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Yan S, Bi Y, Liu Q, Song S, Ma L, Ji G. hUC-MSCs Prevent Acute High-Altitude Injury through Apoe/Pdgf-b/p-Erk1/2 Axis in Mice. Stem Cell Rev Rep 2025; 21:834-848. [PMID: 39871082 PMCID: PMC11965259 DOI: 10.1007/s12015-024-10840-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/26/2024] [Indexed: 01/29/2025]
Abstract
BACKGROUND The hypobaric hypoxic atmosphere can cause adverse reactions or sickness. The purpose of this study was to explore the preventive effect and mechanism of human umbilical cord mesenchymal stem cells (hUC-MSCs) on acute pathological injury in mice exposed to high-altitude. METHODS We pretreated C57BL/6 mice with hUC-MSCs via the tail vein injection, and then the mice were subjected to hypobaric hypoxic conditions for five days. The effects of hUC-MSCs on the pathological injury of lung, heart, brain were assessed by biochemical analysis, histopathological testing, quantitative real-time polymerase chain reaction (qPCR), and western blot (WB). Further, transcriptome sequencing was used to screen for the potential therapeutic targets of hUC-MSCs in acute pathological injury, the identified signaling axis was characterized using Apoe-/- mice, qPCR and WB. RESULTS hUC-MSCs administration notably prevented and relieved gastrointestinal symptoms and inflammation of lung and heart, increased blood oxygen saturation and serum superoxide dismutase (SOD) level, decreased serum malondialdehyde (MDA) level, rescued lung tissue injury and myocardial mitochondrial disorder, elevated nissl bodies number in brain tissue and reduced the degree of pulmonary and cerebral edema. Furthermore, hUC-MSCs pretreatment reversed the down-regulated Apoe and up-regulated Pdgf-b and p-Erk1/2 in the lung of hypobaric hypoxic mice. Thus, hUC-MSCs protected against acute pathological injury caused by hypobaric hypoxic condition via the Apoe/Pdgf-b/p-Erk1/2 axis, and the identified pathway was confirmed by the negative results of Apoe-/- mice. CONCLUSION hUC-MSCs possess the preventive effect on acute pathological injury caused by hypobaric hypoxia environment at high-altitude.
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Affiliation(s)
- Siyu Yan
- Chinese Academy of Medical Sciences & Peking Union Medical College Fuwai Hospital, Beijing, China
| | - Youkun Bi
- Chinese Academy of Medical Sciences & Peking Union Medical College Fuwai Hospital, Beijing, China
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Qun Liu
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Shaole Song
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Lihong Ma
- Chinese Academy of Medical Sciences & Peking Union Medical College Fuwai Hospital, Beijing, China.
| | - Guangju Ji
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
- Henan Academy of Sciences, Zhengzhou, 450000, China.
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Zhang S, Zhao X, Lv Y, Niu J, Wei X, Luo Z, Wang X, Chen XL. Exosomes of different cellular origins: prospects and challenges in the treatment of acute lung injury after burns. J Mater Chem B 2025; 13:1531-1547. [PMID: 39704476 DOI: 10.1039/d4tb02351j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2024]
Abstract
Acute lung injury (ALI) is a critical clinical disease caused by direct factors (inhalation injury, gastroesophageal reflux, etc.) or indirect factors (including infection, sepsis, burn, shock, trauma, acute pancreatitis, fat embolism, drug overdose, etc.). ALI is characterized mainly by diffuse interstitial and alveolar edema caused by an uncontrolled inflammatory response and damage to the alveoli-capillary barrier and has very high morbidity and mortality rates. Currently, there is no effective treatment strategy other than mechanical ventilation, fluid management or other supportive treatments. Exosomes are nanovesicle-like vesicles with double-membrane structures detached from the cell membrane or secreted by cells. These vesicles can be used as drug carriers because of their unique biological properties, such as anti-inflammatory, anti-apoptotic, pro-cell growth and immunomodulatory functions, and have been applied in the treatment of ALI in recent years. In this study, the mechanism and pathophysiological characteristics of ALI were first systematically described. The different cellular sources and characteristics of exosomes are summarized, and their functions and value as drug carriers in the treatment of ALI are discussed, as are the challenges that may be faced in the treatment of ALI with exosomes.
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Affiliation(s)
- Shuo Zhang
- Department of Burns, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
| | - Xinyu Zhao
- Department of Burns, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
| | - Yang Lv
- Plastic Surgery Department, The Second Affiliated Hospital of Anhui Medical University, 230061, P. R. China
| | - Jianguo Niu
- School of Biomedical Engineering, Anhui Medical University, Hefei 230022, China.
| | - Xiaolong Wei
- School of Biomedical Engineering, Anhui Medical University, Hefei 230022, China.
| | - Zhiwen Luo
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai 200040, P. R. China.
| | - Xianwen Wang
- School of Biomedical Engineering, Anhui Medical University, Hefei 230022, China.
| | - Xu-Lin Chen
- Department of Burns, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
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Bang Y, Hwang S, Kim YE, Sung DK, Yang M, Ahn SY, Sung SI, Joo KM, Chang YS. Therapeutic efficacy of thrombin-preconditioned mesenchymal stromal cell-derived extracellular vesicles on Escherichia coli-induced acute lung injury in mice. Respir Res 2024; 25:303. [PMID: 39112999 PMCID: PMC11308396 DOI: 10.1186/s12931-024-02908-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: 04/16/2024] [Accepted: 07/07/2024] [Indexed: 08/10/2024] Open
Abstract
BACKGROUND Acute lung injury (ALI) following pneumonia involves uncontrolled inflammation and tissue injury, leading to high mortality. We previously confirmed the significantly increased cargo content and extracellular vesicle (EV) production in thrombin-preconditioned human mesenchymal stromal cells (thMSCs) compared to those in naïve and other preconditioning methods. This study aimed to investigate the therapeutic efficacy of EVs derived from thMSCs in protecting against inflammation and tissue injury in an Escherichia coli (E. coli)-induced ALI mouse model. METHODS In vitro, RAW 264.7 cells were stimulated with 0.1 µg/mL liposaccharides (LPS) for 1 h, then were treated with either PBS (LPS Ctrl) or 5 × 107 particles of thMSC-EVs (LPS + thMSC-EVs) for 24 h. Cells and media were harvested for flow cytometry and ELISA. In vivo, ICR mice were anesthetized, intubated, administered 2 × 107 CFU/100 µl of E. coli. 50 min after, mice were then either administered 50 µL saline (ECS) or 1 × 109 particles/50 µL of thMSC-EVs (EME). Three days later, the therapeutic efficacy of thMSC-EVs was assessed using extracted lung tissue, bronchoalveolar lavage fluid (BALF), and in vivo computed tomography scans. One-way analysis of variance with post-hoc TUKEY test was used to compare the experimental groups statistically. RESULTS In vitro, IL-1β, CCL-2, and MMP-9 levels were significantly lower in the LPS + thMSC-EVs group than in the LPS Ctrl group. The percentages of M1 macrophages in the normal control, LPS Ctrl, and LPS + thMSC-EV groups were 12.5, 98.4, and 65.9%, respectively. In vivo, the EME group exhibited significantly lower histological scores for alveolar congestion, hemorrhage, wall thickening, and leukocyte infiltration than the ECS group. The wet-dry ratio for the lungs was significantly lower in the EME group than in the ECS group. The BALF levels of CCL2, TNF-a, and IL-6 were significantly lower in the EME group than in the ECS group. In vivo CT analysis revealed a significantly lower percentage of damaged lungs in the EME group than in the ECS group. CONCLUSION Intratracheal thMSC-EVs administration significantly reduced E. coli-induced inflammation and lung tissue damage. Overall, these results suggest therapeutically enhanced thMSC-EVs as a novel promising therapeutic option for ARDS/ALI.
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Affiliation(s)
- Yuna Bang
- Cell and Gene Therapy Institute, Samsung Medical Center, Seoul, 06351, Republic of Korea
- Department of Anatomy & Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea
| | - Sein Hwang
- Cell and Gene Therapy Institute, Samsung Medical Center, Seoul, 06351, Republic of Korea
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06351, Republic of Korea
| | - Young Eun Kim
- Cell and Gene Therapy Institute, Samsung Medical Center, Seoul, 06351, Republic of Korea
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea
| | - Dong Kyung Sung
- Cell and Gene Therapy Institute, Samsung Medical Center, Seoul, 06351, Republic of Korea
| | - Misun Yang
- Cell and Gene Therapy Institute, Samsung Medical Center, Seoul, 06351, Republic of Korea
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea
| | - So Yoon Ahn
- Cell and Gene Therapy Institute, Samsung Medical Center, Seoul, 06351, Republic of Korea
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea
| | - Se In Sung
- Cell and Gene Therapy Institute, Samsung Medical Center, Seoul, 06351, Republic of Korea
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea
| | - Kyeung Min Joo
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06351, Republic of Korea
- Department of Anatomy & Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea
| | - Yun Sil Chang
- Cell and Gene Therapy Institute, Samsung Medical Center, Seoul, 06351, Republic of Korea.
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06351, Republic of Korea.
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea.
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Arefnezhad R, Helfi M, Okhravijouybari R, Goleij P, Sargolzaeimoghaddam M, Mohammadi H, Mahdaviyan N, Fatemian H, Sarg A, Jahani S, Rezaei-Tazangi F, Nazari A. Umbilical cord mesenchymal stem cells and lung cancer: We should be hopeful or hopeless? Tissue Cell 2024; 88:102410. [PMID: 38772275 DOI: 10.1016/j.tice.2024.102410] [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: 03/24/2024] [Revised: 05/10/2024] [Accepted: 05/15/2024] [Indexed: 05/23/2024]
Abstract
Lung cancer (LC) is one of the leading causes of cancer-caused death that possesses a poor prognosis and low survival rate worldwide. In general, LC is classified into small-cell (SCLC) and non-small-cell carcinoma (NSCLC) (involving 80% of patients). Although chemotherapy, radiotherapy, surgery, and molecular-targeted therapy are considered standard approaches for LC treatment, these options have low success with detrimental effects on the life quality of patients. Ergo, recommending treatment with maximum effectiveness and minimum side effects for LC patients has been a substantial challenge for researchers and clinicians in the present era. Recently, mesenchymal stem cells (MSCs)-based strategies have sparked much interest in preventing or treating numerous illnesses. These multipotent stem cells can be isolated from diverse sources, such as umbilical cord, bone marrow, and adipose tissue. Among these sources, umbilical cord mesenchymal stem cells (UC-MSCs) have been in the spotlight of MSCs-based therapies thanks to their considerable advantages, such as high proliferation ability, low immune reactions and tumorigenesis, and easiness in collection and isolation. Some experimental studies have investigated the functionality of intact UC-MSCs and extracellular vesicles, exosomes, and conditioned medium derived from UC-MSCs, as well as genetically engineered UC-MSCs. In this review, we aimed to highlight the influences of these UMSCs-based methods in LC treatment with cellular and molecular insights.
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Affiliation(s)
- Reza Arefnezhad
- Coenzyme R Research Institute, Tehran, Iran; Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Maryam Helfi
- Department of Medical Physics, School of Medicine, Mashhad University of Medical Science, Mashhad, Iran
| | | | - Pouya Goleij
- Department of Genetics, Sana Institute of Higher Education, Sari, Iran; International Network of Stem Cell (INSC), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | | | - Hanieh Mohammadi
- Student Research Committee, Tehran University of Medical Science, Tehran, Iran
| | | | - Hossein Fatemian
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Arya Sarg
- Istanbul Medipol University, Medical Student, Istanbul, Turkey
| | - Saleheh Jahani
- Department of pathology, University of California, San Diego, United states
| | - Fatemeh Rezaei-Tazangi
- Department of Anatomy, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran.
| | - Ahmad Nazari
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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5
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Cui E, Lv L, Wang B, Li L, Lu H, Hua F, Chen W, Chen N, Yang L, Pan R. Umbilical cord MSC-derived exosomes improve alveolar macrophage function and reduce LPS-induced acute lung injury. J Cell Biochem 2024; 125:e30519. [PMID: 38224137 DOI: 10.1002/jcb.30519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 11/20/2023] [Accepted: 12/22/2023] [Indexed: 01/16/2024]
Abstract
Acute lung injury (ALI) is a severe condition that can progress to acute respiratory distress syndrome (ARDS), with a high mortality rate. Currently, no specific and compelling drug treatment plan exists. Mesenchymal stem cells (MSCs) have shown promising results in preclinical and clinical studies as a potential treatment for ALI and other lung-related conditions due to their immunomodulatory properties and ability to regenerate various cell types. The present study focuses on analyzing the role of umbilical cord MSC (UC-MSC))-derived exosomes in reducing lipopolysaccharide-induced ALI and investigating the mechanism involved. The study demonstrates that UC-MSC-derived exosomes effectively improved the metabolic function of alveolar macrophages and promoted their shift to an anti-inflammatory phenotype, leading to a reduction in ALI. The findings also suggest that creating three-dimensional microspheres from the MSCs first can enhance the effectiveness of the exosomes. Further research is needed to fully understand the mechanism of action and optimize the therapeutic potential of MSCs and their secretome in ALI and other lung-related conditions.
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Affiliation(s)
- Enhai Cui
- Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, Zhejiang, China
| | - Lu Lv
- Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, Zhejiang, China
| | - Bin Wang
- Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, Zhejiang, China
| | - Liqin Li
- TCM Key Laboratory Cultivation Base of Zhejiang Province for the Development and Clinical Transformation of Immunomodulatory Drugs, Huzhou, Zhejiang, China
| | - Huadong Lu
- Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, Zhejiang, China
| | - Feng Hua
- Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, Zhejiang, China
| | - Wenyan Chen
- Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, Zhejiang, China
| | - Na Chen
- Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, Zhejiang, China
| | - Liwei Yang
- Department of Obstetrics, Center for Reproductive Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Ruolang Pan
- Key Laboratory of Cell-Based Drug and Applied Technology Development in Zhejiang Province, Institute for Cell-Based Drug Development of Zhejiang Province, S-Evans Biosciences, Hangzhou, Zhejiang, China
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Kim YE, Sung DK, Bang Y, Sung SI, Yang M, Ahn SY, Chang YS. SOCS3 Protein Mediates the Therapeutic Efficacy of Mesenchymal Stem Cells against Acute Lung Injury. Int J Mol Sci 2023; 24:ijms24098256. [PMID: 37175961 PMCID: PMC10179427 DOI: 10.3390/ijms24098256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 04/25/2023] [Accepted: 04/28/2023] [Indexed: 05/15/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have been studied as novel therapeutic agents because of their immunomodulatory properties in inflammatory diseases. The suppressor of cytokine signaling (SOCS) proteins are key regulators of the immune response and macrophage modulation. In the present study, we hypothesized that SOCS in MCSs might mediate macrophage modulation and tested this in a bacteria-induced acute lung injury (ALI) mouse model. The macrophage phenotype was observed in RAW264.7 alveolar macrophages exposed to lipopolysaccharide (LPS) in an in vitro model, and in the ALI mouse model induced by tracheal administration of Escherichia coli (1 × 107 CFU in 0.05mL PBS). In LPS-exposed RAW264.7 cells, the levels of markers of M1 macrophages, such as CD86 and pro-inflammatory cytokines (IL-1α, IL-1β, IL-6 and TNF-α), significantly increased, but they significantly reduced after MSC treatment. Meanwhile, the levels of markers of M2 macrophages, such as CD204 and anti-inflammatory cytokines (IL-4 and IL-10), increased after LPS exposure, and further significantly increased after MSC treatment. This regulatory effect of MSCs on M1/M2 macrophage polarization was significantly abolished by SOCS3 inhibition. In the E. coli-induced ALI model, tissue injury and inflammation in the mouse lung were significantly attenuated by the transplantation of MSCs, but not by SOCS3-inhibited MSCs. The regulatory effect of MSCs on M1/M2 macrophage polarization was observed in the lung injury model but was significantly abolished by SOCS3 inhibition. Taken together, our findings suggest that SOCS3 is an important mediator for macrophage modulation in anti-inflammatory properties of MSCs.
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Affiliation(s)
- Young Eun Kim
- Cell and Gene Therapy Institute, Samsung Medical Center, Seoul 06351, Republic of Korea
| | - Dong Kyung Sung
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| | - Yuna Bang
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
- Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Suwon 16419, Republic of Korea
| | - Se In Sung
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| | - Misun Yang
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| | - So Yoon Ahn
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| | - Yun Sil Chang
- Cell and Gene Therapy Institute, Samsung Medical Center, Seoul 06351, Republic of Korea
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 06351, Republic of Korea
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Ramji HF, Hafiz M, Altaq HH, Hussain ST, Chaudry F. Acute Respiratory Distress Syndrome; A Review of Recent Updates and a Glance into the Future. Diagnostics (Basel) 2023; 13:diagnostics13091528. [PMID: 37174920 PMCID: PMC10177247 DOI: 10.3390/diagnostics13091528] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 04/14/2023] [Accepted: 04/15/2023] [Indexed: 05/15/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS) is a rapidly progressive form of respiratory failure that accounts for 10% of admissions to the ICU and is associated with approximately 40% mortality in severe cases. Despite significant mortality and healthcare burden, the mainstay of management remains supportive care. The recent pandemic of SARS-CoV-2 has re-ignited a worldwide interest in exploring the pathophysiology of ARDS, looking for innovative ideas to treat this disease. Recently, many trials have been published utilizing different pharmacotherapy targets; however, the long-term benefits of these agents remain unknown. Metabolomics profiling and stem cell transplantation offer strong enthusiasm and may completely change the outlook of ARDS management in the near future.
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Affiliation(s)
- Husayn F Ramji
- University of Oklahoma College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Hudson College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Maida Hafiz
- Department of Sleep Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Hiba Hammad Altaq
- Department of Pulmonary, Critical Care & Sleep Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Syed Talal Hussain
- Department of Pulmonary, Critical Care & Sleep Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Fawad Chaudry
- Department of Pulmonary, Critical Care & Sleep Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
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Adamič N, Vengust M. Regenerative medicine in lung diseases: A systematic review. Front Vet Sci 2023; 10:1115708. [PMID: 36733636 PMCID: PMC9887049 DOI: 10.3389/fvets.2023.1115708] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 01/02/2023] [Indexed: 01/18/2023] Open
Abstract
Regenerative medicine has opened the door to the exploration of new therapeutic methods for the treatment of various diseases, especially those associated with local or general disregulation of the immune system. In pulmonary diseases, new therapeutic strategies have emerged that are aimed at restoring functional lung tissue rather than alleviating symptoms. These strategies focus on tissue regeneration using stem cells and/or their derivatives or replacement of dysfunctional tissue using biomedical engineering. Animal health can directly benefit from regenerative therapy strategies and also serve as a translational experimental model for human disease. Several clinical trials have been conducted to evaluate the effects of cellular treatment on inflammatory lung disease in animals. Data reported to date show several beneficial effects in ex vivo and in vivo models; however, our understanding of the mechanisms that regenerative therapies exert on diseased tissues remains incomplete.
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Hu Y, Shao J, Shen L, Wang S, Xu K, Mao J, Shen J, Chen W. Protection of adipose-derived mesenchymal stromal cells during acute lung injury requires autophagy maintained by mTOR. Cell Death Discov 2022; 8:481. [PMID: 36470863 PMCID: PMC9722689 DOI: 10.1038/s41420-022-01267-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 09/15/2022] [Accepted: 11/18/2022] [Indexed: 12/10/2022] Open
Abstract
Previous studies suggest that mesenchymal stem cells may represent a promising cellular therapy for acute lung injury (ALI); however, the underlying relevant molecular mechanisms remain unclear. Adipose-derived mesenchymal stem cells (ADSCs) were isolated and characterized by alizarin red staining, oil red staining, and flow cytometry. Lung injury and inflammatory cell infiltration were determined using the Evans blue method, wet/dry weight ratio, and H&E staining. An ELISA was used to detect the concentrations of IFN-γ, IL-2, and TNF-α. Autophagy was detected with an mRFP-GFP-LC3 dual-fluorescence autophagy indicator system, Western blotting, and electron microscopy. We first demonstrated that ADSCs did alleviate the inflammatory responses and tissue damage in lipopolysaccharide (LPS)-induced ALI. Next, we further demonstrated in vivo that autophagy plays a key role in the maintenance of ADSC therapeutic efficacy. In vitro experiments demonstrated that ADSCs co-cultured with alveolar epithelial cells depend on autophagy for significant anti-inflammatory functions. Moreover, the mammalian target of rapamycin (mTOR) is a key regulator of autophagy. Taken together, our findings demonstrate that the effect of ADSC on ALI, especially on alveolar epithelial cells, is dependent on mTOR-mediated autophagy maintenance. The significance of our study for ALI therapy is discussed with respect to a more complete understanding of the therapeutic strategy paradigm.
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Affiliation(s)
- Yue Hu
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, 310009, Hangzhou, Zhejiang, China.
| | - Jing Shao
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, 310012, Hangzhou, Zhejiang, China
| | - Lanying Shen
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, 310009, Hangzhou, Zhejiang, China
| | - Shengchao Wang
- Department of Gynecological Oncology, Women's Hospital, Zhejiang University School of Medicine, 310006, Hangzhou, Zhejiang, China
| | - Kaiyan Xu
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, 310009, Hangzhou, Zhejiang, China
| | - Jiayan Mao
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, 310012, Hangzhou, Zhejiang, China
| | - Jian Shen
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, 310012, Hangzhou, Zhejiang, China
| | - Wei Chen
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, 310012, Hangzhou, Zhejiang, China.
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Immunomodulation of Mesenchymal Stem Cells in Acute Lung Injury: From Preclinical Animal Models to Treatment of Severe COVID-19. Int J Mol Sci 2022; 23:ijms23158196. [PMID: 35897770 PMCID: PMC9331939 DOI: 10.3390/ijms23158196] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 07/23/2022] [Indexed: 02/01/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a major public health challenge worldwide. Owing to the emergence of novel viral variants, the risks of reinfections and vaccine breakthrough infections has increased considerably despite a mass of vaccination. The formation of cytokine storm, which subsequently leads to acute respiratory distress syndrome, is the major cause of mortality in patients with COVID-19. Based on results of preclinical animal models and clinical trials of acute lung injury and acute respiratory distress syndrome, the immunomodulatory, tissue repair, and antiviral properties of MSCs highlight their potential to treat COVID-19. This review article summarizes the potential mechanisms and outcomes of MSC therapy in COVID-19, along with the pathogenesis of the SARS-CoV-2 infection. The properties of MSCs and lessons from preclinical animal models of acute lung injury are mentioned ahead. Important issues related to the use of MSCs in COVID-19 are discussed finally.
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Human Placental Mesenchymal Stem Cells for the Treatment of ARDS in Rat. Stem Cells Int 2022; 2022:8418509. [PMID: 35756754 PMCID: PMC9226970 DOI: 10.1155/2022/8418509] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 04/21/2022] [Accepted: 06/06/2022] [Indexed: 11/29/2022] Open
Abstract
The acute respiratory distress syndrome (ARDS) is one of the main causes of high mortality in patients with coronavirus (COVID-19). In recent years, due to the coronavirus pandemic, the number of patients with ARDS has increased significantly. Unfortunately, until now, there are no effective treatments for ARDS caused by COVID-19. Many drugs are either ineffective or have a low effect. Currently, there have been reports of efficient use of mesenchymal stem cells (MSCs) for the treatment of ARDS caused by COVID-19. We investigated the influence of freeze-dried human placenta-derived mesenchymal stem cells (HPMSCs) in ARDS rat model. All animals have received intratracheal injection of 6 mg/kg of lipopolysaccharide (LPS). The rats were randomly divided into five groups: I: LPS, II: LPS+dexamethasone, III: LPS+HPMSCs, IV: HPMSC, and V: saline. ARDS observation time was short-term and amounted to 168 hours. The study has shown that HPMSCs are able to migrate and attach to damaged lung tissue, contributing to the resolution of pathology, restoration of function, and tissue repair in the alveolar space. Studies have also shown that the administration of HPMSCs in animals with ARDS model significantly reduced the levels of key cytokines such as IL-1β, IL-6, and TNF-α. Freeze-dried placental stem cell is a very promising biomaterial for the treatment of ARDS. The human placenta can be easily obtained because it is considered as a medical waste. At the same time, a huge number of MSCs can be obtained from the placental tissue, and there is no ethical controversy around their use. The freeze-dried MSCs from human placental tissue can be stored sterile at room temperature for a long time before use.
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12
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Immunomodulation via MyD88-NFκB Signaling Pathway from Human Umbilical Cord-Derived Mesenchymal Stem Cells in Acute Lung Injury. Int J Mol Sci 2022; 23:ijms23105295. [PMID: 35628107 PMCID: PMC9141460 DOI: 10.3390/ijms23105295] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/08/2022] [Accepted: 05/08/2022] [Indexed: 01/01/2023] Open
Abstract
Excess inflammatory processes play a key detrimental role in the pathophysiology of acute lung injury (ALI). Mesenchymal stem cells (MSCs) were reported to be beneficial to ALI, but the underlying mechanisms have not been completely understood. The present study aimed to examine the involvement of MyD88−NFκB signaling in the immunomodulation of MSCs in mice with lipopolysaccharides (LPS)-induced ALI. We found that serum concentrations of IL-6, TNF-α, MCP-1, IL-1β, and IL-8 were significantly decreased at 6 h after LPS-induced ALI in the MSC group (p < 0.05). For each of the five cytokines, the serum concentration of each individual mouse in either group declined to a similar level at 48 h. The intensity of lung injury lessened in the MSC group, as shown by histopathology and lung injury scores (p < 0.001). The expressions of MyD88 and phospho-NFκB in the lung tissue were significantly decreased in mice receiving MSCs as measured by Western blotting and immunohistochemistry. Our data demonstrated that human umbilical cord-derived MSCs could effectively alleviate the cytokine storm in mice after LPS-induced ALI and attenuated lung injury. Firstly, we documented the correlation between the down-regulation of MyD88−NFκB signaling and immunomodulatory effects of MSCs in the situation of ALI.
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13
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Abstract
The lung is the primary site of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced immunopathology whereby the virus enters the host cells by binding to angiotensin-converting enzyme 2 (ACE2). Sophisticated regeneration and repair programs exist in the lungs to replenish injured cell populations. However, known resident stem/progenitor cells have been demonstrated to express ACE2, raising a substantial concern regarding the long-term consequences of impaired lung regeneration after SARS-CoV-2 infection. Moreover, clinical treatments may also affect lung repair from antiviral drug candidates to mechanical ventilation. In this review, we highlight how SARS-CoV-2 disrupts a program that governs lung homeostasis. We also summarize the current efforts of targeted therapy and supportive treatments for COVID-19 patients. In addition, we discuss the pros and cons of cell therapy with mesenchymal stem cells or resident lung epithelial stem/progenitor cells in preventing post-acute sequelae of COVID-19. We propose that, in addition to symptomatic treatments being developed and applied in the clinic, targeting lung regeneration is also essential to restore lung homeostasis in COVID-19 patients.
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Affiliation(s)
- Fuxiaonan Zhao
- Department of Basic Medicine, Haihe Clinical School, Tianjin Medical University, Tianjin, China
| | - Qingwen Ma
- Department of Basic Medicine, Haihe Clinical School, Tianjin Medical University, Tianjin, China
| | - Qing Yue
- Department of Basic Medicine, Haihe Clinical School, Tianjin Medical University, Tianjin, China
| | - Huaiyong Chen
- Department of Basic Medicine, Haihe Clinical School, Tianjin Medical University, Tianjin, China
- Key Research Laboratory for Infectious Disease Prevention for State Administration of Traditional Chinese Medicine, Tianjin Institute of Respiratory Diseases, Tianjin Haihe Hospital, Tianjin, China
- Department of Basic Medicine, Haihe Hospital, Tianjin University, Tianjin, China
- Tianjin Key Laboratory of Lung Regenerative Medicine, Tianjin, China
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14
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Hezam K, Mo R, Wang C, Liu Y, Li Z. Anti-inflammatory Effects of Mesenchymal Stem Cells and Their Secretomes in Pneumonia. Curr Pharm Biotechnol 2021; 23:1153-1167. [PMID: 34493193 DOI: 10.2174/1389201022666210907115126] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/23/2021] [Accepted: 07/26/2021] [Indexed: 11/22/2022]
Abstract
Mesenchymal stem cells (MSCs) are multipotent progenitor cells that play crucial roles in the microenvironment of injured tissues. The potential therapeutics of MSCs have attracted extensive attention for several diseases such as acute respiratory distress syndrome (ARDS) and novel coronavirus disease 2019 (COVID-19) pneumonia. MSC-extracellular vesicles have been isolated from MSC-conditioned media (MSC-CM) with similar functional effects as parent MSCs. The therapeutic role of MSCs can be achieved through the balance between the inflammatory and regenerative microenvironments. Clinical settings of MSCs and their extracellular vesicles remain promising for many diseases, such as ARDS and pneumonia. However, their clinical applications remain limited due to the cost of growing and storage facilities of MSCs with a lack of standardized MSC-CM. This review highlights the proposed role of MSCs in pulmonary diseases and discusses the recent advances of MSC application for pneumonia and other lung disorders.
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Affiliation(s)
- Kamal Hezam
- Nankai University School of Medicine, Tianjin. China
| | - Rigen Mo
- Nankai University School of Medicine, Tianjin. China
| | - Chen Wang
- Nankai University School of Medicine, Tianjin. China
| | - Yue Liu
- Nankai University School of Medicine, Tianjin. China
| | - Zongjin Li
- Nankai University School of Medicine, Tianjin. China
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15
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Hoseinnia S, Ghane M, Norouzi J, Hosseini F. Mesenchymal stem cell and endothelial progenitor cells coinjection improves LPS-induced lung injury via Tie2 activation and downregulation of the TLR4/MyD88 pathway. J Cell Biochem 2021; 122:1791-1804. [PMID: 34397115 DOI: 10.1002/jcb.30133] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 07/29/2021] [Accepted: 08/03/2021] [Indexed: 12/15/2022]
Abstract
Sepsis is one of the most important complications of infection with a high mortality rate. Recently, cell therapy has been widely used to reduce the symptoms of sepsis. It has been previously reported that mesenchymal stem cell (MSC) and endothelial progenitor cells (EPC) therapy have beneficial effects in experimental models of sepsis. The effects of coculture of MSC and EPC have not yet been used to treat sepsis. Therefore, the aim of this study was to investigate the therapeutic potential of EPC + MSC coculture on the residual effects of sepsis in a lipopolysaccharide (LPS)-induced mice model. Coinjections of EPC + MSC significantly enhanced the survival rate of LPS-induced mice, decreased concentrations of pro-inflammatory cytokines, and increased the level of anti-inflammatory cytokine. The LPS-induced mice that were treated with EPC + MSC showed a notable reduction in pulmonary edema, hepatic enzymes, and C-reactive protein level compared with the control group. Our results showed that coinjection of EPC + MSC up and downregulates Tie2 and TLR4/MyD88 signaling pathways in LPS-induced mice, respectively. Also, in vitro study showed that viability, adhesion, and migration in coculture cells is significantly decreased after being induced with 10 μg/ml LPS. Our results showed that LPS impaired the functional activity of the cocultured EPC + MSC via upregulation of the TLR4/MyD88 signaling pathway, which may be associated with decreased pTie2/Tie2 expression. In conclusion, coinjection of EPC and MSC modulated the TLR4/MyD88 signaling pathway that leads to reduce the inflammatory response. This study may provide promising results for the introduction of cocultured cells to manage infectious diseases and balance the immune response through immune regulatory function.
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Affiliation(s)
- Sadaf Hoseinnia
- Department of Microbiology, North Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Maryam Ghane
- Department of Biology, Islamshahr Branch, Islamic Azad University, Islamshahr, Iran
| | - Jamile Norouzi
- Department of Microbiology, North Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Farzaneh Hosseini
- Department of Microbiology, North Tehran Branch, Islamic Azad University, Tehran, Iran
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16
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Rangasamy T, Ghimire L, Jin L, Le J, Periasamy S, Paudel S, Cai S, Jeyaseelan S. Host Defense against Klebsiella pneumoniae Pneumonia Is Augmented by Lung-Derived Mesenchymal Stem Cells. THE JOURNAL OF IMMUNOLOGY 2021; 207:1112-1127. [PMID: 34341173 DOI: 10.4049/jimmunol.2000688] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 06/16/2021] [Indexed: 11/19/2022]
Abstract
Klebsiella pneumoniae is a common cause of Gram-negative pneumonia. The spread of antibiotic-resistant and hypervirulent strains has made treatment more challenging. This study sought to determine the immunomodulatory, antibacterial, and therapeutic potential of purified murine stem cell Ag-1+ (Sca-1+) lung mesenchymal stem cells (LMSCs) using in vitro cell culture and an in vivo mouse model of pneumonia caused by K pneumoniae. Sca-1+ LMSCs are plastic adherent, possess colony-forming capacity, express mesenchymal stem cell markers, differentiate into osteogenic and adipogenic lineages in vitro, and exhibit a high proliferative capacity. Further, these Sca-1+ LMSCs are morphologically similar to fibroblasts but differ ultrastructurally. Moreover, Sca-1+ LMSCs have the capacity to inhibit LPS-induced secretion of inflammatory cytokines by bone marrow-derived macrophages and neutrophils in vitro. Sca-1+ LMSCs inhibit the growth of K pneumoniae more potently than do neutrophils. Sca-1+ LMSCs also possess the intrinsic ability to phagocytize and kill K. pneumoniae intracellularly. Whereas the induction of autophagy promotes bacterial replication, inhibition of autophagy enhances the intracellular clearance of K. pneumoniae in Sca-1+ LMSCs during the early time of infection. Adoptive transfer of Sca-1+ LMSCs in K. pneumoniae-infected mice improved survival, reduced inflammatory cells in bronchoalveolar lavage fluid, reduced inflammatory cytokine levels and pathological lesions in the lung, and enhanced bacterial clearance in the lung and in extrapulmonary organs. To our knowledge, these results together illustrate for the first time the protective role of LMSCs in bacterial pneumonia.
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Affiliation(s)
- Tirumalai Rangasamy
- Center for Lung Biology and Disease, Louisiana State University, Baton Rouge, LA; .,Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA; and
| | - Laxman Ghimire
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA; and
| | - Liliang Jin
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA; and
| | - John Le
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA; and
| | - Sivakumar Periasamy
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA; and
| | - Sagar Paudel
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA; and
| | - Shanshan Cai
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA; and
| | - Samithamby Jeyaseelan
- Center for Lung Biology and Disease, Louisiana State University, Baton Rouge, LA; .,Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA; and.,Division of Pulmonary and Critical Care, Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA
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17
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Shi M, Yang Q, Monsel A, Yan J, Dai C, Zhao J, Shi G, Zhou M, Zhu X, Li S, Li P, Wang J, Li M, Lei J, Xu D, Zhu Y, Qu J. Preclinical efficacy and clinical safety of clinical-grade nebulized allogenic adipose mesenchymal stromal cells-derived extracellular vesicles. J Extracell Vesicles 2021; 10:e12134. [PMID: 34429860 PMCID: PMC8363910 DOI: 10.1002/jev2.12134] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 07/18/2021] [Accepted: 08/01/2021] [Indexed: 12/29/2022] Open
Abstract
Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) turn out to be a promising source of cell-free therapy. Here, we investigated the biodistribution and effect of nebulized human adipose-derived MSC-EVs (haMSC-EVs) in the preclinical lung injury model and explored the safety of nebulized haMSC-EVs in healthy volunteers. DiR-labelled haMSC-EVs were used to explore the distribution of nebulized haMSC-EVs in the murine model. Pseudomonas aeruginosa-induced murine lung injury model was established, and survival rate, as well as WBC counts, histology, IL-6, TNF-α and IL-10 levels in bronchoalveolar lavage fluid (BALF) were measured to explore the optimal therapeutic dose of haMSC-EVs through the nebulized route. Twenty-four healthy volunteers were involved and received the haMSC-EVs once, ranging from 2 × 108 particles to 16 × 108 particles (MEXVT study, NCT04313647). Nebulizing haMSC-EVs improved survival rate to 80% at 96 h in P. aeruginosa-induced murine lung injury model by decreasing lung inflammation and histological severity. All volunteers tolerated the haMSC-EVs nebulization well, and no serious adverse events were observed from starting nebulization to the 7th day after nebulization. These findings suggest that nebulized haMSC-EVs could be a promising therapeutic strategy, offering preliminary evidence to promote the future clinical applications of nebulized haMSC-EVs in lung injury diseases.
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Affiliation(s)
- Meng‐meng Shi
- Department of Pulmonary and Critical Care MedicineRui‐jin HospitalShanghai Jiao‐tong University School of MedicineShanghaiChina
- Institute of Respiratory DiseaseShanghai Jiao‐tong University School of MedicineShanghaiChina
- Key Laboratory of Emergency PreventionDiagnosis and Treatment of Respiratory Infectious DiseasesShanghaiChina
| | - Qing‐yuan Yang
- Department of Pulmonary and Critical Care MedicineRui‐jin HospitalShanghai Jiao‐tong University School of MedicineShanghaiChina
- Institute of Respiratory DiseaseShanghai Jiao‐tong University School of MedicineShanghaiChina
- Key Laboratory of Emergency PreventionDiagnosis and Treatment of Respiratory Infectious DiseasesShanghaiChina
| | - Antoine Monsel
- Multidisciplinary Intensive Care UnitDepartment of Anaesthesiology and Critical CareLa Pitié‐Salpêtrière HospitalAssistance Publique‐Hôpitaux de Paris (APHP)Sorbonne UniversityFrance
- INSERMSorbonne UniversitéUMR S 959, Immunology‐Immunopathology‐ Immunotherapy (I3); F‐75005ParisFrance
- Biotherapy (CIC‐BTi) and Inflammation‐Immunopathology‐Biotherapy Department (DHU i2B)Hôpital Pitié‐SalpêtrièreAP‐HP, F‐75651ParisFrance
| | - Jia‐yang Yan
- Department of Pulmonary and Critical Care MedicineRui‐jin HospitalShanghai Jiao‐tong University School of MedicineShanghaiChina
- Institute of Respiratory DiseaseShanghai Jiao‐tong University School of MedicineShanghaiChina
- Key Laboratory of Emergency PreventionDiagnosis and Treatment of Respiratory Infectious DiseasesShanghaiChina
| | - Cheng‐xiang Dai
- Cellular Biomedicine Group Inc. (CBMG)ShanghaiChina
- Daxing Research InstituteUniversity of Science and Technology BeijingBeijingChina
| | - Jing‐ya Zhao
- Department of Pulmonary and Critical Care MedicineRui‐jin HospitalShanghai Jiao‐tong University School of MedicineShanghaiChina
- Institute of Respiratory DiseaseShanghai Jiao‐tong University School of MedicineShanghaiChina
- Key Laboratory of Emergency PreventionDiagnosis and Treatment of Respiratory Infectious DiseasesShanghaiChina
| | - Guo‐chao Shi
- Department of Pulmonary and Critical Care MedicineRui‐jin HospitalShanghai Jiao‐tong University School of MedicineShanghaiChina
- Institute of Respiratory DiseaseShanghai Jiao‐tong University School of MedicineShanghaiChina
- Key Laboratory of Emergency PreventionDiagnosis and Treatment of Respiratory Infectious DiseasesShanghaiChina
| | - Min Zhou
- Department of Pulmonary and Critical Care MedicineRui‐jin HospitalShanghai Jiao‐tong University School of MedicineShanghaiChina
- Institute of Respiratory DiseaseShanghai Jiao‐tong University School of MedicineShanghaiChina
- Key Laboratory of Emergency PreventionDiagnosis and Treatment of Respiratory Infectious DiseasesShanghaiChina
| | - Xue‐mei Zhu
- Department of Pulmonary and Critical Care MedicineRui‐jin HospitalShanghai Jiao‐tong University School of MedicineShanghaiChina
- Institute of Respiratory DiseaseShanghai Jiao‐tong University School of MedicineShanghaiChina
- Key Laboratory of Emergency PreventionDiagnosis and Treatment of Respiratory Infectious DiseasesShanghaiChina
| | - Su‐ke Li
- Cellular Biomedicine Group Inc. (CBMG)ShanghaiChina
| | - Ping Li
- Cellular Biomedicine Group Inc. (CBMG)ShanghaiChina
| | - Jing Wang
- Cellular Biomedicine Group Inc. (CBMG)ShanghaiChina
| | - Meng Li
- Cellular Biomedicine Group Inc. (CBMG)ShanghaiChina
| | - Ji‐gang Lei
- Cellular Biomedicine Group Inc. (CBMG)ShanghaiChina
| | - Dong Xu
- Cellular Biomedicine Group Inc. (CBMG)ShanghaiChina
| | - Ying‐gang Zhu
- Department of Pulmonary and Critical Care MedicineHua‐dong HospitalFudan UniversityShanghaiChina
| | - Jie‐ming Qu
- Department of Pulmonary and Critical Care MedicineRui‐jin HospitalShanghai Jiao‐tong University School of MedicineShanghaiChina
- Institute of Respiratory DiseaseShanghai Jiao‐tong University School of MedicineShanghaiChina
- Key Laboratory of Emergency PreventionDiagnosis and Treatment of Respiratory Infectious DiseasesShanghaiChina
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18
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Fengyun W, LiXin Z, Xinhua Q, Bin F. Mesenchymal Stromal Cells Attenuate Infection-Induced Acute Respiratory Distress Syndrome in Animal Experiments: A Meta-Analysis. Cell Transplant 2021; 29:963689720969186. [PMID: 33164559 PMCID: PMC7784610 DOI: 10.1177/0963689720969186] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Mesenchymal stromal cell (MSC) therapy is a potential therapy for treating acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), which was widely studied in the last decade. The purpose of our meta-analysis was to investigate the efficacy of MSCs for simulated infection-induced ALI/ARDS in animal trials. PubMed and EMBASE were searched to screen relevant preclinical trials with a prespecified search strategy. 57 studies met the inclusion criteria and were included in our study. Our meta-analysis showed that MSCs can reduce the lung injury score of ALI caused by lipopolysaccharide or bacteria (standardized mean difference (SMD) = −2.97, 95% CI [−3.64 to −2.30], P < 0.00001) and improve the animals’ survival (odds ratio = 3.64, 95% CI [2.55 to 5.19], P < 0.00001). Our study discovered that MSCs can reduce the wet weight to dry weight ratio of the lung (SMD = −2.58, 95% CI [−3.24 to −1.91], P < 0.00001). The proportion of the alveolar sac in the MSC group was higher than that in the control group (SMD = 1.68, 95% CI [1.22 to 2.13], P < 0.00001). Moreover, our study detected that MSCs can downregulate the levels of proinflammatory factors such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α in the lung and it can upregulate the level of anti-inflammatory factor IL-10. MSCs were also found to reduce the level of neutrophils and total protein in bronchoalveolar lavage fluid, decrease myeloperoxidase (MPO) activity in the lung, and improve lung compliance. MSC therapy may be a promising treatment for ALI/ARDS since it may mitigate the severity of lung injury, modulate the immune balance, and ameliorate the permeability of lung vessels in ALI/ARDS, thus facilitating lung regeneration and repair.
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Affiliation(s)
- Wang Fengyun
- Department of Critical Care Medicine, 66278The First People's Hospital of Foshan, Foshan, China
| | - Zhou LiXin
- Department of Critical Care Medicine, 66278The First People's Hospital of Foshan, Foshan, China
| | - Qiang Xinhua
- Department of Critical Care Medicine, 66278The First People's Hospital of Foshan, Foshan, China
| | - Fang Bin
- Department of Critical Care Medicine, 66278The First People's Hospital of Foshan, Foshan, China
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19
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Liu J, Hou Z, Wu J, Liu K, Li D, Gao T, Liu W, An B, Sun Y, Mo F, Wang L, Wang Y, Hao J, Hu B. Infusion of hESC derived Immunity-and-matrix regulatory cells improves cognitive ability in early-stage AD mice. Cell Prolif 2021; 54:e13085. [PMID: 34232542 PMCID: PMC8349653 DOI: 10.1111/cpr.13085] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 05/17/2021] [Accepted: 05/22/2021] [Indexed: 12/20/2022] Open
Abstract
Objectives In this study, we administered immunity‐and‐matrix regulatory cells (IMRCs) via tail vein (IV) and intracerebroventricular (ICV) injection to 3‐month‐old 5×FAD transgenic mice to assess the effects of IMRC transplantation on the behaviour and pathology of early‐stage Alzheimer's disease (AD). Materials and methods Clinical‐grade human embryonic stem cell (hESC)‐derived IMRCs were produced under good manufacturing practice (GMP) conditions. Three‐month‐old 5×FAD mice were administered IMRCs via IV and ICV injection. After 3 months, the mice were subjected to behavioural tests and electrophysiological analysis to evaluate their cognitive function, memory ability and synaptic plasticity. The effect of IMRCs on amyloid‐beta (Aβ)‐related pathology was detected by thioflavin‐S staining and Western blot. Quantitative real‐time PCR, ELISA and immunostaining were used to confirm that IMRCs inhibit neuroinflammation. RNA‐seq analysis was performed to measure changes in gene expression and perform a pathway analysis in response to IMRC treatment. Results IMRC administration via tail vein injection significantly ameliorated cognitive deficits in early‐stage AD (5×FAD) mice. However, no significant change was observed in the characteristic pathology of AD in the ICV group. Plaque analysis revealed that IMRCs did not influence either plaque deposition or BACE1 expression. In addition, IMRCs inhibited inflammatory responses and reduced microglial activation in vivo. Conclusions We have shown that peripheral administration of IMRCs can ameliorate AD pathology and associated cognitive deficits.
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Affiliation(s)
- Jing Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Zongren Hou
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.,Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China
| | - Jun Wu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Kailun Liu
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.,Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China
| | - Da Li
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Tingting Gao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.,National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, China
| | - Wenjing Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.,National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, China
| | - Bin An
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.,National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, China
| | - Yun Sun
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Fan Mo
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Liu Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.,National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, China
| | - Yukai Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.,National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, China
| | - Jie Hao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.,National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, China
| | - Baoyang Hu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.,National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, China
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20
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Zheng Y, Liu J, Chen P, Lin L, Luo Y, Ma X, Lin J, Shen Y, Zhang L. RETRACTED: Exosomal miR-22-3p from human umbilical cord blood-derived mesenchymal stem cells protects against lipopolysaccharid-induced acute lung injury. Life Sci 2021; 269:119004. [PMID: 33417960 DOI: 10.1016/j.lfs.2020.119004] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 12/28/2020] [Accepted: 12/28/2020] [Indexed: 02/06/2023]
Abstract
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. Concern was raised about the reliability of the Western blot results in Figs. 2D/H/L, and 7B/F, which appear to have the same eyebrow shaped phenotype as many other publications tabulated here (https://docs.google.com/spreadsheets/d/149EjFXVxpwkBXYJOnOHb6RhAqT4a2llhj9LM60MBffM/edit#gid=0). Concerns were also raised over the provenance of the flow cytometry plots in Fig. 1C. The journal requested the corresponding author comment on these concerns and provide the raw data. However the authors were not able to satisfactorily fulfil this request and therefore the Editor-in-Chief decided to retract the article.
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Affiliation(s)
- Yuanfang Zheng
- Department of Neonatology, the Affiliated Fuzhou Children Hospital of Fujian Medical University, Fuzhou 350005, Fujian, China
| | - Jiyuan Liu
- Department of Neonatology, the Affiliated Fuzhou Children Hospital of Fujian Medical University, Fuzhou 350005, Fujian, China
| | - Ping Chen
- Department of Neonatology, the Affiliated Fuzhou Children Hospital of Fujian Medical University, Fuzhou 350005, Fujian, China
| | - Lu Lin
- Department of Neonatology, the Affiliated Fuzhou Children Hospital of Fujian Medical University, Fuzhou 350005, Fujian, China
| | - Yinzhu Luo
- Department of Neonatology, the Affiliated Fuzhou Children Hospital of Fujian Medical University, Fuzhou 350005, Fujian, China
| | - Xiaoying Ma
- Department of Neonatology, the Affiliated Fuzhou Children Hospital of Fujian Medical University, Fuzhou 350005, Fujian, China
| | - Jincai Lin
- Department of Neonatology, the Affiliated Fuzhou Children Hospital of Fujian Medical University, Fuzhou 350005, Fujian, China
| | - Ying Shen
- Department of Neonatology, the Affiliated Fuzhou Children Hospital of Fujian Medical University, Fuzhou 350005, Fujian, China
| | - Liyan Zhang
- Department of Neonatology, the Affiliated Fuzhou Children Hospital of Fujian Medical University, Fuzhou 350005, Fujian, China.
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21
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Intra-vital imaging of mesenchymal stromal cell kinetics in the pulmonary vasculature during infection. Sci Rep 2021; 11:5265. [PMID: 33664277 PMCID: PMC7933415 DOI: 10.1038/s41598-021-83894-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 01/20/2021] [Indexed: 01/13/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) have demonstrated efficacy in pre-clinical models of inflammation and tissue injury, including in models of lung injury and infection. Rolling, adhesion and transmigration of MSCs appears to play a role during MSC kinetics in the systemic vasculature. However, a large proportion of MSCs become entrapped within the lungs after intravenous administration, while the initial kinetics and the site of arrest of MSCs in the pulmonary vasculature are unknown. We examined the kinetics of intravascularly administered MSCs in the pulmonary vasculature using a microfluidic system in vitro and intra-vital microscopy of intact mouse lung. In vitro, MSCs bound to endothelium under static conditions but not under laminar flow. VCAM-1 antibodies did not affect MSC binding. Intravital microscopy demonstrated MSC arrest at pulmonary micro-vessel bifurcations due to size obstruction. Retention of MSCs in the pulmonary microvasculature was increased in Escherichia coli-infected animals. Trapped MSCs deformed over time and appeared to release microvesicles. Labelled MSCs retained therapeutic efficacy against pneumonia. Our results suggest that MSCs are physically obstructed in pulmonary vasculature and do not display properties of rolling/adhesion, while retention of MSCs in the infected lung may require receptor interaction.
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22
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Fröhlich E. Therapeutic Potential of Mesenchymal Stem Cells and Their Products in Lung Diseases-Intravenous Administration versus Inhalation. Pharmaceutics 2021; 13:232. [PMID: 33562240 PMCID: PMC7915745 DOI: 10.3390/pharmaceutics13020232] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/29/2021] [Accepted: 02/03/2021] [Indexed: 12/13/2022] Open
Abstract
The number of publications studying the therapeutic use of stem cells has steadily increased since 2000. Compared to other applications, there has been little interest in the evaluation of mesenchymal stem cells (MSCs) and MSC-derived products (mostly extracellular vesicles) for the treatment of respiratory diseases. Due to the lack of efficient treatments for acute respiratory distress syndrome caused by infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the action of MSCs has also been studied. This review describes mode of action and use of MSCs and MSC-derived products in the treatment of lung diseases including the respective advantages and limitations of the products. Further, issues related to standardized production are addressed. Administration by inhalation of MSCs, compared to intravenous injection, could decrease cell damage by shear stress, eliminate the barrier to reach target cells in the alveoli, prevent thrombus formation in the pulmonary vasculature and retention in filter for extracorporeal membrane oxygenation. There is more feasible to deliver extracellular vesicles than MSCs with inhalers, offering the advantage of non-invasive and repeated administration by the patient. Major obstacles for comparison of results are heterogeneity of the products, differences in the treatment protocols and small study cohorts.
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Affiliation(s)
- Eleonore Fröhlich
- Center for Medical Research, Medical University of Graz, Stiftingtalstr 24, 8010 Graz, Austria; ; Tel.: +43-316-385-73011
- Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13, 8010 Graz, Austria
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23
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Jamshidi E, Babajani A, Soltani P, Niknejad H. Proposed Mechanisms of Targeting COVID-19 by Delivering Mesenchymal Stem Cells and Their Exosomes to Damaged Organs. Stem Cell Rev Rep 2021; 17:176-192. [PMID: 33432484 PMCID: PMC7799400 DOI: 10.1007/s12015-020-10109-3] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/13/2020] [Indexed: 12/13/2022]
Abstract
With the outbreak of coronavirus disease (COVID-19) caused by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the world has been facing an unprecedented challenge. Considering the lack of appropriate therapy for COVID-19, it is crucial to develop effective treatments instead of supportive approaches. Mesenchymal stem cells (MSCs) as multipotent stromal cells have been shown to possess treating potency through inhibiting or modulating the pathological events in COVID-19. MSCs and their exosomes participate in immunomodulation by controlling cell-mediated immunity and cytokine release. Furthermore, they repair the renin-angiotensin-aldosterone system (RAAS) malfunction, increase alveolar fluid clearance, and reduce the chance of hypercoagulation. Besides the lung, which is the primary target of SARS-CoV-2, the heart, kidney, nervous system, and gastrointestinal tract are also affected by COVID-19. Thus, the efficacy of targeting these organs via different delivery routes of MSCs and their exosomes should be evaluated to ensure safe and effective MSCs administration in COVID-19. This review focuses on the proposed therapeutic mechanisms and delivery routes of MSCs and their exosomes to the damaged organs. It also discusses the possible application of primed and genetically modified MSCs as a promising drug delivery system in COVID-19. Moreover, the recent advances in the clinical trials of MSCs and MSCs-derived exosomes as one of the promising therapeutic approaches in COVID-19 have been reviewed.
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Affiliation(s)
- Elham Jamshidi
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amirhesam Babajani
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Pegah Soltani
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hassan Niknejad
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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24
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Shi M, Zhu Y, Yan J, Rouby J, Summah H, Monsel A, Qu J. Role of miR-466 in mesenchymal stromal cell derived extracellular vesicles treating inoculation pneumonia caused by multidrug-resistant Pseudomonas aeruginosa. Clin Transl Med 2021; 11:e287. [PMID: 33463070 PMCID: PMC7805403 DOI: 10.1002/ctm2.287] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 12/27/2020] [Accepted: 12/29/2020] [Indexed: 12/15/2022] Open
Abstract
RATIONALE The effects of mesenchymal stromal cells (MSCs) and MSC-derived extracellular vesicles (MSC EVs) on multidrug-resistant pseudomonas aeruginosa (MDR-PA)-induced pneumonia remain unclear. MATERIALS AND METHODS MicroRNA array and RT-PCR were used to select the major microRNA in MSC EVs. Human peripheral blood monocytes were obtained and isolated from qualified patients. The crosstalk between MSCs/MSC EVs and macrophages in vitro was studied. MDR-PA pneumonia models were further established in C57BL/6 mice and MSC EVs or miR-466 overexpressing MSC EVs were intratracheally instilled. RESULTS MiR-466 was highly expressed in MSC EVs. MSCs and miR-466 promoted macrophage polarization toward Type 2 phenotype through TIRAP-MyD88-NFκB axis. Moreover, cocultured macrophages with miR-466 overexpressing MSCs significantly increased the phagocytosis of macrophages. MSC EVs significantly reduced mortality and decreased influx of BALF neutrophils, proinflammatory factor levels, protein, and bacterial load in murine MDR-PA pneumonia. Administration of miR-466 overexpressing MSC EVs further alleviated the inflammatory severity. CONCLUSIONS MSC-derived EVs containing high levels of miR-466 may partly participate in host immune responses to MDR-PA. Both MSCs and MSC EVs have therapeutic effects in treating MDR-PA-induced pneumonia.
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Affiliation(s)
- Meng‐meng Shi
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
- Institute of Respiratory Diseases, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Ying‐gang Zhu
- Department of Pulmonary and Critical Care Medicine, Hua‐dong HospitalFudan UniversityShanghaiChina
| | - Jia‐yang Yan
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
- Institute of Respiratory Diseases, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Jean‐Jacques Rouby
- Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié‐Salpêtrière Hospital, Assistance Publique‐Hôpitaux de Paris (APHP)Sorbonne UniversityParisFrance
| | - Hanssa Summah
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
- Institute of Respiratory Diseases, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Antoine Monsel
- Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié‐Salpêtrière Hospital, Assistance Publique‐Hôpitaux de Paris (APHP)Sorbonne UniversityParisFrance
- INSERM, UMR S 959, Immunology‐Immunopathology‐ Immunotherapy (I3)Sorbonne UniversitéParisF‐75005France
- Biotherapy (CIC‐BTi) and Inflammation‐Immunopathology‐Biotherapy Department (DHU i2B)Hôpital Pitié‐SalpêtrièreAP‐HPParisF‐75651France
| | - Jie‐ming Qu
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
- Institute of Respiratory Diseases, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
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25
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Qin H, Zhao A. Mesenchymal stem cell therapy for acute respiratory distress syndrome: from basic to clinics. Protein Cell 2020; 11:707-722. [PMID: 32519302 PMCID: PMC7282699 DOI: 10.1007/s13238-020-00738-2] [Citation(s) in RCA: 96] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 05/12/2020] [Indexed: 01/08/2023] Open
Abstract
The 2019 novel coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has occurred in China and around the world. SARS-CoV-2-infected patients with severe pneumonia rapidly develop acute respiratory distress syndrome (ARDS) and die of multiple organ failure. Despite advances in supportive care approaches, ARDS is still associated with high mortality and morbidity. Mesenchymal stem cell (MSC)-based therapy may be an potential alternative strategy for treating ARDS by targeting the various pathophysiological events of ARDS. By releasing a variety of paracrine factors and extracellular vesicles, MSC can exert anti-inflammatory, anti-apoptotic, anti-microbial, and pro-angiogenic effects, promote bacterial and alveolar fluid clearance, disrupt the pulmonary endothelial and epithelial cell damage, eventually avoiding the lung and distal organ injuries to rescue patients with ARDS. An increasing number of experimental animal studies and early clinical studies verify the safety and efficacy of MSC therapy in ARDS. Since low cell engraftment and survival in lung limit MSC therapeutic potentials, several strategies have been developed to enhance their engraftment in the lung and their intrinsic, therapeutic properties. Here, we provide a comprehensive review of the mechanisms and optimization of MSC therapy in ARDS and highlighted the potentials and possible barriers of MSC therapy for COVID-19 patients with ARDS.
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Affiliation(s)
- Hua Qin
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department, PLA General Hospital and PLA Medical College, Beijing, 100853, China.
| | - Andong Zhao
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department, PLA General Hospital and PLA Medical College, Beijing, 100853, China
- Tianjin Medical University, Tianjin, 300070, China
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26
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Deus IA, Mano JF, Custódio CA. Perinatal tissues and cells in tissue engineering and regenerative medicine. Acta Biomater 2020; 110:1-14. [PMID: 32418650 DOI: 10.1016/j.actbio.2020.04.035] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 04/09/2020] [Accepted: 04/20/2020] [Indexed: 02/07/2023]
Abstract
Perinatal tissues are an abundant source of human extracellular matrix proteins, growth factors and stem cells with proved potential use in a wide range of therapeutic applications. Due to their placental origin, these tissues possess unique biological properties, including being angiogenic, anti-inflammatory, anti-fibrotic, anti-microbial and immune privileged. Additionally, as a temporary organ, placenta is usually discarded as a medical waste, thus providing an easily available, cost effective, 'unlimited' and ethical source of raw materials. Although some of these tissues, such as the amniotic membrane and umbilical cord, have been used in clinical practices, most of them continue to be highly under explored. This review aims to outline the most relevant applications of perinatal tissues as a source of biomaterials and stem cells in the exciting fields of tissue engineering and regenerative medicine (TERM), as well as highlight how these solutions can be used to overcome the shortage of adequate scaffolds and cell sources that currently hampers the translation of TERM strategies towards clinical settings. STATEMENT OF SIGNIFICANCE: Stem cells and extracellular matrix derived from perinatal tissues such as placenta and umbilical cord, have drawn great attention for use in a wide variety of applications in the biomedical field. Due to their origin, these tissues possess unique biological properties, including being angiogenic, anti-inflammatory, anti-fibrotic, anti-microbial and immune privileged. Also they are typically considered medical waste, thus providing an easily available, cost effective, 'unlimited' and ethical source of raw materials. This work aims to present and discuss the most relevant applications of perinatal tissues as a source of biomaterials and stem cells in the exciting fields of tissue engineering and regenerative medicine (TERM).
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27
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Kim SY, Joglekar MV, Hardikar AA, Phan TH, Khanal D, Tharkar P, Limantoro C, Johnson J, Kalionis B, Chrzanowski W. Placenta Stem/Stromal Cell-Derived Extracellular Vesicles for Potential Use in Lung Repair. Proteomics 2020; 19:e1800166. [PMID: 31318160 DOI: 10.1002/pmic.201800166] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 06/26/2019] [Indexed: 12/28/2022]
Abstract
Many acute and chronic lung injuries are incurable and rank as the fourth leading cause of death globally. While stem cell treatment for lung injuries is a promising approach, there is growing evidence that the therapeutic efficacy of stem cells originates from secreted extracellular vesicles (EVs). Consequently, EVs are emerging as next-generation therapeutics. While EVs are extensively researched for diagnostic applications, their therapeutic potential to promote tissue repair is not fully elucidated. By housing and delivering tissue-repairing cargo, EVs refine the cellular microenvironment, modulate inflammation, and ultimately repair injury. Here, the potential use of EVs derived from two placental mesenchymal stem/stromal cell (MSC) lines is presented; a chorionic MSC line (CMSC29) and a decidual MSC cell line (DMSC23) for applications in lung diseases. Functional analyses using in vitro models of injury demonstrate that these EVs have a role in ameliorating injuries caused to lung cells. It is also shown that EVs promote repair of lung epithelial cells. This study is fundamental to advancing the field of EVs and to unlock the full potential of EVs in regenerative medicine.
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Affiliation(s)
- Sally Yunsun Kim
- Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, New South Wales, 2006, Australia.,Nano Institute, The University of Sydney, New South Wales, 2006, Australia
| | - Mugdha V Joglekar
- Islet Biology and Diabetes Group, National Health and Medical Research Council Clinical Trials Center, Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, 2050, Australia
| | - Anandwardhan A Hardikar
- Islet Biology and Diabetes Group, National Health and Medical Research Council Clinical Trials Center, Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, 2050, Australia
| | - Thanh Huyen Phan
- Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, New South Wales, 2006, Australia.,Nano Institute, The University of Sydney, New South Wales, 2006, Australia
| | - Dipesh Khanal
- Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, New South Wales, 2006, Australia.,Nano Institute, The University of Sydney, New South Wales, 2006, Australia
| | - Priyanka Tharkar
- Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, New South Wales, 2006, Australia.,Nano Institute, The University of Sydney, New South Wales, 2006, Australia
| | - Christina Limantoro
- Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, New South Wales, 2006, Australia.,Nano Institute, The University of Sydney, New South Wales, 2006, Australia
| | - Jancy Johnson
- Department of Maternal fetal Medicine, Royal Women's Hospital, Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Bill Kalionis
- Department of Maternal fetal Medicine, Royal Women's Hospital, Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Wojciech Chrzanowski
- Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, New South Wales, 2006, Australia.,Nano Institute, The University of Sydney, New South Wales, 2006, Australia
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28
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Sadeghian Chaleshtori S, Mokhber Dezfouli MR, Jabbari Fakhr M. Mesenchymal stem/stromal cells: the therapeutic effects in animal models of acute pulmonary diseases. Respir Res 2020; 21:110. [PMID: 32393278 PMCID: PMC7213547 DOI: 10.1186/s12931-020-01373-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 04/23/2020] [Indexed: 02/06/2023] Open
Abstract
The pulmonary diseases are one of the most important causes of death in the world. The successful therapies in the field of lung diseases are very limited and the medical treatments available are ineffective in many of the lung diseases. Many studies have evaluated the new therapies in the acute pulmonary diseases, and the transplantation of mesenchymal stem/stromal cells (MSCs), which is a branch of cell therapy, has a special place among the new medical techniques. The MSCs are present throughout the body and are thought to play a role in tissue regeneration and inflammation control. In the event of injury, the local MSCs traverse the shortest possible distance from the tissue or blood vessels to reach the affected site. But, there are few undifferentiated cells in the tissues. The exogenous MSCs are used to immunity modify or regenerative treatments in preclinical models of acute pulmonary diseases. Several studies have shown the positive effects of MSCs replacement in the acute lung disorders. The effection mechanism of the MSCs include the differentiation ability and the secretion of paracrine agents such as the anti-inflammatory mediators. Many studies suggest that this treatment method is safe and is probably to be widely used in future clinical trials. This review will describe the therapeutic effects of the MSCs in the experimental models of the acute pulmonary diseases for use as a method of treatment in clinical trials in future.
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Affiliation(s)
- Sirous Sadeghian Chaleshtori
- Department of Internal Medicine, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.,Institute of Biomedical Research, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Mohammad Reza Mokhber Dezfouli
- Department of Internal Medicine, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran. .,Institute of Biomedical Research, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.
| | - Massoumeh Jabbari Fakhr
- Institute of Biomedical Research, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.,Department of Tissue Engineering, Faculty of Medicine, Qom University of Medical Sciences, Qom, Iran
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Kong D, Liu X, Li X, Hu J, Li X, Xiao J, Dai Y, He M, Liu X, Jiang Y, Cui R, Zhang L, Wang J, Li A, Wang F, Zhang Y, Xiao J, Wang W, Zheng C. Mesenchymal stem cells significantly improved treatment effects of Linezolid on severe pneumonia in a rabbit model. Biosci Rep 2019; 39:BSR20182455. [PMID: 31484796 PMCID: PMC6746999 DOI: 10.1042/bsr20182455] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2018] [Revised: 08/19/2019] [Accepted: 09/03/2019] [Indexed: 12/13/2022] Open
Abstract
The present study aimed to investigate whether co-administration of mesenchymal stromal cells (MSC) and linezolid (LZD) into a rabbit model of methicillin-resistant Staphylococcus aureus (MRSA)-infected pneumonia would bring a synergistic therapeutic effect. Human umbilical cord-derived MSCs (hUMSCs) were isolated and characterized. A rabbit model of pneumonia was constructed by delivering 1 × 1010 CFU MRSA via a bronchoscope into the basal segment of lower lobe of right lung. Through analyzing vital sign, pulmonary auscultation, SpO2, chest imaging, bronchoscopic manifestations, pathology, neutrophil percentage, and inflammatory factors, we verified that a rabbit model of MRSA-induced pneumonia was successfully constructed. Individual treatment with LZD (50 mg/kg for two times/day) resulted in improvement of body weight, chest imaging, bronchoscopic manifestations, histological parameters, and IL-10 concentration in plasma (P<0.01), decreasing pulmonary auscultation, and reduction of IL-8, IL-6, CRP, and TNF-α concentrations in plasma (P<0.01) compared with the pneumonia model group at 48 and 168 h. Compared with LZD group, co-administration of hUMSCs (1 × 106/kg for two times at 6 and 72 h after MRSA instillation) and LZD further increased the body weight (P<0.05). The changes we observed from chest imaging, bronchoscopic manifestations and pathology revealed that co-administration of hUMSCs and LZD reduced lung inflammation more significantly than that of LZD group. The plasma levels of IL-8, IL-6, CRP, and TNF-α in combined group decreased dramatically compared with the LZD group (P<0.05). In conclusion, hUMSCs administration significantly improved therapeutic effects of LZD on pneumonia resulted from MRSA infection in a rabbit model.
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Affiliation(s)
- Dexiao Kong
- Department of hematology of the Second Hospital, Institute of Biotherapy for Hematological Malignancies, Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, Shandong Province, China
- Department of Hematology, Zhaoyuan Sorting-Yingcheng Hospital, Second Hospital of Shandong University, Yantai, Shandong Province, China
| | - Xia Liu
- Department of Respiratory Intervention, Qilu Children's Hospital of Shandong University, Jinan, Shandong Province, China
| | - Xiaomei Li
- Cancer Center, The Second Hospital of Shandong University, Jinan, Shandong Province, China
| | - Jianting Hu
- Shandong Pharmaceutical Academy, Shandong Provincial Key Laboratory of Chemical Drugs, Jinan, Shandong Province, China
| | - Xiaoyan Li
- Department of hematology of the Second Hospital, Institute of Biotherapy for Hematological Malignancies, Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, Shandong Province, China
| | - Juan Xiao
- Department of hematology of the Second Hospital, Institute of Biotherapy for Hematological Malignancies, Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, Shandong Province, China
| | - Yibo Dai
- Department of hematology of the Second Hospital, Institute of Biotherapy for Hematological Malignancies, Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, Shandong Province, China
| | - Mingming He
- Department of hematology of the Second Hospital, Institute of Biotherapy for Hematological Malignancies, Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, Shandong Province, China
| | - Xiaoli Liu
- Department of hematology of the Second Hospital, Institute of Biotherapy for Hematological Malignancies, Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, Shandong Province, China
- Department of Hematology, Zhaoyuan Sorting-Yingcheng Hospital, Second Hospital of Shandong University, Yantai, Shandong Province, China
| | - Yang Jiang
- Department of hematology of the Second Hospital, Institute of Biotherapy for Hematological Malignancies, Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, Shandong Province, China
- Department of Hematology, Zhaoyuan Sorting-Yingcheng Hospital, Second Hospital of Shandong University, Yantai, Shandong Province, China
| | - Ruodi Cui
- Department of Radiology, Qilu Children's Hospital of Shandong University, Jinan, Shandong Province, China
| | - Lihong Zhang
- Department of Pathology, Qilu Children's Hospital of Shandong University, Jinan, Shandong Province, China
| | - Juandong Wang
- Department of hematology of the Second Hospital, Institute of Biotherapy for Hematological Malignancies, Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, Shandong Province, China
- Department of Hematology, Zhaoyuan Sorting-Yingcheng Hospital, Second Hospital of Shandong University, Yantai, Shandong Province, China
| | - Ai Li
- Department of hematology of the Second Hospital, Institute of Biotherapy for Hematological Malignancies, Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, Shandong Province, China
- Department of Hematology, Zhaoyuan Sorting-Yingcheng Hospital, Second Hospital of Shandong University, Yantai, Shandong Province, China
| | - Fang Wang
- Clinical Laboratory, The Second Hospital of Shandong University, Jinan, Shandong Province, China
| | - Yuan Zhang
- Center of Evidence-Based Medicine, The Second Hospital of Shandong University, Jinan, Shandong Province, China
| | - Juan Xiao
- Center of Evidence-Based Medicine, The Second Hospital of Shandong University, Jinan, Shandong Province, China
| | - Wei Wang
- Department of Respiratory Medicine, The Second Hospital of Shandong University, Jinan, Shandong Province, China
| | - Chengyun Zheng
- Department of hematology of the Second Hospital, Institute of Biotherapy for Hematological Malignancies, Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, Shandong Province, China
- Department of Hematology, Zhaoyuan Sorting-Yingcheng Hospital, Second Hospital of Shandong University, Yantai, Shandong Province, China
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Lopes-Pacheco M, Robba C, Rocco PRM, Pelosi P. Current understanding of the therapeutic benefits of mesenchymal stem cells in acute respiratory distress syndrome. Cell Biol Toxicol 2019; 36:83-102. [PMID: 31485828 PMCID: PMC7222160 DOI: 10.1007/s10565-019-09493-5] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 08/27/2019] [Indexed: 12/20/2022]
Abstract
The acute respiratory distress syndrome (ARDS) is a multifaceted lung disorder in which no specific therapeutic intervention is able to effectively improve clinical outcomes. Despite an improved understanding of molecular mechanisms and advances in supportive care strategies, ARDS remains associated with high mortality, and survivors usually face long-term morbidity. In recent years, preclinical studies have provided mounting evidence of the potential of mesenchymal stem cell (MSC)-based therapies in lung diseases and critical illnesses. In several models of ARDS, MSCs have been demonstrated to induce anti-inflammatory and anti-apoptotic effects, improve epithelial and endothelial cell recovery, and enhance microbial and alveolar fluid clearance, thus resulting in improved lung and distal organ function and survival. Early-stage clinical trials have also demonstrated the safety of MSC administration in patients with ARDS, but further, large-scale investigations are required to assess the safety and efficacy profile of these therapies. In this review, we summarize the main mechanisms whereby MSCs have been shown to exert therapeutic effects in experimental ARDS. We also highlight questions that need to be further elucidated and barriers that must be overcome in order to efficiently translate MSC research into clinical practice.
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Affiliation(s)
- Miquéias Lopes-Pacheco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.,National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil
| | - Chiara Robba
- Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neurosciences, Genoa, Italy
| | - Patricia Rieken Macêdo Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. .,National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil.
| | - Paolo Pelosi
- Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neurosciences, Genoa, Italy. .,Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa, Italy.
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31
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Hoogduijn MJ, Lombardo E. Mesenchymal Stromal Cells Anno 2019: Dawn of the Therapeutic Era? Concise Review. Stem Cells Transl Med 2019; 8:1126-1134. [PMID: 31282113 PMCID: PMC6811696 DOI: 10.1002/sctm.19-0073] [Citation(s) in RCA: 109] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 06/17/2019] [Indexed: 12/11/2022] Open
Abstract
2018 was the year of the first marketing authorization of an allogeneic stem cell therapy by the European Medicines Agency. The authorization concerns the use of allogeneic adipose tissue-derived mesenchymal stromal cells (MSCs) for treatment of complex perianal fistulas in Crohn's disease. This is a breakthrough in the field of MSC therapy. The last few years have, furthermore, seen some breakthroughs in the investigations into the mechanisms of action of MSC therapy. Although the therapeutic effects of MSCs have largely been attributed to their secretion of immunomodulatory and regenerative factors, it has now become clear that some of the effects are mediated through host phagocytic cells that clear administered MSCs and in the process adapt an immunoregulatory and regeneration supporting function. The increased interest in therapeutic use of MSCs and the ongoing elucidation of the mechanisms of action of MSCs are promising indicators that 2019 may be the dawn of the therapeutic era of MSCs and that there will be revived interest in research to more efficient, practical, and sustainable MSC-based therapies. Stem Cells Translational Medicine 2019;8:1126-1134.
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Affiliation(s)
- Martin J Hoogduijn
- Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
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32
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Wang L, Shi M, Tong L, Wang J, Ji S, Bi J, Chen C, Jiang J, Bai C, Zhou J, Song Y. Lung-Resident Mesenchymal Stem Cells Promote Repair of LPS-Induced Acute Lung Injury via Regulating the Balance of Regulatory T cells and Th17 cells. Inflammation 2019; 42:199-210. [PMID: 30187337 DOI: 10.1007/s10753-018-0884-6] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are associated with high morbidity and mortality. Mesenchymal stem cells (MSCs) have been shown to improve ALI, and the imbalance of regulatory T cells (Tregs) and Th17 cells is associated with mortality in ALI/ARDS patients. However, whether administration of lung-resident MSC (LRMSC) improves lung injury and regulates the balance of Tregs and Th17 cells remains unknown. An ALI animal model was induced by LPS, and PBS or LRMSC were administered via tail vein after 4 h. LRMSC were subsequently detected in the lungs by a live imaging system (Berthold LB983, Germany). Lung morphology; lung wet-to-dry weight ratio; and total protein concentration, inflammatory cells, and cytokines in bronchoalveolar lavage fluid (BALF) and plasma were determined. The percentage of Tregs in lung and spleen, and of Th17 cells in lung and blood, were also evaluated. The results showed that LRMSC not only attenuated histopathological damage but also mediated the downregulation of lung wet-to-dry weight ratio and the reduction of total protein concentration and inflammatory cells in BALF. LRMSC also decreased inflammatory cytokines in both BALF and plasma and increased KGF-2 and surfactant protein C (SPC) expression in the lung. Flow cytometry revealed the upregulation of Tregs and the downregulation of Th17 cells, and the increase in the ratio of Tregs and Th17 cells. The live imaging system showed that LRMSC migrated to and were retained in the injured area. In conclusion, the results indicated that administration of LRMSC attenuates LPS-induced ALI via upregulating the balance of Tregs and Th17 cells.
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Affiliation(s)
- Linlin Wang
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Meng Shi
- Department of Cardiothoracic Surgery, Huashan Hospital, Fudan University, Shanghai, 200032, China
| | - Lin Tong
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Jian Wang
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Shimeng Ji
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Jing Bi
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Cuicui Chen
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Jinjun Jiang
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Chunxue Bai
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
| | - Jian Zhou
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
| | - Yuanlin Song
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China. .,Shanghai Public Health Clinical Center, Shanghai, 201508, China. .,Zhongshan Hospital, Qingpu Branch, Fudan University, Shanghai, 201700, China.
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33
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Perlee D, de Vos AF, Scicluna BP, Mancheño P, de la Rosa O, Dalemans W, Nürnberg P, Lombardo E, van der Poll T. Human Adipose-Derived Mesenchymal Stem Cells Modify Lung Immunity and Improve Antibacterial Defense in Pneumosepsis Caused by Klebsiella pneumoniae. Stem Cells Transl Med 2019; 8:785-796. [PMID: 31033196 PMCID: PMC6646807 DOI: 10.1002/sctm.18-0260] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Accepted: 03/14/2019] [Indexed: 12/20/2022] Open
Abstract
Adult mesenchymal stem cells exert immunomodulatory effects that might improve the host response during sepsis. Knowledge on the effect of adipose-derived mesenchymal stem cells (ASCs) in sepsis is limited. Klebsiella (K.) pneumoniae is a common cause of gram-negative pneumonia and sepsis. This study sought to determine the effect of human ASCs on the host response during pneumosepsis in mice. Mice were infected with K. pneumoniae via the airways to induce a gradually evolving infection in the lung culminating pneumosepsis. One or 6 hours after infection, mice were infused intravenously with ASCs or vehicle, and euthanized after 16 hours or 48 hours, respectively. The effects of freshly cultured and cryopreserved ASCs were compared, the latter formulation being more clinically relevant. Intravenously administered ASCs were visualized in lung tissue by immunostaining at 1 and 3 hours, but not at 15 hours after infusion. Although early after infection, ASCs did not or only modestly influence bacterial loads, they reduced bacterial burdens in lungs and distant organs at 48 hours. ASCs reduced the lung levels of pro-inflammatory cytokines and attenuated lung pathology, but did not influence distant organ injury. ASCs strongly modified the lung transcriptome in uninfected mice and especially mice with pneumosepsis. Cryopreserved and cultured ASCs induced largely similar effects on the lung transcriptome. These data indicate that human ASCs induce profound immune modulatory effects in the lungs, resulting in reduced bacterial burdens and lung inflammation during pneumosepsis caused by a common human pathogen, suggesting that ASCs may be an adjunctive therapeutic in this condition. Stem Cells Translational Medicine 2019;8:785&796.
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Affiliation(s)
- Desiree Perlee
- Center of Experimental & Molecular Medicine, University of Amsterdam, Amsterdam, The Netherlands
| | - Alex F de Vos
- Center of Experimental & Molecular Medicine, University of Amsterdam, Amsterdam, The Netherlands
| | - Brendon P Scicluna
- Center of Experimental & Molecular Medicine, University of Amsterdam, Amsterdam, The Netherlands.,Department of Clinical Epidemiology, Biostatistics, and Bioinformatics, University of Amsterdam, Amsterdam, The Netherlands
| | | | | | | | - Peter Nürnberg
- Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.,Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.,Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | | | - Tom van der Poll
- Center of Experimental & Molecular Medicine, University of Amsterdam, Amsterdam, The Netherlands.,Division of Infectious Diseases, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
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Marrazzo P, Crupi AN, Alviano F, Teodori L, Bonsi L. Exploring the roles of MSCs in infections: focus on bacterial diseases. J Mol Med (Berl) 2019; 97:437-450. [PMID: 30729280 DOI: 10.1007/s00109-019-01752-6] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 01/24/2019] [Accepted: 01/25/2019] [Indexed: 02/08/2023]
Abstract
Despite human healthcare advances, some microorganisms continuously react evolving new survival strategies, choosing between a commensal fitness and a pathogenic attitude. Many opportunistic microbes are becoming an increasing cause of clinically evident infections while several renowned infectious diseases sustain a considerable number of deaths. Besides the primary and extensively investigated role of immune cells, other cell types are involved in the microbe-host interaction during infection. Interestingly, mesenchymal stem cells (MSCs), the current leading players in cell therapy approaches, have been suggested to contribute to tackling pathogens and modulating the host immune response. In this context, this review critically explores MSCs' role in E. coli, S. aureus, and polymicrobial infections. Summarizing from various studies, in vitro and in vivo results support the mechanistic involvement of MSCs and their derivatives in fighting infection and in contributing to microbial spreading. Our work outlines the double face of MSCs during infection, disease, and sepsis, highlighting potential pitfalls in MSC-based therapy due to the MSCs' susceptibility to pathogens' weapons. We also identify potential targets to improve infection treatments, and propose the potential applications of MSCs for vaccine research.
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Affiliation(s)
- Pasquale Marrazzo
- Department of Experimental, Diagnostic and Specialty Medicine, Unit of Histology, Embryology and Applied Biology, University of Bologna, Via Belmeloro 8, 40126, Bologna, Italy
| | | | - Francesco Alviano
- Department of Experimental, Diagnostic and Specialty Medicine, Unit of Histology, Embryology and Applied Biology, University of Bologna, Via Belmeloro 8, 40126, Bologna, Italy.
| | - Laura Teodori
- Diagnostics and Metrology, FSN-TECFIS-DIM, Enea Frascati, Rome, Italy
| | - Laura Bonsi
- Department of Experimental, Diagnostic and Specialty Medicine, Unit of Histology, Embryology and Applied Biology, University of Bologna, Via Belmeloro 8, 40126, Bologna, Italy
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35
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Bao CT, Xiao JM, Liu BJ, Liu JF, Zhu RN, Jiang P, Li L, Langford PR, Lei LC. Establishment and comparison of Actinobacillus pleuropneumoniae experimental infection model in mice and piglets. Microb Pathog 2019; 128:381-389. [PMID: 30664928 DOI: 10.1016/j.micpath.2019.01.028] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2018] [Revised: 01/15/2019] [Accepted: 01/17/2019] [Indexed: 02/07/2023]
Abstract
Actinobacillus pleuropneumoniae (APP) causes porcine pleuropneumonia, a disease responsible for substantial losses in the worldwide pig industry. In this study, outbred Kunming (KM) and Institute of Cancer Research (ICR) mice were evaluated as alternative mice models for APP research. After intranasal infection of serotype 5 reference strain L20, there was less lung damage and a lower clinical sign score in ICR compared to KM mice. However, ICR mice showed more obvious changes in body weight loss, the amount of immune cells (such as neutrophils and lymphocytes) and cytokines (such as IL-6, IL-1β and TNF-α) in blood and bronchoalveolar lavage fluid (BALF). The immunological changes observed in ICR mice closely mimicked those found in piglets infected with L20. While both ICR and KM mice are susceptible to APP and induce pathological lesions, we suggest that ICR and KM mice are more suitable for immunological and pathogenesis studies, respectively. The research lays the theoretical basis for determine that mice could replace pigs as the APP infection model and it is of significance for the study of APP infection in the laboratory.
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Affiliation(s)
- Chun-Tong Bao
- College of Veterinary Medicine, Jilin University, Changchun, PR China
| | - Jia-Meng Xiao
- College of Veterinary Medicine, Jilin University, Changchun, PR China
| | - Bai-Jun Liu
- College of Veterinary Medicine, Jilin University, Changchun, PR China
| | - Jian-Fang Liu
- College of Veterinary Medicine, Jilin University, Changchun, PR China
| | - Ri-Ning Zhu
- College of Veterinary Medicine, Jilin University, Changchun, PR China
| | - Peng Jiang
- College of Veterinary Medicine, Jilin University, Changchun, PR China
| | - Lei Li
- College of Veterinary Medicine, Jilin University, Changchun, PR China
| | | | - Lian-Cheng Lei
- College of Veterinary Medicine, Jilin University, Changchun, PR China.
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36
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O'Rourke F, Kempf VAJ. Interaction of bacteria and stem cells in health and disease. FEMS Microbiol Rev 2019; 43:162-180. [DOI: 10.1093/femsre/fuz003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Accepted: 01/11/2019] [Indexed: 12/11/2022] Open
Affiliation(s)
- Fiona O'Rourke
- Institut für Medizinische Mikrobiologie und Krankenhaushygiene, University Hospital, Goethe University, Paul-Ehrlich-Str. 40, D-60596 Frankfurt am Main, Germany
| | - Volkhard A J Kempf
- Institut für Medizinische Mikrobiologie und Krankenhaushygiene, University Hospital, Goethe University, Paul-Ehrlich-Str. 40, D-60596 Frankfurt am Main, Germany
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37
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Antebi B, Rodriguez LA, Walker KP, Asher AM, Kamucheka RM, Alvarado L, Mohammadipoor A, Cancio LC. Short-term physiological hypoxia potentiates the therapeutic function of mesenchymal stem cells. Stem Cell Res Ther 2018; 9:265. [PMID: 30305185 PMCID: PMC6180371 DOI: 10.1186/s13287-018-1007-x] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 08/20/2018] [Accepted: 09/06/2018] [Indexed: 12/13/2022] Open
Abstract
Background In the bone marrow, MSCs reside in a hypoxic milieu (1–5% O2) that is thought to preserve their multipotent state. Typically, in vitro expansion of MSCs is performed under normoxia (~ 21% O2), a process that has been shown to impair their function. Here, we evaluated the characteristics and function of MSCs cultured under hypoxia and hypothesized that, when compared to normoxia, dedicated hypoxia will augment the functional characteristics of MSCs. Methods Human and porcine bone marrow MSCs were obtained from fresh mononuclear cells. The first study evaluated MSC function following both long-term (10 days) and short-term (48 h) hypoxia (1% O2) culture. In our second study, we evaluated the functional characteristics of MSC cultured under short-term 2% and 5% hypoxia. MSCs were evaluated for their metabolic activity, proliferation, viability, clonogenicity, gene expression, and secretory capacity. Results In long-term culture, common MSC surface marker expression (CD44 and CD105) dropped under hypoxia. Additionally, in long-term culture, MSCs proliferated significantly slower and provided lower yields under hypoxia. Conversely, in short-term culture, MSCs proliferated significantly faster under hypoxia. In both long-term and short-term cultures, MSC metabolic activity was significantly higher under hypoxia. Furthermore, MSCs cultured under hypoxia had upregulated expression of VEGF with concomitant downregulation of HMGB1 and the apoptotic genes BCL-2 and CASP3. Finally, in both hypoxia cultures, the pro-inflammatory cytokine, IL-8, was suppressed, while levels of the anti-inflammatories, IL-1ra and GM-CSF, were elevated in short-term hypoxia only. Conclusions In this study, we demonstrate that hypoxia augments the therapeutic characteristics of both porcine and human MSCs. Yet, short-term 2% hypoxia offers the greatest benefit overall, exemplified by the increase in proliferation, self-renewing capacity, and modulation of key genes and the inflammatory milieu as compared to normoxia. These data are important for generating robust MSCs with augmented function for clinical applications.
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Affiliation(s)
- Ben Antebi
- United States Army Institute of Surgical Research, San Antonio, TX, USA.
| | - Luis A Rodriguez
- United States Army Institute of Surgical Research, San Antonio, TX, USA
| | - Kerfoot P Walker
- United States Army Institute of Surgical Research, San Antonio, TX, USA.,Oak Ridge Institute for Science and Education, Oak Ridge, TN, USA
| | - Amber M Asher
- United States Army Institute of Surgical Research, San Antonio, TX, USA.,Oak Ridge Institute for Science and Education, Oak Ridge, TN, USA
| | - Robin M Kamucheka
- United States Army Institute of Surgical Research, San Antonio, TX, USA.,Oak Ridge Institute for Science and Education, Oak Ridge, TN, USA
| | - Lucero Alvarado
- United States Army Institute of Surgical Research, San Antonio, TX, USA.,Oak Ridge Institute for Science and Education, Oak Ridge, TN, USA
| | - Arezoo Mohammadipoor
- United States Army Institute of Surgical Research, San Antonio, TX, USA.,Oak Ridge Institute for Science and Education, Oak Ridge, TN, USA
| | - Leopoldo C Cancio
- United States Army Institute of Surgical Research, San Antonio, TX, USA
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38
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Liu J, Chen Q, Liu S, Yang X, Zhang Y, Huang F. Sini decoction alleviates E. coli induced acute lung injury in mice via equilibrating ACE-AngII-AT1R and ACE2-Ang-(1-7)-Mas axis. Life Sci 2018; 208:139-148. [DOI: 10.1016/j.lfs.2018.07.013] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Revised: 07/04/2018] [Accepted: 07/06/2018] [Indexed: 11/13/2022]
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Huh JW, Kim WY, Park YY, Lim CM, Koh Y, Kim MJ, Hong SB. Anti-inflammatory Role of Mesenchymal Stem Cells in an Acute Lung Injury Mouse Model. Acute Crit Care 2018; 33:154-161. [PMID: 31723879 PMCID: PMC6786701 DOI: 10.4266/acc.2018.00619] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2017] [Revised: 04/06/2018] [Accepted: 07/04/2018] [Indexed: 01/11/2023] Open
Abstract
Background Mesenchymal stem cells (MSCs) attenuate injury in various lung injury models through paracrine effects. We hypothesized that intratracheal transplantation of allogenic MSCs could attenuate lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice, mediated by anti-inflammatory responses. Methods Six-week-old male mice were randomized to either the control or the ALI group. ALI was induced by intratracheal LPS instillation. Four hours after LPS instillation, MSCs or phosphate-buffered saline was randomly intratracheally administered. Neutrophil count and protein concentration in bronchoalveolar lavage fluid (BALF); lung histology; levels of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and macrophage inflammatory protein-2; and the expression of proliferation cell nuclear antigen (PCNA), caspase-3, and caspase-9 were evaluated at 48 hours after injury. Results Treatment with MSCs attenuated lung injury in ALI mice by decreasing protein level and neutrophil recruitment into the BALF and improving the histologic change. MSCs also decreased the protein levels of proinflammatory cytokines including IL-1β, IL-6, and TNF-α, but had little effect on the protein expression of PCNA, caspase-3, and caspase-9. Conclusions Intratracheal injection of bone marrow-derived allogenic MSCs attenuates LPS-induced ALI via immunomodulatory effects.
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Affiliation(s)
- Jin Won Huh
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Won Young Kim
- Department of Emergency Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | | | - Chae-Man Lim
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Younsuck Koh
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Mi-Jung Kim
- Asan Institute for Life Sciences, Seoul, Korea
| | - Sang-Bum Hong
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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40
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Zhu Y, Chen X, Yang X, El-Hashash A. Stem cells in lung repair and regeneration: Current applications and future promise. J Cell Physiol 2018; 233:6414-6424. [PMID: 29271480 DOI: 10.1002/jcp.26414] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Accepted: 12/19/2017] [Indexed: 12/18/2022]
Abstract
Lung diseases are major cause of morbidity and mortality worldwide. The progress in regenerative medicine and stem cell research in the lung are currently a fast-growing research topic that can provide solutions to these major health problems. Under normal conditions, the rate of cellular proliferation is relatively low in the lung in vivo, compared to other major organ systems. Lung injury leads to the activation of stem/progenitor cell populations that re-enter the cell cycle. Yet, little is known about stem cells in the lung, despite common thoughts that these cells could play a critical role in the repair of lung injuries. Nor do we fully understand the cellular and architectural complexity of the respiratory tract, and the diverse stem/progenitor cells that are involved in the lung repair and regeneration. In this review, we discuss the conceptual framework of lung stem/progenitor cell biology, and describe lung diseases, in which stem cell manipulations may be physiologically significant. In addition, we highlight the challenges of lung stem cell-based therapy.
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Affiliation(s)
- Yuqing Zhu
- Centre of Stem cell and Regenerative Medicine, Schools of Medicine and Basic Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiao Chen
- Centre of Stem cell and Regenerative Medicine, Schools of Medicine and Basic Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xu Yang
- Section of Environmental Biomedicine, School of Life Science, Central China Normal University, Wuhan, Hubei, China
| | - Ahmed El-Hashash
- Centre of Stem cell and Regenerative Medicine, Schools of Medicine and Basic Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,University of Edinburgh-Zhejiang University Institute (UoE-ZJU Institute), Haining, Zhejiang, China.,Edinburgh Medical School, University of Edinburgh, Edinburgh, UK
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41
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Abnave P, Ghigo E. Role of the immune system in regeneration and its dynamic interplay with adult stem cells. Semin Cell Dev Biol 2018; 87:160-168. [PMID: 29635020 DOI: 10.1016/j.semcdb.2018.04.002] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Revised: 04/02/2018] [Accepted: 04/06/2018] [Indexed: 12/11/2022]
Abstract
The immune system plays an indispensable role in the process of tissue regeneration following damage as well as during homeostasis. Inflammation and immune cell recruitment are signs of early onset injury. At the wound site, immune cells not only help to clear debris but also secrete numerous signalling molecules that induce appropriate cell proliferation and differentiation programmes essential for successful regeneration. However, the immune system does not always perform a complementary role in regeneration and several reports have suggested that increased inflammation can inhibit the regeneration process. Successful regeneration requires a balanced immune cell response, with the recruitment of accurately polarised immune cells in an appropriate quantity. The regulatory interactions of the immune system with regeneration are not unidirectional. Stem cells, as key players in regeneration, can also modulate the immune system in several ways to facilitate regeneration. In this review, we will focus on recent research demonstrating the key role of immune system in the regeneration process as well as the immunomodulatory effects of stem cells. Finally, we propose that research investigating the interplay between the immune system and stem cells within highly regenerating animals can benefit the identification of the key interactions and molecules required for successful regeneration.
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Affiliation(s)
- Prasad Abnave
- URMITE, CNRS UMR 7278, IRD198, INSERM U1095, APHM, Institut Hospitalier Universitaire Méditerranée-Infection, Aix-Marseille Université, 19-21 Bd Jean Moulin, 13385 Marseille Cedex 05, France.
| | - Eric Ghigo
- Institut Hospitalier Universitaire Méditerranée-Infection, 19-21 Bd Jean Moulin, 13385 Marseille Cedex 05, France; CNRS, 21 chemin de Joseph Aiguier, 13009 Marseille.
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Strategies to enhance paracrine potency of transplanted mesenchymal stem cells in intractable neonatal disorders. Pediatr Res 2018; 83:214-222. [PMID: 28972960 DOI: 10.1038/pr.2017.249] [Citation(s) in RCA: 86] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Accepted: 09/21/2017] [Indexed: 12/12/2022]
Abstract
Mesenchymal stem cell (MSC) transplantation represents the next breakthrough in the treatment of currently intractable and devastating neonatal disorders with complex multifactorial etiologies, including bronchopulmonary dysplasia, hypoxic ischemic encephalopathy, and intraventricular hemorrhage. Absent engraftment and direct differentiation of transplanted MSCs, and the "hit-and-run" therapeutic effects of these MSCs suggest that their pleiotropic protection might be attributable to paracrine activity via the secretion of various biologic factors rather than to regenerative activity. The transplanted MSCs, therefore, exert their therapeutic effects not by acting as "stem cells," but rather by acting as "paracrine factors factory." The MSCs sense the microenvironment of the injury site and secrete various paracrine factors that serve several reparative functions, including antiapoptotic, anti-inflammatory, antioxidative, antifibrotic, and/or antibacterial effects in response to environmental cues to enhance regeneration of the damaged tissue. Therefore, the therapeutic efficacy of MSCs might be dependent on their paracrine potency. In this review, we focus on recent investigations that elucidate the specifically regulated paracrine mechanisms of MSCs by injury type and discuss potential strategies to enhance paracrine potency, and thus therapeutic efficacy, of transplanted MSCs, including determining the appropriate source and preconditioning strategy for MSCs and the route and timing of their administration.
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Abstract
Abstract
Sepsis is a life-threatening syndrome resulting in shock and organ dysfunction stemming from a microbial infection. Sepsis has a mortality of 40% and is implicated in half of all in-hospital deaths. The host immune response to microbial infection is critical, with early-phase sepsis characterized by a hyperinflammatory immune response, whereas the later phase of sepsis is often complicated by suppression. Sepsis has no treatment, and management remains supportive.
Stem cells constitute exciting potential therapeutic agents for sepsis. In this review, we examine the rationale for stem cells in sepsis, focusing on mesenchymal stem/stromal cells, which currently demonstrate the greatest therapeutic promise. We examine the preclinical evidence base and evaluate potential mechanisms of action of these cells that are important in the setting of sepsis. We discuss early-phase clinical trials and critically appraise translational barriers to the use of mesenchymal stem/stromal cells in patients with sepsis.
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Janczewski AM, Wojtkiewicz J, Malinowska E, Doboszyńska A. Can Youthful Mesenchymal Stem Cells from Wharton's Jelly Bring a Breath of Fresh Air for COPD? Int J Mol Sci 2017; 18:ijms18112449. [PMID: 29156550 PMCID: PMC5713416 DOI: 10.3390/ijms18112449] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 11/13/2017] [Accepted: 11/14/2017] [Indexed: 12/13/2022] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a major global cause of morbidity and mortality, projected to become the 3rd cause of disease mortality worldwide by 2020. COPD is characterized by persistent and not fully reversible airflow limitation that is usually progressive and is associated with an abnormal chronic inflammatory response of the lung to noxious agents including cigarette smoke. Currently available therapeutic strategies aim to ease COPD symptoms but cannot prevent its progress or regenerate physiological lung structure or function. The urgently needed new approaches for the treatment of COPD include stem cell therapies among which transplantation of mesenchymal stem cells derived from Wharton’s jelly (WJ-MSCs) emerges as a promising therapeutic strategy because of the unique properties of these cells. The present review discusses the main biological properties of WJ-MSCs pertinent to their potential application for the treatment of COPD in the context of COPD pathomechanisms with emphasis on chronic immune inflammatory processes that play key roles in the development and progression of COPD.
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Affiliation(s)
- Andrzej M Janczewski
- Department of Pulmonology, Faculty of Heath Sciences, University of Warmia and Mazury in Olsztyn, Jagiellońska 78, 10-357 Olsztyn, Poland.
| | - Joanna Wojtkiewicz
- Department of Pathophysiology, Faculty of Medicine, University of Warmia and Mazury in Olsztyn, Warszawska 30, 10-082 Olsztyn, Poland.
- Laboratory for Regenerative Medicine, Faculty of Medicine, University of Warmia and Mazury in Olsztyn, Warszawska 30, 10-082 Olsztyn, Poland.
- Foundation for the Nerve Cells Regeneration, Warszawska 30, 10-082 Olsztyn, Poland.
| | - Ewa Malinowska
- Department of Pulmonology, Faculty of Heath Sciences, University of Warmia and Mazury in Olsztyn, Jagiellońska 78, 10-357 Olsztyn, Poland.
| | - Anna Doboszyńska
- Department of Pulmonology, Faculty of Heath Sciences, University of Warmia and Mazury in Olsztyn, Jagiellońska 78, 10-357 Olsztyn, Poland.
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Meng M. Digitoflavone (DG) attenuates LPS-induced acute lung injury through reducing oxidative stress and inflammatory response dependent on the suppression of TXNIP/NLRP3 and NF-κB. Biomed Pharmacother 2017; 94:712-725. [DOI: 10.1016/j.biopha.2017.07.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2017] [Revised: 06/23/2017] [Accepted: 07/03/2017] [Indexed: 01/23/2023] Open
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Combination therapy of human umbilical cord mesenchymal stem cells and FTY720 attenuates acute lung injury induced by lipopolysaccharide in a murine model. Oncotarget 2017; 8:77407-77414. [PMID: 29100396 PMCID: PMC5652788 DOI: 10.18632/oncotarget.20491] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Accepted: 07/26/2017] [Indexed: 01/09/2023] Open
Abstract
ALI/ARDS remain the main reason of morbidity and mortality in the critically ill. Studies have indicated that human umbilical cord mesenchymal stem cells (hUC-MSCs) can be useful in the treatment of ALI/ARDS. Sphingosine-1-phosphate (S1P) and its analog FTY720 significantly reduce lipopolysaccharide (LPS)-induced lung edema and inflammatory lung injury. This study aimed to assess the therapeutic effects of hUC-MSCs combined with FTY720 in an LPS-induced murine model of ALI. Eight-week-old female C57BL/6 mice were divided into a normal control group, an LPS group, an hUC-MSC group, an FTY720 group, and an hUC-MSCs+FTY720 group randomly. At 24 hours post injury, mice were administrated hUC-MSCs via the tail vein and/or intraperitoneally injected with FTY720. We assessed histopathology and histologic scores, lung wet/dry weight ratio, micro-CT scans, and total protein in the bronchoalveolar lavage fluid (BALF), as well as cytokines in the BALF at 48 h post injury. All treatment groups showed higher survival rates and attenuated lung injuries. The hUC-MSCs+FTY720 group yielded better results than hUC-MSCs or FTY720 alone. While the underlying mechanism requires further study, we anticipate that combination therapy of hUC-MSCs and FTY720 could be an effective strategy for ALI.
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Mei SHJ, Dos Santos CC, Stewart DJ. Advances in Stem Cell and Cell-Based Gene Therapy Approaches for Experimental Acute Lung Injury: A Review of Preclinical Studies. Hum Gene Ther 2017; 27:802-812. [PMID: 27531647 DOI: 10.1089/hum.2016.063] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Given the failure of pharmacological interventions in acute respiratory distress syndrome (ARDS), researchers have been actively pursuing novel strategies to treat this devastating, life-threatening condition commonly seen in the intensive care unit. There has been considerable research on harnessing the reparative properties of stem and progenitor cells to develop more effective therapeutic approaches for respiratory diseases with limited treatment options, such as ARDS. This review discusses the preclinical literature on the use of stem and progenitor cell therapy and cell-based gene therapy for the treatment of preclinical animal models of acute lung injury (ALI). A variety of cell types that have been used in preclinical models of ALI, such as mesenchymal stem cells, endothelial progenitor cells, and induced pluripotent stem cells, were evaluated. At present, two phase I trials have been completed and one phase I/II clinical trial is well underway in order to translate the therapeutic benefit gleaned from preclinical studies in complex animal models of ALI to patients with ARDS, paving the way for what could potentially develop into transformative therapy for critically ill patients. As we await the results of these early cell therapy trials, future success of stem cell therapy for ARDS will depend on selection of the most appropriate cell type, route and timing of cell delivery, enhancing effectiveness of cells (i.e., potency), and potentially combining beneficial cells and genes (cell-based gene therapy) to maximize therapeutic efficacy. The experimental models and scientific methods exploited to date have provided researchers with invaluable knowledge that will be leveraged to engineer cells with enhanced therapeutic capabilities for use in the next generation of clinical trials.
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Affiliation(s)
- Shirley H J Mei
- 1 Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Claudia C Dos Santos
- 2 The Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada.,3 Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Duncan J Stewart
- 1 Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,4 Department of Medicine, University of Ottawa , Ottawa, Ontario, Canada
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Sun L, Li D, Song K, Wei J, Yao S, Li Z, Su X, Ju X, Chao L, Deng X, Kong B, Li L. Exosomes derived from human umbilical cord mesenchymal stem cells protect against cisplatin-induced ovarian granulosa cell stress and apoptosis in vitro. Sci Rep 2017; 7:2552. [PMID: 28566720 PMCID: PMC5451424 DOI: 10.1038/s41598-017-02786-x] [Citation(s) in RCA: 103] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 04/20/2017] [Indexed: 01/04/2023] Open
Abstract
Human umbilical cord mesenchymal stem cells (huMSCs) can treat primary ovarian insufficiency (POI) related to ovarian granulosa cell (OGC) apoptosis caused by cisplatin chemotherapy. Exosomes are a class of membranous vesicles with diameters of 30–200 nm that are constitutively released by eukaryotic cells. Exosomes mediate local cell-to-cell communication by transferring microRNAs and proteins. In the present study, we demonstrated the effects of exosomes derived from huMSCs (huMSC-EXOs) on a cisplatin-induced OGC model in vitro and discussed the preliminary mechanisms involved in these effects. We successfully extracted huMSC-EXOs from huMSC culture supernatant and observed the effective uptake of exosomes by cells with fluorescent staining. Using flow cytometry (with annexin-V/PI labelling), we found that huMSC-EXOs increased the number of living cells. Western blotting showed that the expression of Bcl-2 and caspase-3 were upregulated, whilst the expression of Bax, cleaved caspase-3 and cleaved PARP were downregulated to protect OGCs. These results suggest that huMSC-EXOs can be used to prevent and treat chemotherapy-induced OGC apoptosis in vitro. Therefore, this work provides insight and further evidence of stem cell function and indicates that huMSC-EXOs protect OGCs from cisplatin-induced injury in vitro.
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Affiliation(s)
- Liping Sun
- Department of obstetrics and gynecology, Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong Province, P.R. China
| | - Dong Li
- Cryomedicine Laboratory, Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong Province, P.R. China
| | - Kun Song
- Department of obstetrics and gynecology, Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong Province, P.R. China.
| | - Jianlu Wei
- Department of Orthopedics, Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong Province, P.R. China
| | - Shu Yao
- Department of obstetrics and gynecology, Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong Province, P.R. China
| | - Zhao Li
- Department of obstetrics and gynecology, Qianfoshan Hospital, Shandong University, 16766 Jingshi Road, Jinan, 250014, Shandong Province, P.R. China
| | - Xuantao Su
- Institute of Biomedical Engineering, School of Control Science and Engineering, Shandong University, 17923 Jingshi Road, Jinan, Shandong, 250061, P.R. China
| | - Xiuli Ju
- Cryomedicine Laboratory, Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong Province, P.R. China
| | - Lan Chao
- Department of obstetrics and gynecology, Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong Province, P.R. China.,Reproduction Medicine Center, Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong Province, P.R. China
| | - Xiaohui Deng
- Department of obstetrics and gynecology, Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong Province, P.R. China.,Reproduction Medicine Center, Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong Province, P.R. China
| | - Beihua Kong
- Department of obstetrics and gynecology, Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong Province, P.R. China
| | - Li Li
- Department of obstetrics and gynecology, Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong Province, P.R. China. .,Reproduction Medicine Center, Qilu Hospital, Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong Province, P.R. China.
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Cryopreserved, Xeno-Free Human Umbilical Cord Mesenchymal Stromal Cells Reduce Lung Injury Severity and Bacterial Burden in Rodent Escherichia coli-Induced Acute Respiratory Distress Syndrome. Crit Care Med 2017; 45:e202-e212. [PMID: 27861182 DOI: 10.1097/ccm.0000000000002073] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
OBJECTIVE Although mesenchymal stem/stromal cells represent a promising therapeutic strategy for acute respiratory distress syndrome, clinical translation faces challenges, including scarcity of bone marrow donors, and reliance on bovine serum during mesenchymal stem/stromal cell proliferation. We wished to compare mesenchymal stem/stromal cells from human umbilical cord, grown in xeno-free conditions, with mesenchymal stem/stromal cells from human bone marrow, in a rat model of Escherichia coli pneumonia. In addition, we wished to determine the potential for umbilical cord-mesenchymal stem/stromal cells to reduce E. coli-induced oxidant injury. DESIGN Randomized animal study. SETTING University research laboratory. SUBJECTS Male Sprague-Dawley rats. INTERVENTIONS Acute respiratory distress syndrome was induced in rats by intratracheal instillation of E. coli (1.5-2 × 10 CFU/kg). "Series 1" compared the effects of freshly thawed cryopreserved umbilical cord-mesenchymal stem/stromal cells with bone marrow-mesenchymal stem/stromal cells on physiologic indices of lung injury, cellular infiltration, and E. coli colony counts in bronchoalveolar lavage. "Series 2" examined the effects of cryopreserved umbilical cord-mesenchymal stem/stromal cells on survival, as well as measures of injury, inflammation and oxidant stress, including production of reactive oxidative species, reactive oxidative species scavenging by superoxide dismutase-1 and superoxide dismutase-2. MEASUREMENTS AND MAIN RESULTS In "Series 1," animals subjected to E. coli pneumonia who received umbilical cord-mesenchymal stem/stromal cells had improvements in oxygenation, respiratory static compliance, and wet-to-dry ratios comparable to bone marrow-mesenchymal stem/stromal cell treatment. E. coli colony-forming units in bronchoalveolar lavage were reduced in both cell therapy groups, despite a reduction in bronchoalveolar lavage neutrophils. In series 2, umbilical cord-mesenchymal stem/stromal cells enhanced animal survival and decreased alveolar protein and proinflammatory cytokine concentrations, whereas increasing interleukin-10 concentrations. Umbilical cord-mesenchymal stem/stromal cell therapy decreased nicotinamide adenine dinucleotide phosphate-oxidase 2 and inducible nitric oxide synthase and enhanced lung concentrations of superoxide dismutase-2, thereby reducing lung tissue reactive oxidative species concentrations. CONCLUSIONS Our results demonstrate that freshly thawed cryopreserved xeno-free human umbilical cord-mesenchymal stem/stromal cells reduce the severity of rodent E. coli-induced acute respiratory distress syndrome. Umbilical cord-mesenchymal stem/stromal cells, therefore, represent an attractive option for future clinical trials in acute respiratory distress syndrome.
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Zorzopulos J, Opal SM, Hernando-Insúa A, Rodriguez JM, Elías F, Fló J, López RA, Chasseing NA, Lux-Lantos VA, Coronel MF, Franco R, Montaner AD, Horn DL. Immunomodulatory oligonucleotide IMT504: Effects on mesenchymal stem cells as a first-in-class immunoprotective/immunoregenerative therapy. World J Stem Cells 2017; 9:45-67. [PMID: 28396715 PMCID: PMC5368622 DOI: 10.4252/wjsc.v9.i3.45] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 10/12/2016] [Accepted: 12/19/2016] [Indexed: 02/06/2023] Open
Abstract
The immune responses of humans and animals to insults (i.e., infections, traumas, tumoral transformation and radiation) are based on an intricate network of cells and chemical messengers. Abnormally high inflammation immediately after insult or abnormally prolonged pro-inflammatory stimuli bringing about chronic inflammation can lead to life-threatening or severely debilitating diseases. Mesenchymal stem cell (MSC) transplant has proved to be an effective therapy in preclinical studies which evaluated a vast diversity of inflammatory conditions. MSCs lead to resolution of inflammation, preparation for regeneration and actual regeneration, and then ultimate return to normal baseline or homeostasis. However, in clinical trials of transplanted MSCs, the expectations of great medical benefit have not yet been fulfilled. As a practical alternative to MSC transplant, a synthetic drug with the capacity to boost endogenous MSC expansion and/or activation may also be effective. Regarding this, IMT504, the prototype of a major class of immunomodulatory oligonucleotides, induces in vivo expansion of MSCs, resulting in a marked improvement in preclinical models of neuropathic pain, osteoporosis, diabetes and sepsis. IMT504 is easily manufactured and has an excellent preclinical safety record. In the small number of patients studied thus far, IMT504 has been well-tolerated, even at very high dosage. Further clinical investigation is necessary to demonstrate the utility of IMT504 for resolution of inflammation and regeneration in a broad array of human diseases that would likely benefit from an immunoprotective/immunoregenerative therapy.
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