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1
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Shen YZ, Yang GP, Ma QM, Wang YS, Wang X. Regulation of lncRNA-ENST on Myc-mediated mitochondrial apoptosis in mesenchymal stem cells: In vitro evidence implicated for acute lung injury therapeutic potential. World J Stem Cells 2025; 17:100079. [DOI: 10.4252/wjsc.v17.i3.100079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 12/04/2024] [Accepted: 02/05/2025] [Indexed: 03/21/2025] Open
Abstract
BACKGROUND Acute lung injury (ALI) is a fatal and heterogeneous disease. While bone marrow mesenchymal stem cells (BMSCs) have shown promise in ALI repair, their efficacy is compromised by a high apoptotic percentage. Preliminary findings have indicated that long noncoding RNA (lncRNA)-ENST expression is markedly downregulated in MSCs under ischemic and hypoxic conditions, establishing a rationale for in vitro exploration.
AIM To elucidate the role of lncRNA-ENST00000517482 (lncRNA-ENST) in modulating MSC apoptosis.
METHODS Founded on ALI in BEAS-2B cells with lipopolysaccharide, this study employed a transwell co-culture system to study BMSC tropism. BMSCs were genetically modified to overexpress or knockdown lncRNA-ENST. After analyzing the effects on autophagy, apoptosis and cell viability, the lncRNA-ENST/miR-539/c-MYC interaction was confirmed by dual-luciferase assays.
RESULTS These findings have revealed a strong correlation between lncRNA-ENST levels and the apoptotic and autophagic status of BMSCs. On the one hand, the over-expression of lncRNA-ENST, as determined by Cell Counting Kit-8 assays, increased the expression of autophagy markers LC3B, ATG7, and ATG5. On the other hand, it reduced apoptosis and boosted BMSC viability. In co-cultures with BEAS-2B cells, lncRNA-ENST overexpression also improved cell vitality. Additionally, by downregulating miR-539 and upregulating c-MYC, lncRNA-ENST was found to influence mitochondrial membrane potential, enhance BMSC autophagy, mitigate apoptosis and lower the secretion of pro-inflammatory cytokines interleukin-6 and interleukin-1β. Collectively, within the in vitro framework, these results have highlighted the therapeutic potential of BMSCs in ALI and the pivotal regulatory role of lncRNA-ENST in miR-539 and apoptosis in lipopolysaccharide-stimulated BEAS-2B cells.
CONCLUSION Our in vitro results show that enhanced lncRNA ENST expression can promote BMSC proliferation and viability by modulating the miR-539/c-MYC axis, reduce apoptosis and induce autophagy, which has suggested its therapeutic potential in the treatment of ALI.
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Affiliation(s)
- Ye-Zhou Shen
- Department of Critical Care Medicine, Shanghai East Hospital, Tongji University, Shanghai 200120, China
| | - Guang-Ping Yang
- Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Qi-Min Ma
- Department of Critical Care Medicine, Shanghai East Hospital, Tongji University, Shanghai 200120, China
| | - Yu-Song Wang
- Department of Critical Care Medicine, Shanghai East Hospital, Tongji University, Shanghai 200120, China
| | - Xin Wang
- Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
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2
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Miyashita Y, Kanou T, Fukui E, Matsui T, Kimura T, Ose N, Funaki S, Shintani Y. A Novel Peroxisome Proliferator-Activated Receptor Gamma/Nuclear Factor-Kappa B Activation Pathway is Involved in the Protective Effect of Adipose-Derived Mesenchymal Stem Cells Against Ischemia-Reperfusion Lung Injury. Transplant Proc 2024; 56:369-379. [PMID: 38320873 DOI: 10.1016/j.transproceed.2024.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 10/04/2023] [Accepted: 01/16/2024] [Indexed: 02/08/2024]
Abstract
BACKGROUND Adipose-derived stem cells (ADSCs) are well-recognized for their remarkable ability to suppress ischemia-reperfusion lung injury (IRLI). The primary objective of this investigation was to elucidate the underlying mechanism through which ADSCs exert protective effects against IRLI. METHODS A warm hilar occlusion model in C57BL6J mice was used. Hilar occlusion was achieved for 1 hour (ischemic), and after 1 hour the occlusion was released (reperfusion) to recover for 3 hours. RNA sequencing, the physiological function, pathway activation, and expression of inflammatory cytokines were evaluated. RESULTS Lung gas exchange and pulmonary edema were significantly improved in the IRLI/ADSCs group compared with the IRLI group. RNA sequencing results suggested that the peroxisome proliferator-activated receptor gamma (PPARγ)/nuclear factor-kappa B (NF-κB) pathway was involved in the effect of the ADSCs. Administration of a PPARγ antagonist in the IRLI/ADSC group resulted in the deterioration of the physiological function. Furthermore, the PPARγ protein expression level decreased, the NF-κB protein expression level increased, and inflammatory cytokine parameters from lung tissue and blood sample worsened in the PPARγ antagonist-administered group. CONCLUSION Administration of ADSCs exerted a significant protective effect against IRLI in mice, and the effect is attributed to the activation of the PPARγ/NF-κB pathway.
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Affiliation(s)
- Yudai Miyashita
- Department of General Thoracic Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Takashi Kanou
- Department of General Thoracic Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
| | - Eriko Fukui
- Department of General Thoracic Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Takahiro Matsui
- Department of Pathology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Toru Kimura
- Department of General Thoracic Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Naoko Ose
- Department of General Thoracic Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Soichiro Funaki
- Department of General Thoracic Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yasushi Shintani
- Department of General Thoracic Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
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3
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Miceli V, Bulati M, Gallo A, Iannolo G, Busà R, Conaldi PG, Zito G. Role of Mesenchymal Stem/Stromal Cells in Modulating Ischemia/Reperfusion Injury: Current State of the Art and Future Perspectives. Biomedicines 2023; 11:689. [PMID: 36979668 PMCID: PMC10045387 DOI: 10.3390/biomedicines11030689] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 02/15/2023] [Accepted: 02/21/2023] [Indexed: 02/26/2023] Open
Abstract
Ischemia/reperfusion injury (IRI) is a multistep damage that occurs in several tissues when a blood flow interruption is inevitable, such as during organ surgery or transplantation. It is responsible for cell death and tissue dysfunction, thus leading, in the case of transplantation, to organ rejection. IRI takes place during reperfusion, i.e., when blood flow is restored, by activating inflammation and reactive oxygen species (ROS) production, causing mitochondrial damage and apoptosis of parenchymal cells. Unfortunately, none of the therapies currently in use are definitive, prompting the need for new therapeutic approaches. Scientific evidence has proven that mesenchymal stem/stromal cells (MSCs) can reduce inflammation and ROS, prompting this cellular therapy to also be investigated for treatment of IRI. Moreover, it has been shown that MSC therapeutic effects were mediated in part by their secretome, which appears to be involved in immune regulation and tissue repair. For these reasons, mediated MSC paracrine function might be key for injury amelioration upon IRI damage. In this review, we highlight the scientific literature on the potential beneficial use of MSCs and their products for improving IRI outcomes in different tissues/organs, focusing in particular on the paracrine effects mediated by MSCs, and on the molecular mechanisms behind these effects.
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Affiliation(s)
- Vitale Miceli
- Research Department, IRCSS ISMETT (Istituto Mediterraneo per I Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy
| | | | | | | | | | | | - Giovanni Zito
- Research Department, IRCSS ISMETT (Istituto Mediterraneo per I Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy
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4
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Miceli V, Bertani A. Mesenchymal Stromal/Stem Cells and Their Products as a Therapeutic Tool to Advance Lung Transplantation. Cells 2022; 11:cells11050826. [PMID: 35269448 PMCID: PMC8909054 DOI: 10.3390/cells11050826] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 02/18/2022] [Accepted: 02/25/2022] [Indexed: 02/07/2023] Open
Abstract
Lung transplantation (LTx) has become the gold standard treatment for end-stage respiratory failure. Recently, extended lung donor criteria have been applied to decrease the mortality rate of patients on the waiting list. Moreover, ex vivo lung perfusion (EVLP) has been used to improve the number/quality of previously unacceptable lungs. Despite the above-mentioned progress, the morbidity/mortality of LTx remains high compared to other solid organ transplants. Lungs are particularly susceptible to ischemia-reperfusion injury, which can lead to graft dysfunction. Therefore, the success of LTx is related to the quality/function of the graft, and EVLP represents an opportunity to protect/regenerate the lungs before transplantation. Increasing evidence supports the use of mesenchymal stromal/stem cells (MSCs) as a therapeutic strategy to improve EVLP. The therapeutic properties of MSC are partially mediated by secreted factors. Hence, the strategy of lung perfusion with MSCs and/or their products pave the way for a new innovative approach that further increases the potential for the use of EVLP. This article provides an overview of experimental, preclinical and clinical studies supporting the application of MSCs to improve EVLP, the ultimate goal being efficient organ reconditioning in order to expand the donor lung pool and to improve transplant outcomes.
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Affiliation(s)
- Vitale Miceli
- Research Department, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), 90127 Palermo, Italy
- Correspondence: (V.M.); (A.B.); Tel.: +39-091-21-92-430 (V.M.); +39-091-21-92-111 (A.B.)
| | - Alessandro Bertani
- Thoracic Surgery and Lung Transplantation Unit, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy
- Correspondence: (V.M.); (A.B.); Tel.: +39-091-21-92-430 (V.M.); +39-091-21-92-111 (A.B.)
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Wu G, Chang F, Fang H, Zheng X, Zhuang M, Liu X, Hou W, Xu L, Chen Z, Tang C, Wu Y, Sun Y, Zhu F. Non-muscle myosin II knockdown improves survival and therapeutic effects of implanted bone marrow-derived mesenchymal stem cells in lipopolysaccharide-induced acute lung injury. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:262. [PMID: 33708889 PMCID: PMC7940885 DOI: 10.21037/atm-20-4851] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Background Bone marrow-derived mesenchymal stem cells (BMSCs) have been shown to have some beneficial effects in acute lung injury (ALI), but the therapeutic effects are limited due to apoptosis or necrosis after transplantation into injured lungs. Here, we aim to explore whether Non-muscle myosin II (NM-II) knockdown could enhance BMSCs survival and improve therapeutic effects in ALI. Methods MSCs, isolated from rat bone marrow, were transfected with the small interfering RNA (siRNA) targeted to NM-II mRNA by a lentivirus vector. Rats were equally randomized to four groups: the control group was given normal saline via tail vein; the other three groups underwent intratracheal lipopolysaccharide (LPS) instillation followed by administration with either normal saline, BMSCs transduced with lentivirus-enhanced green fluorescent protein (eGFP) empty vector, or BMSCs transduced with lentivirus-eGFP NM-II siRNA. Hematoxylin and eosin staining was used to evaluate lung histopathologic changes and Masson trichrome staining was used to assess lung fibrosis. The myeloperoxidase activity was also tested in lung tissues. The mRNA expression of inflammatory cytokines in lung tissues was determined via quantitative reverse transcription PCR. Sex-determining region of the Y chromosome gene expression was measured by fluorescence in situ hybridization (FISH) assay. The expression of self-renewal activity and apoptosis-associated proteins were measured by Western blot. Results Transplantation of NM-II siRNA-modified BMSCs could improve histopathological morphology, decrease inflammatory infiltrates, down-regulate the expression levels of inflammatory cytokines, and reduce pulmonary interstitial edema. NM-II siRNA-modified BMSCs showed antifibrotic properties and alleviated the degrees of pulmonary fibrosis induced by endotoxin. In addition, NM-II knockdown BMSCs showed slightly better therapeutic effect on lung inflammation when compared with control BMSCs. The beneficial effects of NM-II siRNA-modified BMSCs may be attributed to enhanced self-renewal activity and decreased apoptosis. Conclusions NM-II knockdown could inhibit the apoptosis of implanted BMSCs in lung tissues and improve its self-renewal activity. NM-II siRNA-modified BMSCs have a slightly enhanced ability to attenuate lung injury after LPS challenge.
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Affiliation(s)
- Guosheng Wu
- Department of Burn Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Fei Chang
- Department of Burn and Plastic Surgery, The Affiliated Zhang Jiagang Hospital of Soochow University, Suzhou, China
| | - He Fang
- Department of Burn Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Xingfeng Zheng
- Department of Burn Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Mingzhu Zhuang
- Clinical BioBank, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Xiaobin Liu
- Department of Burn Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Wenjia Hou
- Department of Burn Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Long Xu
- Department of Burn Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Zhengli Chen
- Department of Burn Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Chenqi Tang
- Department of Burn Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Yu Wu
- Department of Anesthesiology, Bethune International Peace Hospital, Shijiazhuang, China
| | - Yu Sun
- Department of Burn Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Feng Zhu
- Department of Burn Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
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Ellison-Hughes GM, Colley L, O'Brien KA, Roberts KA, Agbaedeng TA, Ross MD. The Role of MSC Therapy in Attenuating the Damaging Effects of the Cytokine Storm Induced by COVID-19 on the Heart and Cardiovascular System. Front Cardiovasc Med 2020; 7:602183. [PMID: 33363221 PMCID: PMC7756089 DOI: 10.3389/fcvm.2020.602183] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 11/17/2020] [Indexed: 01/08/2023] Open
Abstract
The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has led to 47 m infected cases and 1. 2 m (2.6%) deaths. A hallmark of more severe cases of SARS-CoV-2 in patients with acute respiratory distress syndrome (ARDS) appears to be a virally-induced over-activation or unregulated response of the immune system, termed a "cytokine storm," featuring elevated levels of pro-inflammatory cytokines such as IL-2, IL-6, IL-7, IL-22, CXCL10, and TNFα. Whilst the lungs are the primary site of infection for SARS-CoV-2, in more severe cases its effects can be detected in multiple organ systems. Indeed, many COVID-19 positive patients develop cardiovascular complications, such as myocardial injury, myocarditis, cardiac arrhythmia, and thromboembolism, which are associated with higher mortality. Drug and cell therapies targeting immunosuppression have been suggested to help combat the cytokine storm. In particular, mesenchymal stromal cells (MSCs), owing to their powerful immunomodulatory ability, have shown promise in early clinical studies to avoid, prevent or attenuate the cytokine storm. In this review, we will discuss the mechanistic underpinnings of the cytokine storm on the cardiovascular system, and how MSCs potentially attenuate the damage caused by the cytokine storm induced by COVID-19. We will also address how MSC transplantation could alleviate the long-term complications seen in some COVID-19 patients, such as improving tissue repair and regeneration.
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Affiliation(s)
- Georgina M. Ellison-Hughes
- Faculty of Life Sciences & Medicine, Centre for Human and Applied Physiological Sciences, School of Basic and Medical Biosciences, King's College London Guy's Campus, London, United Kingdom
| | - Liam Colley
- School of Sport, Health, and Exercise Sciences, Bangor University, Bangor, United Kingdom
| | - Katie A. O'Brien
- Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Kirsty A. Roberts
- Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, United Kingdom
| | - Thomas A. Agbaedeng
- Faculty of Health & Medical Sciences, Centre for Heart Rhythm Disorders, School of Medicine, The University of Adelaide, Adelaide, SA, Australia
| | - Mark D. Ross
- School of Applied Sciences, Edinburgh Napier University, Edinburgh, United Kingdom
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7
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Mesenchymal Stem Cell-Based Therapy of Inflammatory Lung Diseases: Current Understanding and Future Perspectives. Stem Cells Int 2019; 2019:4236973. [PMID: 31191672 PMCID: PMC6525794 DOI: 10.1155/2019/4236973] [Citation(s) in RCA: 133] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Revised: 02/06/2019] [Accepted: 02/14/2019] [Indexed: 12/16/2022] Open
Abstract
During acute or chronic lung injury, inappropriate immune response and/or aberrant repair process causes irreversible damage in lung tissue and most usually results in the development of fibrosis followed by decline in lung function. Inhaled corticosteroids and other anti-inflammatory drugs are very effective in patients with inflammatory lung disorders, but their long-term use is associated with severe side effects. Accordingly, new therapeutic agents that will attenuate ongoing inflammation and, at the same time, promote regeneration of injured alveolar epithelial cells are urgently needed. Mesenchymal stem cells (MSCs) are able to modulate proliferation, activation, and effector function of all immune cells that play an important role in the pathogenesis of acute and chronic inflammatory lung diseases. In addition to the suppression of lung-infiltrated immune cells, MSCs have potential to differentiate into alveolar epithelial cells in vitro and, accordingly, represent new players in cell-based therapy of inflammatory lung disorders. In this review article, we described molecular mechanisms involved in MSC-based therapy of acute and chronic pulmonary diseases and emphasized current knowledge and future perspectives related to the therapeutic application of MSCs in patients suffering from acute respiratory distress syndrome, pneumonia, asthma, chronic obstructive pulmonary diseases, and idiopathic pulmonary fibrosis.
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8
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Peng CK, Wu SY, Tang SE, Li MH, Lin SS, Chu SJ, Huang KL. Protective Effects of Neural Crest-Derived Stem Cell-Conditioned Media against Ischemia-Reperfusion-Induced Lung Injury in Rats. Inflammation 2018; 40:1532-1542. [PMID: 28534140 PMCID: PMC7102066 DOI: 10.1007/s10753-017-0594-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Current treatments for ischemia-reperfusion (IR)-induced acute lung injury are limited. Mesenchymal stem cell-conditioned medium (CM) has been reported to attenuate lung injury. Neural crest stem cells (NCSCs), a type of multipotent stem cells, are more easily obtained than mesenchymal stem cells. We hypothesize that NCSC-CM has anti-inflammatory properties that could protect against IR-induced lung injury in rats. In this study, NCSC-CM was derived from rat NCSCs. Typical acute lung injury was induced by 30-min ischemia followed by 90-min reperfusion in adult male Sprague–Dawley rats. Bronchoalveolar lavage fluid (BALF) and lung tissues were collected to analyze the degree of lung injury after the experiment. NCSC-CM was administered before ischemia and after reperfusion. NCSC-CM treatment significantly attenuated IR-induced lung edema, as indicated by decreases in pulmonary vascular permeability, lung weight gain, wet to dry weight ratio, lung weight to body weight ratio, pulmonary arterial pressure, and protein level in BALF. The levels of tumor necrosis factor-α and interleukin-6 in the BALF were also significantly decreased. Additionally, NCSC-CM improved lung pathology and neutrophil infiltration in the lung tissue, and significantly suppressed nuclear factor (NF)-κB activity and IκB-α degradation in the lung. However, heating NCSC-CM eliminated these protective effects. Our experiment demonstrates that NCSC-CM treatment decreases IR-induced acute lung injury and that the protective mechanism may be attributable to the inhibition of NF-κB activation and the inflammatory response. Therefore, NCSC-CM may be a novel approach for treating IR-induced lung injury.
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Affiliation(s)
- Chung-Kan Peng
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Shu-Yu Wu
- Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan
| | - Shih-En Tang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Min-Hui Li
- Department of Physical Medicine and Rehabilitation, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Shih-Shiuan Lin
- Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan
| | - Shi-Jye Chu
- Division of Rheumatology, Immunology and Allergy, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. .,Institute of Aerospace and Undersea Medicine, National Defense Medical Center, 161 Ming-Chuan East Road, Section 6, Neihu 114, Taipei, Taiwan, Republic of China.
| | - Kun-Lun Huang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. .,Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan. .,Institute of Aerospace and Undersea Medicine, National Defense Medical Center, 161 Ming-Chuan East Road, Section 6, Neihu 114, Taipei, Taiwan, Republic of China.
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9
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Zhang SE, Wen SH, Su YX, Zheng GS, Wang DK, Liang YJ, Liao GQ. Synergistic effects of ischemic preconditioning and immediate post-conditioning in the protection against ischemia/reperfusion injury in rabbit submandibular glands. Eur J Oral Sci 2018; 126:282-291. [PMID: 30006965 DOI: 10.1111/eos.12540] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/01/2018] [Indexed: 12/23/2022]
Abstract
Submandibular gland autotransplantation is an effective approach for treating severe keratoconjunctivitis sicca. However, ischemia/reperfusion (I/R) injury, which inevitably occurs during transplantation, is involved in the hypofunction and structural damage that occur early after transplantation. Therefore, it is critical to identify effective strategies to ameliorate I/R injury in submandibular glands. In this study, we investigated the ability of immediate post-conditioning combined with ischemic preconditioning to attenuate I/R injury. We observed that after I/R injury, the level of reactive oxygen species was increased, inflammatory response was strengthened, and severe apoptosis had occurred. In addition, the salivary flow rate was greatly decreased. However, the pathogenesis of I/R injury was significantly ameliorated by ischemia post-conditioning or ischemia preconditioning treatments. In addition, the combination of ischemia preconditioning and post-conditioning achieved synergistic protective effects against I/R injury compared with ischemia preconditioning or ischemia post-conditioning alone. The secretion function was restored in the combination group. Furthermore, the combination treatment involved the same mechanisms of ischemia preconditioning or ischemia post-conditioning, including suppression of the inflammatory reaction and neutrophil accumulation, attenuation of oxidation stress, and inhibition of apoptosis. In conclusion, the combination of ischemia preconditioning and ischemia post-conditioning treatment is a simple and effective approach for treating I/R injury in submandibular glands.
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Affiliation(s)
- Si-En Zhang
- Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, China
| | - Shi-Hong Wen
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yu-Xiong Su
- Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, China
- Discipline of Oral & Maxillofacial Surgery, Faculty of Dentistry, The University of Hong Kong, Hong Kong, China
| | - Guang-Sen Zheng
- Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, China
| | - Di-Kan Wang
- Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, China
| | - Yu-Jie Liang
- Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, China
| | - Gui-Qing Liao
- Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, China
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10
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Rosso L, Zanella A, Righi I, Barilani M, Lazzari L, Scotti E, Gori F, Mendogni P. Lung transplantation, ex-vivo reconditioning and regeneration: state of the art and perspectives. J Thorac Dis 2018; 10:S2423-S2430. [PMID: 30123580 DOI: 10.21037/jtd.2018.04.151] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Lung transplantation is the only therapeutic option for end-stage pulmonary failure. Nevertheless, the shortage of donor pool available for transplantation does not allow to satisfy the requests, thus the mortality on the waiting list remains high. One of the tools to overcome the donor pool shortage is the use of ex-vivo lung perfusion (EVLP) to preserve, evaluate and recondition selected lung grafts not otherwise suitable for transplantation. EVLP is nowadays a clinical reality and have several destinations of use. After a narrative review of the literature and looking at our experience we can assume that one of the chances to improve the outcome of lung transplantation and to overcome the donor pool shortage could be the tissue regeneration of the graft during EVLP and the immunomodulation of the recipient. Both these strategies are performed using mesenchymal stem cells (MSC). The results of the models of lung perfusion with MSC-based cell therapy open the way to a new innovative approach that further increases the potential for using of the lung perfusion platform.
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Affiliation(s)
- Lorenzo Rosso
- Thoracic Surgery and Lung Transplant Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Alberto Zanella
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.,Department of Anesthesiology, Intensive Care and Emergency, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Ilaria Righi
- Thoracic Surgery and Lung Transplant Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Mario Barilani
- Unit of Regenerative Medicine-Cell Factory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,EPIGET LAB, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Lorenza Lazzari
- Unit of Regenerative Medicine-Cell Factory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Eleonora Scotti
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Francesca Gori
- Department of Anesthesiology, Intensive Care and Emergency, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Paolo Mendogni
- Thoracic Surgery and Lung Transplant Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
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11
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Yabuki H, Wakao S, Kushida Y, Dezawa M, Okada Y. Human Multilineage-differentiating Stress-Enduring Cells Exert Pleiotropic Effects to Ameliorate Acute Lung Ischemia-Reperfusion Injury in a Rat Model. Cell Transplant 2018; 27:979-993. [PMID: 29707971 PMCID: PMC6050908 DOI: 10.1177/0963689718761657] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Accepted: 01/29/2018] [Indexed: 12/26/2022] Open
Abstract
Posttransplantation lung ischemia-reperfusion (IR) injuries affect both patient survival and graft function. In this study, we evaluated the protective effects of infused human multilineage-differentiating stress-enduring (Muse) cells, a novel, easily harvested type of nontumorigenic endogenous reparative stem cell, against acute IR lung injury in a rat model. After a 2-h warm IR injury induction in a left rat lung, human Muse cells, human mesenchymal stem cells (MSCs), and vehicle were injected via the left pulmonary artery after reperfusion. Functionality, histological findings, and protein expression were subsequently assessed in the injured lung. In vitro, we also compared human Muse cells with human MSCs in terms of migration abilities and the secretory properties of protective substances. The arterial oxygen partial pressure to fractional inspired oxygen ratio, alveolar-arterial oxygen gradient, left lung compliance, and histological injury score on hematoxylin-eosin sections were significantly better in the Muse group relative to the MSC and vehicle groups. Compared to MSCs, human Muse cells homed more efficiently to the injured lung, where they suppressed the apoptosis and stimulated proliferation of host alveolar cells. Human Muse cells also migrated to serum from lung-injured model rats and produced beneficial substances (keratinocyte growth factor [KGF], hepatocyte growth factor, angiopoietin-1, and prostaglandin E2) in vitro. Western blot of lung tissue confirmed high expression of KGF and their target molecules (interleukin-6, protein kinase B, and B-cell lymphoma-2) in the Muse group. Thus, Muse cells efficiently ameliorated lung IR injury via pleiotropic effects in a rat model. These findings support further investigation on the use of human Muse cells for lung IR injury.
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Affiliation(s)
- Hiroshi Yabuki
- Department of Thoracic Surgery, Institute of Development, Aging and Cancer,
Tohoku University, Sendai, Miyagi, Japan
| | - Shohei Wakao
- Department of Stem Cell Biology and Histology, Tohoku University Graduate
School of Medicine, Sendai, Miyagi, Japan
| | - Yoshihiro Kushida
- Department of Stem Cell Biology and Histology, Tohoku University Graduate
School of Medicine, Sendai, Miyagi, Japan
| | - Mari Dezawa
- Department of Stem Cell Biology and Histology, Tohoku University Graduate
School of Medicine, Sendai, Miyagi, Japan
| | - Yoshinori Okada
- Department of Thoracic Surgery, Institute of Development, Aging and Cancer,
Tohoku University, Sendai, Miyagi, Japan
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12
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Abstract
During the past decades, stem cell-based therapy has acquired a promising role in regenerative medicine. The application of novel cell therapeutics for the treatment of cardiovascular diseases could potentially achieve the ambitious aim of effective cardiac regeneration. Despite the highly positive results from preclinical studies, data from phase I/II clinical trials are inconsistent and the improvement of cardiac remodeling and heart performance was found to be quite limited. The major issues which cardiac stem cell therapy is facing include inefficient cell delivery to the site of injury, accompanied by low cell retention and weak effectiveness of remaining stem cells in tissue regeneration. According to preclinical and clinical studies, various stem cells (adult stem cells, embryonic stem cells, and induced pluripotent stem cells) represent the most promising cell types so far. Beside the selection of the appropriate cell type, researchers have developed several strategies to produce “second-generation” stem cell products with improved regenerative capacity. Genetic and nongenetic modifications, chemical and physical preconditioning, and the application of biomaterials were found to significantly enhance the regenerative capacity of transplanted stem cells. In this review, we will give an overview of the recent developments in stem cell engineering with the goal to facilitate stem cell delivery and to promote their cardiac regenerative activity.
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13
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Muse Cells and Ischemia-Reperfusion Lung Injury. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1103:293-303. [DOI: 10.1007/978-4-431-56847-6_16] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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14
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Irudayaswamy A, Muthiah M, Zhou L, Hung H, Jumat NHB, Haque J, Teoh N, Farrell G, Riehle KJ, Lin JS, Su LL, Chan JK, Choolani M, Wong PC, Wee A, Lim SG, Campbell J, Fausto N, Dan YY. Long-Term Fate of Human Fetal Liver Progenitor Cells Transplanted in Injured Mouse Livers. Stem Cells 2017; 36:103-113. [PMID: 28960647 DOI: 10.1002/stem.2710] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 08/25/2017] [Accepted: 09/13/2017] [Indexed: 12/15/2022]
Abstract
Liver progenitor cells have the potential to repair and regenerate a diseased liver. The success of any translational efforts, however, hinges on thorough understanding of the fate of these cells after transplant, especially in terms of long-term safety and efficacy. Here, we report transplantation of a liver progenitor population isolated from human fetal livers into immune-permissive mice with follow-up up to 36 weeks after transplant. We found that human progenitor cells engraft and differentiate into functional human hepatocytes in the mouse, producing albumin, alpha-1-antitrypsin, and glycogen. They create tight junctions with mouse hepatocytes, with no evidence of cell fusion. Interestingly, they also differentiate into functional endothelial cell and bile duct cells. Transplantation of progenitor cells abrogated carbon tetrachloride-induced fibrosis in recipient mice, with downregulation of procollagen and anti-smooth muscle actin. Paradoxically, the degree of engraftment of human hepatocytes correlated negatively with the anti-fibrotic effect. Progenitor cell expansion was most prominent in cirrhotic animals, and correlated with transcript levels of pro-fibrotic genes. Animals that had resolution of fibrosis had quiescent native progenitor cells in their livers. No evidence of neoplasia was observed, even up to 9 months after transplantation. Human fetal liver progenitor cells successfully attenuate liver fibrosis in mice. They are activated in the setting of liver injury, but become quiescent when injury resolves, mimicking the behavior of de novo progenitor cells. Our data suggest that liver progenitor cells transplanted into injured livers maintain a functional role in the repair and regeneration of the liver. Stem Cells 2018;36:103-113.
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Affiliation(s)
| | - Mark Muthiah
- Department of Medicine, National University Singapore, Singapore.,Division of Gastroenterology and Hepatology, National University Hospital. National University Health System, Singapore
| | - Lei Zhou
- Department of Medicine, National University Singapore, Singapore
| | - Hau Hung
- Department of Medicine, National University Singapore, Singapore
| | | | - Jamil Haque
- Department of Pathology, University of Washington, Seattle, Washington, USA
| | - Narcissus Teoh
- Department of Medicine, Australian National University, Canberra, Australia
| | - Geoffrey Farrell
- Department of Medicine, Australian National University, Canberra, Australia
| | - Kimberly J Riehle
- Department of Pathology, University of Washington, Seattle, Washington, USA.,Department of Surgery, University of Washington, Seattle, Washington, USA
| | - Jaymie Siqi Lin
- Department of Medicine, National University Singapore, Singapore
| | - Lin Lin Su
- Department of Obstetrics and Gynecology, National University Singapore, Singapore
| | - Jerry Ky Chan
- Department of Obstetrics and Gynecology, National University Singapore, Singapore.,Department of Reproductive Medicine, KK Women's and Children's Hospital, Singapore
| | - Mahesh Choolani
- Department of Obstetrics and Gynecology, National University Singapore, Singapore
| | - Peng Cheang Wong
- Department of Obstetrics and Gynecology, National University Singapore, Singapore
| | - Aileen Wee
- Department of Pathology, National University Singapore, Singapore
| | - Seng Gee Lim
- Department of Medicine, National University Singapore, Singapore.,Division of Gastroenterology and Hepatology, National University Hospital. National University Health System, Singapore
| | - Jean Campbell
- Clinical Research Divison, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Nelson Fausto
- Department of Pathology, University of Washington, Seattle, Washington, USA
| | - Yock Young Dan
- Department of Medicine, National University Singapore, Singapore.,Division of Gastroenterology and Hepatology, National University Hospital. National University Health System, Singapore.,Cancer Science Institute, National University Singapore, Singapore.,Genome Institute Singapore, ASTAR, Singapore
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15
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Inan M, Bakar E, Cerkezkayabekir A, Sanal F, Ulucam E, Subaşı C, Karaöz E. Mesenchymal stem cells increase antioxidant capacity in intestinal ischemia/reperfusion damage. J Pediatr Surg 2017; 52:1196-1206. [PMID: 28118930 DOI: 10.1016/j.jpedsurg.2016.12.024] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Revised: 12/03/2016] [Accepted: 12/23/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) may have beneficial effects in reversing intestinal damage resulting from circulatory disorders. The hypothesis of this study is that MSCs increase antioxidant capacity of small bowel tissue following intestinal ischemia reperfusion (I/R) damage. METHODS A total of 100 rats were used for the control group and three experimental groups, as follows: the sham control, local MSC, and systemic MSC groups. Each group consisted of 10 animals on days 1, 4, and 7 of the experiment. Ischemia was established by clamping the superior mesenteric artery (SMA) for 45min; following this, reperfusion was carried out for 1, 4, and 7days in all groups. In the local and systemic groups, MSCs were administered intravenously and locally just after the ischemia, and they were investigated after 1, 4, and 7days. The superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (Gpx) activities, as well as malondialdehyde (MDA) and total protein levels, were measured. Histopathological analysis was performed using light and electron microscopy. The indicators of proliferation from the effects of anti- and pro-inflammatory cytokines were evaluated using immunohistochemistry. RESULTS MDA was increased (P<0.05) in the sham control group and decreased (P<0.05) in the MSC groups. SOD, CAT, and Gpx were decreased in the local MSC group (P<0.05). The highest level of amelioration was observed on day 7 in the local MSC group via light and electron microscopy. It was found that the MSCs arrived at the damaged intestinal wall in the MSC groups immediately after injection. Pro-inflammatory cytokines interleukin-1β (IL1β), transforming growth factor-β1 (TGFβ1), tumor necrosis factor-α (TNFα), IL6, MIP2, and MPO decreased (P<0.05), while anti-inflammatory cytokines EP3 and IL1ra increased (p<0.05) in the local and systemic MSC groups. In addition, proliferation indicators, such as PCNA and KI67, increased (P<0.05) in the local and systemic MSC groups. CONCLUSIONS Parallel to our hypothesis, MSC increases the antioxidant capacity of small bowel tissue after intestinal I/R damage. The MSCs migrated to the reperfused small intestine by homing and reduced oxidative stress via the effects of SOD, CAT, and Gpx, as well as reducing the MDA level; thus, they could increase antioxidant capacity of intestine and have a therapeutic effect on the damaged tissue. We think that this effect was achieved via scavenging of oxygen radicals, suppression of pro-inflammatory cytokines, and increasing the expression of anti-inflammatory cytokines.
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Affiliation(s)
- M Inan
- Department of Pediatric Surgery, Trakya University Faculty of Medicine, Edirne, Turkey.
| | - E Bakar
- Department of Pharmaceutical Technology, Trakya University Faculty of Pharmacy, Edirne, Turkey
| | - A Cerkezkayabekir
- Division of Molecular Biology, Department of Biology, Trakya University Faculty of Science, Edirne, Turkey
| | - F Sanal
- Division of Molecular Biology, Department of Biology, Trakya University Faculty of Science, Edirne, Turkey
| | - E Ulucam
- Department of Anatomy, Trakya University Faculty of Medicine, Edirne, Turkey
| | - C Subaşı
- Department of Histology and Embryology, Faculty of Medicine, İstinye University, İstanbul, Turkey
| | - E Karaöz
- Department of Histology and Embryology, Faculty of Medicine, İstinye University, İstanbul, Turkey
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16
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Ceccaldi C, Bushkalova R, Cussac D, Duployer B, Tenailleau C, Bourin P, Parini A, Sallerin B, Girod Fullana S. Elaboration and evaluation of alginate foam scaffolds for soft tissue engineering. Int J Pharm 2017; 524:433-442. [DOI: 10.1016/j.ijpharm.2017.02.060] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Revised: 02/17/2017] [Accepted: 02/20/2017] [Indexed: 01/18/2023]
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17
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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: 6] [Impact Index Per Article: 0.8] [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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18
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Chen S, Chen X, Wu X, Wei S, Han W, Lin J, Kang M, Chen L. Hepatocyte growth factor-modified mesenchymal stem cells improve ischemia/reperfusion-induced acute lung injury in rats. Gene Ther 2016; 24:3-11. [DOI: 10.1038/gt.2016.64] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Revised: 07/26/2016] [Accepted: 08/04/2016] [Indexed: 12/20/2022]
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19
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Ezquer FE, Ezquer ME, Vicencio JM, Calligaris SD. Two complementary strategies to improve cell engraftment in mesenchymal stem cell-based therapy: Increasing transplanted cell resistance and increasing tissue receptivity. Cell Adh Migr 2016; 11:110-119. [PMID: 27294313 PMCID: PMC5308221 DOI: 10.1080/19336918.2016.1197480] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Over the past 2 decades, therapies based on mesenchymal stem cells (MSC) have been tested to treat several types of diseases in clinical studies, due to their potential for tissue repair and regeneration. Currently, MSC-based therapy is considered a biologically safe procedure, with the therapeutic results being very promising. However, the benefits of these therapies are not stable in the long term, and the final outcomes manifest with high inter-patient variability. The major cause of these therapeutic limitations results from the poor engraftment of the transplanted cells. Researchers have developed separate strategies to improve MSC engraftment. One strategy aims at increasing the survival of the transplanted MSCs in the recipient tissue, rendering them more resistant to the hostile microenvironment (cell-preconditioning). Another strategy aims at making the damaged tissue more receptive to the transplanted cells, favoring their interactions (tissue-preconditioning). In this review, we summarize several approaches using these strategies, providing an integral and updated view of the recent developments in MSC-based therapies. In addition, we propose that the combined use of these different conditioning strategies could accelerate the process to translate experimental evidences from pre-clinic studies to the daily clinical practice.
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Affiliation(s)
- Fernando E Ezquer
- a Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo , Santiago , Chile
| | - Marcelo E Ezquer
- a Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo , Santiago , Chile
| | | | - Sebastián D Calligaris
- a Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo , Santiago , Chile
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20
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Mesenchymal Stem Cells after Polytrauma: Actor and Target. Stem Cells Int 2016; 2016:6289825. [PMID: 27340408 PMCID: PMC4909902 DOI: 10.1155/2016/6289825] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Accepted: 05/09/2016] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent cells that are considered indispensable in regeneration processes after tissue trauma. MSCs are recruited to damaged areas via several chemoattractant pathways where they function as “actors” in the healing process by the secretion of manifold pro- and anti-inflammatory, antimicrobial, pro- and anticoagulatory, and trophic/angiogenic factors, but also by proliferation and differentiation into the required cells. On the other hand, MSCs represent “targets” during the pathophysiological conditions after severe trauma, when excessively generated inflammatory mediators, complement activation factors, and damage- and pathogen-associated molecular patterns challenge MSCs and alter their functionality. This in turn leads to complement opsonization, lysis, clearance by macrophages, and reduced migratory and regenerative abilities which culminate in impaired tissue repair. We summarize relevant cellular and signaling mechanisms and provide an up-to-date overview about promising future therapeutic MSC strategies in the context of severe tissue trauma.
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21
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McIntyre LA, Moher D, Fergusson DA, Sullivan KJ, Mei SHJ, Lalu M, Marshall J, Mcleod M, Griffin G, Grimshaw J, Turgeon A, Avey MT, Rudnicki MA, Jazi M, Fishman J, Stewart DJ. Efficacy of Mesenchymal Stromal Cell Therapy for Acute Lung Injury in Preclinical Animal Models: A Systematic Review. PLoS One 2016; 11:e0147170. [PMID: 26821255 PMCID: PMC4731557 DOI: 10.1371/journal.pone.0147170] [Citation(s) in RCA: 97] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Accepted: 12/30/2015] [Indexed: 01/02/2023] Open
Abstract
The Acute Respiratory Distress Syndrome (ARDS) is a devastating clinical condition that is associated with a 30–40% risk of death, and significant long term morbidity for those who survive. Mesenchymal stromal cells (MSC) have emerged as a potential novel treatment as in pre-clinical models they have been shown to modulate inflammation (a major pathophysiological hallmark of ARDS) while enhancing bacterial clearance and reducing organ injury and death. A systematic search of MEDLINE, EMBASE, BIOSIS and Web of Science was performed to identify pre-clinical studies that examined the efficacy MSCs as compared to diseased controls for the treatment of Acute Lung Injury (ALI) (the pre-clinical correlate of human ARDS) on mortality, a clinically relevant outcome. We assessed study quality and pooled results using random effect meta-analysis. A total of 54 publications met our inclusion criteria of which 17 (21 experiments) reported mortality and were included in the meta-analysis. Treatment with MSCs, as compared to controls, significantly decreased the overall odds of death in animals with ALI (Odds Ratio 0.24, 95% Confidence Interval 0.18–0.34, I2 8%). Efficacy was maintained across different types of animal models and means of ALI induction; MSC origin, source, route of administration and preparation; and the clinical relevance of the model (timing of MSC administration, administration of fluids and or antibiotics). Reporting of standard MSC characterization for experiments that used human MSCs and risks of bias was generally poor, and although not statistically significant, a funnel plot analysis for overall mortality suggested the presence of publication bias. The results from our meta-analysis support that MSCs substantially reduce the odds of death in animal models of ALI but important reporting elements were sub optimal and limit the strength of our conclusions.
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Affiliation(s)
- Lauralyn A. McIntyre
- Department of Medicine (Division of Critical Care), University of Ottawa, Ottawa, Ontario, Canada
- The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada
- * E-mail:
| | - David Moher
- The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada
- Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Dean A. Fergusson
- The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | | | | | - Manoj Lalu
- The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Department of Anesthesiology, University of Ottawa, Ottawa, Ontario, Canada
| | - John Marshall
- Department of Surgery and Critical Care Medicine, Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michaels Hospital, The University of Toronto, Toronto, Ontario, Canada
| | - Malcolm Mcleod
- Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, Scotland, United Kingdom
| | - Gilly Griffin
- The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Jeremy Grimshaw
- The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada
- Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Alexis Turgeon
- Department of Anesthesiology and Critical Care Medicine, Division of Critical Care Medicine, Université Laval, Laval, Québec City, Québec, Canada
- Population Health and Optimal Health Practice Research Unit (Trauma—Emergency—Critical Care Medicine), CHU de Québec Research Center, CHU de Québec (Hôpital de l'Enfant-Jésus), Laval, Québec City, Québec, Canada
| | - Marc T. Avey
- The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Michael A. Rudnicki
- Department of Medicine (Division of Critical Care), University of Ottawa, Ottawa, Ontario, Canada
- The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Department of Cell and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | | | - Jason Fishman
- Department of Anesthesiology and Critical Care Medicine, Division of Critical Care Medicine, Université Laval, Laval, Québec City, Québec, Canada
| | - Duncan J. Stewart
- The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Department of Cell and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
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22
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Mesenchymal stromal cells improve cardiac function and left ventricular remodeling in a heart transplantation model. J Heart Lung Transplant 2015; 34:1481-8. [DOI: 10.1016/j.healun.2015.05.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Revised: 05/02/2015] [Accepted: 05/28/2015] [Indexed: 01/04/2023] Open
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23
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Lu W, Si YI, Ding J, Chen X, Zhang X, Dong Z, Fu W. Mesenchymal stem cells attenuate acute ischemia-reperfusion injury in a rat model. Exp Ther Med 2015; 10:2131-2137. [PMID: 26668605 PMCID: PMC4665152 DOI: 10.3892/etm.2015.2806] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Accepted: 09/01/2015] [Indexed: 01/06/2023] Open
Abstract
Ischemia-reperfusion injury (IRI) following lung transplantation is associated with increased pulmonary inflammatory responses during reperfusion. Mesenchymal stem cells (MSCs) may be able to modulate inflammatory responses in IRI. The aim of the present study was to evaluate the beneficial effects of an intravenous infusion of bone marrow-derived MSCs (BMSCs) in a rat model of pulmonary IRI. IRI was induced in male Lewis rats by 1-h ischemia followed by 2-h reperfusion. The rats received phosphate-buffered saline (PBS) or BMSC infusion at the onset of reperfusion. Pulmonary injury was determined based on the mean blood oxygenation, lung edema and vascular permeability, and performing histopathological examination. Pulmonary inflammation was also evaluated through the examination of the levels of inflammatory cytokines. Compared with the PBS infusion, the BMSC infusion significantly preserved lung function, reduced lung edema and pulmonary microvascular permeability, and decreased the total injury score in rats with IRI. The mRNA levels of the pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6, were significantly reduced, while the expression of anti-inflammatory cytokine IL-10 was increased in the rats receiving BMSC infusion. The levels of cytokine-induced neutrophil chemoattractant-1, IL-1β, and TNF-α in bronchoalveolar lavage fluid were also markedly reduced following BMCS infusion. In conclusion, the present results suggested that BMSC infusion exerts protective effects against pulmonary IRI by alleviating IRI-induced inflammation. These findings provide experimental evidence for the treatment of pulmonary IRI using BMSC cell therapy.
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Affiliation(s)
- Weifeng Lu
- Department of Vascular Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian 361004, P.R. China
| | - Y I Si
- Department of Cardiovascular Surgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai 200032, P.R. China
| | - Jianyong Ding
- Department of Thoracic Surgery, Zhongshan Hospital Fudan University, Shanghai 200032, P.R. China
| | - Xiaoli Chen
- Cancer Research Center, Medical College of Xiamen University, Xiamen, Fujian 361004, P.R. China
| | - Xiangman Zhang
- Institute of Vascular Surgery, Zhongshan Hospital Fudan University, Shanghai 200032, P.R. China
| | - Zhihui Dong
- Institute of Vascular Surgery, Zhongshan Hospital Fudan University, Shanghai 200032, P.R. China
| | - Weiguo Fu
- Institute of Vascular Surgery, Zhongshan Hospital Fudan University, Shanghai 200032, P.R. China
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24
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Cell-based therapy for acute organ injury: preclinical evidence and ongoing clinical trials using mesenchymal stem cells. Anesthesiology 2014; 121:1099-121. [PMID: 25211170 DOI: 10.1097/aln.0000000000000446] [Citation(s) in RCA: 105] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Critically ill patients often suffer from multiple organ failures involving lung, kidney, liver, or brain. Genomic, proteomic, and metabolomic approaches highlight common injury mechanisms leading to acute organ failure. This underlines the need to focus on therapeutic strategies affecting multiple injury pathways. The use of adult stem cells such as mesenchymal stem or stromal cells (MSC) may represent a promising new therapeutic approach as increasing evidence shows that MSC can exert protective effects following injury through the release of promitotic, antiapoptotic, antiinflammatory, and immunomodulatory soluble factors. Furthermore, they can mitigate metabolomic and oxidative stress imbalance. In this work, the authors review the biological capabilities of MSC and the results of clinical trials using MSC as therapy in acute organ injuries. Although preliminary results are encouraging, more studies concerning safety and efficacy of MSC therapy are needed to determine their optimal clinical use. (ANESTHESIOLOGY 2014; 121:1099-121).
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25
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Infusion of mesenchymal stem cells protects lung transplants from cold ischemia-reperfusion injury in mice. Lung 2014; 193:85-95. [PMID: 25344633 DOI: 10.1007/s00408-014-9654-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Accepted: 10/07/2014] [Indexed: 01/10/2023]
Abstract
BACKGROUND Cold ischemia-reperfusion injury (IRI) is a major cause of graft failure in lung transplantation. Despite therapeutic benefits of mesenchymal stem cells (MSCs) in attenuating acute lung injury, their protection of lung transplants from cold IRI remains elusive. The present study was to test the efficacy of MSCs in the prevention of cold IRI using a novel murine model of orthotopic lung transplantation. METHODS Donor lungs from C57BL/6 mice were exposed to 6 h of cold ischemia before transplanted to syngeneic recipients. MSCs were isolated from the bone marrows of C57BL/6 mice for recipient treatment. Gas exchange was determined by the measurement of blood oxygenation, and lung injury and inflammation were assessed by histological analyses. RESULTS Intravenously delivered MSC migration/trafficking to the lung grafts occurred within 4-hours post-transplantation. As compared to untreated controls, the graft arterial blood oxygenation (PaO2/FiO2) capacity was significantly improved in MSC-treated recipients as early as 4 h post-reperfusion and such improvement continued over time. By 72 h, oxygenation reached normal level that was not seen in controls. MSCs treatment conferred significant protection of the grafts from cold IRI and cell apoptosis, which is correlated with less cellular infiltration, a decrease in proinflammatory cytokines (TNF-α, IL-6) and toll-like receptor 4, and an increase in anti-inflammatory TSG-6 generation. CONCLUSIONS MSCs provide significant protection against cold IRI in lung transplants, and thus may be a promising strategy to improve outcomes after lung transplantation.
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Kavanagh DPJ, Robinson J, Kalia N. Mesenchymal Stem Cell Priming: Fine-tuning Adhesion and Function. Stem Cell Rev Rep 2014; 10:587-99. [DOI: 10.1007/s12015-014-9510-7] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Wu X, Wang Z, Qian M, Wang L, Bai C, Wang X. Adrenaline stimulates the proliferation and migration of mesenchymal stem cells towards the LPS-induced lung injury. J Cell Mol Med 2014; 18:1612-22. [PMID: 24684532 PMCID: PMC4190907 DOI: 10.1111/jcmm.12283] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Accepted: 02/14/2014] [Indexed: 01/11/2023] Open
Abstract
Bone marrow-derived mesenchymal stem cells (BMSCs) could modulate inflammation in experimental lung injury. On the other hand, adrenergic receptor agonists could increase DNA synthesis of stem cells. Therefore, we investigated the therapeutic role of adrenaline-stimulated BMSCs on lipopolysaccharide (LPS)-induced lung injury. BMSCs were cultured with adrenergic receptor agonists or antagonists. Suspensions of lung cells or sliced lung tissue from animals with or without LPS-induced injury were co-cultured with BMSCs. LPS-stimulated alveolar macrophages were co-cultured with BMSCs (with adrenaline stimulation or not) in Transwell for 6 hrs. A preliminary animal experiment was conducted to validate the findings in ex vivo study. We found that adrenaline at 10 μM enhanced proliferation of BMSCs through both α- and β-adrenergic receptors. Adrenaline promoted the migration of BMSCs towards LPS-injured lung cells or lung tissue. Adrenaline-stimulated BMSCs decreased the inflammation of LPS-stimulated macrophages, probably through the expression and secretion of several paracrine factors. Adrenaline reduced the extent of injury in LPS-injured rats. Our data indicate that adrenaline-stimulated BMSCs might contribute to the prevention from acute lung injury through the activation of adrenergic receptors, promotion of proliferation and migration towards injured lung, and modulation of inflammation.
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Affiliation(s)
- Xiaodan Wu
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
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Zhu YG, Hao Q, Monsel A, Feng XM, Lee JW. Adult stem cells for acute lung injury: remaining questions and concerns. Respirology 2014; 18:744-56. [PMID: 23578018 DOI: 10.1111/resp.12093] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Accepted: 04/02/2013] [Indexed: 12/22/2022]
Abstract
Acute lung injury (ALI) or acute respiratory distress syndrome remains a major cause of morbidity and mortality in hospitalized patients. The pathophysiology of ALI involves complex interactions between the inciting event, such as pneumonia, sepsis or aspiration, and the host immune response resulting in lung protein permeability, impaired resolution of pulmonary oedema, an intense inflammatory response in the injured alveolus and hypoxemia. In multiple preclinical studies, adult stem cells have been shown to be therapeutic due to both the ability to mitigate injury and inflammation through paracrine mechanisms and perhaps to regenerate tissue by virtue of their multi-potency. These characteristics have stimulated intensive research efforts to explore the possibility of using stem or progenitor cells for the treatment of lung injury. A variety of stem or progenitor cells have been isolated, characterized and tested experimentally in preclinical animal models of ALI. However, questions remain concerning the optimal dose, route and the adult stem or progenitor cell to use. Here, the current mechanisms underlying the therapeutic effect of stem cells in ALI as well as the questions that will arise as clinical trials for ALI are planned are reviewed.
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Affiliation(s)
- Ying-Gang Zhu
- Department of Pulmonary Medicine, Huadong Hospital, Fudan University, Shanghai, China
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Hsiao ST, Dilley RJ, Dusting GJ, Lim SY. Ischemic preconditioning for cell-based therapy and tissue engineering. Pharmacol Ther 2013; 142:141-53. [PMID: 24321597 DOI: 10.1016/j.pharmthera.2013.12.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Accepted: 12/02/2013] [Indexed: 01/07/2023]
Abstract
Cell- and tissue-based therapies are innovative strategies to repair and regenerate injured hearts. Despite major advances achieved in optimizing these strategies in terms of cell source and delivery method, the clinical outcome of cell-based therapy remains unsatisfactory. The non-genetic approach of ischemic/hypoxic preconditioning to enhance cell- and tissue-based therapies has received much attention in recent years due to its non-invasive drug-free application. Here we discuss the current development of hypoxic/ischemic preconditioning to enhance stem cell-based cardiac repair and regeneration.
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Affiliation(s)
- Sarah T Hsiao
- Department of Cardiovascular Science, University of Sheffield, United Kingdom
| | - Rodney J Dilley
- Ear Science Institute Australia and Ear Sciences Centre, School of Surgery, University of Western Australia, Nedlands, Western Australia, Australia
| | - Gregory J Dusting
- Centre for Eye Research Australia and Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia; Department of Ophthalmology, University of Melbourne, East Melbourne, Victoria, Australia; Department of Surgery, University of Melbourne, Fitzroy, Victoria, Australia; O'Brien Institute, Fitzroy, Victoria, Australia
| | - Shiang Y Lim
- Department of Surgery, University of Melbourne, Fitzroy, Victoria, Australia; O'Brien Institute, Fitzroy, Victoria, Australia.
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30
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English K, Wood KJ. Mesenchymal stromal cells in transplantation rejection and tolerance. Cold Spring Harb Perspect Med 2013; 3:a015560. [PMID: 23637312 PMCID: PMC3633184 DOI: 10.1101/cshperspect.a015560] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Mesenchymal stromal cells (MSCs) have recently emerged as promising candidates for cell-based immunotherapy in solid organ transplantation (SOT). In addition to immune modulation, MSCs possess proreparative properties and preclinical studies indicate that MSCs have the capacity to prolong graft survival and in some cases induce tolerance. Currently, the application of MSCs in SOT is being evaluated in phase I/II clinical trials. Whereas the mechanisms of action used by MSC immunomodulation have been somewhat elucidated in vitro, the data from preclinical transplant models have been unclear. Furthermore, the optimal timing, dose, and route of administration remain to be elucidated. Importantly, MSCs have the ability to sense their environment, which may influence their function. In this article, we discuss the impact of the local microenvironment on MSCs and the mechanisms of MSC immunomodulation in the setting of SOT.
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Affiliation(s)
- Karen English
- Cellular Immunology Group, Institute of Immunology, National University of Ireland Maynooth, County Kildare, Ireland.
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Abstract
PURPOSE OF REVIEW Organ transplantation and other major surgeries are impacted by ischemia-reperfusion injury (IRI). Mesenchymal stromal cells (MSCs) recently became an attractive alternative therapeutic tool to combat IRI. The present review highlights the effects of MSCs in the preclinical animal models of IRI and clinical trials, and explains their potential modes of action based on the pathophysiological IRI cascade. RECENT FINDINGS The application of MSCs in animal models of IRI show anti-inflammatory and anti-apoptotic effects, particularly for damage to the kidneys, heart and lungs. The mechanism of MSC action remains unclear, but may involve paracrine factors which could include the transfer of microvesicles, RNA or mitochondria. Although few clinical trials have reached completion, adverse effects appear minimal. SUMMARY MSCs show promise in protecting against IRI-induced damage. They appear to help recovery mainly by affecting the levels of inflammation and apoptosis during the organ repair process. In addition, they may mediate immunomodulatory effects on the innate and adaptive immune processes triggered during reperfusion and reduce fibrosis. Success in preclinical animal models has led to the initiation of ongoing clinical trials.
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Sinclair K, Yerkovich ST, Chambers DC. Mesenchymal stem cells and the lung. Respirology 2013; 18:397-411. [DOI: 10.1111/resp.12050] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2012] [Revised: 11/28/2012] [Accepted: 01/01/2013] [Indexed: 12/20/2022]
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New insight of ischemic postconditioning on stem cell therapy. J Surg Res 2012; 183:91-3. [PMID: 22534254 DOI: 10.1016/j.jss.2012.03.070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2012] [Revised: 03/27/2012] [Accepted: 03/28/2012] [Indexed: 11/22/2022]
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