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Park KS, Lässer C, Lötvall J. Extracellular vesicles and the lung: from disease pathogenesis to biomarkers and treatments. Physiol Rev 2025; 105:1733-1821. [PMID: 40125970 DOI: 10.1152/physrev.00032.2024] [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: 08/14/2024] [Revised: 10/14/2024] [Accepted: 03/12/2025] [Indexed: 03/25/2025] Open
Abstract
Nanosized extracellular vesicles (EVs) are released by all cells to convey cell-to-cell communication. EVs, including exosomes and microvesicles, carry an array of bioactive molecules, such as proteins and RNAs, encapsulated by a membrane lipid bilayer. Epithelial cells, endothelial cells, and various immune cells in the lung contribute to the pool of EVs in the lung microenvironment and carry molecules reflecting their cellular origin. EVs can maintain lung health by regulating immune responses, inducing tissue repair, and maintaining lung homeostasis. They can be detected in lung tissues and biofluids such as bronchoalveolar lavage fluid and blood, offering information about disease processes, and can function as disease biomarkers. Here, we discuss the role of EVs in lung homeostasis and pulmonary diseases such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, pulmonary fibrosis, and lung injury. The mechanistic involvement of EVs in pathogenesis and their potential as disease biomarkers are discussed. Finally, the pulmonary field benefits from EVs as clinical therapeutics in severe pulmonary inflammatory disease, as EVs from mesenchymal stem cells attenuate severe respiratory inflammation in multiple clinical trials. Further, EVs can be engineered to carry therapeutic molecules for enhanced and broadened therapeutic opportunities, such as the anti-inflammatory molecule CD24. Finally, we discuss the emerging opportunity of using different types of EVs for treating severe respiratory conditions.
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Affiliation(s)
- Kyong-Su Park
- Krefting Research Centre, Institute of Medicine at the Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
| | - Cecilia Lässer
- Krefting Research Centre, Institute of Medicine at the Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
| | - Jan Lötvall
- Krefting Research Centre, Institute of Medicine at the Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
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Poorkazem H, Saber M, Moradmand A, Yakhkeshi S, Seydi H, Hajizadeh-Saffar E, Shekari F, Hassani SN. Comparative effects of various extracellular vesicle subpopulations derived from clonal mesenchymal stromal cells on cultured fibroblasts in wound healing-related process. Int J Biochem Cell Biol 2025; 180:106737. [PMID: 39828140 DOI: 10.1016/j.biocel.2025.106737] [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: 10/23/2024] [Revised: 12/25/2024] [Accepted: 01/09/2025] [Indexed: 01/22/2025]
Abstract
INTRODUCTION Non-healing wounds pose significant challenges and require effective therapeutic interventions. Extracellular vesicles (EVs) have emerged as promising cell-free therapeutic agents in tissue regeneration. However, the functional differences between different subpopulations of EVs in wound healing remain understudied. This study aimed to evaluate the effects of two distinct subpopulations of clonal mesenchymal stromal cells (cMSC)-derived EVs (cMSC-EVs), namely 20 K and 110K-cMSC-EVs, primarily on in vitro wound healing process, providing fast and cost-effective alternatives to animal models. METHODS In vitro assays were conducted to compare the effects of 20 K and 110K-cMSC-EVs, isolated through high-speed centrifugation and differential ultracentrifugation, respectively. For evaluation the main mechanisms of wound healing, including cell proliferation, cell migration, angiogenesis, and contraction. Human dermal fibroblasts (HDF) were considered as the main cells for analysis of these procedures. Moreover, gene expression analysis was performed to assess the impact of these EV subpopulations on the related process of wound healing on HDF. RESULTS The results demonstrated that both 20 K and 110K-cMSC-EVs exhibited beneficial effects on cell proliferation, cell migration, angiogenesis, and gel contraction. RT-qPCR revealed that both EV types downregulated interleukin 6 (IL6), induced proliferation by upregulating proliferating cell nuclear antigen (PCNA), and regulated remodeling by upregulating matrix metallopeptidase 1 (MMP1) and downregulating collagen type 1 (COL1). DISCUSSION This study highlights the effects of both 20 K and 110K-cMSC-EVs on the potency of HDFs in wound healing-related process. As the notable finding, 20K-cMSC-EVs offer a more feasible and cost-effective subpopulation for isolation and follow the GMP standard, recommended to utilize this fraction for therapeutic application.
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Affiliation(s)
- Hedie Poorkazem
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; Department of Developmental Biology, School of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, Tehran, Iran
| | - Maryam Saber
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Azadeh Moradmand
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Saeed Yakhkeshi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Homeyra Seydi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Ensiyeh Hajizadeh-Saffar
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; Department of Regenerative Biomedicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Faezeh Shekari
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; Department of Regenerative Biomedicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
| | - Seyedeh-Nafiseh Hassani
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; Department of Regenerative Biomedicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
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Lingappan K, Matthay MA. Unlocking the Therapeutic Code of Mesenchymal Stromal Cells. Am J Respir Crit Care Med 2025; 211:313-315. [PMID: 39847724 PMCID: PMC11936120 DOI: 10.1164/rccm.202412-2349ed] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Accepted: 01/22/2025] [Indexed: 01/25/2025] Open
Affiliation(s)
- Krithika Lingappan
- Children's Hospital of Philadelphia University of Pennsylvania Philadelphia, Pennsylvania
| | - Michael A Matthay
- Cardiovascular Research Institute University of California San Francisco, California
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Saneh H, Wanczyk H, Walker J, Finck C. Stem cell-derived extracellular vesicles: a potential intervention for Bronchopulmonary Dysplasia. Pediatr Res 2025; 97:497-509. [PMID: 39251881 PMCID: PMC12014501 DOI: 10.1038/s41390-024-03471-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 06/06/2024] [Accepted: 07/16/2024] [Indexed: 09/11/2024]
Abstract
Despite advances in neonatal care, the incidence of Bronchopulmonary Dysplasia (BPD) remains high among extreme preterm infants. The pathogenesis of BPD is multifactorial, with inflammation playing a central role. There is strong evidence that stem cell therapy reduces inflammatory changes and restores normal lung morphology in animal models of hyperoxia-induced lung injury. These therapeutic effects occur without significant engraftment of the stem cells in the host lung, suggesting more of a paracrine mechanism mediated by their secretome. In addition, there are multiple concerns with stem cell therapy which may be alleviated by administering only the effective vesicles instead of the cells themselves. Extracellular vesicles (EVs) are cell-derived components secreted by most eukaryotic cells. They can deliver their bioactive cargo (mRNAs, microRNAs, proteins, growth factors) to recipient cells, which makes them a potential therapeutic vehicle in many diseases, including BPD. The following review will highlight recent studies that investigate the effectiveness of EVs derived from stem cells in preventing or repairing injury in the preterm lung, and the potential mechanisms of action that have been proposed. Current limitations will also be discussed as well as suggestions for advancing the field and easing the transition towards clinical translation in evolving or established BPD. IMPACT: Extracellular vesicles (EVs) derived from stem cells are a potential intervention for neonatal lung diseases. Their use might alleviate the safety concerns associated with stem cell therapy. This review highlights recent studies that investigate the effectiveness of stem cell-derived EVs in preclinical models of bronchopulmonary dysplasia. It adds to the existing literature by elaborating on the challenges associated with EV research. It also provides suggestions to advance the field and ease the transition towards clinical applications. Optimizing EV research could ultimately improve the quality of life of extreme preterm infants born at vulnerable stages of lung development.
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Affiliation(s)
- Hala Saneh
- Department of Neonatal Medicine, Connecticut Children's Medical Center, Hartford, CT, USA.
- Department of Pediatrics, University of Connecticut Health Center, Farmington, CT, USA.
| | - Heather Wanczyk
- Department of Pediatrics, University of Connecticut Health Center, Farmington, CT, USA
| | - Joanne Walker
- Department of Pediatrics, University of Connecticut Health Center, Farmington, CT, USA
| | - Christine Finck
- Department of Pediatrics, University of Connecticut Health Center, Farmington, CT, USA
- Department of Pediatric Surgery, Connecticut Children's Medical Center, Hartford, CT, USA
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Dunbar H, Hawthorne IJ, Tunstead C, Dunlop M, Volkova E, Weiss DJ, dos Santos CC, Armstrong ME, Donnelly SC, English K. The VEGF-Mediated Cytoprotective Ability of MIF-Licensed Mesenchymal Stromal Cells in House Dust Mite-Induced Epithelial Damage. Eur J Immunol 2025; 55:e202451205. [PMID: 39502000 PMCID: PMC11739667 DOI: 10.1002/eji.202451205] [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: 04/18/2024] [Revised: 10/16/2024] [Accepted: 10/23/2024] [Indexed: 01/06/2025]
Abstract
Enhancing mesenchymal stromal cell (MSC) therapeutic efficacy through licensing with proinflammatory cytokines is now well established. We have previously shown that macrophage migration inhibitory factor (MIF)-licensed MSCs exerted significantly enhanced therapeutic efficacy in reducing inflammation in house dust mite (HDM)-driven allergic asthma. Soluble mediators released into the MSC secretome boast cytoprotective properties equal to those associated with the cell itself. In asthma, epithelial barrier damage caused by the inhalation of allergens like HDM drives goblet cell hyperplasia. Vascular endothelial growth factor (VEGF) plays a pivotal role in the repair and maintenance of airway epithelial integrity. Human bone marrow-derived MSCs expressed the MIF receptors CD74, CXCR2, and CXCR4. Endogenous MIF from high MIF expressing CATT7 bone marrow-derived macrophages increased MSC production of VEGF through the MIF CXCR4 chemokine receptor, where preincubation with CXCR4 inhibitor mitigated this effect. CATT7-MIF licensed MSC conditioned media containing increased levels of VEGF significantly enhanced bronchial epithelial wound healing via migration and proliferation in vitro. Blocking VEGFR2 or the use of mitomycin C abrogated this effect. Furthermore, CATT7-MIF MSC CM significantly decreased goblet cell hyperplasia after the HDM challenge in vivo. This was confirmed to be VEGF-dependent, as the use of anti-human VEGF neutralising antibody abrogated this effect. Overall, this study highlights that MIF-licenced MSCs show enhanced production of VEGF, which has the capacity to repair the lung epithelium.
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Affiliation(s)
- Hazel Dunbar
- Kathleen Lonsdale Institute for Human Health ResearchMaynooth UniversityMaynooth, Co. KildareIreland
- Department of BiologyMaynooth UniversityMaynooth, Co. KildareIreland
| | - Ian J. Hawthorne
- Kathleen Lonsdale Institute for Human Health ResearchMaynooth UniversityMaynooth, Co. KildareIreland
- Department of BiologyMaynooth UniversityMaynooth, Co. KildareIreland
| | - Courteney Tunstead
- Kathleen Lonsdale Institute for Human Health ResearchMaynooth UniversityMaynooth, Co. KildareIreland
- Department of BiologyMaynooth UniversityMaynooth, Co. KildareIreland
| | - Molly Dunlop
- Kathleen Lonsdale Institute for Human Health ResearchMaynooth UniversityMaynooth, Co. KildareIreland
- Department of BiologyMaynooth UniversityMaynooth, Co. KildareIreland
| | - Evelina Volkova
- Kathleen Lonsdale Institute for Human Health ResearchMaynooth UniversityMaynooth, Co. KildareIreland
- Department of BiologyMaynooth UniversityMaynooth, Co. KildareIreland
| | - Daniel J. Weiss
- Department of Medicine, 226 Health Sciences Research Facility, Larner College of MedicineUniversity of VermontBurlingtonVermontUSA
| | - Claudia C. dos Santos
- The Keenan Research Centre for Biomedical Science of St. Michael's HospitalTorontoOntarioCanada
- Institute of Medical Sciences and Interdepartmental Division of Critical CareFaculty of MedicineUniversity of TorontoTorontoOntarioCanada
| | | | - Seamas C. Donnelly
- Department of MedicineTrinity College Dublin and Tallaght HospitalDublinIreland
| | - Karen English
- Kathleen Lonsdale Institute for Human Health ResearchMaynooth UniversityMaynooth, Co. KildareIreland
- Department of BiologyMaynooth UniversityMaynooth, Co. KildareIreland
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Wang D, Xu L, Liu Y, Wang C, Qi S, Li Z, Bai X, Liao Y, Wang Y. Role of mesenchymal stem cells in sepsis and their therapeutic potential in sepsis‑associated myopathy (Review). Int J Mol Med 2024; 54:92. [PMID: 39219272 PMCID: PMC11374154 DOI: 10.3892/ijmm.2024.5416] [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: 12/06/2023] [Accepted: 08/01/2024] [Indexed: 09/04/2024] Open
Abstract
Sepsis‑induced myopathy (SIM) is one of the leading causes of death in critically ill patients. SIM mainly involves the respiratory and skeletal muscles of patients, resulting in an increased risk of lung infection, aggravated respiratory failure, and prolonged mechanical ventilation and hospital stay. SIM is also an independent risk factor associated with increased mortality in critically ill patients. At present, no effective treatment for SIM has yet been established. However, mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach and have been utilized in the treatment of various clinical conditions. A significant body of basic and clinical research supports the efficacy of MSCs in managing sepsis and muscle‑related diseases. This literature review aims to explore the relationship between MSCs and sepsis, as well as their impact on skeletal muscle‑associated diseases. Additionally, the present review discusses the potential mechanisms and therapeutic benefits of MSCs in the context of SIM.
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Affiliation(s)
- Dongfang Wang
- Trauma Center/Department of Emergency and Traumatic Surgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Ligang Xu
- Trauma Center/Department of Emergency and Traumatic Surgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Yukun Liu
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Chuntao Wang
- Trauma Center/Department of Emergency and Traumatic Surgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Siyuan Qi
- Trauma Center/Department of Emergency and Traumatic Surgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Zhanfei Li
- Trauma Center/Department of Emergency and Traumatic Surgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Xiangjun Bai
- Trauma Center/Department of Emergency and Traumatic Surgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Yiliu Liao
- Trauma Center/Department of Emergency and Traumatic Surgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Yuchang Wang
- Trauma Center/Department of Emergency and Traumatic Surgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
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Cui X, Fu J. Reinitiating lung development: a novel approach in the management of bronchopulmonary dysplasia. Respir Res 2024; 25:384. [PMID: 39449014 PMCID: PMC11515458 DOI: 10.1186/s12931-024-02996-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 09/30/2024] [Indexed: 10/26/2024] Open
Abstract
Bronchopulmonary dysplasia (BPD) is the predominant chronic lung disease in preterm infants, linked with various adverse long-term outcomes. Multiple prenatal and postnatal risk factors can impede lung development, leading to BPD. Current management of BPD relies heavily on pharmacotherapies and alterations in ventilatory strategies. However, these interventions only mitigate BPD symptoms without addressing underlying alveolar, vascular, structural, and functional deficiencies. Given the retarded lung development in infants with BPD and the limitations of existing modalities, new therapeutic approaches are imperative. The induced differentiation of stem/progenitor cells and the spatiotemporal expression patterns of growth factors associated with lung developmental processes are critical for lung development reactivation in BPD, which focuses on stimulating pulmonary vasculogenesis and alveolarization. This review summarizes the process of lung development and offers a comprehensive overview of advancements in therapies designed to reinitiate lung development in BPD. Furthermore, we assessed the potential of these therapies for maintaining lung homeostasis and effectively restoring pulmonary structure and function through stem/progenitor cells and growth factors, which have been widely researched.
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Affiliation(s)
- Xuewei Cui
- Department of Pediatrics, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang, 110004, China
| | - Jianhua Fu
- Department of Pediatrics, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang, 110004, China.
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Chang YS, Yang M, Ahn SY, Sung SI, Park WS. Improving the future of clinical trials and translation of mesenchymal stromal cell therapies for neonatal disorders. Stem Cells Transl Med 2024; 13:941-948. [PMID: 39120439 PMCID: PMC11465171 DOI: 10.1093/stcltm/szae060] [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: 12/27/2023] [Accepted: 06/23/2024] [Indexed: 08/10/2024] Open
Abstract
Despite recent advances in neonatal intensive care medicine, neonatal disorders such as (bronchopulmonary dysplasia [BPD], intraventricular hemorrhage [IVH], and hypoxic ischemic encephalopathy [HIE]) remain major causes of death and morbidity in survivors, with few effective treatments being available. Recent preclinical studies have demonstrated the pleiotropic host injury-responsive paracrine protective effects of cell therapy especially with mesenchymal stromal cells (MSCs) against BPD, IVH, and HIE. These findings suggest that MSCs therapy might emerge as a novel therapeutic modality for these currently devastating neonatal disorders with complex multifactorial etiologies. Although early-phase clinical trials suggest their safety and feasibility, their clinical therapeutic benefits have not yet been proven. Therefore, based on currently available preclinical research and clinical trial data, we focus on critical issues that need to be addressed for future successful clinical trials and eventual clinical translation such as selecting the right patient and optimal cell type, route, dose, and timing of MSCs therapy for neonatal disorders such as BPD, HIE, and IVH.
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Affiliation(s)
- Yun Sil Chang
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, Korea
- Cell and Gene Therapy Institute, Samsung Medical Center, Seoul, Korea
| | - Misun Yang
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- Cell and Gene Therapy Institute, Samsung Medical Center, Seoul, Korea
| | - So Yoon Ahn
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- Cell and Gene Therapy Institute, Samsung Medical Center, Seoul, Korea
| | - Se In Sung
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- Cell and Gene Therapy Institute, Samsung Medical Center, Seoul, Korea
| | - Won Soon Park
- Department of Pediatrics, Gangnam Cha Hospital, Cha University, Seoul, Korea
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Rao T, Zhou Y, Chen C, Chen J, Zhang J, Lin W, Jia D. Recent progress in neonatal hyperoxic lung injury. Pediatr Pulmonol 2024; 59:2414-2427. [PMID: 38742254 DOI: 10.1002/ppul.27062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 03/28/2024] [Accepted: 05/04/2024] [Indexed: 05/16/2024]
Abstract
With the progress in neonatal intensive care, there has been an increase in the survival rates of premature infants. However, this has also led to an increased incidence of neonatal hyperoxia lung injury and bronchopulmonary dysplasia (BPD), whose pathogenesis is believed to be influenced by various prenatal and postnatal factors, although the exact mechanisms remain unclear. Recent studies suggest that multiple mechanisms might be involved in neonatal hyperoxic lung injury and BPD, with sex also possibly playing an important role, and numerous drugs have been proposed and shown promise for improving the treatment outcomes of hyperoxic lung injury. Therefore, this paper aims to analyze and summarize sex differences in neonatal hyperoxic lung injury, potential pathogenesis and treatment progress to provide new ideas for basic and clinical research in this field.
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Affiliation(s)
- Tian Rao
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yiyang Zhou
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Chizhang Chen
- Department of Clinical Medicine, Chinese Medicine Hospital of Pingyang, Wenzhou, Zhejiang, China
| | - Jiayi Chen
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jie Zhang
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Wei Lin
- Department of Pediatrics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Danyun Jia
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, Zhejiang, China
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Kumar N, Bidkhori HR, Yawno T, Lim R, Inocencio IM. Therapeutic potential of extracellular vesicles derived from human amniotic epithelial cells for perinatal cerebral and pulmonary injury. Stem Cells Transl Med 2024; 13:711-723. [PMID: 38895873 PMCID: PMC11328935 DOI: 10.1093/stcltm/szae037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Accepted: 04/19/2024] [Indexed: 06/21/2024] Open
Abstract
Lung and brain injury that occurs during the perinatal period leads to lifelong disability and is often driven and/or exacerbated by inflammation. Human amniotic epithelial cells (hAEC), which demonstrate immunomodulatory, anti-fibrotic, and regenerative capabilities, are being explored as a therapeutic candidate for perinatal injury. However, limitations regarding scalable manufacturing, storage, transport, and dose-related toxicity have impeded clinical translation. Isolated therapeutic extracellular vesicles (EVs) from stem and stem-like cells are thought to be key paracrine mediators of therapeutic efficacy. The unique characteristics of EVs suggest that they potentially circumvent the limitations of traditional cell-based therapies. However, given the novelty of EVs as a therapeutic, recommendations around ideal methods of production, isolation, storage, and delivery have not yet been created by regulatory agencies. In this concise review, we discuss the pertinence and limitations of cell-based therapeutics in perinatal medicine. We also review the preclinical evidence supporting the use of therapeutic EVs for perinatal therapy. Further, we summarize the arising considerations regarding adequate cell source, biodistribution, isolation and storage methods, and regulatory roadblocks for the development of therapeutic EVs.
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Affiliation(s)
- Naveen Kumar
- The Ritchie Centre, The Hudson Institute of Medical Research, Clayton 3168, Victoria, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton 3168, Victoria, Australia
| | - Hamid Reza Bidkhori
- The Ritchie Centre, The Hudson Institute of Medical Research, Clayton 3168, Victoria, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton 3168, Victoria, Australia
| | - Tamara Yawno
- The Ritchie Centre, The Hudson Institute of Medical Research, Clayton 3168, Victoria, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton 3168, Victoria, Australia
- Department of Paediatrics, Monash University, Clayton 3168, Victoria, Australia
| | - Rebecca Lim
- The Ritchie Centre, The Hudson Institute of Medical Research, Clayton 3168, Victoria, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton 3168, Victoria, Australia
| | - Ishmael Miguel Inocencio
- The Ritchie Centre, The Hudson Institute of Medical Research, Clayton 3168, Victoria, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton 3168, Victoria, Australia
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Gao R, Lin P, Fang Z, Yang W, Gao W, Wang F, Pan X, Yu W. Cell-derived biomimetic nanoparticles for the targeted therapy of ALI/ARDS. Drug Deliv Transl Res 2024; 14:1432-1457. [PMID: 38117405 DOI: 10.1007/s13346-023-01494-6] [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] [Accepted: 12/06/2023] [Indexed: 12/21/2023]
Abstract
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common clinical critical diseases with high morbidity and mortality. Especially since the COVID-19 outbreak, the mortality rates of critically ill patients with ARDS can be as high as 60%. Therefore, this problem has become a matter of concern to respiratory critical care. To date, the main clinical measures for ALI/ARDS are mechanical ventilation and drug therapy. Although ventilation treatment reduces mortality, it increases the risk of hyperxemia, and drug treatment lacks safe and effective delivery methods. Therefore, novel therapeutic strategies for ALI/ARDS are urgently needed. Developments in nanotechnology have allowed the construction of a safe, efficient, precise, and controllable drug delivery system. However, problems still encounter in the treatment of ALI/ARDS, such as the toxicity, poor targeting ability, and immunogenicity of nanomaterials. Cell-derived biomimetic nanodelivery drug systems have the advantages of low toxicity, long circulation, high targeting, and high bioavailability and show great therapeutic promises for ALI/ARDS owing to their acquired cellular biological features and some functions. This paper reviews ALI/ARDS treatments based on cell membrane biomimetic technology and extracellular vesicle biomimetic technology, aiming to achieve a significant breakthrough in ALI/ARDS treatments.
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Affiliation(s)
- Rui Gao
- School of Pharmacy, Hangzhou Medical College, Hangzhou, 310013, China
| | - Peihong Lin
- School of Pharmacy, Hangzhou Medical College, Hangzhou, 310013, China
| | - Zhengyu Fang
- School of Pharmacy, Hangzhou Medical College, Hangzhou, 310013, China
| | - Wenjing Yang
- School of Pharmacy, Hangzhou Medical College, Hangzhou, 310013, China
| | - Wenyan Gao
- School of Pharmacy, Hangzhou Medical College, Hangzhou, 310013, China
- Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, 310013, China
| | - Fangqian Wang
- School of Pharmacy, Hangzhou Medical College, Hangzhou, 310013, China
| | - Xuwang Pan
- Department of Pharmaceutical Preparation, Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, Hangzhou, 310013, China.
| | - Wenying Yu
- School of Pharmacy, Hangzhou Medical College, Hangzhou, 310013, China.
- Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, 310013, China.
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Ransom MA, Blatt AM, Pua HH, Sucre JMS. The emerging role of extracellular vesicles in bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 2024; 326:L517-L523. [PMID: 38469633 PMCID: PMC11380955 DOI: 10.1152/ajplung.00244.2023] [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: 08/02/2023] [Revised: 03/01/2024] [Accepted: 03/02/2024] [Indexed: 03/13/2024] Open
Abstract
Extracellular vesicle (EV) biology in neonatal lung development and disease is a rapidly growing area of investigation. Although EV research in the neonatal population lags behind EV research in adult lung diseases, recent discoveries demonstrate promise in furthering our understanding of the pathophysiology of bronchopulmonary dysplasia and the potential use of EVs in the clinical setting, as both biomarkers and therapeutic agents. This review article explores some of the recent advances in this field and our evolving knowledge of the role of EVs in bronchopulmonary dysplasia.
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Affiliation(s)
- Meaghan A Ransom
- Department of Pediatrics, Vanderbilt University Medical Center; Nashville, Tennessee, United States
| | - Alexander M Blatt
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States
| | - Heather H Pua
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Vanderbilt Center for Immunobiology and Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, United States
| | - Jennifer M S Sucre
- Department of Pediatrics, Vanderbilt University Medical Center; Nashville, Tennessee, United States
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee, United States
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13
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McDonald J, Mohak S, Fabian Z. Stem Cell-Derived Extracellular Vesicles in the Treatment of Cardiovascular Diseases. Pharmaceutics 2024; 16:381. [PMID: 38543275 PMCID: PMC10974254 DOI: 10.3390/pharmaceutics16030381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 02/26/2024] [Accepted: 03/06/2024] [Indexed: 01/03/2025] Open
Abstract
Cardiovascular disease constitutes a noteworthy public health challenge characterized by a pronounced incidence, frequency, and mortality rate, particularly impacting specific demographic groups, and imposing a substantial burden on the healthcare infrastructure. Certain risk factors, such as age, gender, and smoking, contribute to the prevalence of fatal cardiovascular disease, highlighting the need for targeted interventions. Current challenges in clinical practice involve medication complexities, the lack of a systematic decision-making approach, and prevalent drug therapy problems. Stem cell-derived extracellular vesicles stand as versatile entities with a unique molecular fingerprint, holding significant therapeutic potential across a spectrum of applications, particularly in the realm of cardio-protection. Their lipid, protein, and nucleic acid compositions, coupled with their multifaceted functions, underscore their role as promising mediators in regenerative medicine and pave the way for further exploration of their intricate contributions to cellular physiology and pathology. Here, we overview our current understanding of the possible role of stem cell-derived extracellular vesicles in the clinical management of human cardiovascular pathologies.
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Affiliation(s)
- Jennifer McDonald
- School of Medicine and Dentistry, Faculty of Clinical and Biomedical Sciences, University of Central Lancashire, Fylde Road, Preston PR1 2HE, UK;
| | - Sidhesh Mohak
- Department of Internal Medicine, South Texas Health System, McAllen, TX 78503, USA;
| | - Zsolt Fabian
- School of Medicine and Dentistry, Faculty of Clinical and Biomedical Sciences, University of Central Lancashire, Fylde Road, Preston PR1 2HE, UK;
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14
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Ao M, Ma H, Guo M, Dai X, Zhang X. Research hotspots and emerging trends in mesenchymal stem/stromal cells in bronchopulmonary dysplasia. Hum Cell 2024; 37:381-393. [PMID: 38159195 DOI: 10.1007/s13577-023-01018-x] [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: 07/28/2023] [Accepted: 11/30/2023] [Indexed: 01/03/2024]
Abstract
Bronchopulmonary dysplasia (BPD) is a prevalent lung disease in neonates that is associated with numerous complications and high mortality. The promising approach to treat BPD is the use of mesenchymal stem cells (MSCs), However, the current treatment of MSCs presents safety concerns, including occlusion of blood vessels and tumorigenicity. In this study, relevant publications from the Web of Science Core Collection were downloaded in January 2023. The acquired data were analyzed and predicted for trends and hotspots in this field using CiteSpace software. Results revealed that in recent years, the focus of co-cited references has been primarily on the clinical studies of MSCs and the application of MSCs derivatives for treating BPD models. The keywords that have gained attention are extracellular vesicles and exosomes. The United States has emerged as the most influential co-authoring country in this field. Among the co-cited journals, the American Journal of Respiratory and Critical Care Medicine holds the highest influence. Thus, this study provides trends in publications, collaboration, research interests, and hotspots, and provides clues for novel ideas and strategies in to further MSCs treatments for BPD.
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Affiliation(s)
- Meng Ao
- The School of Public Health, Guilin Medical University, 1 Zhiyuan Road, Lingui District, Guilin, 541100, People's Republic of China
- The Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Heath, 1 Zhiyuan Road, Lingui District, Guilin, 541199, People's Republic of China
- Guangxi Health Commission Key Laboratory of Entire Lifecycle Health and Care, 1 Zhiyuan Road, Lingui District, Guilin, 541199, People's Republic of China
| | - Heqian Ma
- The School of Public Health, Guilin Medical University, 1 Zhiyuan Road, Lingui District, Guilin, 541100, People's Republic of China
- The Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Heath, 1 Zhiyuan Road, Lingui District, Guilin, 541199, People's Republic of China
- Guangxi Health Commission Key Laboratory of Entire Lifecycle Health and Care, 1 Zhiyuan Road, Lingui District, Guilin, 541199, People's Republic of China
| | - Meizhen Guo
- The School of Public Health, Guilin Medical University, 1 Zhiyuan Road, Lingui District, Guilin, 541100, People's Republic of China
- The Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Heath, 1 Zhiyuan Road, Lingui District, Guilin, 541199, People's Republic of China
- Guangxi Health Commission Key Laboratory of Entire Lifecycle Health and Care, 1 Zhiyuan Road, Lingui District, Guilin, 541199, People's Republic of China
| | - Xuelin Dai
- The School of Public Health, Guilin Medical University, 1 Zhiyuan Road, Lingui District, Guilin, 541100, People's Republic of China
- The Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Heath, 1 Zhiyuan Road, Lingui District, Guilin, 541199, People's Republic of China
- Guangxi Health Commission Key Laboratory of Entire Lifecycle Health and Care, 1 Zhiyuan Road, Lingui District, Guilin, 541199, People's Republic of China
| | - Xiaoying Zhang
- The School of Public Health, Guilin Medical University, 1 Zhiyuan Road, Lingui District, Guilin, 541100, People's Republic of China.
- The Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Heath, 1 Zhiyuan Road, Lingui District, Guilin, 541199, People's Republic of China.
- Guangxi Health Commission Key Laboratory of Entire Lifecycle Health and Care, 1 Zhiyuan Road, Lingui District, Guilin, 541199, People's Republic of China.
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15
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Jasim SA, Aziz DZ, Mustafa YF, Margiana R, Al-Alwany AA, Hjazi A, Alawadi A, Yumashev A, Alsalamy A, Fenjan MN. Role of genetically engineered mesenchymal stem cell exosomes and LncRNAs in respiratory diseases treatment. Pathol Res Pract 2024; 254:155135. [PMID: 38295461 DOI: 10.1016/j.prp.2024.155135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 01/08/2024] [Accepted: 01/10/2024] [Indexed: 02/02/2024]
Abstract
The term acute respiratory disease encompasses a wide range of acute lung diseases, which in recent years have been ranked among the top three deadly diseases in the world. Since conventional treatment methods, including the use of anti-inflammatory drugs, have had no significant effect on the treatment process of these diseases, the attention of the medical community has been drawn to alternative methods. Mesenchymal stem cells (MSC) are multipotential stem/progenitor cells that have extensive immunomodulatory and anti-inflammatory properties and also play a critical role in the microenvironment of injured tissue. MSC secretomes (containing large extracellular vesicles, microvesicles, and exosomes) are a newly introduced option for cell-free therapies that can circumvent the hurdles of cell-based therapies while maintaining the therapeutic role of MSC themselves. The therapeutic capabilities of MSCs have been showed in many acute respiratory diseases, including chronic respiratory disease (CRD), novel coronavirus 2019 (COVID -19), and pneumonia. MSCs offer novel therapeutic approaches for chronic and acute lung diseases due to their anti-inflammatory and immunomodulatory properties. In this review, we summarize the current evidence on the efficacy and safety of MSC-derived products in preclinical models of lung diseases and highlight the biologically active compounds present in the MSC secretome and their mechanisms involved in anti-inflammatory activity and tissue regeneration.
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Affiliation(s)
| | - Dhifaf Zeki Aziz
- College of Science, Department of pathological Analyses, University of Kufa, Al-Najaf, Iraq.
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, Iraq.
| | - Ria Margiana
- Department of Anatomy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; Master's Programme Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
| | | | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Saudi Arabia.
| | - Ahmed Alawadi
- College of technical engineering, the Islamic University, Najaf, Iraq; College of technical engineering, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq; College of technical engineering, the Islamic University of Babylon, Babylon, Iraq
| | - Alexey Yumashev
- Department of Prosthetic Dentistry, Sechenov First Moscow State Medical University, Russia.
| | - Ali Alsalamy
- College of technical engineering, Imam Ja'afar Al-Sadiq University, Al-Muthanna 66002, Iraq.
| | - Mohammed N Fenjan
- College of Health and Medical Technology, Al-Ayen University, Thi-Qar, Iraq.
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16
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Mehrabadi S. Extracellular Vesicles: A Promising Therapeutic Approach to Alzheimer's Disease. Curr Alzheimer Res 2024; 21:615-624. [PMID: 39878107 DOI: 10.2174/0115672050365314250112042136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Revised: 12/12/2024] [Accepted: 12/17/2024] [Indexed: 01/31/2025]
Abstract
Extracellular vesicles (EVs) are nano-sized membranous particles that are secreted by various cell types and play a critical role in intercellular communication. Their unique properties and remarkable ability to deliver bioactive cargo to target cells have made them promising tools in the treatment of various diseases, including Alzheimer's disease (AD). AD is a devastating neurodegenerative disease characterized by progressive cognitive decline and neuropathological hallmarks, such as amyloid-beta plaques and neurofibrillary tangles. Despite extensive research, no disease-modifying therapy for AD is currently available. However, EVs have emerged as a potential therapeutic agent in AD due to their ability to cross the blood-brain barrier, deliver bioactive cargo, and modulate neuroinflammation. This review provides a comprehensive overview of the current knowledge on the role of EVs in AD and discusses their potential as a therapeutic approach. It covers the mechanisms of action, potential therapeutic targets, and challenges and limitations of EV-based therapies for AD.
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Affiliation(s)
- Shima Mehrabadi
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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17
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Cui E, Lv L, Chen W, Chen N, Pan R. Mesenchymal stem/stromal cell-based cell-free therapy for the treatment of acute lung injury. J Cell Biochem 2023; 124:1241-1248. [PMID: 37668145 DOI: 10.1002/jcb.30469] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 08/16/2023] [Accepted: 08/28/2023] [Indexed: 09/06/2023]
Abstract
Acute lung injury (ALI) is a severe medical condition that causes inflammation and fluid buildup in the lung, resulting in respiratory distress. Moreover, ALI often occurs as a complication of other medical conditions or injuries, including the coronavirus disease of 2019. Mesenchymal stem/stromal cells (MSCs) are being studied extensively for their therapeutic potential in various diseases, including ALI. The results of recent studies suggest that the beneficial effects of MSCs may not be primarily due to the replacement of damaged cells but rather the release of extracellular vesicles (EVs) and other soluble factors through a paracrine mechanism. Furthermore, EVs derived from MSCs preserve the therapeutic action of the parent MSCs and this approach avoids the safety issues associated with live cell therapy. Thus, MSC-based cell-free therapy may be the focus of future clinical treatments.
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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, China
| | - Lu Lv
- Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, China
| | - Wenyan Chen
- Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, China
| | - Na Chen
- Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, 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, China
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18
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Rosado-Galindo H, Domenech M. Substrate topographies modulate the secretory activity of human bone marrow mesenchymal stem cells. Stem Cell Res Ther 2023; 14:208. [PMID: 37605275 PMCID: PMC10441765 DOI: 10.1186/s13287-023-03450-0] [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: 09/15/2022] [Accepted: 08/11/2023] [Indexed: 08/23/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) secrete a diversity of factors with broad therapeutic potential, yet current culture methods limit potency outcomes. In this study, we used topographical cues on polystyrene films to investigate their impact on the secretory profile and potency of bone marrow-derived MSCs (hBM-MSCs). hBM-MSCs from four donors were cultured on topographic substrates depicting defined roughness, curvature, grooves and various levels of wettability. METHODS The topographical PS-based array was developed using razor printing, polishing and plasma treatment methods. hBM-MSCs from four donors were purchased from RoosterBio and used in co-culture with peripheral blood mononuclear cells (PBMCs) from Cell Applications Inc. in an immunopotency assay to measure immunosuppressive capacity. Cells were cultured on low serum (2%) for 24-48 h prior to analysis. Image-based analysis was used for cell quantification and morphology assessment. Metabolic activity of BM-hMSCs was measured as the mitochondrial oxygen consumption rate using an extracellular flux analyzer. Conditioned media samples of BM-hMSCs were used to quantify secreted factors, and the data were analyzed using R statistics. Enriched bioprocesses were identify using the Gene Ontology tool enrichGO from the clusterprofiler. One-way and two-way ANOVAs were carried out to identify significant changes between the conditions. Results were deemed statistically significant for combined P < 0.05 for at least three independent experiments. RESULTS Cell viability was not significantly affected in the topographical substrates, and cell elongation was enhanced at least twofold in microgrooves and surfaces with a low contact angle. Increased cell elongation correlated with a metabolic shift from oxidative phosphorylation to a glycolytic state which is indicative of a high-energy state. Differential protein expression and gene ontology analyses identified bioprocesses enriched across donors associated with immune modulation and tissue regeneration. The growth of peripheral blood mononuclear cells (PBMCs) was suppressed in hBM-MSCs co-cultures, confirming enhanced immunosuppressive potency. YAP/TAZ levels were found to be reduced on these topographies confirming a mechanosensing effect on cells and suggesting a potential role in the immunomodulatory function of hMSCs. CONCLUSIONS This work demonstrates the potential of topographical cues as a culture strategy to improve the secretory capacity and enrich for an immunomodulatory phenotype in hBM-MSCs.
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Affiliation(s)
- Heizel Rosado-Galindo
- Bioengineering Program, University of Puerto Rico-Mayagüez, Road 108, KM 1.1., Mayagüez, PR, 00680, USA
| | - Maribella Domenech
- Bioengineering Program, University of Puerto Rico-Mayagüez, Road 108, KM 1.1., Mayagüez, PR, 00680, USA.
- Department of Chemical Engineering, University of Puerto Rico-Mayagüez, Road 108, KM 1.1., Mayagüez, PR, 00680, USA.
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19
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Ding JY, Chen MJ, Wu LF, Shu GF, Fang SJ, Li ZY, Chu XR, Li XK, Wang ZG, Ji JS. Mesenchymal stem cell-derived extracellular vesicles in skin wound healing: roles, opportunities and challenges. Mil Med Res 2023; 10:36. [PMID: 37587531 PMCID: PMC10433599 DOI: 10.1186/s40779-023-00472-w] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 07/24/2023] [Indexed: 08/18/2023] Open
Abstract
Skin wounds are characterized by injury to the skin due to trauma, tearing, cuts, or contusions. As such injuries are common to all human groups, they may at times represent a serious socioeconomic burden. Currently, increasing numbers of studies have focused on the role of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) in skin wound repair. As a cell-free therapy, MSC-derived EVs have shown significant application potential in the field of wound repair as a more stable and safer option than conventional cell therapy. Treatment based on MSC-derived EVs can significantly promote the repair of damaged substructures, including the regeneration of vessels, nerves, and hair follicles. In addition, MSC-derived EVs can inhibit scar formation by affecting angiogenesis-related and antifibrotic pathways in promoting macrophage polarization, wound angiogenesis, cell proliferation, and cell migration, and by inhibiting excessive extracellular matrix production. Additionally, these structures can serve as a scaffold for components used in wound repair, and they can be developed into bioengineered EVs to support trauma repair. Through the formulation of standardized culture, isolation, purification, and drug delivery strategies, exploration of the detailed mechanism of EVs will allow them to be used as clinical treatments for wound repair. In conclusion, MSC-derived EVs-based therapies have important application prospects in wound repair. Here we provide a comprehensive overview of their current status, application potential, and associated drawbacks.
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Affiliation(s)
- Jia-Yi Ding
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, Lishui, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Min-Jiang Chen
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, Lishui, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Ling-Feng Wu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui, 323000, Zhejiang, China
| | - Gao-Feng Shu
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, Lishui, China
- Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui, 323000, Zhejiang, China
| | - Shi-Ji Fang
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, Lishui, China
- Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui, 323000, Zhejiang, China
| | - Zhao-Yu Li
- Department of Overseas Education College, Jimei University, Xiamen, 361021, Fujian, China
| | - Xu-Ran Chu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Department of Medicine II, Internal Medicine, Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig University Giessen, 35392, Giessen, Germany
- Pulmonary and Critical Care, Department of Medicine V, Internal Medicine, Infectious Diseases and Infection Control, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig University Giessen, 35392, Giessen, Germany
| | - Xiao-Kun Li
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
| | - Zhou-Guang Wang
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, Lishui, China.
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
| | - Jian-Song Ji
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, the Fifth Affiliated Hospital of Wenzhou Medical University, Zhejiang, 323000, Lishui, China.
- Clinical College of the Affiliated Central Hospital, School of Medicine, Lishui University, Lishui, 323000, Zhejiang, China.
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Zhang W, Wang T, Xue Y, Zhan B, Lai Z, Huang W, Peng X, Zhou Y. Research progress of extracellular vesicles and exosomes derived from mesenchymal stem cells in the treatment of oxidative stress-related diseases. Front Immunol 2023; 14:1238789. [PMID: 37646039 PMCID: PMC10461809 DOI: 10.3389/fimmu.2023.1238789] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 07/24/2023] [Indexed: 09/01/2023] Open
Abstract
There is growing evidence that mesenchymal stem cell-derived extracellular vesicles and exosomes can significantly improve the curative effect of oxidative stress-related diseases. Mesenchymal stem cell extracellular vesicles and exosomes (MSC-EVs and MSC-Exos) are rich in bioactive molecules and have many biological regulatory functions. In this review, we describe how MSC-EVs and MSC-Exos reduce the related markers of oxidative stress and inflammation in various systemic diseases, and the molecular mechanism of MSC-EVs and MSC-Exos in treating apoptosis and vascular injury induced by oxidative stress. The results of a large number of experimental studies have shown that both local and systemic administration can effectively inhibit the oxidative stress response in diseases and promote the survival and regeneration of damaged parenchymal cells. The mRNA and miRNAs in MSC-EVs and MSC-Exos are the most important bioactive molecules in disease treatment, which can inhibit the apoptosis, necrosis and oxidative stress of lung, heart, kidney, liver, bone, skin and other cells, and promote their survive and regenerate.
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Affiliation(s)
- Wenwen Zhang
- The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan, Guangdong, China
- Department of Pathophysiology, Guangdong Medical University, Dongguan, Guangdong, China
| | - Tingyu Wang
- The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan, Guangdong, China
- Department of Pathophysiology, Guangdong Medical University, Dongguan, Guangdong, China
| | - Yuanye Xue
- The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan, Guangdong, China
- Department of Pathophysiology, Guangdong Medical University, Dongguan, Guangdong, China
| | - Bingbing Zhan
- School of Pharmaceutical Sciences, Guangdong Medical University, Dongguan, China
| | - Zengjie Lai
- The Second Clinical Medical College of Guangdong Medical University, Dongguan, China
| | - Wenjie Huang
- School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Xinsheng Peng
- Biomedical Innovation Center, Guangdong Medical University, Dongguan, China
- Institute of Marine Medicine, Guangdong Medical University, Zhanjiang, China
| | - Yanfang Zhou
- The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan, Guangdong, China
- Department of Pathophysiology, Guangdong Medical University, Dongguan, Guangdong, China
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21
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Wu S, Benny M, Duara J, Williams K, Tan A, Schmidt A, Young KC. Extracellular vesicles: pathogenic messengers and potential therapy for neonatal lung diseases. Front Pediatr 2023; 11:1205882. [PMID: 37397144 PMCID: PMC10311919 DOI: 10.3389/fped.2023.1205882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 05/31/2023] [Indexed: 07/04/2023] Open
Abstract
Extracellular vesicles (EVs) are a heterogeneous group of nano-sized membranous structures increasingly recognized as mediators of intercellular and inter-organ communication. EVs contain a cargo of proteins, lipids and nucleic acids, and their cargo composition is highly dependent on the biological function of the parental cells. Their cargo is protected from the extracellular environment by the phospholipid membrane, thus allowing for safe transport and delivery of their intact cargo to nearby or distant target cells, resulting in modification of the target cell's gene expression, signaling pathways and overall function. The highly selective, sophisticated network through which EVs facilitate cell signaling and modulate cellular processes make studying EVs a major focus of interest in understanding various biological functions and mechanisms of disease. Tracheal aspirate EV-miRNA profiling has been suggested as a potential biomarker for respiratory outcome in preterm infants and there is strong preclinical evidence showing that EVs released from stem cells protect the developing lung from the deleterious effects of hyperoxia and infection. This article will review the role of EVs as pathogenic messengers, biomarkers, and potential therapies for neonatal lung diseases.
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Affiliation(s)
- Shu Wu
- Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
- Batchelor Children’s Research Institute, University of Miami Miller School of Medicine, Miami, FL, United States
- Holtz Children’s Hospital, Jackson Memorial Medical Center, Miami, FL, United States
| | - Merline Benny
- Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
- Batchelor Children’s Research Institute, University of Miami Miller School of Medicine, Miami, FL, United States
- Holtz Children’s Hospital, Jackson Memorial Medical Center, Miami, FL, United States
| | - Joanne Duara
- Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
- Batchelor Children’s Research Institute, University of Miami Miller School of Medicine, Miami, FL, United States
- Holtz Children’s Hospital, Jackson Memorial Medical Center, Miami, FL, United States
| | - Kevin Williams
- Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
- Batchelor Children’s Research Institute, University of Miami Miller School of Medicine, Miami, FL, United States
- Holtz Children’s Hospital, Jackson Memorial Medical Center, Miami, FL, United States
| | - April Tan
- Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
- Batchelor Children’s Research Institute, University of Miami Miller School of Medicine, Miami, FL, United States
- Holtz Children’s Hospital, Jackson Memorial Medical Center, Miami, FL, United States
| | - Augusto Schmidt
- Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
- Batchelor Children’s Research Institute, University of Miami Miller School of Medicine, Miami, FL, United States
- Holtz Children’s Hospital, Jackson Memorial Medical Center, Miami, FL, United States
| | - Karen C. Young
- Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
- Batchelor Children’s Research Institute, University of Miami Miller School of Medicine, Miami, FL, United States
- Holtz Children’s Hospital, Jackson Memorial Medical Center, Miami, FL, United States
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, United States
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Dong J, Wu B, Tian W. Human adipose tissue-derived small extracellular vesicles promote soft tissue repair through modulating M1-to-M2 polarization of macrophages. Stem Cell Res Ther 2023; 14:67. [PMID: 37024970 PMCID: PMC10080905 DOI: 10.1186/s13287-023-03306-7] [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: 08/31/2022] [Accepted: 03/28/2023] [Indexed: 04/08/2023] Open
Abstract
BACKGROUND Successful regenerative medicine strategies need the manipulation and control of macrophages' phenotypic switching. Our previous study indicated that rat and porcine adipose tissue-derived small extracellular vesicles could successfully promote soft tissue repair. However, whether human adipose tissue-derived small extracellular vesicles (h-sEV-AT) showed the same ability to promote soft tissue regeneration and whether adipose tissue-derived small extracellular vesicles (sEV-AT) contribute to modulating the polarization of macrophages were unknown. METHODS In this study, we, for the first time, isolated h-sEV-AT from liposuction adipose tissue and characterized the morphology, size distribution, and marker protein. In vitro, we treated adipose-derived stromal/stem cells (ASCs), endothelial cells (ECs), and M1 macrophages with h-sEV-AT. In vivo, the ability of h-sEV-AT to promote soft tissue regeneration and polarize macrophages was investigated. RESULTS The results indicated that h-sEV-AT possessed the characteristics of small extracellular vesicles (sEVs). In vitro, an obvious increase in adipogenesis and angiogenesis was induced by h-sEV-AT. In vivo, h-sEV-AT successfully induced the regeneration of adipose tissue and effectively accelerated full-thickness skin wound healing. Besides, we found that h-sEV-AT showed the ability to increase the percentage of M2 macrophages both in vivo and in vitro, which had been reported to contribute to tissue repair and regeneration. CONCLUSIONS Taken together, these results suggested that h-sEV-AT showed the ability to induce soft tissue repair supported by not only the differentiation of ASCs and ECs but also the polarization of macrophages. Considering the abundant sources, high yield, and guaranteed effectiveness, this study provided a cell-free strategy for soft tissue regeneration that directly isolated small extracellular vesicles from human liposuction adipose tissue.
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Affiliation(s)
- Jia Dong
- State Key Laboratory of Oral Disease and National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Oral Regenerative Medicine, West China School of Stomatology, Sichuan University, Sichuan, 610041, Chengdu, China.
- Department of Stomatology, People's Hospital of Longhua Shenzhen, Shenzhen, 518109, Guangdong, China.
| | - Bin Wu
- Department of Stomatology, People's Hospital of Longhua Shenzhen, Shenzhen, 518109, Guangdong, China
| | - Weidong Tian
- State Key Laboratory of Oral Disease and National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Oral Regenerative Medicine, West China School of Stomatology, Sichuan University, Sichuan, 610041, Chengdu, China.
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Tung S, Delavogia E, Fernandez-Gonzalez A, Mitsialis SA, Kourembanas S. Harnessing the therapeutic potential of the stem cell secretome in neonatal diseases. Semin Perinatol 2023; 47:151730. [PMID: 36990921 PMCID: PMC10133192 DOI: 10.1016/j.semperi.2023.151730] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/31/2023]
Abstract
Preterm birth and intrapartum related complications account for a substantial amount of mortality and morbidity in the neonatal period despite significant advancements in neonatal-perinatal care. Currently, there is a noticeable lack of curative or preventative therapies available for any of the most common complications of prematurity including bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage, periventricular leukomalacia and retinopathy of prematurity or hypoxic-ischemic encephalopathy, the main cause of perinatal brain injury in term infants. Mesenchymal stem/stromal cell-derived therapy has been an active area of investigation for the past decade and has demonstrated encouraging results in multiple experimental models of neonatal disease. It is now widely acknowledged that mesenchymal stem/stromal cells exert their therapeutic effects via their secretome, with the principal vector identified as extracellular vesicles. This review will focus on summarizing the current literature and investigations on mesenchymal stem/stromal cell-derived extracellular vesicles as a treatment for neonatal diseases and examine the considerations to their application in the clinical setting.
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Affiliation(s)
- Stephanie Tung
- Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA, United States; Department of Pediatrics, Harvard Medical School, Boston, MA, United States
| | - Eleni Delavogia
- Department of Pediatrics, Harvard Medical School, Boston, MA, United States; Department of Pediatrics, Massachusetts General Hospital for Children, Boston, MA, United States
| | - Angeles Fernandez-Gonzalez
- Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA, United States; Department of Pediatrics, Harvard Medical School, Boston, MA, United States
| | - S Alex Mitsialis
- Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA, United States; Department of Pediatrics, Harvard Medical School, Boston, MA, United States
| | - Stella Kourembanas
- Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA, United States; Department of Pediatrics, Harvard Medical School, Boston, MA, United States.
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Ahn SY, Chang YS, Park WS. Stem cells for neonatal brain injury - Lessons from the bench. Semin Perinatol 2023; 47:151726. [PMID: 37003920 DOI: 10.1016/j.semperi.2023.151726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/03/2023]
Abstract
Neonatal brain injury resulting from various intractable disorders including intraventricular hemorrhage and hypoxic ischemic encephalopathy still remains a major cause of mortality and morbidities with few effective treatments. Recent preclinical research results showing the pleiotropic neuroprotective effects of stem cell therapy, specifically mesenchymal stem cells (MSCs), suggest that MSCs transplantation might be a promising new therapeutic modality for neuroprotection against the currently intractable and devastating neonatal brain injury with complex multifactorial etiology. This review summarizes recent advances in preclinical stem cell research for treating neonatal brain injury with a focus on the important issues including the mechanism of neuroprotection, and determining the ideal cell source, route, timing and dose of MSCs transplantation.
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Affiliation(s)
- So Yoon Ahn
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea; Cell and Gene Therapy Institute, Samsung Medical Center, Seoul 06351, South Korea
| | - Yun Sil Chang
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea; Cell and Gene Therapy Institute, Samsung Medical Center, Seoul 06351, South Korea; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology (SAHIST), Samsung Medical Center, Seoul 06351, South Korea
| | - Won Soon Park
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea; Cell and Gene Therapy Institute, Samsung Medical Center, Seoul 06351, South Korea; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology (SAHIST), Samsung Medical Center, Seoul 06351, South Korea.
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25
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Williams S, Fernandez-Rhodes M, Law A, Peacock B, Lewis MP, Davies OG. Comparison of extracellular vesicle isolation processes for therapeutic applications. J Tissue Eng 2023; 14:20417314231174609. [PMID: 37251735 PMCID: PMC10214056 DOI: 10.1177/20417314231174609] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 04/23/2023] [Indexed: 05/31/2023] Open
Abstract
While extracellular vesicles (EVs) continue to gain interest for therapeutic applications, their clinical translation is limited by a lack of optimal isolation methods. We sought to determine how universally applied isolation methods impact EV purity and yield. EVs were isolated by ultracentrifugation (UC), polyethylene glycol precipitation, Total Exosome Isolation Reagent, an aqueous two-phase system with and without repeat washes or size exclusion chromatography (SEC). EV-like particles could be detected for all isolation methods but varied in their purity and relative expression of surface markers (Alix, Annexin A2, CD9, CD63 and CD81). Assessments of sample purity were dependent on the specificity of characterisation method applied, with total particle counts and particle to protein (PtP) ratios often not aligning with quantitative measures of tetraspanin surface markers obtained using high-resolution nano-flow cytometry. While SEC resulted in the isolation of fewer particles with a relatively low PtP ratio (1.12 × 107 ± 1.43 × 106 vs highest recorded; ATPS/R 2.01 × 108 ± 1.15 × 109, p ⩽ 0.05), EVs isolated using this method displayed a comparatively high level of tetraspanin positivity (e.g. ExoELISA CD63⁺ particles; 1.36 × 1011 ± 1.18 × 1010 vs ATPS/R 2.58 × 1010 ± 1.92 × 109, p ⩽ 0.001). Results originating from an accompanying survey designed to evaluate pragmatic considerations surrounding method implementation (e.g. scalability and cost) identified that SEC and UC were favoured for overall efficiency. However, reservations were highlighted in the scalability of these methods, which could potentially hinder downstream therapeutic applications. In conclusion, variations in sample purity and yield were evident between isolation methods, while standard non-specific assessments of sample purity did not align with advanced quantitative high-resolution analysis of EV surface markers. Reproducible and specific assessments of EV purity will be critical for informing therapeutic studies.
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Affiliation(s)
- Soraya Williams
- School of Sport, Exercise and Health
Sciences, Loughborough University, Loughborough, UK
| | - Maria Fernandez-Rhodes
- School of Sport, Exercise and Health
Sciences, Loughborough University, Loughborough, UK
| | - Alice Law
- NanoFCM Co., Ltd, Medicity, Nottingham,
UK
| | | | - Mark P. Lewis
- School of Sport, Exercise and Health
Sciences, Loughborough University, Loughborough, UK
| | - Owen G. Davies
- School of Sport, Exercise and Health
Sciences, Loughborough University, Loughborough, UK
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26
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Dong J, Wu B, Tian W. Adipose tissue-derived small extracellular vesicles modulate macrophages to improve the homing of adipocyte precursors and endothelial cells in adipose tissue regeneration. Front Cell Dev Biol 2022; 10:1075233. [PMID: 36561367 PMCID: PMC9763459 DOI: 10.3389/fcell.2022.1075233] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 11/28/2022] [Indexed: 12/12/2022] Open
Abstract
Rapid infiltration of endogenous cells induced by cell-free biomaterials is the first and crucial step in tissue regeneration and macrophage is largely involved. Our previous study reported adipose tissue-derived small extracellular vesicles (sEV-AT) could successfully promote adipose tissue regeneration. However, the role of macrophages in this process was unknown. In this study, we isolated sEV-AT and subcutaneously implanted it into the back of SD rats. The results showed sEV-AT increased macrophage infiltration significantly, which was followed by improving homing of adipocyte precursors (APs) and endothelial cells (ECs). However, when macrophages were depleted by clodronate liposome within 1 week, the homing of APs and ECs, and adipose tissue regeneration were destroyed. In vitro, sEV-AT showed the ability to promote the migration of macrophages directly. Besides, sEV-AT-pretreated macrophages improved the migration of APs and ECs, accompanied by the increase of chemokines (MCP-1, SDF-1, VEGF, and FGF) and the activation of NF-kB signaling pathway. These findings indicated sEV-AT might regulate the secretion of chemokines via activating NF-kB signaling pathway to improve homing of APs and ECs and facilitate adipose tissue regeneration. These findings deepened our understanding of small extracellular vesicle-induced tissue regeneration and laid a theoretical foundation for the clinical application of sEV-AT.
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Affiliation(s)
- Jia Dong
- Department of Stomatology, The People’s Hospital of Longhua Shenzhen, Shenzhen, China
| | - Bin Wu
- Department of Stomatology, The People’s Hospital of Longhua Shenzhen, Shenzhen, China
| | - Weidong Tian
- State Key Laboratory of Oral Disease, National Engineering Laboratory for Oral Regenerative Medicine, National Clinical Research Center for Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, China,Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China,*Correspondence: Weidong Tian,
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27
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Bonadies L, De Vos B, Muraca M, Baraldi E. Extracellular Vesicles: A New Promise for the Prevention of Bronchopulmonary Dysplasia. Am J Perinatol 2022; 39:S23-S25. [PMID: 36356588 DOI: 10.1055/s-0042-1757351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Bronchopulmonary dysplasia (BPD) despite numerous efforts of neonatologists remains one of the most frequent and long-lasting chronic respiratory diseases consequent to extreme preterm birth. New clinical trials are exploring the possible use of mesenchymal stem cells (MSCs) and especially their products, extracellular vesicles (EVs), that overcome some of the possible issues related to the use of live cells. MSCs already reached clinical implementation; MSC-EVs, on the contrary, showed extremely promising results in the preclinical setting but are still waiting their first in human results that are likely to happen soon. KEY POINTS: · BPD is one of the most frequent complications of preterm birth, and its prevention lacks an effective tool.. · EVs have shown encouraging results in preclinical animal models.. · Technical and biological advancements are needed before routine clinical use..
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Affiliation(s)
- Luca Bonadies
- Department of Woman's and Child's Health, Neonatal Intensive Care Unit, University of Padova, Padova, Italy.,Department of Woman's and Child's Health, Institute of Pediatric Research, "Città della Speranza", Italy
| | | | - Maurizio Muraca
- Department of Woman's and Child's Health, Institute of Pediatric Research, "Città della Speranza", Italy.,Department of Women's and Children's Health, Stem Cell and Regenerative Medicine Laboratory, University of Padova, Padova, Italy
| | - Eugenio Baraldi
- Department of Woman's and Child's Health, Neonatal Intensive Care Unit, University of Padova, Padova, Italy.,Department of Woman's and Child's Health, Institute of Pediatric Research, "Città della Speranza", Italy
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28
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Delavogia E, Ntentakis DP, Cortinas JA, Fernandez-Gonzalez A, Alex Mitsialis S, Kourembanas S. Mesenchymal Stromal/Stem Cell Extracellular Vesicles and Perinatal Injury: One Formula for Many Diseases. Stem Cells 2022; 40:991-1007. [PMID: 36044737 PMCID: PMC9707037 DOI: 10.1093/stmcls/sxac062] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 08/05/2022] [Indexed: 11/12/2022]
Abstract
Over the past decades, substantial advances in neonatal medical care have increased the survival of extremely premature infants. However, there continues to be significant morbidity associated with preterm birth with common complications including bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), neuronal injury such as intraventricular hemorrhage (IVH) or hypoxic ischemic encephalopathy (HIE), as well as retinopathy of prematurity (ROP). Common developmental immune and inflammatory pathways underlie the pathophysiology of such complications providing the opportunity for multisystem therapeutic approaches. To date, no single therapy has proven to be effective enough to prevent or treat the sequelae of prematurity. In the past decade mesenchymal stem/stromal cell (MSC)-based therapeutic approaches have shown promising results in numerous experimental models of neonatal diseases. It is now accepted that the therapeutic potential of MSCs is comprised of their secretome, and several studies have recognized the small extracellular vesicles (sEVs) as the paracrine vector. Herein, we review the current literature on the MSC-EVs as potential therapeutic agents in neonatal diseases and comment on the progress and challenges of their translation to the clinical setting.
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Affiliation(s)
- Eleni Delavogia
- Division of Newborn Medicine, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Dimitrios P Ntentakis
- Retina Service, Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
| | - John A Cortinas
- Division of Newborn Medicine, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Angeles Fernandez-Gonzalez
- Division of Newborn Medicine, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - S Alex Mitsialis
- Division of Newborn Medicine, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Stella Kourembanas
- Division of Newborn Medicine, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA
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29
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Kim YE, Ahn SY, Sung DK, Chang YS, Park WS. Mesenchymal Stem Cells and Formyl Peptide Receptor 2 Activity in Hyperoxia-Induced Lung Injury in Newborn Mice. Int J Mol Sci 2022; 23:10604. [PMID: 36142517 PMCID: PMC9500980 DOI: 10.3390/ijms231810604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/20/2022] [Accepted: 09/09/2022] [Indexed: 11/26/2022] Open
Abstract
Formyl peptide receptor (FPR) 2 is known to play a critical role in regulating inflammation, including either the pro-inflammatory or pro-resolving effects. However, its role in neonatal hyperoxia-induced lung injury has not been delineated. In this study, we investigate whether mesenchymal stem cells (MSCs) attenuate hyperoxia-induced neonatal lung injury by regulating FPR2 activity. We observed a significant increase in FPR2 levels in alveolar macrophages (RAW264.7 cells) after H2O2-induced stress, which decreased after MSC treatment. In the H2O2-induction model, increased levels of inflammatory cytokines (IL-1α and TNF-α) were significantly reduced in RAW264.7 cells after treatment with WRW4, an inhibitor of FPR2, or MSCs. Viability of lung epithelial cells and endothelial cells was significantly improved when cultured in the conditioned media of RAW264.7 cells treated with WRW4 or MSCs, compared to when cultured in the conditioned media of control RAW265.7 cells exposed to H2O2. For the in vivo study, wild-type and FPR2 knockout (FPR2-/-) C57/BL6 mouse pups were randomly exposed to 80% oxygen or room air from postnatal day (P) 1 to P14. At P5, 2 × 105 MSCs were transplanted intratracheally. MSCs reduced the elevated FPR2 activity at P7 and improved the decreased FPR2 activity as well as the increased immuno-stained FPR2 activity in alveolar macrophages in hyperoxic lungs at P14. Both FPR2-/- and MSCs similarly attenuated impaired alveolarization and angiogenesis, and increased apoptosis and inflammation of hyperoxic lungs without synergistic effects. Our findings suggest that the protective effects of MSCs in hyperoxic lung injury might be related to indirect modulation of FPR2 activity, at least of alveolar macrophages in neonatal mice.
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Affiliation(s)
- Young Eun Kim
- Cell and Gene Therapy Institute, Samsung Medical Center, Seoul 06351, Korea
- Department of Health Sciences and Technology, SAIHST, Samsung Medical Center, Seoul 06351, Korea
| | - So Yoon Ahn
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Dong Kyung Sung
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Yun Sil Chang
- Cell and Gene Therapy Institute, Samsung Medical Center, Seoul 06351, Korea
- Department of Health Sciences and Technology, SAIHST, Samsung Medical Center, Seoul 06351, Korea
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Won Soon Park
- Cell and Gene Therapy Institute, Samsung Medical Center, Seoul 06351, Korea
- Department of Health Sciences and Technology, SAIHST, Samsung Medical Center, Seoul 06351, Korea
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
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Endometrial Regenerative Cell-Derived Exosomes Attenuate Experimental Colitis through Downregulation of Intestine Ferroptosis. Stem Cells Int 2022; 2022:3014123. [PMID: 36045952 PMCID: PMC9424030 DOI: 10.1155/2022/3014123] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 07/20/2022] [Indexed: 12/03/2022] Open
Abstract
Background Endometrial regenerative cells (ERCs) have been identified to ameliorate colitis in mice; however, whether exosomes derived from ERCs (ERC-exos) own similar effects on colitis remains unclear. Ferroptosis, an iron-dependent cell programmed death form, has been reported to promote inflammation in UC. Thus, in this study, whether ERC-exos can treat colitis and regulate intestine ferroptosis will be explored. Methods In this study, iron, malondialdehyde (MDA) production, glutathione (GSH) synthesis, and acyl-CoA synthetase long-chain family member (ACSL) 4 and glutathione peroxidase 4 (GPX4) expressions were measured in colon samples from healthy people and UC patients to explore the effects of ferroptosis. In vitro, ERC-exos were cocultured with ferroptosis inducer erastin-treated NCM460 human intestinal epithelial cell line, and ferroptotic parameters were measured. In vivo, colitis was induced by 3% dextran sulfate sodium (DSS) in BALB/c mice, and animals were randomly assigned to normal, untreated, and ERC-exos-treated groups. The Disease Activity Index (DAI) score, histological features, tissue iron, MDA, GSH, ACSL4, and GPX4 were measured to verify the role of ERC-exos in attenuating UC. Results Compared with healthy people, UC samples exhibited higher levels of iron, MDA, and ACSL4, while less levels of GSH and GPX4. In vitro, the CCK-8 assay showed that ERC-exos rescued erastin-induced cell death, and ERC-exos treatment significantly increased the levels of GSH and expression of GPX4, while markedly decreasing the levels of iron, MDA, and expression of ACSL4. In vivo, ERC-exos treatment effectively reduced DAI score, ameliorated colon pathological damage, and improved disease symptoms. Moreover, ERC-exos treatment further enhanced the levels of GSH and the expression of GPX4 but reduced the levels of iron, MDA, and expression of ACSL4 in the colon of colitis mice. Conclusions Ferroptosis was involved in the pathogenesis of UC, and ERC-exos attenuated DSS-induced colitis through downregulating intestine ferroptosis. This study may provide a novel insight into treating UC in the future.
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31
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Liu C, Xiao K, Xie L. Advances in mesenchymal stromal cell therapy for acute lung injury/acute respiratory distress syndrome. Front Cell Dev Biol 2022; 10:951764. [PMID: 36036014 PMCID: PMC9399751 DOI: 10.3389/fcell.2022.951764] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 07/19/2022] [Indexed: 11/29/2022] Open
Abstract
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) develops rapidly and has high mortality. ALI/ARDS is mainly manifested as acute or progressive hypoxic respiratory failure. At present, there is no effective clinical intervention for the treatment of ALI/ARDS. Mesenchymal stromal cells (MSCs) show promise for ALI/ARDS treatment due to their biological characteristics, easy cultivation, low immunogenicity, and abundant sources. The therapeutic mechanisms of MSCs in diseases are related to their homing capability, multidirectional differentiation, anti-inflammatory effect, paracrine signaling, macrophage polarization, the polarization of the MSCs themselves, and MSCs-derived exosomes. In this review, we discuss the pathogenesis of ALI/ARDS along with the biological characteristics and mechanisms of MSCs in the treatment of ALI/ARDS.
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Affiliation(s)
- Chang Liu
- School of Medicine, Nankai University, Tianjin, China
- Center of Pulmonary and Critical Care Medicine, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Medical School of Chinese People’s Liberation Army (PLA), Beijing, China
| | - Kun Xiao
- Center of Pulmonary and Critical Care Medicine, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Medical School of Chinese People’s Liberation Army (PLA), Beijing, China
- *Correspondence: Kun Xiao, ; Lixin Xie,
| | - Lixin Xie
- School of Medicine, Nankai University, Tianjin, China
- Center of Pulmonary and Critical Care Medicine, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Medical School of Chinese People’s Liberation Army (PLA), Beijing, China
- *Correspondence: Kun Xiao, ; Lixin Xie,
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32
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Cao H, Ji X, Wang Q, Guan X, Wei W, Li Y, Zou W, Liu J. PTBP-1 and TNF-α/NF-κB are involved in repair mechanisms of human umbilical cord mesenchymal stem cell transplantation in mice with spinal cord injury. Am J Transl Res 2022; 14:4443-4456. [PMID: 35958465 PMCID: PMC9360871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 05/19/2022] [Indexed: 06/15/2023]
Abstract
OBJECTIVES To explore the possible mechanism of human umbilical cord mesenchymal stem cell (hUC-MSC) transplantation in mice after spinal cord hemisection. METHODS Thoracic spinal cord hemisection injuries were performed on adult female Kunming mice. The mice with spinal cord injury (SCI) were injected with hUC-MSCs suspended in normal saline, while the control mice received an equal volume of normal saline. The histological HE staining and Nissl staining were performed 4 and 8 weeks after hUC-MSC transplantation in SCI mice. The Basso-Beattie-Bresnahan (BBB) locomotor rating scale was used to assess functional recovery after SCI. Western blotting was performed to determine the protein expressions. RESULTS hUC-MSCs transplantation decreased cavitation and tissue loss and increased the number of Nissl bodies in the damaged areas of the spinal cord after 4 and 8 weeks. The BBB locomotor performance of the transplanted mice was significantly improved (P<0.01). The wet weight of the injured side of the gastrocnemius muscle was significantly higher in the transplant group than that in the control group. Western blotting showed that TUJ1 and Olig2 expressions were significantly higher in hUC-MSC-grafted mice than those in vehicle controls. Three days after hUC-MSC transplantation, the expressions of TNF-α and NF-κB were higher in MSC-grafted mice than those in vehicle controls. However, 4 weeks after stem cell transplantation, the expressions of these two factors decreased in hUC-MSC-grafted mice compared with those in the vehicle controls. At 8 weeks after hUC-MSC transplantation, the expression of PTBP-1 was decreased in hUC-MSC-grafted mice compared with that in vehicle controls. CONCLUSIONS hUC-MSC transplantation can protect neuron survival, promote myelin repair, and control glial scar formation in SCI mice.
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Affiliation(s)
- Hua Cao
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, The First Affiliated Hospital of Dalian Medical UniversityDalian, Liaoning, China
| | - Xiaofei Ji
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, The First Affiliated Hospital of Dalian Medical UniversityDalian, Liaoning, China
| | - Qi Wang
- Department of Pathology, The Affiliated Sixth People’s Hospital of Dalian Medical UniversityDalian, Liaoning, China
| | - Xin Guan
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, The First Affiliated Hospital of Dalian Medical UniversityDalian, Liaoning, China
| | - Wenjuan Wei
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, The First Affiliated Hospital of Dalian Medical UniversityDalian, Liaoning, China
| | - Ying Li
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, The First Affiliated Hospital of Dalian Medical UniversityDalian, Liaoning, China
| | - Wei Zou
- College of Life Science, Liaoning Normal UniversityDalian, Liaoning, China
| | - Jing Liu
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, The First Affiliated Hospital of Dalian Medical UniversityDalian, Liaoning, China
- Dalian Innovation Institute of Stem Cell and Precision MedicineDalian, Liaoning, China
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Kim YE, Ahn SY, Park WS, Sung DK, Sung SI, Yang MS, Chang YS. Mesenchymal-Stem-Cell-Derived Extracellular Vesicles Attenuate Brain Injury in Escherichia coli Meningitis in Newborn Rats. LIFE (BASEL, SWITZERLAND) 2022; 12:life12071030. [PMID: 35888118 PMCID: PMC9319453 DOI: 10.3390/life12071030] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 06/30/2022] [Accepted: 07/08/2022] [Indexed: 11/22/2022]
Abstract
We recently reported that transplantation of mesenchymal stem cells (MSCs) significantly reduced bacterial growth and brain injury in neonatal meningitis induced by Escherichia coli (E. coli) infection in newborn rats. As a next step, to verify whether the MSCs protect against brain injury in a paracrine manner, this study was designed to estimate the efficacy of MSC-derived extracellular vesicles (MSC-EVs) in E. coli meningitis in newborn rats. E. coli meningitis was induced without concomitant bacteremia by the intra-cerebroventricular injection of 5 × 102 colony-forming units of K1 (-) E. coli in rats, at postnatal day 11. MSC-EVs were intra-cerebroventricularly transplanted 6 h after the induction of meningitis, and antibiotics were administered for three consecutive days starting at 24 h after the induction of meningitis. The increase in bacterial growth in the cerebrospinal fluid measured at 24 h after the meningitis induction was not significantly reduced following MSC-EV transplantation. However, an increase in brain cell death, reactive gliosis, and inflammation following meningitis were significantly attenuated after MSC-EV transplantation. Taken together, our results indicate that MSCs show anti-apoptotic, anti-gliosis, and anti-inflammatory, but not antibacterial effects, in an EV-mediated paracrine manner in E. coli-induced neonatal meningitis.
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Affiliation(s)
- Young-Eun Kim
- Cell and Gene Therapy Institute, Samsung Medical Center, Seoul 06351, Korea; (Y.-E.K.); (W.-S.P.)
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Samsung Medical Center, Seoul 06351, Korea
| | - So-Yoon Ahn
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (S.-Y.A.); (D.-K.S.); (S.-I.S.); (M.-S.Y.)
| | - Won-Soon Park
- Cell and Gene Therapy Institute, Samsung Medical Center, Seoul 06351, Korea; (Y.-E.K.); (W.-S.P.)
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Samsung Medical Center, Seoul 06351, Korea
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (S.-Y.A.); (D.-K.S.); (S.-I.S.); (M.-S.Y.)
| | - Dong-Kyung Sung
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (S.-Y.A.); (D.-K.S.); (S.-I.S.); (M.-S.Y.)
| | - Se-In Sung
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (S.-Y.A.); (D.-K.S.); (S.-I.S.); (M.-S.Y.)
| | - Mi-Sun Yang
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (S.-Y.A.); (D.-K.S.); (S.-I.S.); (M.-S.Y.)
| | - Yun-Sil Chang
- Cell and Gene Therapy Institute, Samsung Medical Center, Seoul 06351, Korea; (Y.-E.K.); (W.-S.P.)
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Samsung Medical Center, Seoul 06351, Korea
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (S.-Y.A.); (D.-K.S.); (S.-I.S.); (M.-S.Y.)
- Correspondence: ; Tel.: +82-2-3410-3528
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Zhou O, You J, Xu X, Liu J, Qiu H, Hao C, Zou W, Wu W, Fu Z, Tian D, Zou L. Microvesicles Derived from Human Umbilical Cord Mesenchymal Stem Cells Enhance Alveolar Type II Cell Proliferation and Attenuate Lung Inflammation in a Rat Model of Bronchopulmonary Dysplasia. Stem Cells Int 2022; 2022:8465294. [PMID: 35795773 PMCID: PMC9252687 DOI: 10.1155/2022/8465294] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 06/06/2022] [Accepted: 06/09/2022] [Indexed: 01/08/2023] Open
Abstract
Although it is known that exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSCs) alleviate hyperoxic lung injury of bronchopulmonary dysplasia (BPD) in animal models, the role of microvesicles (MVs) derived from hUCMSCs in BPD is poorly defined. Furthermore, antenatal inflammation has been linked to high risk of BPD in preterm infants. The purpose of this study was to explore whether MVs derived from hUCMSCs can preserve lung structure and function in an antenatal lipopolysaccharide- (LPS-) induced BPD rat model and to clarify the underlying mechanism. We demonstrate that antenatal LPS induced alveolar simplification, altered lung function, and dysregulated pulmonary vasculature, which restored by hUCMSCs and MVs treatment. Furthermore, MVs were large vesicles with a diameter of 100-900 nanometers and mostly uptaken by alveolar epithelial type II cells (AT2) and macrophages. Compared with the LPS-exposed group, MVs restored the AT2 cell number and SP-C expression in vivo and promoted the proliferation of AT2 cells in vitro. MVs also restored the level of IL-6 and IL-10 in lung homogenate. Additionally, PTEN/AKT and MAPK pathways were associated with the protection of MVs. Taken together, this study suggests MVs derived from hUCMSCs improve lung architecture and function in an antenatal LPS-induced BPD rat model by promoting AT2 cell proliferation and attenuating lung inflammation; thus, MVs provide a promising therapeutic vehicle for BPD treatment.
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Affiliation(s)
- Ou Zhou
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing Engineering Research Center of Stem Cell Therapy, Chongqing 400014, China
| | - Jingyi You
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing Engineering Research Center of Stem Cell Therapy, Chongqing 400014, China
| | - Xiaochuan Xu
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing Engineering Research Center of Stem Cell Therapy, Chongqing 400014, China
| | - Jiang Liu
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing Engineering Research Center of Stem Cell Therapy, Chongqing 400014, China
| | - Huijun Qiu
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing Engineering Research Center of Stem Cell Therapy, Chongqing 400014, China
| | - Chang Hao
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing Engineering Research Center of Stem Cell Therapy, Chongqing 400014, China
| | - Wenjing Zou
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing Engineering Research Center of Stem Cell Therapy, Chongqing 400014, China
| | - Wenjie Wu
- Department of Pediatrics, Chongqing Youyoubaobei Women and Children's Hospital, Chongqing 401122, China
| | - Zhou Fu
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing Engineering Research Center of Stem Cell Therapy, Chongqing 400014, China
| | - Daiyin Tian
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing Engineering Research Center of Stem Cell Therapy, Chongqing 400014, China
| | - Lin Zou
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing Engineering Research Center of Stem Cell Therapy, Chongqing 400014, China
- Center of Clinical Molecular Medicine, Children's Hospital of Chongqing Medical University, Chongqing 400014, China
- Clinical Research Unit, Children's Hospital of Shanghai Jiaotong University, Shanghai 200062, China
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Zargar MJ, Kaviani S, Vasei M, Soufi Zomorrod M, Heidari Keshel S, Soleimani M. Therapeutic role of mesenchymal stem cell-derived exosomes in respiratory disease. Stem Cell Res Ther 2022; 13:194. [PMID: 35550188 PMCID: PMC9096764 DOI: 10.1186/s13287-022-02866-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 03/07/2022] [Indexed: 12/29/2022] Open
Abstract
Exosomes are extracellular vesicles found in various tissues, blood circulation, and tissue fluids, secreted into the extracellular environment by fusing a multivesicular body with a plasma membrane. Various cell types release these vesicles to contribute to many cellular functions, including intercellular communication, cell proliferation, differentiation, angiogenesis, response to stress, and immune system signaling. These natural nanoparticles have therapeutic effects in various diseases and exhibit a behavior similar to the cell from which they originated. In the meantime, exosomes derived from mesenchymal stem cells have attracted the attention of many researchers and physicians due to their unique ability to modulate the immune system, repair tissue and reduce inflammation. Numerous clinical and preclinical studies have examined the effect of MSC-derived exosomes in various diseases, and their results have been published in prestigious journals. This review article discusses the biogenesis and sources of exosomes, MSC-derived exosomes, the use of these exosomes in regenerative medicine, and treatments based on exosomes derived from stem cells in respiratory diseases.
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Affiliation(s)
- Mehdi Jahedi Zargar
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Saeid Kaviani
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Mohammad Vasei
- Cell Therapy Based Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Mina Soufi Zomorrod
- Applied Cell Science and Hematology Department, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran
| | - Saeed Heidari Keshel
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Masoud Soleimani
- Applied Cell Science and Hematology Department, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran.
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Omar SA, Abdul-Hafez A, Ibrahim S, Pillai N, Abdulmageed M, Thiruvenkataramani RP, Mohamed T, Madhukar BV, Uhal BD. Stem-Cell Therapy for Bronchopulmonary Dysplasia (BPD) in Newborns. Cells 2022; 11:cells11081275. [PMID: 35455954 PMCID: PMC9025385 DOI: 10.3390/cells11081275] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/30/2022] [Accepted: 04/07/2022] [Indexed: 11/17/2022] Open
Abstract
Premature newborns are at a higher risk for the development of respiratory distress syndrome (RDS), acute lung injury (ALI) associated with lung inflammation, disruption of alveolar structure, impaired alveolar growth, lung fibrosis, impaired lung angiogenesis, and development of bronchopulmonary dysplasia (BPD) with severe long-term developmental adverse effects. The current therapy for BPD is limited to supportive care including high-oxygen therapy and pharmacotherapy. Recognizing more feasible treatment options to improve lung health and reduce complications associated with BPD is essential for improving the overall quality of life of premature infants. There is a reduction in the resident stem cells in lungs of premature infants with BPD, which strongly suggests a critical role of stem cells in BPD pathogenesis; this warrants the exploration of the potential therapeutic use of stem-cell therapy. Stem-cell-based therapies have shown promise for the treatment of many pathological conditions including acute lung injury and BPD. Mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (EVs) including exosomes are promising and effective therapeutic modalities for the treatment of BPD. Treatment with MSCs and EVs may help to reduce lung inflammation, improve pulmonary architecture, attenuate pulmonary fibrosis, and increase the survival rate.
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Affiliation(s)
- Said A. Omar
- Division of Neonatology, Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA; (A.A.-H.); (S.I.); (N.P.); (M.A.); (R.P.T.); (T.M.); (B.V.M.)
- Regional Neonatal Intensive Care Unit, Sparrow Health System, Lansing, MI 48912, USA
- Correspondence: ; Tel.: +1-517-364-2948
| | - Amal Abdul-Hafez
- Division of Neonatology, Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA; (A.A.-H.); (S.I.); (N.P.); (M.A.); (R.P.T.); (T.M.); (B.V.M.)
| | - Sherif Ibrahim
- Division of Neonatology, Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA; (A.A.-H.); (S.I.); (N.P.); (M.A.); (R.P.T.); (T.M.); (B.V.M.)
| | - Natasha Pillai
- Division of Neonatology, Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA; (A.A.-H.); (S.I.); (N.P.); (M.A.); (R.P.T.); (T.M.); (B.V.M.)
| | - Mohammed Abdulmageed
- Division of Neonatology, Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA; (A.A.-H.); (S.I.); (N.P.); (M.A.); (R.P.T.); (T.M.); (B.V.M.)
- Regional Neonatal Intensive Care Unit, Sparrow Health System, Lansing, MI 48912, USA
| | - Ranga Prasanth Thiruvenkataramani
- Division of Neonatology, Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA; (A.A.-H.); (S.I.); (N.P.); (M.A.); (R.P.T.); (T.M.); (B.V.M.)
- Regional Neonatal Intensive Care Unit, Sparrow Health System, Lansing, MI 48912, USA
| | - Tarek Mohamed
- Division of Neonatology, Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA; (A.A.-H.); (S.I.); (N.P.); (M.A.); (R.P.T.); (T.M.); (B.V.M.)
- Regional Neonatal Intensive Care Unit, Sparrow Health System, Lansing, MI 48912, USA
| | - Burra V. Madhukar
- Division of Neonatology, Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA; (A.A.-H.); (S.I.); (N.P.); (M.A.); (R.P.T.); (T.M.); (B.V.M.)
| | - Bruce D. Uhal
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA;
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Mesenchymal Stromal Cell-Derived Extracellular Vesicles for Neonatal Lung Disease: Tiny Particles, Major Promise, Rigorous Requirements for Clinical Translation. Cells 2022; 11:cells11071176. [PMID: 35406742 PMCID: PMC8997376 DOI: 10.3390/cells11071176] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 03/28/2022] [Accepted: 03/29/2022] [Indexed: 01/01/2023] Open
Abstract
Extreme preterm birth disrupts late lung development and puts newborns at risk of developing chronic lung disease, known as bronchopulmonary dysplasia (BPD). BPD can be associated with life-long complications, and currently no effective treatment is available. Cell therapies are entering the clinics to curb complications of extreme preterm birth with several clinical trials testing the feasibility, safety and efficacy of mesenchymal stromal cells (MSCs). The therapeutic effect of MSCs is contained in their secretome, and nanosized membranous structures released by the MSCs, known as extracellular vesicles (EVs), have been shown to be the therapeutic vectors. Driven by this discovery, the efficacy of EV-based therapy is currently being explored in models of BPD. EVs derived from MSCs, contain a rich cargo of anti-inflammatory and pro-angiogenic molecules, making them suitable candidates to treat multifactorial diseases such as BPD. Here, we review the state-of-the-art of preclinical studies involving MSC-derived EVs in models of BPD and highlight technical and regulatory challenges that need to be addressed before clinical translation. In addition, we aim at increasing awareness regarding the importance of rigorous reporting of experimental details of EV experiments and to increase the outreach of the current established guidelines amongst researchers in the BPD field.
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38
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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; 11:826. [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
| | - Alessandro Bertani
- Thoracic Surgery and Lung Transplantation Unit, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy
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Ma Y, Liu X, Long Y, Chen Y. Emerging Therapeutic Potential of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Chronic Respiratory Diseases: An Overview of Recent Progress. Front Bioeng Biotechnol 2022; 10:845042. [PMID: 35284423 PMCID: PMC8913891 DOI: 10.3389/fbioe.2022.845042] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 01/31/2022] [Indexed: 12/21/2022] Open
Abstract
Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are able to carry genetic and protein goods to mediate the interaction between MSCs and target cells. Recently, more and more researches have focused on the therapeutic role of MSC-EVs in chronic respiratory diseases. In this review, we summarize the cumulative strategies and mechanisms of MSC-EVs in treating chronic respiratory diseases. This review suggests that MSC-EVs may serve as a novel cell-free-based therapy for chronic respiratory diseases, including COPD, asthma, pulmonary fibrosis, and pulmonary arterial hypertension. In current studies of chronic respiratory diseases, umbilical cord and bone marrow are main sources of MSC-EVs, while adipose tissue, lung, and induced pluripotent stem cells are also applied. Isolation methods of MSC-EVs in treating chronic respiratory diseases involve ultracentrifugation, exosome extraction kits and anion-exchange chromatography. Intratracheal delivery and intravenous administration are the most widely used routes of MSC-EVs. MSC-EVs are able to transfer microRNAs and protein to target cells and further magnify the therapeutic effects.
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Affiliation(s)
| | | | | | - Yan Chen
- *Correspondence: Yan Chen, ; Yingjiao Long,
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40
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Chua JKE, Lim J, Foong LH, Mok CY, Tan HY, Tung XY, Ramasamy TS, Govindasamy V, Then KY, Das AK, Cheong SK. Mesenchymal Stem Cell-Derived Extracellular Vesicles: Progress and Remaining Hurdles in Developing Regulatory Compliant Quality Control Assays. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1401:191-211. [DOI: 10.1007/5584_2022_728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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41
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Xi Y, Ju R, Wang Y. Mesenchymal Stem Cell-Derived Extracellular Vesicles for the Treatment of Bronchopulmonary Dysplasia. Front Pediatr 2022; 10:852034. [PMID: 35444971 PMCID: PMC9013803 DOI: 10.3389/fped.2022.852034] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 02/25/2022] [Indexed: 11/13/2022] Open
Abstract
Bronchopulmonary dysplasia (BPD) is the most common chronic respiratory disease in premature infants. However, there is a lack of effective treatment. Mesenchymal stromal cells derived extracellular vesicles (MSC-EVs), as nano- and micron-sized heterogeneous vesicles secreted by MSCs, are the main medium for information exchange between MSCs and injured tissue and organ, playing an important role in repairing tissue and organ injury. EVs include exosomes, microvesicles and so on. They are rich with various proteins, nucleic acids, and lipids. Now, EVs are considered as a new way of cell-to-cell communication. EVs mainly induce regeneration and therapeutic effects in different tissues and organs through the biomolecules they carry. The surface membrane protein or loaded protein and nucleic acid molecules carried by EVs, can activate the signal transduction of target cells and regulate the biological behavior of target cells after binding and cell internalization. MSC-EVs can promote the development of pulmonary vessels and alveoli and reduce pulmonary hypertension (PH) and inflammation and play an important role in the repair of lung injury in BPD. The regeneration potential of MSC-EVs is mainly due to the regulation of cell proliferation, survival, migration, differentiation, angiogenesis, immunoregulation, anti-inflammatory, mitochondrial activity and oxidative stress. As a new type of cell-free therapy, MSC-EVs have non-immunogenic, and are small in size and go deep into most tissues. What's more, it has good biological stability and can be modified and loaded with drugs of interest. Obviously, MSC-EVs have a good application prospect in the treatment of lung injury and BPD. However, there are still many challenges to make MSC-EVs really enter clinical application.
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Affiliation(s)
- Yufeng Xi
- Department of Neonatology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Rong Ju
- Department of Neonatology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yujia Wang
- Department of Neonatology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.,Department of Dermatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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42
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Esquivel-Ruiz S, González-Rodríguez P, Lorente JA, Pérez-Vizcaíno F, Herrero R, Moreno L. Extracellular Vesicles and Alveolar Epithelial-Capillary Barrier Disruption in Acute Respiratory Distress Syndrome: Pathophysiological Role and Therapeutic Potential. Front Physiol 2021; 12:752287. [PMID: 34887773 PMCID: PMC8650589 DOI: 10.3389/fphys.2021.752287] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 09/27/2021] [Indexed: 12/11/2022] Open
Abstract
Extracellular vesicles (EVs) mediate intercellular communication by transferring genetic material, proteins and organelles between different cells types in both health and disease. Recent evidence suggests that these vesicles, more than simply diagnostic markers, are key mediators of the pathophysiology of acute respiratory distress syndrome (ARDS) and other lung diseases. In this review, we will discuss the contribution of EVs released by pulmonary structural cells (alveolar epithelial and endothelial cells) and immune cells in these diseases, with particular attention to their ability to modulate inflammation and alveolar-capillary barrier disruption, a hallmark of ARDS. EVs also offer a unique opportunity to develop new therapeutics for the treatment of ARDS. Evidences supporting the ability of stem cell-derived EVs to attenuate the lung injury and ongoing strategies to improve their therapeutic potential are also discussed.
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Affiliation(s)
- Sergio Esquivel-Ruiz
- Department of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.,Ciber de Enfermedades Respiratorias (CIBERES), Madrid, Spain
| | - Paloma González-Rodríguez
- Ciber de Enfermedades Respiratorias (CIBERES), Madrid, Spain.,Department of Critical Care, Hospital Universitario de Getafe, Madrid, Spain
| | - José A Lorente
- Ciber de Enfermedades Respiratorias (CIBERES), Madrid, Spain.,Department of Critical Care, Hospital Universitario de Getafe, Madrid, Spain.,Clinical Section, School of Medicine, European University of Madrid, Madrid, Spain
| | - Francisco Pérez-Vizcaíno
- Department of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.,Ciber de Enfermedades Respiratorias (CIBERES), Madrid, Spain
| | - Raquel Herrero
- Ciber de Enfermedades Respiratorias (CIBERES), Madrid, Spain.,Department of Critical Care, Hospital Universitario de Getafe, Madrid, Spain
| | - Laura Moreno
- Department of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.,Ciber de Enfermedades Respiratorias (CIBERES), Madrid, Spain
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Lenzini S, Debnath K, Joshi JC, Wong SW, Srivastava K, Geng X, Cho IS, Song A, Bargi R, Lee JC, Mo GCH, Mehta D, Shin JW. Cell-Matrix Interactions Regulate Functional Extracellular Vesicle Secretion from Mesenchymal Stromal Cells. ACS NANO 2021; 15:17439-17452. [PMID: 34677951 PMCID: PMC9023614 DOI: 10.1021/acsnano.1c03231] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/10/2023]
Abstract
Extracellular vesicles (EVs) are cell-secreted particles with broad potential to treat tissue injuries by delivering cargo to program target cells. However, improving the yield of functional EVs on a per cell basis remains challenging due to an incomplete understanding of how microenvironmental cues regulate EV secretion at the nanoscale. We show that mesenchymal stromal cells (MSCs) seeded on engineered hydrogels that mimic the elasticity of soft tissues with a lower integrin ligand density secrete ∼10-fold more EVs per cell than MSCs seeded on a rigid plastic substrate, without compromising their therapeutic activity or cargo to resolve acute lung injury in mice. Mechanistically, intracellular CD63+ multivesicular bodies (MVBs) transport faster within MSCs on softer hydrogels, leading to an increased frequency of MVB fusion with the plasma membrane to secrete more EVs. Actin-related protein 2/3 complex but not myosin-II limits MVB transport and EV secretion from MSCs on hydrogels. The results provide a rational basis for biomaterial design to improve EV secretion while maintaining their functionality.
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Thinking Quantitatively of RNA-Based Information Transfer via Extracellular Vesicles: Lessons to Learn for the Design of RNA-Loaded EVs. Pharmaceutics 2021; 13:pharmaceutics13111931. [PMID: 34834346 PMCID: PMC8617734 DOI: 10.3390/pharmaceutics13111931] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 11/01/2021] [Accepted: 11/10/2021] [Indexed: 02/06/2023] Open
Abstract
Extracellular vesicles (EVs) are 50–1000 nm vesicles secreted by virtually any cell type in the body. They are expected to transfer information from one cell or tissue to another in a short- or long-distance way. RNA-based transfer of information via EVs at long distances is an interesting well-worn hypothesis which is ~15 years old. We review from a quantitative point of view the different facets of this hypothesis, ranging from natural RNA loading in EVs, EV pharmacokinetic modeling, EV targeting, endosomal escape and RNA delivery efficiency. Despite the unique intracellular delivery properties endowed by EVs, we show that the transfer of RNA naturally present in EVs might be limited in a physiological context and discuss the lessons we can learn from this example to design efficient RNA-loaded engineered EVs for biotherapies. We also discuss other potential EV mediated information transfer mechanisms, among which are ligand–receptor mechanisms.
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Wu J, Piao Y, Liu Q, Yang X. Platelet-rich plasma-derived extracellular vesicles: A superior alternative in regenerative medicine? Cell Prolif 2021; 54:e13123. [PMID: 34609779 PMCID: PMC8666280 DOI: 10.1111/cpr.13123] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 08/13/2021] [Accepted: 08/31/2021] [Indexed: 02/06/2023] Open
Abstract
Platelet-rich plasma (PRP), due to its promising therapeutic properties, has been used in regenerative medicine for more than 30 years and numerous encouraging outcomes have been obtained. Currently, by benefiting from new insights into PRP mechanisms and the excellent performance of extracellular vesicles (EVs) in the field of tissue repair and regeneration, studies have found that a large number of EVs released from activated platelets also participate in the regulation of tissue repair. A growing number of preclinical studies are exploring the functions of PRP-derived EVs (PRP-EVs), especially in tissue regeneration. Here, we summarize the latest progress in PRP-EVs as a superior alternative cell-free therapeutic strategy in regenerative medicine, clarify their underlying molecular mechanisms, and discuss the advantages and limitations of the upcoming clinical applications. This review highlights the potential of PRP-EVs to replace the application of PRP or even become a superior alternative in regenerative medicine.
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Affiliation(s)
- Jiuping Wu
- Department of Orthopaedics, The Second Hospital, Jilin University, Changchun, China
| | - Yingxin Piao
- Hospital of Stomatology, Jilin University, Changchun, China
| | - Qinyi Liu
- Department of Orthopaedics, The Second Hospital, Jilin University, Changchun, China
| | - Xiaoyu Yang
- Department of Orthopaedics, The Second Hospital, Jilin University, Changchun, China
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Tieu A, Hu K, Gnyra C, Montroy J, Fergusson DA, Allan DS, Stewart DJ, Thébaud B, Lalu MM. Mesenchymal stromal cell extracellular vesicles as therapy for acute and chronic respiratory diseases: A meta-analysis. J Extracell Vesicles 2021; 10:e12141. [PMID: 34596349 PMCID: PMC8485337 DOI: 10.1002/jev2.12141] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 07/30/2021] [Accepted: 08/23/2021] [Indexed: 12/15/2022] Open
Abstract
Preclinical studies suggest mesenchymal stromal cell extracellular vesicles (MSC-EVs) reduce inflammation and improve organ function in lung diseases; however, an objective analysis of all available data is needed prior to translation. Using rigorous meta-research methods, we determined the effectiveness of MSC-EVs for preclinical respiratory diseases and identified experimental conditions that may further refine this therapy. A systematic search of MEDLINE/Embase identified 1167 records. After screening, 52 articles were included for data extraction and evaluated for risk of bias and quality of reporting in study design. A random effects meta-analysis was conducted for acute lung injury (ALI; N = 23), bronchopulmonary dysplasia (BPD; N = 8) and pulmonary arterial hypertension (PAH; N = 7). Subgroup analyses identified EV methods/characteristics that may be associated with improved efficacy. Data is presented as standardized mean differences (SMD) or risk ratios (RR) with 95% confidence intervals (CI). For ALI, MSC-EVs markedly reduced lung injury (SMD -4.33, CI -5.73 to -2.92), vascular permeability (SMD -2.43, CI -3.05 to -1.82), and mortality (RR 0.39, CI 0.22 to 0.68). Small EVs were more consistently effective than large EVs whereas no differences were observed between tissue sources, immunocompatibility or isolation techniques. For BPD, alveolarization was improved by MSC-EVs (SMD -1.45, CI -2.08 to -0.82) with small EVs more consistently beneficial then small/large EVs. In PAH, right ventricular systolic pressure (SMD -4.16, CI -5.68 to -2.64) and hypertrophy (SMD -2.80, CI -3.68 to -1.91) were significantly attenuated by EVs. In BPD and PAH, EVs isolated by ultracentrifugation demonstrated therapeutic benefit whereas tangential flow filtration (N = 2) displayed minimal efficacy. Lastly, risk of bias and quality of reporting for experimental design were consistently unclear across all studies. Our findings demonstrate clear potential of MSC-EVs to be developed as therapy for acute and chronic lung diseases. However, greater transparency in research design and direct comparisons of isolation technique and EV subtypes are needed to generate robust evidence to guide clinical translation. Protocol Registration: PROSPERO CRD42020145334.
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Affiliation(s)
- Alvin Tieu
- Department of Cellular and Molecular MedicineUniversity of OttawaOttawaOntarioCanada
- Clinical Epidemiology ProgramBLUEPRINT Translational Research Group, Ottawa Hospital Research InstituteOttawaOntarioCanada
- Regenerative Medicine ProgramOttawa Hospital Research InstituteOttawaOntarioCanada
| | - Kevin Hu
- Clinical Epidemiology ProgramBLUEPRINT Translational Research Group, Ottawa Hospital Research InstituteOttawaOntarioCanada
| | - Catherine Gnyra
- Clinical Epidemiology ProgramBLUEPRINT Translational Research Group, Ottawa Hospital Research InstituteOttawaOntarioCanada
| | - Joshua Montroy
- Clinical Epidemiology ProgramBLUEPRINT Translational Research Group, Ottawa Hospital Research InstituteOttawaOntarioCanada
| | - Dean A. Fergusson
- Clinical Epidemiology ProgramBLUEPRINT Translational Research Group, Ottawa Hospital Research InstituteOttawaOntarioCanada
- Department of MedicineThe Ottawa HospitalOttawaOntarioCanada
| | - David S. Allan
- Clinical Epidemiology ProgramBLUEPRINT Translational Research Group, Ottawa Hospital Research InstituteOttawaOntarioCanada
- Regenerative Medicine ProgramOttawa Hospital Research InstituteOttawaOntarioCanada
- Department of MedicineThe Ottawa HospitalOttawaOntarioCanada
| | - Duncan J. Stewart
- Department of Cellular and Molecular MedicineUniversity of OttawaOttawaOntarioCanada
- Regenerative Medicine ProgramOttawa Hospital Research InstituteOttawaOntarioCanada
- Department of MedicineThe Ottawa HospitalOttawaOntarioCanada
| | - Bernard Thébaud
- Department of Cellular and Molecular MedicineUniversity of OttawaOttawaOntarioCanada
- Regenerative Medicine ProgramOttawa Hospital Research InstituteOttawaOntarioCanada
- Division of NeonatologyDepartment of PediatricsChildren's Hospital of Eastern OntarioOttawaOntarioCanada
| | - Manoj M. Lalu
- Department of Cellular and Molecular MedicineUniversity of OttawaOttawaOntarioCanada
- Clinical Epidemiology ProgramBLUEPRINT Translational Research Group, Ottawa Hospital Research InstituteOttawaOntarioCanada
- Regenerative Medicine ProgramOttawa Hospital Research InstituteOttawaOntarioCanada
- Departments of Anesthesiology and Pain Medicine, The Ottawa HospitalOttawaOntarioCanada
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Qiao Q, Liu X, Yang T, Cui K, Kong L, Yang C, Zhang Z. Nanomedicine for acute respiratory distress syndrome: The latest application, targeting strategy, and rational design. Acta Pharm Sin B 2021; 11:3060-3091. [PMID: 33977080 PMCID: PMC8102084 DOI: 10.1016/j.apsb.2021.04.023] [Citation(s) in RCA: 103] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 03/22/2021] [Accepted: 04/06/2021] [Indexed: 01/08/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS) is characterized by the severe inflammation and destruction of the lung air-blood barrier, leading to irreversible and substantial respiratory function damage. Patients with coronavirus disease 2019 (COVID-19) have been encountered with a high risk of ARDS, underscoring the urgency for exploiting effective therapy. However, proper medications for ARDS are still lacking due to poor pharmacokinetics, non-specific side effects, inability to surmount pulmonary barrier, and inadequate management of heterogeneity. The increased lung permeability in the pathological environment of ARDS may contribute to nanoparticle-mediated passive targeting delivery. Nanomedicine has demonstrated unique advantages in solving the dilemma of ARDS drug therapy, which can address the shortcomings and limitations of traditional anti-inflammatory or antioxidant drug treatment. Through passive, active, or physicochemical targeting, nanocarriers can interact with lung epithelium/endothelium and inflammatory cells to reverse abnormal changes and restore homeostasis of the pulmonary environment, thereby showing good therapeutic activity and reduced toxicity. This article reviews the latest applications of nanomedicine in pre-clinical ARDS therapy, highlights the strategies for targeted treatment of lung inflammation, presents the innovative drug delivery systems, and provides inspiration for strengthening the therapeutic effect of nanomedicine-based treatment.
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Key Words
- ACE2, angiotensin-converting enzyme 2
- AEC II, alveolar type II epithelial cells
- AM, alveolar macrophages
- ARDS, acute respiratory distress syndrome
- Acute lung injury
- Acute respiratory distress syndrome
- Anti-inflammatory therapy
- BALF, bronchoalveolar lavage fluid
- BSA, bovine serum albumin
- CD, cyclodextrin
- CLP, cecal ligation and perforation
- COVID-19
- COVID-19, coronavirus disease 2019
- DOPE, phosphatidylethanolamine
- DOTAP, 1-diolefin-3-trimethylaminopropane
- DOX, doxorubicin
- DPPC, dipalmitoylphosphatidylcholine
- Drug delivery
- ECM, extracellular matrix
- ELVIS, extravasation through leaky vasculature and subsequent inflammatory cell-mediated sequestration
- EPCs, endothelial progenitor cells
- EPR, enhanced permeability and retention
- EVs, extracellular vesicles
- EphA2, ephrin type-A receptor 2
- Esbp, E-selectin-binding peptide
- FcgR, Fcγ receptor
- GNP, peptide-gold nanoparticle
- H2O2, hydrogen peroxide
- HO-1, heme oxygenase-1
- ICAM-1, intercellular adhesion molecule-1
- IKK, IκB kinase
- IL, interleukin
- LPS, lipopolysaccharide
- MERS, Middle East respiratory syndrome
- MPMVECs, mouse pulmonary microvascular endothelial cells
- MPO, myeloperoxidase
- MSC, mesenchymal stem cells
- NAC, N-acetylcysteine
- NE, neutrophil elastase
- NETs, neutrophil extracellular traps
- NF-κB, nuclear factor-κB
- Nanomedicine
- PC, phosphatidylcholine
- PCB, poly(carboxybetaine)
- PDA, polydopamine
- PDE4, phosphodiesterase 4
- PECAM-1, platelet-endothelial cell adhesion molecule
- PEG, poly(ethylene glycol)
- PEI, polyetherimide
- PEVs, platelet-derived extracellular vesicles
- PLGA, poly(lactic-co-glycolic acid)
- PS-PEG, poly(styrene-b-ethylene glycol)
- Pathophysiologic feature
- RBC, red blood cells
- RBD, receptor-binding domains
- ROS, reactive oxygen species
- S1PLyase, sphingosine-1-phosphate lyase
- SARS, severe acute respiratory syndrome
- SARS-CoV-2, severe acute respiratory syndrome coronavirus 2
- SDC1, syndecan-1
- SORT, selective organ targeting
- SP, surfactant protein
- Se, selenium
- Siglec, sialic acid-binding immunoglobulin-like lectin
- TLR, toll-like receptor
- TNF-α, tumor necrosis factor-α
- TPP, triphenylphosphonium cation
- Targeting strategy
- YSA, YSAYPDSVPMMS
- cRGD, cyclic arginine glycine-d-aspartic acid
- iNOS, inducible nitric oxide synthase
- rSPANb, anti-rat SP-A nanobody
- scFv, single chain variable fragments
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Affiliation(s)
- Qi Qiao
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiong Liu
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ting Yang
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Kexin Cui
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Li Kong
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Conglian Yang
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Zhiping Zhang
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China
- National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Engineering Research Center for Novel Drug Delivery System, Huazhong University of Science and Technology, Wuhan 430030, China
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Wang M, Zhou T, Zhang Z, Liu H, Zheng Z, Xie H. Current therapeutic strategies for respiratory diseases using mesenchymal stem cells. MedComm (Beijing) 2021; 2:351-380. [PMID: 34766151 PMCID: PMC8554668 DOI: 10.1002/mco2.74] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 03/15/2021] [Accepted: 03/18/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stromal/stem cells (MSCs) have a great potential to proliferate, undergo multi-directional differentiation, and exert immunoregulatory effects. There is already much enthusiasm for their therapeutic potentials for respiratory inflammatory diseases. Although the mechanism of MSCs-based therapy has been well explored, only a few articles have summarized the key advances in this field. We hereby provide a review over the latest progresses made on the MSCs-based therapies for four types of inflammatory respiratory diseases, including idiopathic pulmonary fibrosis, acute respiratory distress syndrome, chronic obstructive pulmonary disease, and asthma, and the uncovery of their underlying mechanisms from the perspective of biological characteristics and functions. Furthermore, we have also discussed the advantages and disadvantages of the MSCs-based therapies and prospects for their optimization.
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Affiliation(s)
- Ming‐yao Wang
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Ting‐yue Zhou
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Zhi‐dong Zhang
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Hao‐yang Liu
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Zhi‐yao Zheng
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Hui‐qi Xie
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
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Zhang LS, Yu Y, Yu H, Han ZC. Therapeutic prospects of mesenchymal stem/stromal cells in COVID-19 associated pulmonary diseases: From bench to bedside. World J Stem Cells 2021; 13:1058-1071. [PMID: 34567425 PMCID: PMC8422925 DOI: 10.4252/wjsc.v13.i8.1058] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/10/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
The ongoing outbreak of coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 has become a sudden public emergency of international concern and seriously threatens millions of people’s life health. Two current studies have indicated a favorable role for mesenchymal stem/stromal cells (MSCs) in clinical remission of COVID-19 associated pulmonary diseases, yet the systematical elaboration of the therapeutics and underlying mechanism is far from satisfaction. In the present review, we summarize the therapeutic potential of MSCs in COVID-19 associated pulmonary diseases such as pneumonia induced acute lung injury, acute respiratory distress syndrome, and pulmonary fibrosis. Furthermore, we review the underlying mechanism of MSCs including direct- and trans-differentiation, autocrine and paracrine anti-inflammatory effects, homing, and neovascularization, as well as constitutive microenvironment. Finally, we discuss the prospects and supervision of MSC-based cytotherapy for COVID-19 management before large-scale application in clinical practice. Collectively, this review supplies overwhelming new references for understanding the landscapes of MSCs in the remission of COVID-19 associated pulmonary diseases.
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Affiliation(s)
- Lei-Sheng Zhang
- Qianfoshan Hospital & The First Affiliated Hospital, Shandong First Medical University, Jinan 250014, Shandong Province, China
- State Key Laboratory of Experimental Hematology & National Clinical Research Center for Blood Disease, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
- School of Medicine, Nankai University, Tianjin 300071, China
- Precision Medicine Division, Health-Biotech (Tianjin) Stem Cell Research Institute Co., Ltd., Tianjin 301700, China
| | - Yi Yu
- State Key Laboratory of Experimental Hematology & National Clinical Research Center for Blood Disease, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
- The First Affiliated Hospital, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Hao Yu
- School of Medicine, Nankai University, Tianjin 300071, China
- Cell Products of National Engineering Center & National Stem Cell Engineering Research Center, Tianjin IMCELL Stem Cell and Gene Technology Co., Ltd., Tianjin 300457, China
| | - Zhong-Chao Han
- State Key Laboratory of Experimental Hematology & National Clinical Research Center for Blood Disease, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
- Precision Medicine Division, Health-Biotech (Tianjin) Stem Cell Research Institute Co., Ltd., Tianjin 301700, China
- Cell Products of National Engineering Center & National Stem Cell Engineering Research Center, Tianjin IMCELL Stem Cell and Gene Technology Co., Ltd., Tianjin 300457, China
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50
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Hassanzadeh A, Rahman HS, Markov A, Endjun JJ, Zekiy AO, Chartrand MS, Beheshtkhoo N, Kouhbanani MAJ, Marofi F, Nikoo M, Jarahian M. Mesenchymal stem/stromal cell-derived exosomes in regenerative medicine and cancer; overview of development, challenges, and opportunities. Stem Cell Res Ther 2021; 12:297. [PMID: 34020704 PMCID: PMC8138094 DOI: 10.1186/s13287-021-02378-7] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 05/10/2021] [Indexed: 12/13/2022] Open
Abstract
Recently, mesenchymal stem/stromal cells (MSCs) and their widespread biomedical applications have attracted great consideration from the scientific community around the world. However, reports have shown that the main populations of the transplanted MSCs are trapped in the liver, spleen, and lung upon administration, highlighting the importance of the development of cell-free therapies. Concerning rising evidence suggesting that the beneficial effects of MSC therapy are closely linked to MSC-released components, predominantly MSC-derived exosomes, the development of an MSC-based cell-free approach is of paramount importance. The exosomes are nano-sized (30100nm) lipid bilayer membrane vesicles, which are typically released by MSCs and are found in different body fluids. They include various bioactive molecules, such as messenger RNA (mRNA), microRNAs, proteins, and bioactive lipids, thus showing pronounced therapeutic competence for tissues recovery through the maintenance of their endogenous stem cells, the enhancement of regenerative phenotypic traits, inhibition of apoptosis concomitant with immune modulation, and stimulation of the angiogenesis. Conversely, the specific roles of MSC exosomes in the treatment of various tumors remain challenging. The development and clinical application of novel MSC-based cell-free strategies can be supported by better understanding their mechanisms, classifying the subpopulation of exosomes, enhancing the conditions of cell culture and isolation, and increasing the production of exosomes along with engineering exosomes to deliver drugs and therapeutic molecules to the target sites. In the current review, we deliver a brief overview of MSC-derived exosome biogenesis, composition, and isolation methods and discuss recent investigation regarding the therapeutic potential of MSC exosomes in regenerative medicine accompanied by their double-edged sword role in cancer.
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Affiliation(s)
- Ali Hassanzadeh
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Heshu Sulaiman Rahman
- Department of Physiology, College of Medicine, University of Suleimanyah, Sulaymaniyah, Iraq
| | | | - Judi Januadi Endjun
- Medical Faculty, UPN Veteran, Jakarta, Indonesia.,Gatot Soebroto Indonesia Army Hospital, Jakarta, Indonesia
| | | | | | - Nasrin Beheshtkhoo
- Department of Medical Nanotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Amin Jadidi Kouhbanani
- Department of Medical Nanotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Faroogh Marofi
- Immunology Research Center (IRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Marzieh Nikoo
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mostafa Jarahian
- Toxicology and Chemotherapy Unit (G401), German Cancer Research Center, 69120, Heidelberg, Germany.
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