted with Smad1/5/8 to regulate TGF-β1 expression in MSCs. These findings suggest that COX-2 overexpression leads to increase BMP9’s osteogenic ability, resulting from TGF-β1 upregulation which then activates p38 signaling in MSCs.
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Affiliation(s)
- Yan Deng
- Department of Orthopedics, Children's Hospital of Chongqing Medical University, Chongqing 400014, China.,Chongqing Key Laboratory of Pediatrics, Chongqing Medical University, Chongqing 400014, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Medical University, Chongqing 400014, China.,National Clinical Research Center for Child Health and Disorders, Chongqing Medical University, Chongqing 400014, China.,China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Medical University, Chongqing 400014, China.,Children's Hospital of Chongqing Medical University, Chongqing 400014, China.,Key Laboratory of Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing 400016, China.,Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, China
| | - Ling Li
- Key Laboratory of Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing 400016, China.,Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, China
| | - Jia-Hui Zhu
- Key Laboratory of Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing 400016, China.,Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, China
| | - Pei-Pei Li
- Key Laboratory of Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing 400016, China.,Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, China
| | - Yi-Xuan Deng
- Key Laboratory of Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing 400016, China.,Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, China
| | - Hong-Hong Luo
- Key Laboratory of Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing 400016, China.,Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, China
| | - Yuan-Yuan Yang
- Key Laboratory of Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing 400016, China.,Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, China
| | - Bai-Cheng He
- Key Laboratory of Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing 400016, China.,Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, China
| | - Yuxi Su
- Department of Orthopedics, Children's Hospital of Chongqing Medical University, Chongqing 400014, China.,Chongqing Key Laboratory of Pediatrics, Chongqing Medical University, Chongqing 400014, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Medical University, Chongqing 400014, China.,National Clinical Research Center for Child Health and Disorders, Chongqing Medical University, Chongqing 400014, China.,China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Medical University, Chongqing 400014, China.,Children's Hospital of Chongqing Medical University, Chongqing 400014, China
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40
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Üçal M, Maurer C, Etschmaier V, Hamberger D, Grünbacher G, Tögl L, Roosen MJ, Molcanyi M, Vorholt D, Hatay FF, Hescheler J, Pallasch C, Schäfer U, Patz S. Inflammatory Pre-Conditioning of Adipose-Derived Stem Cells with Cerebrospinal Fluid from Traumatic Brain Injury Patients Alters the Immunomodulatory Potential of ADSC Secretomes. J Neurotrauma 2021; 38:2311-2322. [PMID: 33514282 DOI: 10.1089/neu.2020.7017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Immunomodulation by adipose-tissue-derived stem cells (ADSCs) is of special interest for the alleviation of damaging inflammatory responses in central nervous system injuries. The present study explored the effects of cerebrospinal fluid (CSF) from traumatic brain injury (TBI) patients on this immunomodulatory potential of ADSCs. CSF conditioning of ADSCs increased messenger RNA levels of both pro- and anti-inflammatory genes compared to controls. Exposure of phorbol-12-myristate-13-acetate-differentiated THP1 macrophages to the secretome of CSF-conditioned ADSCs downregulated both proinflammatory (cyclooxygenase-2, tumor necrosis factor alpha) and anti-inflammatory (suppressor of cytokine signaling 3, interleukin-1 receptor antagonist, and transforming growth factor beta) genes in these cells. Interleukin-10 expression was elevated in both naïve and conditioned secretomes. ADSC secretome treatment, further, induced macrophage maturation of THP1 cells and increased the percentage of CD11b+, CD14+, CD86+, and, to a lesser extent, CD206+ cells. This, moreover, enhanced the phagocytic activity of CD14+ and CD86+ cells, though independently of pre-conditioning. Secretome exposure, finally, also induced a reduction in the percentage of CD192+ adherent cells in cultures of peripheral blood mononuclear cells (PBMCs) from both healthy subjects and TBI patients. This limited efficacy (of both naïve and pre-conditioned secretomes) suggests that the effects of lymphocyte-monocyte paracrine signaling on the fate of cultured PBMCs are strongest upon adherent cell populations.
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Affiliation(s)
- Muammer Üçal
- Department of Neurosurgery, Medical University Graz, Graz, Austria
| | - Christa Maurer
- Department of Neurosurgery, Medical University Graz, Graz, Austria.,Ruprecht-Karls-University Heidelberg, Institute for Anatomy and Cell Biology, Division for Medical Cell Biology, Heidelberg, Germany
| | | | - Daniel Hamberger
- Department of Neurosurgery, Medical University Graz, Graz, Austria.,National Centre for Tumour Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
| | - Gerda Grünbacher
- Department of Neurosurgery, Medical University Graz, Graz, Austria
| | - Lennart Tögl
- Department of Neurosurgery, Medical University Graz, Graz, Austria
| | - Marvin J Roosen
- Department of Neurosurgery, Medical University Graz, Graz, Austria
| | - Marek Molcanyi
- Department of Neurosurgery, Medical University Graz, Graz, Austria.,Institute of Neurophysiology, Medical Faculty, University of Cologne, Cologne, Germany
| | - Daniela Vorholt
- Department of Internal Medicine, Centre for Integrated Oncology Aachen Bonn Cologne Düsseldorf, CECAD Centre of Excellence on Cellular Stress Responses in Aging-Associated Diseases, Centre for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.,Miltenyi Biotec B.V. & Co. KG, Bergisch Gladbach, Germany
| | - F Fulya Hatay
- Institute of Neurophysiology, Medical Faculty, University of Cologne, Cologne, Germany
| | - Jürgen Hescheler
- Institute of Neurophysiology, Medical Faculty, University of Cologne, Cologne, Germany
| | - Christian Pallasch
- Department of Internal Medicine, Centre for Integrated Oncology Aachen Bonn Cologne Düsseldorf, CECAD Centre of Excellence on Cellular Stress Responses in Aging-Associated Diseases, Centre for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Ute Schäfer
- Department of Neurosurgery, Medical University Graz, Graz, Austria
| | - Silke Patz
- Department of Neurosurgery, Medical University Graz, Graz, Austria
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41
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Tynecka M, Moniuszko M, Eljaszewicz A. Old Friends with Unexploited Perspectives: Current Advances in Mesenchymal Stem Cell-Based Therapies in Asthma. Stem Cell Rev Rep 2021; 17:1323-1342. [PMID: 33649900 PMCID: PMC7919631 DOI: 10.1007/s12015-021-10137-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/10/2021] [Indexed: 02/07/2023]
Abstract
Mesenchymal stem cells (MSCs) have a great regenerative and immunomodulatory potential that was successfully tested in numerous pre-clinical and clinical studies of various degenerative, hematological and inflammatory disorders. Over the last few decades, substantial immunoregulatory effects of MSC treatment were widely observed in different experimental models of asthma. Therefore, it is tempting to speculate that stem cell-based treatment could become an attractive means to better suppress asthmatic airway inflammation, especially in subjects resistant to currently available anti-inflammatory therapies. In this review, we discuss mechanisms accounting for potent immunosuppressive properties of MSCs and the rationale for their use in asthma. We describe in detail an intriguing interplay between MSCs and other crucial players in the immune system as well as lung microenvironment. Finally, we reveal the potential of MSCs in maintaining airway epithelial integrity and alleviating lung remodeling.
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Affiliation(s)
- Marlena Tynecka
- Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, ul. Waszyngtona 13, 15-269, Białystok, Poland
| | - Marcin Moniuszko
- Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, ul. Waszyngtona 13, 15-269, Białystok, Poland.
- Department of Allergology and Internal Medicine, Medical University of Bialystok, ul. M. Skłodowskiej-Curie 24A, Białystok, 15-276, Poland.
| | - Andrzej Eljaszewicz
- Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, ul. Waszyngtona 13, 15-269, Białystok, Poland.
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Ridzuan N, Zakaria N, Widera D, Sheard J, Morimoto M, Kiyokawa H, Mohd Isa SA, Chatar Singh GK, Then KY, Ooi GC, Yahaya BH. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles ameliorate airway inflammation in a rat model of chronic obstructive pulmonary disease (COPD). Stem Cell Res Ther 2021; 12:54. [PMID: 33436065 PMCID: PMC7805108 DOI: 10.1186/s13287-020-02088-6] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 12/08/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Chronic obstructive pulmonary disease (COPD) is an incurable and debilitating chronic disease characterized by progressive airflow limitation associated with abnormal levels of tissue inflammation. Therefore, stem cell-based approaches to tackle the condition are currently a focus of regenerative therapies for COPD. Extracellular vesicles (EVs) released by all cell types are crucially involved in paracrine, extracellular communication. Recent advances in the field suggest that stem cell-derived EVs possess a therapeutic potential which is comparable to the cells of their origin. METHODS In this study, we assessed the potential anti-inflammatory effects of human umbilical cord mesenchymal stem cell (hUC-MSC)-derived EVs in a rat model of COPD. EVs were isolated from hUC-MSCs and characterized by the transmission electron microscope, western blotting, and nanoparticle tracking analysis. As a model of COPD, male Sprague-Dawley rats were exposed to cigarette smoke for up to 12 weeks, followed by transplantation of hUC-MSCs or application of hUC-MSC-derived EVs. Lung tissue was subjected to histological analysis using haematoxylin and eosin staining, Alcian blue-periodic acid-Schiff (AB-PAS) staining, and immunofluorescence staining. Gene expression in the lung tissue was assessed using microarray analysis. Statistical analyses were performed using GraphPad Prism 7 version 7.0 (GraphPad Software, USA). Student's t test was used to compare between 2 groups. Comparison among more than 2 groups was done using one-way analysis of variance (ANOVA). Data presented as median ± standard deviation (SD). RESULTS Both transplantation of hUC-MSCs and application of EVs resulted in a reduction of peribronchial and perivascular inflammation, alveolar septal thickening associated with mononuclear inflammation, and a decreased number of goblet cells. Moreover, hUC-MSCs and EVs ameliorated the loss of alveolar septa in the emphysematous lung of COPD rats and reduced the levels of NF-κB subunit p65 in the tissue. Subsequent microarray analysis revealed that both hUC-MSCs and EVs significantly regulate multiple pathways known to be associated with COPD. CONCLUSIONS In conclusion, we show that hUC-MSC-derived EVs effectively ameliorate by COPD-induced inflammation. Thus, EVs could serve as a new cell-free-based therapy for the treatment of COPD.
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Affiliation(s)
- Noridzzaida Ridzuan
- Lung Stem Cell and Gene Therapy Group, Regenerative Medicine Cluster, Advanced Medical and Dental Institute (IPPT), SAINS@BERTAM, Universiti Sains Malaysia, 13200, Bertam, Penang, Malaysia
| | - Norashikin Zakaria
- Lung Stem Cell and Gene Therapy Group, Regenerative Medicine Cluster, Advanced Medical and Dental Institute (IPPT), SAINS@BERTAM, Universiti Sains Malaysia, 13200, Bertam, Penang, Malaysia
| | - Darius Widera
- Stem Cell Biology and Regenerative Medicine, School of Pharmacy, University of Reading, Reading, RG6 6AP, UK
| | - Jonathan Sheard
- Stem Cell Biology and Regenerative Medicine, School of Pharmacy, University of Reading, Reading, RG6 6AP, UK
| | - Mitsuru Morimoto
- RIKEN Centre for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuou-ku, Kobe, 650-0047, Japan
| | - Hirofumi Kiyokawa
- RIKEN Centre for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuou-ku, Kobe, 650-0047, Japan
| | - Seoparjoo Azmel Mohd Isa
- Department of Pathology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, 16150, Kubang Kerian, Malaysia
| | - Gurjeet Kaur Chatar Singh
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, 11800, Gelugor, Penang, Malaysia
| | - Kong-Yong Then
- CryoCord Sdn Bhd, Bio-X Centre, 63000, Cyberjaya, Selangor, Malaysia
| | - Ghee-Chien Ooi
- CryoCord Sdn Bhd, Bio-X Centre, 63000, Cyberjaya, Selangor, Malaysia
| | - Badrul Hisham Yahaya
- Lung Stem Cell and Gene Therapy Group, Regenerative Medicine Cluster, Advanced Medical and Dental Institute (IPPT), SAINS@BERTAM, Universiti Sains Malaysia, 13200, Bertam, Penang, Malaysia.
- USM-RIKEN International Centre for Ageing Science (URICAS), Universiti Sains Malaysia, 11800, Gelugor, Penang, Malaysia.
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Ischemia-reperfusion Injury in the Transplanted Lung: A Literature Review. Transplant Direct 2021; 7:e652. [PMID: 33437867 PMCID: PMC7793349 DOI: 10.1097/txd.0000000000001104] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/04/2020] [Accepted: 11/06/2020] [Indexed: 02/07/2023] Open
Abstract
Lung ischemia-reperfusion injury (LIRI) and primary graft dysfunction are leading causes of morbidity and mortality among lung transplant recipients. Although extensive research endeavors have been undertaken, few preventative and therapeutic treatments have emerged for clinical use. Novel strategies are still needed to improve outcomes after lung transplantation. In this review, we discuss the underlying mechanisms of transplanted LIRI, potential modifiable targets, current practices, and areas of ongoing investigation to reduce LIRI and primary graft dysfunction in lung transplant recipients.
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Easter M, Bollenbecker S, Barnes JW, Krick S. Targeting Aging Pathways in Chronic Obstructive Pulmonary Disease. Int J Mol Sci 2020; 21:E6924. [PMID: 32967225 PMCID: PMC7555616 DOI: 10.3390/ijms21186924] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 09/05/2020] [Accepted: 09/15/2020] [Indexed: 12/17/2022] Open
Abstract
Chronic obstructive pulmonary disease (COPD) has become a global epidemic and is the third leading cause of death worldwide. COPD is characterized by chronic airway inflammation, loss of alveolar-capillary units, and progressive decline in lung function. Major risk factors for COPD are cigarette smoking and aging. COPD-associated pathomechanisms include multiple aging pathways such as telomere attrition, epigenetic alterations, altered nutrient sensing, mitochondrial dysfunction, cell senescence, stem cell exhaustion and chronic inflammation. In this review, we will highlight the current literature that focuses on the role of age and aging-associated signaling pathways as well as their impact on current treatment strategies in the pathogenesis of COPD. Furthermore, we will discuss established and experimental COPD treatments including senolytic and anti-aging therapies and their potential use as novel treatment strategies in COPD.
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Affiliation(s)
- Molly Easter
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; (M.E.); (S.B.); (J.W.B.)
| | - Seth Bollenbecker
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; (M.E.); (S.B.); (J.W.B.)
| | - Jarrod W. Barnes
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; (M.E.); (S.B.); (J.W.B.)
- Gregory Fleming James Cystic Fibrosis Center, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Stefanie Krick
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA; (M.E.); (S.B.); (J.W.B.)
- Gregory Fleming James Cystic Fibrosis Center, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Cabezas J, Rojas D, Wong Y, Telleria F, Manriquez J, Mançanares ACF, Rodriguez-Alvarez LL, Castro FO. In vitro preconditioning of equine adipose mesenchymal stem cells with prostaglandin E 2, substance P and their combination changes the cellular protein secretomics and improves their immunomodulatory competence without compromising stemness. Vet Immunol Immunopathol 2020; 228:110100. [PMID: 32871408 DOI: 10.1016/j.vetimm.2020.110100] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 07/27/2020] [Accepted: 08/02/2020] [Indexed: 02/06/2023]
Abstract
Mesenchymal stem cells (MSC) are modern tools in regenerative therapies of humans and animals owed to their immunomodulatory properties, which are activated in a pro-inflammatory environment. Different preconditioning strategies had been devised to enhance the immunomodulatory properties of MSC. In this research, we evaluated the immunological attributes of equine adipose MSC (eAMSC) before and after preconditioning in vitro with prostaglandin E2 (PGE2), substance P (SP), their combination and IFNγ. PGE2/SP was the best combination to keep or enhance the mesodermal lineage differentiation of eAMSC. Alongside with this, preconditioning of eMSC with PGE2 and SP did not affect expression of stemness MSC surface phenotype: CD90+, CD44+, MHC class I+, MHC class II- and CD45-, assessed by cytometry. Both naïve and preconditioned eAMSC expressed genes related with immune properties, such as MHC-I, PTGES, IL6, IL1A, TNFα and IL8 assessed by qPCR. Only TNFα was under expressed in treated cells, while the other markers were either overexpressed or not changed. In no cases MHC-II expression was detected. The antiproliferative effect of preconditioned eAMSC exposed to activated peripheral blood mononuclear cells (PBMC) showed that SP treatment significantly inhibited proliferation of LPS stimulated PBMC. When eAMSC were stimulated with Poly I:C, all the treatments significantly inhibited proliferation of stimulated PBMC (p < 0.05). Direct contact (coculture) between the preconditioned eAMSC and PBMC, induced a shift of significantly more (CD4/CD25/FOXP3)+ T-regulatory PBMC than naïve eAMSC. In the experiments of this research, we investigated the secreted proteomic profile of naïve and preconditioned eAMSC, 42 up-regulated and 40 down-regulated proteins were found in the proteomic assay. Our proteomic data revealed profound changes in the secretory pattern of MSC exposed to different treatments, compared to naïve eAMSC as well as among treatments. In overall, compared to naïve cells, the protein profile of preconditioned cells resembled the mesenchymal-epithelial transition (MET). Here we showed that the combined use of PGE2 and SP provoked in overall the highest expression of anti-inflammatory markers as well as lead to an increased acquisition of a T-regulatory phenotype in preconditioned eAMSC without affecting their "stemness".
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Affiliation(s)
- J Cabezas
- Universidad de Concepción, Campus Chillan, Faculty of Veterinary Science, Department of Animal Science, Laboratorio de Biotecnología Animal, Chile.
| | - D Rojas
- Universidad de Concepción, Campus Chillan, Faculty of Veterinary Sciences, Department of Animal Pathology, Chile.
| | - Y Wong
- Universidad de Concepción, Campus Chillan, Faculty of Veterinary Science, Department of Animal Science, Laboratorio de Biotecnología Animal, Chile.
| | - F Telleria
- Universidad de Concepción, Campus Chillan, Faculty of Veterinary Science, Department of Animal Science, Laboratorio de Biotecnología Animal, Chile.
| | - J Manriquez
- Universidad de Concepción, Campus Chillan, Faculty of Veterinary Science, Department of Animal Science, Laboratorio de Biotecnología Animal, Chile.
| | - A C F Mançanares
- Universidad de Concepción, Campus Chillan, Faculty of Veterinary Science, Department of Animal Science, Laboratorio de Biotecnología Animal, Chile.
| | - L L Rodriguez-Alvarez
- Universidad de Concepción, Campus Chillan, Faculty of Veterinary Science, Department of Animal Science, Laboratorio de Biotecnología Animal, Chile.
| | - F O Castro
- Universidad de Concepción, Campus Chillan, Faculty of Veterinary Science, Department of Animal Science, Laboratorio de Biotecnología Animal, Chile.
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Halim NSS, Ch'ng ES, Kardia E, Ali SA, Radzi R, Yahaya BH. Aerosolised Mesenchymal Stem Cells Expressing Angiopoietin-1 Enhances Airway Repair. Stem Cell Rev Rep 2020; 15:112-125. [PMID: 30178289 DOI: 10.1007/s12015-018-9844-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND The aim of this study was to investigate the effects of MSCs and MSC-expressing ANGPT1 (MSC-pANGPT1) treatment via aerosolisation in alleviating the asthma-related airway inflammation in the rabbit model. METHODS Rabbits were sensitised and challenged with both intraperitoneal injection and inhalation of ovalbumin (Ova). MSCs and MSC-pANGPT1 cells were aerosolised into rabbit lungs using the MicroSprayer® Aerosolizer Model IA-1B 48 h after injury. The post mortem was performed 3 days following cell delivery. Histopathological assessments of the lung tissues and inflammatory response were quantitatively scored following treatments. RESULT(S) Administration of aerosolised MSCs and MSC-pANGPT1 were significantly reduced inflammation of the airways (p < 0.001), as reflected by improved of structural changes such as thickness of the basement membrane, epithelium, mucosa and sub-mucosa regions. The airway inflammation score of both treatment groups revealed a significant reduction of inflammation and granulocyte infiltration at the peribronchiale and perivascular regions (p < 0.05). Administration of aerosolised MSCs alone was resulted in significant reduction in the levels of pro-inflammatory genes (IL-4 and TGF-β) while treatment with aerosolised MSC-pANGPT1 led to further reduction of various pro-inflammatory genes to the base-line values (IL4, TNF, MMP9 and TGF-β). Treatment with both aerosolised MSCs and MSC-pANGPT1 cells was also alleviated the number of airway inflammatory cells in the bronchoalveolar lavage (BAL) fluid and goblet cell hyperplasia. CONCLUSION(S) Our findings suggest that treatment with MSCs alone attenuated airway inflammation and structural changes of the airway. Treatment with MSC-pANGPT1 provided an additional effect in reducing the expression levels of various pro-inflammatory genes. Both of these treatment enhancing airway repair and therefore may provide a basis for the development of an innovative approach for the treatment and prevention of airway inflammatory diseases.
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Affiliation(s)
- N S S Halim
- Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, 13200, Bertam, Penang, Malaysia
| | - E S Ch'ng
- Oncological and Radiological Science Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, 13200, Bertam, Penang, Malaysia
| | - E Kardia
- Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, 13200, Bertam, Penang, Malaysia
| | - S A Ali
- Oncological and Radiological Science Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, 13200, Bertam, Penang, Malaysia
| | - R Radzi
- Animal Research Facilities, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, 13200 Bertam, Penang, Malaysia
| | - B H Yahaya
- Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, 13200, Bertam, Penang, Malaysia.
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Mani A, Hotra JW, Blackwell SC, Goetzl L, Refuerzo JS. Mesenchymal Stem Cells Attenuate Lipopolysaccharide-Induced Inflammatory Response in Human Uterine Smooth Muscle Cells. AJP Rep 2020; 10:e335-e341. [PMID: 33094025 PMCID: PMC7571561 DOI: 10.1055/s-0040-1715166] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 04/24/2020] [Indexed: 01/06/2023] Open
Abstract
Objective The aim of this study was to determine if mesenchymal stem cells (MSCs) would suppress the inflammatory response in human uterine cells in an in vitro lipopolysaccharide (LPS)-based preterm birth (PTB) model. Study Design Cocultures of human uterine smooth muscle cells (HUtSMCs) and MSCs were exposed to 5 μg/mL LPS for 4 hours and further challenged with 1 μg/mL LPS for a subsequent 24 hours. Key elements of the parturition cascade regulated by toll-like receptors (TLRs) through activation of mitogen-activated protein kinases (MAPKs) were quantified in culture supernatant as biomarkers of MSC modulation. Results Coculture with MSCs significantly attenuated TLR-4, p-JNK, and p- extracellular signal-regulated kinase 1/2 (ERK1/2) protein levels compared with HUtSMCs monoculture ( p = 0.05). In addition, coculture was associated with significant inhibition of proinflammatory cytokines interleukin (IL)-6 and IL-8 ( p = 0.0001) and increased production of anti-inflammatory cytokines IL-10 and transforming growth factor (TGF)-β1 ( p = 0.0001). Conclusion MSCs appear to play a role in significantly attenuating LPS-mediated inflammation via alteration of down-stream MAPKs. MSCs may represent a novel, cell-based therapy in women with increased risk of inflammatory-mediated preterm birth.
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Affiliation(s)
- Arunmani Mani
- Division of Maternal Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, UT Health-McGovern Medical School, Houston, Texas
| | - John W Hotra
- Division of Maternal Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, UT Health-McGovern Medical School, Houston, Texas
| | - Sean C Blackwell
- Division of Maternal Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, UT Health-McGovern Medical School, Houston, Texas
| | - Laura Goetzl
- Division of Maternal Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, UT Health-McGovern Medical School, Houston, Texas
| | - Jerrie S Refuerzo
- Division of Maternal Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, UT Health-McGovern Medical School, Houston, Texas
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Choi DW, Cho KA, Lee HJ, Kim YH, Woo KJ, Park JW, Ryu KH, Woo SY. Co‑transplantation of tonsil‑derived mesenchymal stromal cells in bone marrow transplantation promotes thymus regeneration and T cell diversity following cytotoxic conditioning. Int J Mol Med 2020; 46:1166-1174. [PMID: 32582998 PMCID: PMC7387097 DOI: 10.3892/ijmm.2020.4657] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 06/10/2020] [Indexed: 12/11/2022] Open
Abstract
Bone marrow (BM) transplantation (BMT) represents a curative treatment for various hematological disorders. Prior to BMT, a large amount of the relevant anticancer drug needed to be administered to eliminate cancer cells. However, during this pre-BMT cytotoxic conditioning regimen, hematopoietic stem cells in the BM and thymic epithelial cells were also destroyed. The T cell receptor (TCR) recognizes diverse pathogen, tumor and environmental antigens, and confers immunological memory and self-tolerance. Delayed thymus reconstitution following pre-BMT cytotoxic conditioning impedes de novo thymopoiesis and limits T cell-mediated immunity. Several cytokines, such as RANK ligand, interleukin (IL)-7, IL-22 and stem cell factor, were recently reported to improve thymopoiesis and immune function following BMT. In the present study, it was found that the co-transplantation of tonsil-derived mesenchymal stromal cells (T-MSCs) with BM-derived cells (BMCs) accelerated the recovery of involuted thymuses in mice following partial pre-BMT conditioning with busulfan-cyclophosphamide treatment, possibly by inducing FMS-like tyrosine kinase 3 ligand (FLT3L) and fibroblast growth factor 7 (FGF7) production in T-MSCs. The co-transplantation of T-MSCs with BMCs also replenished the CD3+ cell population by inhibiting thymocyte apoptosis following pre-BMT cytotoxic conditioning. Furthermore, T-MSC co-transplantation improved the recovery of the TCR repertoire and led to increased thymus-generated T cell diversity.
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Affiliation(s)
- Da-Won Choi
- Department of Microbiology, College of Medicine, Ewha Womans University, Seoul 07804, Republic of Korea
| | - Kyung-Ah Cho
- Department of Microbiology, College of Medicine, Ewha Womans University, Seoul 07804, Republic of Korea
| | - Hyun-Ji Lee
- Department of Microbiology, College of Medicine, Ewha Womans University, Seoul 07804, Republic of Korea
| | - Yu-Hee Kim
- Department of Microbiology, College of Medicine, Ewha Womans University, Seoul 07804, Republic of Korea
| | - Kyong-Je Woo
- Department of Plastic and Reconstructive Surgery, College of Medicine, Ewha Womans University, Seoul 07804, Republic of Korea
| | - Joo-Won Park
- Department of Biochemistry, College of Medicine, Ewha Womans University, Seoul 07804, Republic of Korea
| | - Kyung-Ha Ryu
- Department of Pediatrics, College of Medicine, Ewha Womans University, Seoul 07804, Republic of Korea
| | - So-Youn Woo
- Department of Microbiology, College of Medicine, Ewha Womans University, Seoul 07804, Republic of Korea
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Kang MK, Kim TJ, Kim YJ, Kang L, Kim J, Lee N, Hyeon T, Lim MS, Mo HJ, Shin JH, Ko SB, Yoon BW. Targeted Delivery of Iron Oxide Nanoparticle-Loaded Human Embryonic Stem Cell-Derived Spherical Neural Masses for Treating Intracerebral Hemorrhage. Int J Mol Sci 2020; 21:ijms21103658. [PMID: 32455909 PMCID: PMC7279437 DOI: 10.3390/ijms21103658] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 05/13/2020] [Accepted: 05/20/2020] [Indexed: 12/16/2022] Open
Abstract
This study evaluated the potential of iron oxide nanoparticle-loaded human embryonic stem cell (ESC)-derived spherical neural masses (SNMs) to improve the transportation of stem cells to the brain, ameliorate brain damage from intracerebral hemorrhage (ICH), and recover the functional status after ICH under an external magnetic field of a magnet attached to a helmet. At 24 h after induction of ICH, rats were randomly separated into three experimental groups: ICH with injection of phosphate-buffered saline (PBS group), ICH with intravenous injection of magnetosome-like ferrimagnetic iron oxide nanocubes (FION)-labeled SNMs (SNMs* group), and ICH with intravenous injection of FION-labeled SNMs followed by three days of external magnetic field exposure for targeted delivery by a magnet-embedded helmet (SNMs*+Helmet group). On day 3 after ICH induction, an increased Prussian blue-stained area and decreased swelling volume were observed in the SNMs*+Helmet group compared with that of the other groups. A significantly decreased recruitment of macrophages and neutrophils and a downregulation of pro-inflammatory cytokines followed by improved neurological function three days after ICH were observed in the SNMs*+Helmet group. Hemispheric atrophy at six weeks after ICH was significantly decreased in the SNMs*+Helmet group compared with that of the PBS group. In conclusion, we have developed a targeted delivery system using FION tagged to stem cells and a magnet-embedded helmet. The targeted delivery of SNMs might have the potential for developing novel therapeutic strategies for ICH.
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Affiliation(s)
- Min Kyoung Kang
- Department of Neurology, Seoul National University Hospital, Seoul 03080, Korea; (M.K.K.); (T.J.K.); (J.H.S.); (S.-B.K.)
- Department of Neurology, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Tae Jung Kim
- Department of Neurology, Seoul National University Hospital, Seoul 03080, Korea; (M.K.K.); (T.J.K.); (J.H.S.); (S.-B.K.)
- Department of Neurology, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Young-Ju Kim
- Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Korea; (Y.-J.K.); (L.K.)
| | - Lamie Kang
- Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Korea; (Y.-J.K.); (L.K.)
| | - Jonghoon Kim
- Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul 08826, Korea; (J.K.); (T.H.)
- School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul 08826, Korea
| | - Nohyun Lee
- School of Advanced Materials Engineering, Kookmin University, Seoul 02707, Korea;
| | - Taeghwan Hyeon
- Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul 08826, Korea; (J.K.); (T.H.)
- School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul 08826, Korea
| | - Mi-sun Lim
- Research and Development Center, Jeil Pharmaceutical Co. Ltd., Yongin-si, Gyeonggi-do 17172, Korea;
- Institute of Reproductive Medicine and Population, Medical Research Center, Seoul National University, Seoul 08826, Korea
| | - Hee Jung Mo
- Department of Neurology, Hallym University Dongtan Sacred Heart Hospital, Gyeonggi-do 14068, Korea;
| | - Jung Hwan Shin
- Department of Neurology, Seoul National University Hospital, Seoul 03080, Korea; (M.K.K.); (T.J.K.); (J.H.S.); (S.-B.K.)
| | - Sang-Bae Ko
- Department of Neurology, Seoul National University Hospital, Seoul 03080, Korea; (M.K.K.); (T.J.K.); (J.H.S.); (S.-B.K.)
- Department of Neurology, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Byung-Woo Yoon
- Department of Neurology, Seoul National University Hospital, Seoul 03080, Korea; (M.K.K.); (T.J.K.); (J.H.S.); (S.-B.K.)
- Department of Neurology, Seoul National University College of Medicine, Seoul 03080, Korea
- Correspondence: ; Tel.: +82-2-2072-2875; Fax: +82-2-3673-1990
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Ceccarelli S, Pontecorvi P, Anastasiadou E, Napoli C, Marchese C. Immunomodulatory Effect of Adipose-Derived Stem Cells: The Cutting Edge of Clinical Application. Front Cell Dev Biol 2020; 8:236. [PMID: 32363193 PMCID: PMC7180192 DOI: 10.3389/fcell.2020.00236] [Citation(s) in RCA: 114] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 03/20/2020] [Indexed: 12/12/2022] Open
Abstract
Adipose-derived stem cells (ASCs) represent a promising tool for soft tissue engineering as well as for clinical treatment of inflammatory and autoimmune pathologies. The well-characterized multi-differentiation potential and self-renewal properties of ASCs are coupled with their immunomodulatory ability in providing therapeutic efficacy. Yet, their impact in immune or inflammatory disorders might rely both on cell contact-dependent mechanisms and paracrine effects, resulting in the release of various soluble factors that regulate immune cells functions. Despite the widespread use of ASCs in clinical trials addressing several pathologies, the pathophysiological mechanisms at the basis of their clinical use have been not yet fully investigated. In particular, a thorough analysis of ASC immunomodulatory potential is mandatory. Here we explore such molecular mechanisms involved in ASC immunomodulatory properties, emphasizing the relevance of the milieu composition. We review the potential clinical use of ASC secretome as a mediator for immunomodulation, with a focus on in vitro and in vivo environmental conditions affecting clinical outcome. We describe some potential strategies for optimization of ASCs immunomodulatory capacity in clinical settings, which act either on adult stem cells gene expression and local microenvironment. Finally, we discuss the limitations of both allogeneic and autologous ASC use, highlighting the issues to be fixed in order to significantly improve the efficacy of ASC-based cell therapy.
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Affiliation(s)
- Simona Ceccarelli
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Paola Pontecorvi
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Eleni Anastasiadou
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Claudio Napoli
- Clinical Department of Internal Medicine and Specialistics, Department of Advanced Clinical and Surgical Sciences, Università della Campania “Luigi Vanvitelli”, Naples, Italy
- IRCCS SDN, Naples, Italy
| | - Cinzia Marchese
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
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