|
1
|
Gasanov VAO, Kashirskikh DA, Khotina VA, Kuzmina DM, Nikitochkina SY, Mukhina IV, Vorotelyak EA, Vasiliev AV. Preclinical Evaluation of the Safety, Toxicity and Efficacy of Genetically Modified Wharton's Jelly Mesenchymal Stem/Stromal Cells Expressing the Antimicrobial Peptide SE-33. Cells 2025; 14:341. [PMID: 40072070 PMCID: PMC11898551 DOI: 10.3390/cells14050341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 02/21/2025] [Accepted: 02/24/2025] [Indexed: 03/15/2025] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) offer promising therapeutic potential in cell-based therapies for various diseases. However, the safety of genetically modified MSCs remains poorly understood. This study aimed to evaluate the general toxicity and safety of Wharton's Jelly-Derived MSCs (WJ-MSCs) engineered to express the antimicrobial peptide SE-33 in an animal model. Genetically modified WJ-MSCs expressing SE-33 were administered to C57BL/6 mice at both therapeutic and excessive doses, either once or repeatedly. Animal monitoring included mortality, clinical signs, and behavioral observations. The toxicity assessment involved histopathological, hematological, and biochemical analyses of major organs and tissues, while immunotoxicity and immunogenicity were examined through humoral and cellular immune responses, macrophage phagocytic activity, and lymphocyte blast transformation. Antimicrobial efficacy was evaluated in a Staphylococcus aureus-induced pneumonia model by monitoring animal mortality and assessing bacterial load and inflammatory processes in the lungs. Mice receiving genetically modified WJ-MSCs exhibited no acute or chronic toxicity, behavioral abnormalities, or pathological changes, regardless of the dose or administration frequency. No significant immunotoxicity or alterations in immune responses were observed, and there were no notable changes in hematological or biochemical serum parameters. Infected animals treated with WJ-MSC-SE33 showed a significant reduction in bacterial load and lung inflammation and improved survival compared to control groups, demonstrating efficacy over native WJ-MSCs. Our findings suggest that WJ-MSCs expressing SE-33 are well tolerated, displaying a favorable safety profile comparable to native WJ-MSCs and potent antimicrobial activity, significantly reducing bacterial load, inflammation, and mortality in an S. aureus pneumonia model. These data support the safety profile of WJ-MSCs expressing SE-33 as a promising candidate for cell-based therapies for bacterial infections, particularly those complicated by antibiotic resistance.
Collapse
Affiliation(s)
- Vagif Ali oglu Gasanov
- Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow 119334, Russia; (D.A.K.); (E.A.V.)
| | | | - Victoria Alexandrovna Khotina
- Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow 119334, Russia; (D.A.K.); (E.A.V.)
| | - Daria Mikhailovna Kuzmina
- Department of Normal Physiology, Privolzhsky Research Medical University of Ministry of Health of the Russian Federation, Nizhny Novgorod 603005, Russia; (D.M.K.); (I.V.M.)
| | - Sofya Yurievna Nikitochkina
- Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow 119334, Russia; (D.A.K.); (E.A.V.)
| | - Irina Vasilievna Mukhina
- Department of Normal Physiology, Privolzhsky Research Medical University of Ministry of Health of the Russian Federation, Nizhny Novgorod 603005, Russia; (D.M.K.); (I.V.M.)
| | - Ekaterina Andreevna Vorotelyak
- Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow 119334, Russia; (D.A.K.); (E.A.V.)
- Department of Cell Biology, Biological Faculty, Lomonosov Moscow State University, Moscow 119234, Russia
| | - Andrey Valentinovich Vasiliev
- Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow 119334, Russia; (D.A.K.); (E.A.V.)
| |
Collapse
|
|
2
|
Ghiasi M, Kheirandish Zarandi P, Dayani A, Salimi A, Shokri E. Potential therapeutic effects and nano-based delivery systems of mesenchymal stem cells and their isolated exosomes to alleviate acute respiratory distress syndrome caused by COVID-19. Regen Ther 2024; 27:319-328. [PMID: 38650667 PMCID: PMC11035022 DOI: 10.1016/j.reth.2024.03.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Revised: 03/03/2024] [Accepted: 03/15/2024] [Indexed: 04/25/2024] Open
Abstract
The severe respiratory effects of the coronavirus disease 2019 (COVID-19) pandemic have necessitated the immediate development of novel treatments. The majority of COVID-19-related fatalities are due to acute respiratory distress syndrome (ARDS). Consequently, this virus causes massive and aberrant inflammatory conditions, which must be promptly managed. Severe respiratory disorders, notably ARDS and acute lung injury (ALI), may be treated safely and effectively using cell-based treatments, mostly employing mesenchymal stem cells (MSCs). Since the high potential of these cells was identified, a great deal of research has been conducted on their use in regenerative medicine and complementary medicine. Multiple investigations have demonstrated that MSCs and their products, especially exosomes, inhibit inflammation. Exosomes serve a critical function in intercellular communication by transporting molecular cargo from donor cells to receiver cells. MSCs and their derived exosomes (MSCs/MSC-exosomes) may improve lung permeability, microbial and alveolar fluid clearance, and epithelial and endothelial repair, according to recent studies. This review focuses on COVID-19-related ARDS clinical studies involving MSCs/MSC-exosomes. We also investigated the utilization of Nano-delivery strategies for MSCs/MSC-exosomes and anti-inflammatory agents to enhance COVID-19 treatment.
Collapse
Affiliation(s)
- Mohsen Ghiasi
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | | | - Abdolreza Dayani
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Salimi
- Nanobiotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Ehsan Shokri
- Department of Nanotechnology, Agricultural Biotechnology Research Institute of Iran (ABRII), Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran
| |
Collapse
|
|
3
|
Regmi S, Ganguly A, Pathak S, Primavera R, Chetty S, Wang J, Patel S, Thakor AS. Evaluating the therapeutic potential of different sources of mesenchymal stem cells in acute respiratory distress syndrome. Stem Cell Res Ther 2024; 15:385. [PMID: 39468662 PMCID: PMC11520775 DOI: 10.1186/s13287-024-03977-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 10/06/2024] [Indexed: 10/30/2024] Open
Abstract
BACKGROUND Mesenchymal stem/stromal cells (MSCs) have attracted interest as a potential therapy given their anti-inflammatory and immunomodulatory properties. However, clinical trials using MSCs for acute respiratory distress syndrome (ARDS) have produced mixed and inconclusive data. In previous work, we performed a "head-to-head" comparison between different sources of MSCs and showed that each source had a unique genomic and proteomic "signature". METHOD This study investigated which sources of MSC: bone marrow derived-MSCs (BM-MSCs), adipose tissue derived-MSCs (AD-MSCs) and umbilical cord derived-MSCs (UC-MSCs) would be the optimal candidate to be used as a therapy in an LPS-induced mouse model of ARDS. Immune cells assessment, tissue transcriptomics, animal survival, and endothelial-epithelial barrier assessment were used to evaluate their effects. RESULTS When comparing the three most commonly used MSC sources, we found that UC-MSCs exhibited greater efficacy compared to other MSCs in improving animal survival, mitigating epithelial/endothelial damage, decreasing lung inflammation via reducing neutrophil infiltration, T cell proliferation, and M1 polarization. Bulk RNA sequencing of lung tissue also showed that UC-MSCs have the capability to downregulate extracellular trap formation, by the downregulation of key genes like Elane and Padi4. Notably, treatment with UC-MSCs demonstrated a significant reduction in Fc-γ R mediated phagocytosis, which has been associated with monocyte pyroptosis and intense inflammation in the context of COVID-19. CONCLUSION Our findings suggest that UC-MSCs are an optimal source of MSC to treat acute inflammatory conditions in the lungs, such as ARDS.
Collapse
Affiliation(s)
- S Regmi
- Interventional Radiology Innovation at Stanford, Department of Radiology, School of Medicine, Stanford University, Stanford, CA, 94304, USA
| | - A Ganguly
- Interventional Radiology Innovation at Stanford, Department of Radiology, School of Medicine, Stanford University, Stanford, CA, 94304, USA
| | - S Pathak
- Division of Blood and Marrow Transplantation and Cellular Therapy, School of Medicine, Stanford University, Stanford, CA, 94305, USA
| | - R Primavera
- Interventional Radiology Innovation at Stanford, Department of Radiology, School of Medicine, Stanford University, Stanford, CA, 94304, USA
| | - S Chetty
- Interventional Radiology Innovation at Stanford, Department of Radiology, School of Medicine, Stanford University, Stanford, CA, 94304, USA
| | - J Wang
- Interventional Radiology Innovation at Stanford, Department of Radiology, School of Medicine, Stanford University, Stanford, CA, 94304, USA
| | - Shaini Patel
- Interventional Radiology Innovation at Stanford, Department of Radiology, School of Medicine, Stanford University, Stanford, CA, 94304, USA
| | - A S Thakor
- Interventional Radiology Innovation at Stanford, Department of Radiology, School of Medicine, Stanford University, Stanford, CA, 94304, USA.
| |
Collapse
|
|
4
|
Byrnes D, Masterson C, Brady J, Horie S, McCarthy SD, Gonzalez H, O’Toole D, Laffey J. Delayed MSC therapy enhances resolution of organized pneumonia induced by antibiotic resistant Klebsiella pneumoniae infection. Front Med (Lausanne) 2023; 10:1132749. [PMID: 37469663 PMCID: PMC10352103 DOI: 10.3389/fmed.2023.1132749] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Accepted: 05/23/2023] [Indexed: 07/21/2023] Open
Abstract
Introduction Mesenchymal stromal cells (MSC) are a promising therapeutic for pneumonia-induced sepsis. Here we sought to determine the efficacy of delayed administration of naïve and activated bone marrow (BM), adipose (AD), and umbilical cord (UC) derived MSCs in organized antibiotic resistant Klebsiella pneumosepsis. Methods Human BM-, AD-, and UC-MSCs were isolated and expanded and used either in the naïve state or following cytokine pre-activation. The effect of MSC tissue source and activation status was assessed first in vitro. Subsequent experiments assessed therapeutic potential as a delayed therapy at 48 h post infection of rodents with Klebsiella pneumoniae, with efficacy assessed at 120 h. Results BM-, AD-, and UC-MSCs accelerated epithelial healing, increased phagocytosis, and reduced ROS-induced epithelial injury in vitro, with AD-MSCs less effective, and naïve MSCs more effective than pre-activated MSCs. Delayed MSC administration in pre-clinical organized Klebsiella pneumosepsis had no effect on physiologic indices, but enhanced resolution of structural lung injury. Delayed therapy with pre-activated MSCs reduced mRNA concentrations of fibrotic factors. Naïve MSC treatment reduced key circulating cell proportions and increased bacterial killing capacity in the lungs whereas pre-activated MSCs enhanced the phagocytic index of pulmonary white cells. Discussion Delayed MSC therapy enhanced resolution of lung injury induced by antibiotic resistant Klebsiella infection and favorably modulated immune cell profile. Overall, AD-MSCs were less effective than either UC- or BM-MSCs, while naïve MSCs had a more favorable effect profile compared to pre-activated MSCs.
Collapse
Affiliation(s)
- Declan Byrnes
- Anaesthesia, School of Medicine, Clinical Sciences Institute, University of Galway, Galway, Ireland
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, Biomedical Sciences Building, University of Galway, Galway, Ireland
| | - Claire Masterson
- Anaesthesia, School of Medicine, Clinical Sciences Institute, University of Galway, Galway, Ireland
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, Biomedical Sciences Building, University of Galway, Galway, Ireland
| | - Jack Brady
- Anaesthesia, School of Medicine, Clinical Sciences Institute, University of Galway, Galway, Ireland
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, Biomedical Sciences Building, University of Galway, Galway, Ireland
| | - Shahd Horie
- Anaesthesia, School of Medicine, Clinical Sciences Institute, University of Galway, Galway, Ireland
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, Biomedical Sciences Building, University of Galway, Galway, Ireland
| | - Sean D. McCarthy
- Anaesthesia, School of Medicine, Clinical Sciences Institute, University of Galway, Galway, Ireland
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, Biomedical Sciences Building, University of Galway, Galway, Ireland
| | - Hector Gonzalez
- Anaesthesia, School of Medicine, Clinical Sciences Institute, University of Galway, Galway, Ireland
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, Biomedical Sciences Building, University of Galway, Galway, Ireland
| | - Daniel O’Toole
- Anaesthesia, School of Medicine, Clinical Sciences Institute, University of Galway, Galway, Ireland
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, Biomedical Sciences Building, University of Galway, Galway, Ireland
| | - John Laffey
- Anaesthesia, School of Medicine, Clinical Sciences Institute, University of Galway, Galway, Ireland
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, Biomedical Sciences Building, University of Galway, Galway, Ireland
- Department of Anaesthesia, Galway University Hospitals, SAOLTA University Hospital Group, Galway, Ireland
| |
Collapse
|
|
5
|
Gonzalez H, McCarthy S, Masterson C, Byrnes D, Sallent I, Horan E, Elliman SJ, Vella G, Mello AP, Silva JD, Krasnodembskaya AD, MacLoughlin R, Laffey JG, O'Toole D. Nebulised mesenchymal stem cell derived extracellular vesicles ameliorate E. coli induced pneumonia in a rodent model. Stem Cell Res Ther 2023; 14:151. [PMID: 37280647 DOI: 10.1186/s13287-023-03385-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 05/24/2023] [Indexed: 06/08/2023] Open
Abstract
BACKGROUND Mesenchymal stem cell (MSC) derived extracellular vesicles (EVs) have been proposed as an alternative to cell therapy, creating new possible delivery modalities such as nebulisation. We wished to investigate the therapeutic potential of directly nebulised MSC-EVs in the mitigation of Escherichia coli-induced pneumonia. METHODS EV size, surface markers and miRNA content were assessed pre- and post-nebulisation. BEAS2B and A459 lung cells were exposed to lipopolysaccharide (LPS) and treated with nebulised bone marrow (BM) or umbilical cord (UC) MSC-EVs. Viability assays (MTT) and inflammatory cytokine assays were performed. THP-1 monocytes were stimulated with LPS and nebulised BM- or UC-EVs and phagocytosis activity was measured. For in vivo experiments, mice received LPS intratracheally (IT) followed by BM- or UC-EVs intravenously (IV) and injury markers assessed at 24 h. Rats were instilled with E. coli bacteria IT and BM- or UC-EVs delivered IV or by direct nebulisation. At 48 h, lung damage was assessed by physiological parameters, histology and inflammatory marker presence. RESULTS MSC-EVs retained their immunomodulatory and wound healing capacity after nebulisation in vitro. EV integrity and content were also preserved. Therapy with IV or nebulised MSC-EVs reduced the severity of LPS-induced lung injury and E. coli-induced pneumonia by reducing bacterial load and oedema, increasing blood oxygenation and improving lung histological scores. MSC-EV treated animals also showed lower levels of inflammatory cytokines and inflammatory-related markers. CONCLUSIONS MSC-EVs given IV attenuated LPS-induced lung injury, and nebulisation of MSC-EVs did not affect their capacity to attenuate lung injury caused by E. coli pneumonia, as evidenced by reduction in bacterial load and improved lung physiology.
Collapse
Affiliation(s)
- Hector Gonzalez
- REMEDI at CÚRAM Centre for Medical Device Research, University of Galway, Galway, Ireland
| | - Sean McCarthy
- REMEDI at CÚRAM Centre for Medical Device Research, University of Galway, Galway, Ireland
| | - Claire Masterson
- REMEDI at CÚRAM Centre for Medical Device Research, University of Galway, Galway, Ireland
| | - Declan Byrnes
- REMEDI at CÚRAM Centre for Medical Device Research, University of Galway, Galway, Ireland
| | - Ignacio Sallent
- REMEDI at CÚRAM Centre for Medical Device Research, University of Galway, Galway, Ireland
| | - Emma Horan
- Orbsen Therapeutics, IDA Business Park, Dangan, Galway, Ireland
| | | | - Gabriele Vella
- Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Adriele P Mello
- Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Johnatas D Silva
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK
| | - Anna D Krasnodembskaya
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK
| | | | - John G Laffey
- REMEDI at CÚRAM Centre for Medical Device Research, University of Galway, Galway, Ireland
| | - Daniel O'Toole
- REMEDI at CÚRAM Centre for Medical Device Research, University of Galway, Galway, Ireland.
| |
Collapse
|
|
6
|
Jerkic M, Szaszi K, Laffey JG, Rotstein O, Zhang H. Key Role of Mesenchymal Stromal Cell Interaction with Macrophages in Promoting Repair of Lung Injury. Int J Mol Sci 2023; 24:ijms24043376. [PMID: 36834784 PMCID: PMC9965074 DOI: 10.3390/ijms24043376] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 01/30/2023] [Accepted: 02/04/2023] [Indexed: 02/11/2023] Open
Abstract
Lung macrophages (Mφs) are essential for pulmonary innate immunity and host defense due to their dynamic polarization and phenotype shifts. Mesenchymal stromal cells (MSCs) have secretory, immunomodulatory, and tissue-reparative properties and have shown promise in acute and chronic inflammatory lung diseases and in COVID-19. Many beneficial effects of MSCs are mediated through their interaction with resident alveolar and pulmonary interstitial Mφs. Bidirectional MSC-Mφ communication is achieved through direct contact, soluble factor secretion/activation, and organelle transfer. The lung microenvironment facilitates MSC secretion of factors that result in Mφ polarization towards an immunosuppressive M2-like phenotype for the restoration of tissue homeostasis. M2-like Mφ in turn can affect the MSC immune regulatory function in MSC engraftment and tissue reparatory effects. This review article highlights the mechanisms of crosstalk between MSCs and Mφs and the potential role of their interaction in lung repair in inflammatory lung diseases.
Collapse
Affiliation(s)
- Mirjana Jerkic
- The Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1T8, Canada
- Correspondence:
| | - Katalin Szaszi
- The Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1T8, Canada
- Department of Surgery, University of Toronto, Toronto, ON M5T 1P5, Canada
| | - John G. Laffey
- The Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1T8, Canada
- Anaesthesia and Intensive Care Medicine, School of Medicine, University of Galway, H91 TK33 Galway, Ireland
| | - Ori Rotstein
- The Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1T8, Canada
- Department of Surgery, University of Toronto, Toronto, ON M5T 1P5, Canada
| | - Haibo Zhang
- The Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1T8, Canada
- Department of Anesthesiology and Pain Medicine, Interdepartmental Division of Critical Care Medicine and Department of Physiology, University of Toronto, Toronto, ON M5G 1E2, Canada
| |
Collapse
|
|
7
|
Alcayaga-Miranda F, Dutra Silva J, Parada N, Andrade da Silva LH, Ferreira Cruz F, Utreras Y, Hidalgo Y, Cádiz MI, Tapia Limonchi R, Espinoza F, Bruhn A, Khoury M, R. M. Rocco P, Cuenca J. Safety and efficacy of clinical-grade, cryopreserved menstrual blood mesenchymal stromal cells in experimental acute respiratory distress syndrome. Front Cell Dev Biol 2023; 11:1031331. [PMID: 36793446 PMCID: PMC9923023 DOI: 10.3389/fcell.2023.1031331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 01/16/2023] [Indexed: 01/31/2023] Open
Abstract
Background: Treatment for critical care conditions, such as acute respiratory distress syndrome (ARDS), requires ready-to-administer injectable mesenchymal stromal cells (MSCs). A validated cryopreserved therapy based on MSCs derived from menstrual blood (MenSCs) is an attractive option that offers advantages over freshly cultured cells and allows its use as an off-the-shelf therapy in acute clinical conditions. The main goal of this study is to provide evidence on the impact of cryopreservation on different biological functions of MenSCs and to determine the optimal therapeutic dose, safety, and efficacy profile of clinical-grade, cryopreserved (cryo)-MenSCs in experimental ARDS. Methods: Biological functions of fresh versus cryo-MenSCs were compared in vitro. The effects of cryo-MenSCs therapy were evaluated in vivo in ARDS-induced (Escherichia coli lipopolysaccharide) C57BL/6 mice. After 24 h, the animals were treated with five doses ranging from 0.25×105 to 1.25×106 cells/animal. At 2 and 7 days after induction of ARDS, safety and efficacy were evaluated. Results: Clinical-grade cryo-MenSCs injections improved lung mechanics and reduced alveolar collapse, tissue cellularity, and remodelling, decreasing elastic and collagen fiber content in alveolar septa. In addition, administration of these cells modulated inflammatory mediators and promoted pro-angiogenic and anti-apoptotic effects in lung-injured animals. More beneficial effects were observed with an optimal dose of 4×106 cells/Kg than with higher or lower doses. Conclusion: From a translational perspective, the results showed that clinical-grade cryopreserved MenSCs retain their biological properties and exert a therapeutic effect in mild to moderate experimental ARDS. The optimal therapeutic dose was well-tolerated, safe, and effective, favouring improved lung function. These findings support the potential value of an off-the-shelf MenSCs-based product as a promising therapeutic strategy for treating ARDS.
Collapse
Affiliation(s)
- Francisca Alcayaga-Miranda
- Laboratory of Nano-Regenerative Medicine, Centro de Investigación e Innovación Biomédica (CIIB), Faculty of Medicine, Universidad de los Andes, Santiago, Chile,Consorcio Regenero, Chilean Consortium for Regenerative Medicine, Santiago, Chile,Cells for Cells, Santiago, Chile,IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | - Johnatas Dutra Silva
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Nicol Parada
- Laboratory of Nano-Regenerative Medicine, Centro de Investigación e Innovación Biomédica (CIIB), Faculty of Medicine, Universidad de los Andes, Santiago, Chile
| | - Luisa Helena Andrade da Silva
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Fernanda Ferreira Cruz
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil,National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil
| | - Yildy Utreras
- Laboratory of Nano-Regenerative Medicine, Centro de Investigación e Innovación Biomédica (CIIB), Faculty of Medicine, Universidad de los Andes, Santiago, Chile
| | - Yessia Hidalgo
- Laboratory of Nano-Regenerative Medicine, Centro de Investigación e Innovación Biomédica (CIIB), Faculty of Medicine, Universidad de los Andes, Santiago, Chile,Consorcio Regenero, Chilean Consortium for Regenerative Medicine, Santiago, Chile,IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | - María Ignacia Cádiz
- Laboratory of Nano-Regenerative Medicine, Centro de Investigación e Innovación Biomédica (CIIB), Faculty of Medicine, Universidad de los Andes, Santiago, Chile,Consorcio Regenero, Chilean Consortium for Regenerative Medicine, Santiago, Chile,Cells for Cells, Santiago, Chile
| | - Rafael Tapia Limonchi
- Consorcio Regenero, Chilean Consortium for Regenerative Medicine, Santiago, Chile,Cells for Cells, Santiago, Chile
| | - Francisco Espinoza
- Cells for Cells, Santiago, Chile,IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | - Alejandro Bruhn
- Departamento de Medicina Intensiva, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Maroun Khoury
- Laboratory of Nano-Regenerative Medicine, Centro de Investigación e Innovación Biomédica (CIIB), Faculty of Medicine, Universidad de los Andes, Santiago, Chile,Consorcio Regenero, Chilean Consortium for Regenerative Medicine, Santiago, Chile,Cells for Cells, Santiago, Chile,IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | - Patricia R. M. Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil,National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil
| | - Jimena Cuenca
- Laboratory of Nano-Regenerative Medicine, Centro de Investigación e Innovación Biomédica (CIIB), Faculty of Medicine, Universidad de los Andes, Santiago, Chile,Consorcio Regenero, Chilean Consortium for Regenerative Medicine, Santiago, Chile,Cells for Cells, Santiago, Chile,IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile,*Correspondence: Jimena Cuenca,
| |
Collapse
|
|
8
|
Azapira N, Pourjafar S, Habibi A, Tayebi L, Keshtkar S, Kaviani M. Mesenchymal Stem Cell-Derived Extracellular Vesicles: Promising Treatment for COVID-19 Pandemic. EXP CLIN TRANSPLANT 2022; 20:980-983. [PMID: 33622217 DOI: 10.6002/ect.2020.0296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The pandemic of severe acute respiratory syndrome coronavirus-2 infection has prompted the urgent need for novel therapeutic approaches, especially for patients in critically severe conditions. To date, the pathogenesis of COVID-19 is not completely understood, and finding an effective new drug is still inconclusive. Mesenchymal stromal cell-derived extracellular vesicles contain large amounts of proteins, messenger RNA, and microRNAs that act as vehicles that transfer the cargo between cells. These nanotherapeutic materials exert anti-inflammatory effects on the immune system, which are necessary for subsidence of acute inflammation and promotion of tissue repair and regeneration. Therefore, the consideration of mesenchymal stromal cell-derived extracellular vesicles as a new, safe, and effective therapeutic approach in the treatment of COVID-19 pneumonia is suggested.
Collapse
Affiliation(s)
- Negar Azapira
- From the Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | | | | | | | | |
Collapse
|
|
9
|
Regenerative mesenchymal stem c
ell‐derived
extracellular vesicles: A potential alternative to c
ell‐based
therapy in viral infection and disease damage control. WIREs Mech Dis 2022; 14:e1574. [DOI: 10.1002/wsbm.1574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 05/24/2022] [Indexed: 11/07/2022]
|
|
10
|
Dave C, Mei SHJ, McRae A, Hum C, Sullivan KJ, Champagne J, Ramsay T, McIntyre L. Comparison of freshly cultured versus cryopreserved mesenchymal stem cells in animal models of inflammation: A pre-clinical systematic review. eLife 2022; 11:75053. [PMID: 35838024 PMCID: PMC9286731 DOI: 10.7554/elife.75053] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 06/05/2022] [Indexed: 12/09/2022] Open
Abstract
Background: Mesenchymal stem cells (MSCs) are multipotent cells that demonstrate therapeutic potential for the treatment of acute and chronic inflammatory-mediated conditions. Although controversial, some studies suggest that MSCs may lose their functionality with cryopreservation which could render them non-efficacious. Hence, we conducted a systematic review of comparative pre-clinical models of inflammation to determine if there are differences in in vivo measures of pre-clinical efficacy (primary outcomes) and in vitro potency (secondary outcomes) between freshly cultured and cryopreserved MSCs. Methods: A systematic search on OvidMEDLINE, EMBASE, BIOSIS, and Web of Science (until January 13, 2022) was conducted. The primary outcome included measures of in vivo pre-clinical efficacy; secondary outcomes included measures of in vitro MSC potency. Risk of bias was assessed by the SYRCLE ‘Risk of Bias’ assessment tool for pre-clinical studies. Results: Eighteen studies were included. A total of 257 in vivo pre-clinical efficacy experiments represented 101 distinct outcome measures. Of these outcomes, 2.3% (6/257) were significantly different at the 0.05 level or less; 2 favoured freshly cultured and 4 favoured cryopreserved MSCs. A total of 68 in vitro experiments represented 32 different potency measures; 13% (9/68) of the experiments were significantly different at the 0.05 level or less, with seven experiments favouring freshly cultured MSC and two favouring cryopreserved MSCs. Conclusions: The majority of preclinical primary in vivo efficacy and secondary in vitro potency outcomes were not significantly different (p<0.05) between freshly cultured and cryopreserved MSCs. Our systematic summary of the current evidence base may provide MSC basic and clinical research scientists additional rationale for considering a cryopreserved MSC product in their pre-clinical studies and clinical trials as well as help identify research gaps and guide future related research. Funding: Ontario Institute for Regenerative Medicine
Collapse
Affiliation(s)
- Chintan Dave
- Division of Critical Care Medicine, Department of Medicine, Western University, London, Canada
| | - Shirley H J Mei
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada
| | - Andrea McRae
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada
| | - Christine Hum
- Knowledge Synthesis Group, Ottawa Hospital Research Institute, Ottawa, Canada.,University of Ottawa, Ottawa, Canada
| | - Katrina J Sullivan
- Knowledge Synthesis Group, Ottawa Hospital Research Institute, Ottawa, Canada
| | - Josee Champagne
- Knowledge Synthesis Group, Ottawa Hospital Research Institute, Ottawa, Canada.,Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, Canada
| | - Tim Ramsay
- Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, Canada
| | - Lauralyn McIntyre
- Knowledge Synthesis Group, Ottawa Hospital Research Institute, Ottawa, Canada.,Division of Critical Care, Department of Medicine, University of Ottawa, Ottawa, Canada
| |
Collapse
|
|
11
|
Horie S, Gonzalez H, Brady J, Devaney J, Scully M, O’Toole D, Laffey JG. Fresh and Cryopreserved Human Umbilical-Cord-Derived Mesenchymal Stromal Cells Attenuate Injury and Enhance Resolution and Repair following Ventilation-Induced Lung Injury. Int J Mol Sci 2021; 22:ijms222312842. [PMID: 34884645 PMCID: PMC8657992 DOI: 10.3390/ijms222312842] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/25/2021] [Accepted: 11/26/2021] [Indexed: 12/15/2022] Open
Abstract
Background: Ventilator-induced lung injury (VILI) frequently worsens acute respiratory distress syndrome (ARDS) severity. Human mesenchymal stem/stromal cells (MSCs) offer considerable therapeutic promise, but the key impediments of clinical translation stem from limitations due to cell source and availability, and concerns regarding the loss of efficacy following cryopreservation. These experiments compared the efficacy of umbilical-cord-derived MSCs (UC-MSCs), a readily available and homogenous tissue source, to the previously more widely utilised bone-marrow-derived MSCs (BM-MSCs). We assessed their capacity to limit inflammation, resolve injury and enhance repair in relevant lung mechanical stretch models, and the impact of cryopreservation on therapeutic efficacy. Methods: In series 1, confluent alveolar epithelial layers were subjected to cyclic mechanical stretch (22% equibiaxial strain) and wound injury, and the potential of the secretome from BM- and UC-derived MSCs to attenuate epithelial inflammation and cell death, and enhance wound repair was determined. In series 2, anesthetized rats underwent VILI, and later received, in a randomised manner, 1 × 107 MSCs/kg intravenously, that were: (i) fresh BM-MSCs, (ii) fresh UC-MSCs or (iii) cryopreserved UC-MSCs. Control animals received a vehicle (PBS). The extent of the resolution of inflammation and injury, and repair was measured at 24 h. Results: Conditioned medium from BM-MSCs and UC-MSCs comparably decreased stretch-induced pulmonary epithelial inflammation and cell death. BM-MSCs and UC-MSCs comparably enhanced wound resolution. In animals subjected to VILI, both fresh BM-MSCs and UC-MSCs enhanced injury resolution and repair, while cryopreserved UC-MSCs comparably retained their efficacy. Conclusions: Cryopreserved UC-MSCs can reduce stretch-induced inflammation and cell death, enhance wound resolution, and enhance injury resolution and repair following VILI. Cryopreserved UC-MSCs represent a more abundant, cost-efficient, less variable and equally efficacious source of therapeutic MSC product.
Collapse
Affiliation(s)
- Shahd Horie
- Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, H91 TK33 Galway, Ireland; (S.H.); (H.G.); (J.B.); (J.D.); (M.S.)
- Regenerative Medicine Institute (REMEDI), CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Biomedical Sciences Building, H91 TK33 Galway, Ireland
| | - Hector Gonzalez
- Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, H91 TK33 Galway, Ireland; (S.H.); (H.G.); (J.B.); (J.D.); (M.S.)
- Regenerative Medicine Institute (REMEDI), CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Biomedical Sciences Building, H91 TK33 Galway, Ireland
| | - Jack Brady
- Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, H91 TK33 Galway, Ireland; (S.H.); (H.G.); (J.B.); (J.D.); (M.S.)
- Regenerative Medicine Institute (REMEDI), CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Biomedical Sciences Building, H91 TK33 Galway, Ireland
| | - James Devaney
- Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, H91 TK33 Galway, Ireland; (S.H.); (H.G.); (J.B.); (J.D.); (M.S.)
- Regenerative Medicine Institute (REMEDI), CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Biomedical Sciences Building, H91 TK33 Galway, Ireland
| | - Michael Scully
- Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, H91 TK33 Galway, Ireland; (S.H.); (H.G.); (J.B.); (J.D.); (M.S.)
- Medicine, School of Medicine, Clinical Sciences Institute, National University of Ireland, H91 TK33 Galway, Ireland
| | - Daniel O’Toole
- Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, H91 TK33 Galway, Ireland; (S.H.); (H.G.); (J.B.); (J.D.); (M.S.)
- Regenerative Medicine Institute (REMEDI), CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Biomedical Sciences Building, H91 TK33 Galway, Ireland
- Correspondence: (D.O.); (J.G.L.)
| | - John G. Laffey
- Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, H91 TK33 Galway, Ireland; (S.H.); (H.G.); (J.B.); (J.D.); (M.S.)
- Regenerative Medicine Institute (REMEDI), CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Biomedical Sciences Building, H91 TK33 Galway, Ireland
- Medicine, School of Medicine, Clinical Sciences Institute, National University of Ireland, H91 TK33 Galway, Ireland
- Department of Anaesthesia, Galway University Hospitals, SAOLTA University Health Group, H91 YR71 Galway, Ireland
- Correspondence: (D.O.); (J.G.L.)
| |
Collapse
|
|
12
|
Dunbar H, Weiss DJ, Rolandsson Enes S, Laffey JG, English K. The Inflammatory Lung Microenvironment; a Key Mediator in MSC Licensing. Cells 2021; 10:cells10112982. [PMID: 34831203 PMCID: PMC8616504 DOI: 10.3390/cells10112982] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 10/28/2021] [Accepted: 10/29/2021] [Indexed: 12/12/2022] Open
Abstract
Recent clinical trials of mesenchymal stromal cell (MSC) therapy for various inflammatory conditions have highlighted the significant benefit to patients who respond to MSC administration. Thus, there is strong interest in investigating MSC therapy in acute inflammatory lung conditions, such as acute respiratory distress syndrome (ARDS). Unfortunately, not all patients respond, and evidence now suggests that the differential disease microenvironment present across patients and sub-phenotypes of disease or across disease severities influences MSC licensing, function and therapeutic efficacy. Here, we discuss the importance of licensing MSCs and the need to better understand how the disease microenvironment influences MSC activation and therapeutic actions, in addition to the need for a patient-stratification approach.
Collapse
Affiliation(s)
- Hazel Dunbar
- Department of Biology, Maynooth University, W23 F2H6 Maynooth, Ireland;
- Kathleen Lonsdale Institute for Human Health Research, Maynooth University, W23 F2H6 Maynooth, Ireland
| | - Daniel J Weiss
- Department of Medicine, 226 Health Science Research Facility, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA;
| | - Sara Rolandsson Enes
- Department of Experimental Medical Science, Faculty of Medicine, Lund University, 22100 Lund, Sweden;
| | - John G Laffey
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, Biomedical Sciences Building, National University of Ireland Galway, H91 W2TY Galway, Ireland;
- Department of Anaesthesia, Galway University Hospitals, SAOLTA University Health Group, H91 YR71 Galway, Ireland
| | - Karen English
- Department of Biology, Maynooth University, W23 F2H6 Maynooth, Ireland;
- Kathleen Lonsdale Institute for Human Health Research, Maynooth University, W23 F2H6 Maynooth, Ireland
- Correspondence: ; Tel.: +353-1-7086290
| |
Collapse
|
|
13
|
Gorman E, Shankar-Hari M, Hopkins P, Tunnicliffe WS, Perkins GD, Silversides J, McGuigan P, Krasnodembskaya A, Jackson C, Boyle R, McFerran J, McDowell C, Campbell C, McFarland M, Smythe J, Thompson J, Williams B, Curley G, Laffey JG, Clarke M, McAuley DF, O'Kane CM. Repair of acute respiratory distress syndrome by stromal cell administration (REALIST) trial: A phase 1 trial. EClinicalMedicine 2021; 41:101167. [PMID: 34746723 PMCID: PMC8551601 DOI: 10.1016/j.eclinm.2021.101167] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 10/04/2021] [Accepted: 10/04/2021] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Mesenchymal stromal cells (MSCs) may be of benefit in acute respiratory distress syndrome (ARDS) due to immunomodulatory, reparative, and antimicrobial actions. ORBCEL-C is a population of CD362 enriched umbilical cord-derived MSCs. The REALIST phase 1 trial investigated the safety and feasibility of ORBCEL-C in patients with moderate to severe ARDS. METHODS REALIST phase 1 was an open label, dose escalation trial in which cohorts of mechanically ventilated patients with moderate to severe ARDS received increasing doses (100, 200 or 400 × 106 cells) of a single intravenous infusion of ORBCEL-C in a 3 + 3 design. The primary safety outcome was the incidence of serious adverse events. Dose limiting toxicity was defined as a serious adverse reaction within seven days. Trial registration clinicaltrials.gov NCT03042143. FINDINGS Nine patients were recruited between the 7th January 2019 and 14th January 2020. Study drug administration was well tolerated and no dose limiting toxicity was reported in any of the three cohorts. Eight adverse events were reported for four patients. Pyrexia within 24 h of study drug administration was reported in two patients as pre-specified adverse events. A further two adverse events (non-sustained ventricular tachycardia and deranged liver enzymes), were reported as adverse reactions. Four serious adverse events were reported (colonic perforation, gastric perforation, bradycardia and myocarditis) but none were deemed related to administration of ORBCEL-C. At day 28 no patients had died in cohort one (100 × 106), three patients had died in cohort two (200 × 106) and one patient had died in cohort three (400 × 106). Overall day 28 mortality was 44% (n = 4/9). INTERPRETATION A single intravenous infusion of ORBCEL-C was well tolerated in patients with moderate to severe ARDS. No dose limiting toxicity was reported up to 400 × 106 cells.
Collapse
Affiliation(s)
- Ellen Gorman
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, United Kingdom
| | - Manu Shankar-Hari
- Guy's and St Thomas’ NHS Foundation Trust, Westminister Bridge Road, London SE1 7EH, United Kingdom
- School of Immunology and Microbial Sciences, King's College London, Strand, London WC2R 2LS, United Kingdom
| | - Phil Hopkins
- Kings Trauma Centre, King's College London, Strand, London WC2R 2LS, United Kingdom
| | - William S. Tunnicliffe
- Queen Elizabeth Hospital Birmingham, Mindelsohn Way, Edgbaston, Birmingham B15 2GW, United Kingdom
| | - Gavin D. Perkins
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom
- University Hospitals Birmingham, Mindelsohn Way, Edgbaston, Birmingham B15 2GW, United Kingdom
| | - Jonathan Silversides
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, United Kingdom
- Belfast Health and Social Care Trust, Royal Victoria Hospital, 274 Grosvenor Road, Belfast BT12 6BA, United Kingdom
| | - Peter McGuigan
- Belfast Health and Social Care Trust, Royal Victoria Hospital, 274 Grosvenor Road, Belfast BT12 6BA, United Kingdom
| | - Anna Krasnodembskaya
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, United Kingdom
| | - Colette Jackson
- Northern Ireland Clinical Trials Unit, 7 Lennoxvale, Belfast BT9 5BY, United Kingdom
| | - Roisin Boyle
- Northern Ireland Clinical Trials Unit, 7 Lennoxvale, Belfast BT9 5BY, United Kingdom
| | - Jamie McFerran
- Northern Ireland Clinical Trials Unit, 7 Lennoxvale, Belfast BT9 5BY, United Kingdom
| | - Cliona McDowell
- Northern Ireland Clinical Trials Unit, 7 Lennoxvale, Belfast BT9 5BY, United Kingdom
| | - Christina Campbell
- Northern Ireland Clinical Trials Unit, 7 Lennoxvale, Belfast BT9 5BY, United Kingdom
| | - Margaret McFarland
- Belfast Health and Social Care Trust, Royal Victoria Hospital, 274 Grosvenor Road, Belfast BT12 6BA, United Kingdom
| | - Jon Smythe
- NHS Blood and Transplant, Headley Way, Oxford OX3 9BU, United Kingdom
| | - Jacqui Thompson
- NHS Blood and Transplant Service, Vincent Drive, Edgbaston, Birmingham B15 2SG, United Kingdom
| | - Barry Williams
- Independent Patient and Public Representative, United Kingdom
| | - Gerard Curley
- Royal College of Surgeons in Ireland, Dublin 9, Ireland
| | - John G. Laffey
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, University Road, Galway H91 TK33, Ireland
| | - Mike Clarke
- Northern Ireland Clinical Trials Unit, 7 Lennoxvale, Belfast BT9 5BY, United Kingdom
- Northern Ireland Methodology Hub, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, United Kingdom
| | - Daniel F. McAuley
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, United Kingdom
| | - Cecilia M. O'Kane
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, United Kingdom
- Corresponding author.
| |
Collapse
|
|
14
|
Lei X, He N, Zhu L, Zhou M, Zhang K, Wang C, Huang H, Chen S, Li Y, Liu Q, Han Z, Guo Z, Han Z, Li Z. Mesenchymal Stem Cell-Derived Extracellular Vesicles Attenuate Radiation-Induced Lung Injury via miRNA-214-3p. Antioxid Redox Signal 2021; 35:849-862. [PMID: 32664737 DOI: 10.1089/ars.2019.7965] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Aims: Radiotherapy is an effective treatment for thoracic malignancies, but it can cause pulmonary injury and may lead to respiratory failure in a subset of patients. Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) are now recognized as a new candidate for cell-free treatment of lung diseases. Here, we investigated whether MSC-derived EVs (MSC-EVs) could ameliorate radiation-induced lung injury. Results: We exposed mice to thoracic radiation with a total dose of 15 Gy and assessed the protective effects of MSC-EVs on endothelial cells damage, vascular permeability, inflammation, and fibrosis. We found that MSC-EVs attenuated radiation-induced lung vascular damage, inflammation, and fibrosis. Moreover, MSC-EVs reduced the levels of radiation-induced DNA damage by downregulating ATM/P53/P21 signaling. Our results confirmed that the downregulation of ataxia telangiectasia mutated (ATM) was regulated by miR-214-3p, which was enriched in MSC-EVs. Further analysis demonstrated that MSC-EVs inhibited the senescence-associated secretory phenotype development and attenuated the radiation-induced injury of endothelial cells. Innovation and Conclusion: Our study reveals that MSC-EVs can reduce pulmonary radiation injury through transferring miR-214-3p, providing new avenues to minimize lung injury from radiation therapy. Antioxid. Redox Signal. 35, 849-862.
Collapse
Affiliation(s)
- Xudan Lei
- Lab of Molecular Imaging and Stem Cell Therapy, Nankai University School of Medicine, Tianjin, China.,The Key Laboratory of Bioactive Materials, Ministry of Education, The College of Life Science, Nankai University, Tianjin, China
| | - Ningning He
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Department of Radiobiology, Institute of Radiation Medicine of Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, China
| | - Lihong Zhu
- Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Manqian Zhou
- Department of Radiation Oncology, Tianjin Union Medical Center, Tianjin, China
| | - Kaiyue Zhang
- Lab of Molecular Imaging and Stem Cell Therapy, Nankai University School of Medicine, Tianjin, China
| | - Chen Wang
- Lab of Molecular Imaging and Stem Cell Therapy, Nankai University School of Medicine, Tianjin, China
| | - Haoyan Huang
- Lab of Molecular Imaging and Stem Cell Therapy, Nankai University School of Medicine, Tianjin, China
| | - Shang Chen
- Lab of Molecular Imaging and Stem Cell Therapy, Nankai University School of Medicine, Tianjin, China
| | - Yuhao Li
- Lab of Molecular Imaging and Stem Cell Therapy, Nankai University School of Medicine, Tianjin, China
| | - Qiang Liu
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Department of Radiobiology, Institute of Radiation Medicine of Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, China
| | - Zhibo Han
- Tianjin Key Laboratory of Engineering Technologies for Cell Pharmaceutical, National Engineering Research Center of Cell Products, AmCellGene Co., Ltd., Tianjin, China.,Jiangxi Engineering Research Center for Stem Cell, Shangrao, China
| | - Zhikun Guo
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
| | - Zhongchao Han
- Tianjin Key Laboratory of Engineering Technologies for Cell Pharmaceutical, National Engineering Research Center of Cell Products, AmCellGene Co., Ltd., Tianjin, China.,Jiangxi Engineering Research Center for Stem Cell, Shangrao, China
| | - Zongjin Li
- Lab of Molecular Imaging and Stem Cell Therapy, Nankai University School of Medicine, Tianjin, China.,The Key Laboratory of Bioactive Materials, Ministry of Education, The College of Life Science, Nankai University, Tianjin, China.,State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing, China
| |
Collapse
|
|
15
|
Williams A, Branscome H, Khatkar P, Mensah GA, Al Sharif S, Pinto DO, DeMarino C, Kashanchi F. A comprehensive review of COVID-19 biology, diagnostics, therapeutics, and disease impacting the central nervous system. J Neurovirol 2021; 27:667-690. [PMID: 34581996 PMCID: PMC8477646 DOI: 10.1007/s13365-021-00998-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 05/17/2021] [Accepted: 07/01/2021] [Indexed: 01/08/2023]
Abstract
The ongoing COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a highly transmissible disease. SARS-CoV-2 is estimated to have infected over 153 million people and to have caused over 3.2 million global deaths since its emergence in December 2019. SARS-CoV-2 is the seventh coronavirus known to infect humans, and like other coronaviruses, SARS-CoV-2 infection is characterized by a variety of symptoms including general flu-like symptoms such as a fever, sore throat, fatigue, and shortness of breath. Severe cases often display signs of pneumonia, lymphopenia, acute kidney injury, cardiac injury, cytokine storms, lung damage, acute respiratory distress syndrome (ARDS), multiple organ failure, sepsis, and death. There is evidence that around 30% of COVID-19 cases have central nervous system (CNS) or peripheral nervous system (PNS) symptoms along with or in the absence of the previously mentioned symptoms. In cases of CNS/PNS impairments, patients display dizziness, ataxia, seizure, nerve pain, and loss of taste and/or smell. This review highlights the neurological implications of SARS-CoV-2 and provides a comprehensive summary of the research done on SARS-CoV-2 pathology, diagnosis, therapeutics, and vaccines up to May 5.
Collapse
Affiliation(s)
- Anastasia Williams
- Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, USA
| | - Heather Branscome
- Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, USA
- American Type Culture Collection (ATCC), Manassas, VA, USA
| | - Pooja Khatkar
- Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, USA
| | - Gifty A Mensah
- Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, USA
| | - Sarah Al Sharif
- Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, USA
| | - Daniel O Pinto
- Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, USA
- Immunology Core, Malaria Biologics Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA
| | - Catherine DeMarino
- Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, USA
| | - Fatah Kashanchi
- Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, USA.
| |
Collapse
|
|
16
|
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.
Collapse
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
| |
Collapse
|
|
17
|
Takao S, Nakashima T, Masuda T, Namba M, Sakamoto S, Yamaguchi K, Horimasu Y, Miyamoto S, Iwamoto H, Fujitaka K, Hamada H, Takahashi S, Nakashima A, Hattori N. Human bone marrow-derived mesenchymal stromal cells cultured in serum-free media demonstrate enhanced antifibrotic abilities via prolonged survival and robust regulatory T cell induction in murine bleomycin-induced pulmonary fibrosis. Stem Cell Res Ther 2021; 12:506. [PMID: 34530920 PMCID: PMC8444523 DOI: 10.1186/s13287-021-02574-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 08/27/2021] [Indexed: 12/29/2022] Open
Abstract
Background Mesenchymal stromal cells (MSCs) are a potential therapeutic tool for pulmonary fibrosis. However, ex vivo MSC expansion using serum poses risks of harmful immune responses or unknown pathogen infections in the recipients. Therefore, MSCs cultured in serum-free media (SF-MSCs) are ideal for clinical settings; however, their efficacy in pulmonary fibrosis is unknown. Here, we investigated the effects of SF-MSCs on bleomycin-induced pulmonary inflammation and fibrosis compared to those of MSCs cultured in serum-containing media (S-MSCs). Methods SF-MSCs and S-MSCs were characterized in vitro using RNA sequence analysis. The in vivo kinetics and efficacy of SF-MSC therapy were investigated using a murine model of bleomycin-induced pulmonary fibrosis. For normally distributed data, Student’s t test and one-way repeated measures analysis of variance followed by post hoc Tukey’s test were used for comparison between two groups and multiple groups, respectively. For non-normally distributed data, Kruskal–Wallis and Mann–Whitney U tests were used for comparison between groups, using e Bonferroni’s correction for multiple comparisons. All tests were two-sided, and P < 0.05 was considered statistically significant. Results Serum-free media promoted human bone marrow-derived MSC expansion and improved lung engraftment of intravenously administered MSCs in recipient mice. SF-MSCs inhibited the reduction in serum transforming growth factor-β1 and the increase of interleukin-6 in both the serum and the bronchoalveolar lavage fluid during bleomycin-induced pulmonary fibrosis. SF-MSC administration increased the numbers of regulatory T cells (Tregs) in the blood and lungs more strongly than in S-MSC administration. Furthermore, SF-MSCs demonstrated enhanced antifibrotic effects on bleomycin-induced pulmonary fibrosis, which were diminished by antibody-mediated Treg depletion. Conclusions SF-MSCs significantly suppressed BLM-induced pulmonary inflammation and fibrosis through enhanced induction of Tregs into the lungs and corrected the dysregulated cytokine balance. Therefore, SF-MSCs could be a useful tool for preventing pulmonary fibrosis progression without the demerits of serum use. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02574-5.
Collapse
Affiliation(s)
- Shun Takao
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Taku Nakashima
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
| | - Takeshi Masuda
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Masashi Namba
- Department of Clinical Oncology, Hiroshima University Hospital, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Shinjiro Sakamoto
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Kakuhiro Yamaguchi
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Yasushi Horimasu
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Shintaro Miyamoto
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Hiroshi Iwamoto
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Kazunori Fujitaka
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Hironobu Hamada
- Department of Physical Analysis and Therapeutic Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Shinya Takahashi
- Department of Cardiovascular Surgery, Graduate School of Medicine, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Ayumu Nakashima
- Department of Stem Cell Biology and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
| | - Noboru Hattori
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| |
Collapse
|
|
18
|
Hezam K, Mo R, Wang C, Liu Y, Li Z. Anti-inflammatory Effects of Mesenchymal Stem Cells and Their Secretomes in Pneumonia. Curr Pharm Biotechnol 2021; 23:1153-1167. [PMID: 34493193 DOI: 10.2174/1389201022666210907115126] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/23/2021] [Accepted: 07/26/2021] [Indexed: 11/22/2022]
Abstract
Mesenchymal stem cells (MSCs) are multipotent progenitor cells that play crucial roles in the microenvironment of injured tissues. The potential therapeutics of MSCs have attracted extensive attention for several diseases such as acute respiratory distress syndrome (ARDS) and novel coronavirus disease 2019 (COVID-19) pneumonia. MSC-extracellular vesicles have been isolated from MSC-conditioned media (MSC-CM) with similar functional effects as parent MSCs. The therapeutic role of MSCs can be achieved through the balance between the inflammatory and regenerative microenvironments. Clinical settings of MSCs and their extracellular vesicles remain promising for many diseases, such as ARDS and pneumonia. However, their clinical applications remain limited due to the cost of growing and storage facilities of MSCs with a lack of standardized MSC-CM. This review highlights the proposed role of MSCs in pulmonary diseases and discusses the recent advances of MSC application for pneumonia and other lung disorders.
Collapse
Affiliation(s)
- Kamal Hezam
- Nankai University School of Medicine, Tianjin. China
| | - Rigen Mo
- Nankai University School of Medicine, Tianjin. China
| | - Chen Wang
- Nankai University School of Medicine, Tianjin. China
| | - Yue Liu
- Nankai University School of Medicine, Tianjin. China
| | - Zongjin Li
- Nankai University School of Medicine, Tianjin. China
| |
Collapse
|
|
19
|
Kiaie N, Ghanavati SPM, Miremadi SS, Hadipour A, Aghdam RM. Mesenchymal Stem Cell-Derived Exosomes for COVID-19 Therapy, Preclinical and Clinical Evidence. Int J Stem Cells 2021; 14:252-261. [PMID: 34158414 PMCID: PMC8429942 DOI: 10.15283/ijsc20182] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 03/31/2021] [Accepted: 04/20/2021] [Indexed: 12/12/2022] Open
Abstract
Since the emergence of the novel coronavirus, named COVID-19, researchers are looking for a treatment to stop the devastating pandemic. During these efforts, mesenchymal stem cells (MSCs), the potential next generation of therapeutic methods with wide application for diseases, have successfully controlled cytokine storm following the virus infection. However, the use of MSCs has been limited due to the ethical issues, immunogenicity, and genetic modifications. Therefore, exosomes were introduced as a suitable substitute for the MSCs. In the case of COVID-19 treatment, both MSCs and exosomes exert their beneficial effect mainly through the management of the cytokine storm. This study provided the underlying mechanisms for the effect of exosomes on COVID-19 treatment and presented several preclinical and clinical studies of exosomes for COVID-19 treatment.
Collapse
Affiliation(s)
- Nasim Kiaie
- School of Metallurgy & Materials Engineering, College of Engineering, University of Tehran, Tehran, Iran.,Research Center for Advanced Technologies in Cardiovascular Medicine, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Sara Sadat Miremadi
- Stem Cell & Regenerative Medicine Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | | | | |
Collapse
|
|
20
|
Rangasamy T, Ghimire L, Jin L, Le J, Periasamy S, Paudel S, Cai S, Jeyaseelan S. Host Defense against Klebsiella pneumoniae Pneumonia Is Augmented by Lung-Derived Mesenchymal Stem Cells. THE JOURNAL OF IMMUNOLOGY 2021; 207:1112-1127. [PMID: 34341173 DOI: 10.4049/jimmunol.2000688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 06/16/2021] [Indexed: 11/19/2022]
Abstract
Klebsiella pneumoniae is a common cause of Gram-negative pneumonia. The spread of antibiotic-resistant and hypervirulent strains has made treatment more challenging. This study sought to determine the immunomodulatory, antibacterial, and therapeutic potential of purified murine stem cell Ag-1+ (Sca-1+) lung mesenchymal stem cells (LMSCs) using in vitro cell culture and an in vivo mouse model of pneumonia caused by K pneumoniae. Sca-1+ LMSCs are plastic adherent, possess colony-forming capacity, express mesenchymal stem cell markers, differentiate into osteogenic and adipogenic lineages in vitro, and exhibit a high proliferative capacity. Further, these Sca-1+ LMSCs are morphologically similar to fibroblasts but differ ultrastructurally. Moreover, Sca-1+ LMSCs have the capacity to inhibit LPS-induced secretion of inflammatory cytokines by bone marrow-derived macrophages and neutrophils in vitro. Sca-1+ LMSCs inhibit the growth of K pneumoniae more potently than do neutrophils. Sca-1+ LMSCs also possess the intrinsic ability to phagocytize and kill K. pneumoniae intracellularly. Whereas the induction of autophagy promotes bacterial replication, inhibition of autophagy enhances the intracellular clearance of K. pneumoniae in Sca-1+ LMSCs during the early time of infection. Adoptive transfer of Sca-1+ LMSCs in K. pneumoniae-infected mice improved survival, reduced inflammatory cells in bronchoalveolar lavage fluid, reduced inflammatory cytokine levels and pathological lesions in the lung, and enhanced bacterial clearance in the lung and in extrapulmonary organs. To our knowledge, these results together illustrate for the first time the protective role of LMSCs in bacterial pneumonia.
Collapse
Affiliation(s)
- Tirumalai Rangasamy
- Center for Lung Biology and Disease, Louisiana State University, Baton Rouge, LA; .,Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA; and
| | - Laxman Ghimire
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA; and
| | - Liliang Jin
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA; and
| | - John Le
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA; and
| | - Sivakumar Periasamy
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA; and
| | - Sagar Paudel
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA; and
| | - Shanshan Cai
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA; and
| | - Samithamby Jeyaseelan
- Center for Lung Biology and Disease, Louisiana State University, Baton Rouge, LA; .,Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA; and.,Division of Pulmonary and Critical Care, Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA
| |
Collapse
|
|
21
|
Zani-Ruttenstock E, Antounians L, Khalaj K, Figueira RL, Zani A. The Role of Exosomes in the Treatment, Prevention, Diagnosis, and Pathogenesis of COVID-19. Eur J Pediatr Surg 2021; 31:326-334. [PMID: 34161984 DOI: 10.1055/s-0041-1731294] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The novel coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), continues to be a major health concern. In search for novel treatment strategies against COVID-19, exosomes have attracted the attention of scientists and pharmaceutical companies worldwide. Exosomes are small extracellular vesicles, secreted by all types of cells, and considered as key mediators of intercellular communication and stem-cell paracrine signaling. Herein, we reviewed the most recent literature about the role of exosomes as potential agents for treatment, prevention, diagnosis, and pathogenesis of COVID-19. Several studies and ongoing clinical trials have been investigating the anti-inflammatory, immunomodulatory, and reparative effects of exosomes derived from mesenchymal stem/stromal cells for COVID-19-related acute lung injury. Other studies reported that exosomes play a key role in convalescent plasma therapy for COVID-19, and that they could be of use for the treatment of COVID-19 Kawasaki's-like multisystem inflammatory syndrome and as drug delivery nanocarriers for antiviral therapy. Harnessing some advantageous aspects of exosome biology, such as their endogenous origin, capability of crossing biological barriers, high stability in circulation, and low toxicity and immunogenicity, several companies have been testing exosome-based vaccines against SARS-CoV-2. As they carry cargos that mimic the status of parent cells, exosomes can be isolated from a variety of sources, including plasma, and employed as biomarkers of COVID-19. Lastly, there is growing evidence supporting the role of exosomes in COVID-19 infection, spread, reactivation, and reinfection. The lessons learned using exosomes for COVID-19 will help determine their efficacy and applicability in other clinical conditions.
Collapse
Affiliation(s)
- Elke Zani-Ruttenstock
- Division of General and Thoracic Surgery, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Lina Antounians
- Division of General and Thoracic Surgery, Hospital for Sick Children, Toronto, Ontario, Canada.,Developmental and Stem Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Kasra Khalaj
- Division of General and Thoracic Surgery, Hospital for Sick Children, Toronto, Ontario, Canada.,Developmental and Stem Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Rebeca L Figueira
- Division of General and Thoracic Surgery, Hospital for Sick Children, Toronto, Ontario, Canada.,Developmental and Stem Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Augusto Zani
- Division of General and Thoracic Surgery, Hospital for Sick Children, Toronto, Ontario, Canada.,Developmental and Stem Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Surgery, University of Toronto, Toronto, Ontario, Canada
| |
Collapse
|
|
22
|
Shi M, Yang Q, Monsel A, Yan J, Dai C, Zhao J, Shi G, Zhou M, Zhu X, Li S, Li P, Wang J, Li M, Lei J, Xu D, Zhu Y, Qu J. Preclinical efficacy and clinical safety of clinical-grade nebulized allogenic adipose mesenchymal stromal cells-derived extracellular vesicles. J Extracell Vesicles 2021; 10:e12134. [PMID: 34429860 PMCID: PMC8363910 DOI: 10.1002/jev2.12134] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 07/18/2021] [Accepted: 08/01/2021] [Indexed: 12/29/2022] Open
Abstract
Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) turn out to be a promising source of cell-free therapy. Here, we investigated the biodistribution and effect of nebulized human adipose-derived MSC-EVs (haMSC-EVs) in the preclinical lung injury model and explored the safety of nebulized haMSC-EVs in healthy volunteers. DiR-labelled haMSC-EVs were used to explore the distribution of nebulized haMSC-EVs in the murine model. Pseudomonas aeruginosa-induced murine lung injury model was established, and survival rate, as well as WBC counts, histology, IL-6, TNF-α and IL-10 levels in bronchoalveolar lavage fluid (BALF) were measured to explore the optimal therapeutic dose of haMSC-EVs through the nebulized route. Twenty-four healthy volunteers were involved and received the haMSC-EVs once, ranging from 2 × 108 particles to 16 × 108 particles (MEXVT study, NCT04313647). Nebulizing haMSC-EVs improved survival rate to 80% at 96 h in P. aeruginosa-induced murine lung injury model by decreasing lung inflammation and histological severity. All volunteers tolerated the haMSC-EVs nebulization well, and no serious adverse events were observed from starting nebulization to the 7th day after nebulization. These findings suggest that nebulized haMSC-EVs could be a promising therapeutic strategy, offering preliminary evidence to promote the future clinical applications of nebulized haMSC-EVs in lung injury diseases.
Collapse
Affiliation(s)
- Meng‐meng Shi
- Department of Pulmonary and Critical Care MedicineRui‐jin HospitalShanghai Jiao‐tong University School of MedicineShanghaiChina
- Institute of Respiratory DiseaseShanghai Jiao‐tong University School of MedicineShanghaiChina
- Key Laboratory of Emergency PreventionDiagnosis and Treatment of Respiratory Infectious DiseasesShanghaiChina
| | - Qing‐yuan Yang
- Department of Pulmonary and Critical Care MedicineRui‐jin HospitalShanghai Jiao‐tong University School of MedicineShanghaiChina
- Institute of Respiratory DiseaseShanghai Jiao‐tong University School of MedicineShanghaiChina
- Key Laboratory of Emergency PreventionDiagnosis and Treatment of Respiratory Infectious DiseasesShanghaiChina
| | - Antoine Monsel
- Multidisciplinary Intensive Care UnitDepartment of Anaesthesiology and Critical CareLa Pitié‐Salpêtrière HospitalAssistance Publique‐Hôpitaux de Paris (APHP)Sorbonne UniversityFrance
- INSERMSorbonne UniversitéUMR S 959, Immunology‐Immunopathology‐ Immunotherapy (I3); F‐75005ParisFrance
- Biotherapy (CIC‐BTi) and Inflammation‐Immunopathology‐Biotherapy Department (DHU i2B)Hôpital Pitié‐SalpêtrièreAP‐HP, F‐75651ParisFrance
| | - Jia‐yang Yan
- Department of Pulmonary and Critical Care MedicineRui‐jin HospitalShanghai Jiao‐tong University School of MedicineShanghaiChina
- Institute of Respiratory DiseaseShanghai Jiao‐tong University School of MedicineShanghaiChina
- Key Laboratory of Emergency PreventionDiagnosis and Treatment of Respiratory Infectious DiseasesShanghaiChina
| | - Cheng‐xiang Dai
- Cellular Biomedicine Group Inc. (CBMG)ShanghaiChina
- Daxing Research InstituteUniversity of Science and Technology BeijingBeijingChina
| | - Jing‐ya Zhao
- Department of Pulmonary and Critical Care MedicineRui‐jin HospitalShanghai Jiao‐tong University School of MedicineShanghaiChina
- Institute of Respiratory DiseaseShanghai Jiao‐tong University School of MedicineShanghaiChina
- Key Laboratory of Emergency PreventionDiagnosis and Treatment of Respiratory Infectious DiseasesShanghaiChina
| | - Guo‐chao Shi
- Department of Pulmonary and Critical Care MedicineRui‐jin HospitalShanghai Jiao‐tong University School of MedicineShanghaiChina
- Institute of Respiratory DiseaseShanghai Jiao‐tong University School of MedicineShanghaiChina
- Key Laboratory of Emergency PreventionDiagnosis and Treatment of Respiratory Infectious DiseasesShanghaiChina
| | - Min Zhou
- Department of Pulmonary and Critical Care MedicineRui‐jin HospitalShanghai Jiao‐tong University School of MedicineShanghaiChina
- Institute of Respiratory DiseaseShanghai Jiao‐tong University School of MedicineShanghaiChina
- Key Laboratory of Emergency PreventionDiagnosis and Treatment of Respiratory Infectious DiseasesShanghaiChina
| | - Xue‐mei Zhu
- Department of Pulmonary and Critical Care MedicineRui‐jin HospitalShanghai Jiao‐tong University School of MedicineShanghaiChina
- Institute of Respiratory DiseaseShanghai Jiao‐tong University School of MedicineShanghaiChina
- Key Laboratory of Emergency PreventionDiagnosis and Treatment of Respiratory Infectious DiseasesShanghaiChina
| | - Su‐ke Li
- Cellular Biomedicine Group Inc. (CBMG)ShanghaiChina
| | - Ping Li
- Cellular Biomedicine Group Inc. (CBMG)ShanghaiChina
| | - Jing Wang
- Cellular Biomedicine Group Inc. (CBMG)ShanghaiChina
| | - Meng Li
- Cellular Biomedicine Group Inc. (CBMG)ShanghaiChina
| | - Ji‐gang Lei
- Cellular Biomedicine Group Inc. (CBMG)ShanghaiChina
| | - Dong Xu
- Cellular Biomedicine Group Inc. (CBMG)ShanghaiChina
| | - Ying‐gang Zhu
- Department of Pulmonary and Critical Care MedicineHua‐dong HospitalFudan UniversityShanghaiChina
| | - Jie‐ming Qu
- Department of Pulmonary and Critical Care MedicineRui‐jin HospitalShanghai Jiao‐tong University School of MedicineShanghaiChina
- Institute of Respiratory DiseaseShanghai Jiao‐tong University School of MedicineShanghaiChina
- Key Laboratory of Emergency PreventionDiagnosis and Treatment of Respiratory Infectious DiseasesShanghaiChina
| |
Collapse
|
|
23
|
Fengyun W, LiXin Z, Xinhua Q, Bin F. Mesenchymal Stromal Cells Attenuate Infection-Induced Acute Respiratory Distress Syndrome in Animal Experiments: A Meta-Analysis. Cell Transplant 2021; 29:963689720969186. [PMID: 33164559 PMCID: PMC7784610 DOI: 10.1177/0963689720969186] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Mesenchymal stromal cell (MSC) therapy is a potential therapy for treating acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), which was widely studied in the last decade. The purpose of our meta-analysis was to investigate the efficacy of MSCs for simulated infection-induced ALI/ARDS in animal trials. PubMed and EMBASE were searched to screen relevant preclinical trials with a prespecified search strategy. 57 studies met the inclusion criteria and were included in our study. Our meta-analysis showed that MSCs can reduce the lung injury score of ALI caused by lipopolysaccharide or bacteria (standardized mean difference (SMD) = −2.97, 95% CI [−3.64 to −2.30], P < 0.00001) and improve the animals’ survival (odds ratio = 3.64, 95% CI [2.55 to 5.19], P < 0.00001). Our study discovered that MSCs can reduce the wet weight to dry weight ratio of the lung (SMD = −2.58, 95% CI [−3.24 to −1.91], P < 0.00001). The proportion of the alveolar sac in the MSC group was higher than that in the control group (SMD = 1.68, 95% CI [1.22 to 2.13], P < 0.00001). Moreover, our study detected that MSCs can downregulate the levels of proinflammatory factors such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α in the lung and it can upregulate the level of anti-inflammatory factor IL-10. MSCs were also found to reduce the level of neutrophils and total protein in bronchoalveolar lavage fluid, decrease myeloperoxidase (MPO) activity in the lung, and improve lung compliance. MSC therapy may be a promising treatment for ALI/ARDS since it may mitigate the severity of lung injury, modulate the immune balance, and ameliorate the permeability of lung vessels in ALI/ARDS, thus facilitating lung regeneration and repair.
Collapse
Affiliation(s)
- Wang Fengyun
- Department of Critical Care Medicine, 66278The First People's Hospital of Foshan, Foshan, China
| | - Zhou LiXin
- Department of Critical Care Medicine, 66278The First People's Hospital of Foshan, Foshan, China
| | - Qiang Xinhua
- Department of Critical Care Medicine, 66278The First People's Hospital of Foshan, Foshan, China
| | - Fang Bin
- Department of Critical Care Medicine, 66278The First People's Hospital of Foshan, Foshan, China
| |
Collapse
|
|
24
|
Liu G, Di Z, Hao C, Wang W, Pei T, Zheng L, Long H, Wang H, Liao W, Wang W, Zhang C, Li X, Mi Y, Yan F, Liu Y. Effects of different concentrations of mesenchymal stem cells treatment on LPS-induced acute respiratory distress syndrome rat model. Exp Lung Res 2021; 47:226-238. [PMID: 33749474 DOI: 10.1080/01902148.2021.1897191] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 02/02/2021] [Accepted: 02/25/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE This study was prospectively designed to investigate the effects of different concentrations of mesenchymal stem cells treatment on respiratory mechanics, oxygenation, hemodynamics and inflammatory response in LPS-induced acute respiratory distress syndrome (ARDS) rat model. Methods: One hundred and twenty six LPS-induced ARDS model rats (weighted 200-220 g) were randomly divided into three groups: 1) Control group (N = 42); 2) low-dose hUC-MSC treatment group (MSC group 1, 1x107 cell/kg, N = 42); 3) high-dose hUC-MSC treatment group (MSC group 2, 2x107 cell/kg, N = 42), sham operation group as healthy group (N = 15). The rats were observed closely for 24 hours after hUC-MSC treatment, and the survival rate was calculated. At 24 hours, all rats were tested for hemodynamics, blood gas analysis, heart, lung, liver and kidney functions, inflammatory factors detection in blood samples and broncho-alveolar lavage fluid (BALF). The lung tissue of the rats was collected for HE staining analysis. Results: After LPS injection, ARDS was obvious in all LPS-infused rat groups, consistent with severe acute lung injury and high death rate. However, compared with the control group, a single intravenous injection hUC-MSC at dose of 1 × 107 cells/kg (low dose group) and 2 × 107 cells/kg (high dose group) reduced the mortality of rats with LPS-induced ARDS, as well as improving the lung function, increased the arterial oxygen pressure, improved the heart function, and reduced the levels of inflammatory factors including IL-1β, IL-6, and TNF-α. In addition, the high dose MSC group showed better lung injury therapeutic effects than the low dose MSC group. Data from this study demonstrated that injection of hUC-MSC had a significant therapeutic effect in treating the rat model of LPS-induced ARDS and multiple organ function injury.
Collapse
Affiliation(s)
- Guangyang Liu
- Stem Cell Biology and Regenerative Medicine Institution, Beijing Yi-Chuang Institute of Bio-Industry, Beijing, China
| | - Zhiquan Di
- State Key Laboratory of Drug Delivery and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China
| | - Chunhua Hao
- State Key Laboratory of Drug Delivery and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China
| | - Weiting Wang
- State Key Laboratory of Drug Delivery and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China
| | - Tianxian Pei
- State Key Laboratory of Drug Delivery and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China
| | - Libo Zheng
- Stem Cell Biology and Regenerative Medicine Institution, Beijing Yi-Chuang Institute of Bio-Industry, Beijing, China
| | - Haomiao Long
- Stem Cell Biology and Regenerative Medicine Institution, Beijing Yi-Chuang Institute of Bio-Industry, Beijing, China
| | - Hao Wang
- Stem Cell Biology and Regenerative Medicine Institution, Beijing Yi-Chuang Institute of Bio-Industry, Beijing, China
| | | | - Wen Wang
- Baylx, Inc, Irvine, California, USA
| | - Chenliang Zhang
- Stem Cell Biology and Regenerative Medicine Institution, Beijing Yi-Chuang Institute of Bio-Industry, Beijing, China
| | - Xin Li
- Stem Cell Biology and Regenerative Medicine Institution, Beijing Yi-Chuang Institute of Bio-Industry, Beijing, China
| | - Yi Mi
- Stem Cell Biology and Regenerative Medicine Institution, Beijing Yi-Chuang Institute of Bio-Industry, Beijing, China
| | - Fengying Yan
- State Key Laboratory of Drug Delivery and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China
| | - Yongjun Liu
- Stem Cell Biology and Regenerative Medicine Institution, Beijing Yi-Chuang Institute of Bio-Industry, Beijing, China
| |
Collapse
|
|
25
|
Medical progress: Stem cells as a new therapeutic strategy for COVID-19. Stem Cell Res 2021; 52:102239. [PMID: 33601098 PMCID: PMC7877901 DOI: 10.1016/j.scr.2021.102239] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Accepted: 02/05/2021] [Indexed: 02/07/2023] Open
Abstract
Currently, the world is facing the SARS-CoV-2 pandemic, coronavirus of acute respiratory distress syndrome 2, causes of COVID-19. Coronaviruses are RNA single-stranded viruses that have an envelope. In addition, coronaviruses are classified into four subfamilies: alpha, beta, gamma and delta coronaviruses. The first of them, cause mildly symptomatic or asymptomatic infections, while beta-coronaviruses are responsible for severe diseases. SARS-CoV-2 belongs to the group of beta-coronaviruses. Current available therapies use corticosteroids to reduce inflammation, non-specific antiviral drugs or antibiotics in the treatment of secondary bacterial infections. In addition, therapies based on the use of hydroxychloroquine, chloroquine, remdesvir, ribavirin, interferon or lopinavir-ritonavir were also initially used. Mesenchemical stem cells (MSCs) are widely used in cell therapies, which include both basic research and clinical trials. Their exceptional effectiveness and safety have been confirmed and documented in many clinical studies, which include a number of inflammatory diseases involving the immune system - one of them is systemic lupus erythematosus. Available data indicate the ability to differentiate MSCs and their immunomodulatory effects. In addition, through interactions with immune cells, which include, but are not limited to, macrophages and dendritic cells, or paracrine secretion, MSCs are able to secrete a number of types of cytokines. MSCs are also characterized by tissue regeneration and regulation of inflammation. Due to their properties, researchers turned to determine whether MSC transplantation is able to improve the outcome of patients with COVID-19 viral pneumonia. The presented review provides not only new knowledge in the field of molecular mechanisms of pro-regenerative action of stem cells, but also have the potential to open up new prospects of action to improve lung tissue regeneration in COVID-19 patients. In addition, in review mentioned about clinical trials using MSCs with a complete status, as well as the latest discoveries in molecular biology, a platform model of pluripotent stem cells in the SARS-CoV-2 study on 3D animal models and nanoconjugates based on stem cells.
Collapse
|
|
26
|
Jerkic M, Litvack ML, Gagnon S, Otulakowski G, Zhang H, Rotstein O, Kavanagh BP, Post M, Laffey JG. Embryonic-Derived Myb- Macrophages Enhance Bacterial Clearance and Improve Survival in Rat Sepsis. Int J Mol Sci 2021; 22:ijms22063190. [PMID: 33804806 PMCID: PMC8004006 DOI: 10.3390/ijms22063190] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 03/15/2021] [Accepted: 03/17/2021] [Indexed: 12/13/2022] Open
Abstract
Peritoneal resident macrophages play a key role in combating sepsis in the peritoneal cavity. We sought to determine if peritoneal transplantation of embryonic Myb- "peritoneal-like" macrophages attenuate abdominal fecal sepsis. Directed differentiation of rodent pluripotent stem cells (PSCs) was used in factor-defined media to produce embryonic-derived large "peritoneal-like" macrophages (Ed-LPM) that expressed peritoneal macrophage markers and demonstrated phagocytic capacity. Preclinical in vivo studies determined Ed-LPM efficacy in rodent abdominal fecal sepsis with or without Meropenem. Ex vivo studies explored the mechanism and effects of Ed-LPM on host immune cell number and function, including phagocytosis, reactive oxygen species (ROS) production, efferocytosis and apoptosis. Ed-LPM reduced sepsis severity by decreasing bacterial load in the liver, spleen and lungs. Ed-LPM therapy significantly improved animal survival by ~30% and reduced systemic bacterial burden to levels comparable to Meropenem therapy. Ed-LPM therapy decreased peritoneal TNFα while increasing IL-10 concentrations. Ed-LPMs enhanced peritoneal macrophage phagocytosis of bacteria, increased macrophage production of ROS and restored homeostasis via apoptosis and efferocytosis-induced clearance of neutrophils. In conclusion, Ed-LPM reduced systemic sepsis severity, improved survival and reduced bacterial load by enhancing peritoneal macrophage bacterial phagocytosis and killing and clearance of intra-peritoneal neutrophils. Macrophage therapy may be a potential strategy to address sepsis.
Collapse
Affiliation(s)
- Mirjana Jerkic
- Keenan Research Centre for Biomedical Science, Unity Health Toronto St. Michael’s, University of Toronto, Toronto, ON M5B 1T8, Canada; (M.J.); (S.G.); (H.Z.); (O.R.)
| | - Michael L. Litvack
- Translational Medicine Program, Hospital for Sick Children, University of Toronto, Toronto, ON M5G 0A4, Canada; (M.L.L.); (G.O.); (B.P.K.); (M.P.)
| | - Stéphane Gagnon
- Keenan Research Centre for Biomedical Science, Unity Health Toronto St. Michael’s, University of Toronto, Toronto, ON M5B 1T8, Canada; (M.J.); (S.G.); (H.Z.); (O.R.)
| | - Gail Otulakowski
- Translational Medicine Program, Hospital for Sick Children, University of Toronto, Toronto, ON M5G 0A4, Canada; (M.L.L.); (G.O.); (B.P.K.); (M.P.)
| | - Haibo Zhang
- Keenan Research Centre for Biomedical Science, Unity Health Toronto St. Michael’s, University of Toronto, Toronto, ON M5B 1T8, Canada; (M.J.); (S.G.); (H.Z.); (O.R.)
| | - Ori Rotstein
- Keenan Research Centre for Biomedical Science, Unity Health Toronto St. Michael’s, University of Toronto, Toronto, ON M5B 1T8, Canada; (M.J.); (S.G.); (H.Z.); (O.R.)
| | - Brian P. Kavanagh
- Translational Medicine Program, Hospital for Sick Children, University of Toronto, Toronto, ON M5G 0A4, Canada; (M.L.L.); (G.O.); (B.P.K.); (M.P.)
- Department of Critical Care Medicine, Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada
- Departments of Anesthesia, Physiology and Interdepartmental Division of Critical Care, University of Toronto, Toronto, ON M5S 1A1, Canada
| | - Martin Post
- Translational Medicine Program, Hospital for Sick Children, University of Toronto, Toronto, ON M5G 0A4, Canada; (M.L.L.); (G.O.); (B.P.K.); (M.P.)
- Departments of Anesthesia, Physiology and Interdepartmental Division of Critical Care, University of Toronto, Toronto, ON M5S 1A1, Canada
| | - John G. Laffey
- Keenan Research Centre for Biomedical Science, Unity Health Toronto St. Michael’s, University of Toronto, Toronto, ON M5B 1T8, Canada; (M.J.); (S.G.); (H.Z.); (O.R.)
- Departments of Anesthesia, Physiology and Interdepartmental Division of Critical Care, University of Toronto, Toronto, ON M5S 1A1, Canada
- Department of Anesthesia and Critical Care Medicine, Unity Health Toronto St. Michael’s, Toronto, ON M5B 1W8, Canada
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, Biomedical Sciences Building, School of Medicine, National University of Ireland Galway, H91 TK33 Galway, Ireland
- Correspondence: ; Tel.: +1-353-91-495662
| |
Collapse
|
|
27
|
Lou S, Duan Y, Nie H, Cui X, Du J, Yao Y. Mesenchymal stem cells: Biological characteristics and application in disease therapy. Biochimie 2021; 185:9-21. [PMID: 33711361 DOI: 10.1016/j.biochi.2021.03.003] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 03/05/2021] [Accepted: 03/05/2021] [Indexed: 12/12/2022]
Abstract
Mesenchymal stem cells (MSCs) are multipotent stem cells. In addition to the capacity for self-renewal and multipotential differentiation, MSCs also have the following characteristics. MSCs can exert immunomodulatory functions through interaction with innate or adaptive immune cells, MSCs with poor immunogenicity can be used for allogeneic transplantation, and MSCs can "home" to inflammation and tumour sites. Based on these biological properties, MSCs demonstrate broad clinical application prospects in the treatment of tissue injury, autoimmune diseases, transplantation, cancer and other inflammation-related diseases. In this review we describe the biological characteristics of MSCs and discuss the research advances of MSCs in regenerative medicine, immunomodulation, oncology, and COVID-19, to fully understand the range of diseases in which MSC therapy may be beneficial.
Collapse
Affiliation(s)
- Songyue Lou
- School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
| | - Yongtao Duan
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Henan, 450018, China.
| | - Huizong Nie
- School of Life Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
| | - Xujie Cui
- School of Life Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
| | - Jialing Du
- School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
| | - Yongfang Yao
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Henan, 450018, China; School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
| |
Collapse
|
|
28
|
Forbes S, Bond AR, Thirlwell KL, Burgoyne P, Samuel K, Noble J, Borthwick G, Colligan D, McGowan NWA, Lewis PS, Fraser AR, Mountford JC, Carter RN, Morton NM, Turner ML, Graham GJ, Campbell JDM. Human umbilical cord perivascular cells improve human pancreatic islet transplant function by increasing vascularization. Sci Transl Med 2021; 12:12/526/eaan5907. [PMID: 31941825 DOI: 10.1126/scitranslmed.aan5907] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Revised: 06/24/2019] [Accepted: 12/03/2019] [Indexed: 12/12/2022]
Abstract
Islet transplantation is an efficacious therapy for type 1 diabetes; however, islets from multiple donor pancreata are required, and a gradual attrition in transplant function is seen. Here, we manufactured human umbilical cord perivascular mesenchymal stromal cells (HUCPVCs) to Good Manufacturing Practice (GMP) standards. HUCPVCs showed a stable phenotype while undergoing rapid ex vivo expansion at passage 2 (p2) to passage 4 (p4) and produced proregenerative factors, strongly suppressing T cell responses in the resting state and in response to inflammation. Transplanting an islet equivalent (IEQ):HUCPVC ratio of 1:30 under the kidney capsule in diabetic NSG mice demonstrated the fastest return to normoglycemia by 3 days after transplant: Superior glycemic control was seen at both early (2.7 weeks) and later stages (7, 12, and 16 weeks) versus ratios of 1:0, 1:10, and 1:50, respectively. Syngeneic islet transplantation in immunocompetent mice using the clinically relevant hepatic portal route with a marginal islet mass showed that mice transplanted with an IEQ:HUCPVC ratio of 1:150 had superior glycemic control versus ratios of 1:0, 1:90, and 1:210 up to 6 weeks after transplant. Immunodeficient mice transplanted with human islets (IEQ:HUCPVC ratio of 1:150) exhibited better glycemic control for 7 weeks after transplant versus islet transplant alone, and islets transplanted via the hepatic portal vein in an allogeneic mouse model using a curative islet mass demonstrated delayed rejection of islets when cotransplanted with HUCPVCs (IEQ:HUCPVC ratio of 1:150). The immunosuppressive and proregenerative properties of HUCPVCs demonstrated long-term positive effects on graft function in vivo, indicating that they may improve long-term human islet allotransplantation outcomes.
Collapse
Affiliation(s)
- Shareen Forbes
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK. .,Clinical Islet Transplantation Programme, Royal Infirmary of Edinburgh, Edinburgh EH16 4SU, UK
| | - Andrew R Bond
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Kayleigh L Thirlwell
- Advanced Therapeutics, Scottish National Blood Transfusion Service, Edinburgh EH14 4BE, UK.,Chemokine Research Group, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK
| | - Paul Burgoyne
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.,Advanced Therapeutics, Scottish National Blood Transfusion Service, Edinburgh EH14 4BE, UK.,Chemokine Research Group, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK
| | - Kay Samuel
- Advanced Therapeutics, Scottish National Blood Transfusion Service, Edinburgh EH14 4BE, UK
| | - June Noble
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Gary Borthwick
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - David Colligan
- Advanced Therapeutics, Scottish National Blood Transfusion Service, Edinburgh EH14 4BE, UK
| | - Neil W A McGowan
- Advanced Therapeutics, Scottish National Blood Transfusion Service, Edinburgh EH14 4BE, UK
| | - Philip Starkey Lewis
- Medical Research Council (MRC) Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Alasdair R Fraser
- Advanced Therapeutics, Scottish National Blood Transfusion Service, Edinburgh EH14 4BE, UK
| | - Joanne C Mountford
- Advanced Therapeutics, Scottish National Blood Transfusion Service, Edinburgh EH14 4BE, UK
| | - Roderick N Carter
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Nicholas M Morton
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Marc L Turner
- Advanced Therapeutics, Scottish National Blood Transfusion Service, Edinburgh EH14 4BE, UK
| | - Gerard J Graham
- Chemokine Research Group, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK
| | - John D M Campbell
- Advanced Therapeutics, Scottish National Blood Transfusion Service, Edinburgh EH14 4BE, UK. .,Chemokine Research Group, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK
| |
Collapse
|
|
29
|
Shi M, Zhu Y, Yan J, Rouby J, Summah H, Monsel A, Qu J. Role of miR-466 in mesenchymal stromal cell derived extracellular vesicles treating inoculation pneumonia caused by multidrug-resistant Pseudomonas aeruginosa. Clin Transl Med 2021; 11:e287. [PMID: 33463070 PMCID: PMC7805403 DOI: 10.1002/ctm2.287] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 12/27/2020] [Accepted: 12/29/2020] [Indexed: 12/15/2022] Open
Abstract
RATIONALE The effects of mesenchymal stromal cells (MSCs) and MSC-derived extracellular vesicles (MSC EVs) on multidrug-resistant pseudomonas aeruginosa (MDR-PA)-induced pneumonia remain unclear. MATERIALS AND METHODS MicroRNA array and RT-PCR were used to select the major microRNA in MSC EVs. Human peripheral blood monocytes were obtained and isolated from qualified patients. The crosstalk between MSCs/MSC EVs and macrophages in vitro was studied. MDR-PA pneumonia models were further established in C57BL/6 mice and MSC EVs or miR-466 overexpressing MSC EVs were intratracheally instilled. RESULTS MiR-466 was highly expressed in MSC EVs. MSCs and miR-466 promoted macrophage polarization toward Type 2 phenotype through TIRAP-MyD88-NFκB axis. Moreover, cocultured macrophages with miR-466 overexpressing MSCs significantly increased the phagocytosis of macrophages. MSC EVs significantly reduced mortality and decreased influx of BALF neutrophils, proinflammatory factor levels, protein, and bacterial load in murine MDR-PA pneumonia. Administration of miR-466 overexpressing MSC EVs further alleviated the inflammatory severity. CONCLUSIONS MSC-derived EVs containing high levels of miR-466 may partly participate in host immune responses to MDR-PA. Both MSCs and MSC EVs have therapeutic effects in treating MDR-PA-induced pneumonia.
Collapse
Affiliation(s)
- Meng‐meng Shi
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
- Institute of Respiratory Diseases, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Ying‐gang Zhu
- Department of Pulmonary and Critical Care Medicine, Hua‐dong HospitalFudan UniversityShanghaiChina
| | - Jia‐yang Yan
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
- Institute of Respiratory Diseases, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Jean‐Jacques Rouby
- Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié‐Salpêtrière Hospital, Assistance Publique‐Hôpitaux de Paris (APHP)Sorbonne UniversityParisFrance
| | - Hanssa Summah
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
- Institute of Respiratory Diseases, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Antoine Monsel
- Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié‐Salpêtrière Hospital, Assistance Publique‐Hôpitaux de Paris (APHP)Sorbonne UniversityParisFrance
- INSERM, UMR S 959, Immunology‐Immunopathology‐ Immunotherapy (I3)Sorbonne UniversitéParisF‐75005France
- Biotherapy (CIC‐BTi) and Inflammation‐Immunopathology‐Biotherapy Department (DHU i2B)Hôpital Pitié‐SalpêtrièreAP‐HPParisF‐75651France
| | - Jie‐ming Qu
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
- Institute of Respiratory Diseases, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
| |
Collapse
|
|
30
|
Xiong J, Chen L, Zhang L, Bao L, Shi Y. Mesenchymal Stromal Cell-Based Therapy: A Promising Approach for Severe COVID-19. Cell Transplant 2021; 30:963689721995455. [PMID: 33650894 PMCID: PMC7930651 DOI: 10.1177/0963689721995455] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 12/22/2020] [Accepted: 01/28/2021] [Indexed: 01/08/2023] Open
Abstract
During the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), many critically ill patients died of severe pneumonia, acute respiratory distress syndrome (ARDS), or multiple organ dysfunction syndrome. To date, no specific treatments have been proven to be effective for coronavirus disease 2019 (COVID-19). In the animal models and clinical applications, mesenchymal stromal/stem cells (MSCs) have been shown safety and efficacy for the treatment of respiratory virus infection through their abilities of differentiation and immunomodulation. Besides, possessing several advantages of MSC-derived extracellular vesicles (EVs) over MSCs, EV-based therapy also holds potential therapeutic effects in respiratory virus infection. In this review, we summarized the basic characteristics and mechanisms of COVID-19 and MSCs, outlined some preclinical and clinical studies of MSCs or MSC-EVs for respiratory virus infection such as influenza virus and SARS-CoV-2, shed light on the common problems that we should overcome to translate MSC therapy into clinical application, and discussed some safe issues related to the use of MSCs.
Collapse
Affiliation(s)
- Jing Xiong
- Department of Neonatology, Children’s Hospital of Chongqing Medical University, Chongqing, China
| | - Long Chen
- Department of Neonatology, Children’s Hospital of Chongqing Medical University, Chongqing, China
| | - Li Zhang
- Department of Pulmonology, Children’s Hospital of Chongqing Medical University, Chongqing, China
| | - Lei Bao
- Department of Neonatology, Children’s Hospital of Chongqing Medical University, Chongqing, China
| | - Yuan Shi
- Department of Neonatology, Children’s Hospital of Chongqing Medical University, Chongqing, China
| |
Collapse
|
|
31
|
Gorman E, Millar J, McAuley D, O'Kane C. Mesenchymal stromal cells for acute respiratory distress syndrome (ARDS), sepsis, and COVID-19 infection: optimizing the therapeutic potential. Expert Rev Respir Med 2020; 15:301-324. [PMID: 33172313 DOI: 10.1080/17476348.2021.1848555] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Introduction: Mesenchymal stromal (stem) cell (MSC) therapies are emerging as a promising therapeutic intervention in patients with Acute Respiratory Distress Syndrome (ARDS) and sepsis due to their reparative, immunomodulatory, and antimicrobial properties.Areas covered: This review provides an overview of Mesenchymal stromal cells (MSCs) and their mechanisms of effect in ARDS and sepsis. The preclinical and clinical evidence to support MSC therapy in ARDS and sepsis is discussed. The potential for MSC therapy in COVID-19 ARDS is discussed with insights from respiratory viral models and early clinical reports of MSC therapy in COVID-19. Strategies to optimize the therapeutic potential of MSCs in ARDS and sepsis are considered including preconditioning, altered gene expression, and alternative cell-free MSC-derived products, such as extracellular vesicles and conditioned medium.Expert opinion: MSC products present considerable therapeutic promise for ARDS and sepsis. Preclinical investigations report significant benefits and early phase clinical studies have not highlighted safety concerns. Optimization of MSC function in preclinical models of ARDS and sepsis has enhanced their beneficial effects. MSC-derived products, as cell-free alternatives, may provide further advantages in this field. These strategies present opportunity for the clinical development of MSCs and MSC-derived products with enhanced therapeutic efficacy.
Collapse
Affiliation(s)
- Ellen Gorman
- School of Medicine Dentistry and Biomedical Science, Queen's University Belfast, UK
| | - Jonathan Millar
- Division of Functional Genetics and Development, Roslin Institute, University of Edinburgh, Edinburgh, UK
| | - Danny McAuley
- School of Medicine Dentistry and Biomedical Science, Queen's University Belfast, UK
| | - Cecilia O'Kane
- School of Medicine Dentistry and Biomedical Science, Queen's University Belfast, UK
| |
Collapse
|
|
32
|
Taghavi-Farahabadi M, Mahmoudi M, Soudi S, Hashemi SM. Hypothesis for the management and treatment of the COVID-19-induced acute respiratory distress syndrome and lung injury using mesenchymal stem cell-derived exosomes. Med Hypotheses 2020; 144:109865. [PMID: 32562911 PMCID: PMC7242964 DOI: 10.1016/j.mehy.2020.109865] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Accepted: 05/21/2020] [Indexed: 12/31/2022]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the coronaviridae that causes respiratory disorders. After infection, large amounts of inflammatory cytokines are secreted, known as the cytokine storm. These cytokines can cause pulmonary damage induced by inflammation resulting in acute respiratory distress syndrome (ARDS), and even death. One of the therapeutic approaches for treatment of ARDS is a mesenchymal stem cell (MSC). MSCs suppress inflammation and reduce lung injury through their immunomodulatory properties. MSCs also have the potential to prevent apoptosis of the lung cells and regenerate them. But our suggestion is using MSCs-derived exosomes. Because these exosomes apply the same immunomodulatory and tissue repair effects of MSCs and they don't have problems associated to cell maintenance and injections. For investigation the hypothesis, MSCs should be isolated from tissues and characterized. Then, the exosomes should be isolated from the supernatants and characterized. These exosomes should be injected into a transgenic animal for COVID-19. In the final section, lung function assessment, histological examination, micro-CT, differential leukocyte, viral load analysis, cytokine assay, and CRP level analysis can be investigated. COVID-19 treatment is currently focused on supportive therapies and no vaccine has been developed for it. So, numerous researches are needed to find potential therapies. Since the pathogenesis of this disease was identified in previous studies and can cause lung injury with ARDS, investigation of the therapeutic approaches that can suppress inflammation, cytokine storm and ARDS can be helpful in finding a novel therapeutic approach for this disease.
Collapse
Affiliation(s)
- Mahsa Taghavi-Farahabadi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Mahmoudi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Sara Soudi
- Department of immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Seyed Mahmoud Hashemi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
33
|
Durand N, Mallea J, Zubair AC. Insights into the use of mesenchymal stem cells in COVID-19 mediated acute respiratory failure. NPJ Regen Med 2020; 5:17. [PMID: 33580031 PMCID: PMC7589470 DOI: 10.1038/s41536-020-00105-z] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 10/06/2020] [Indexed: 12/16/2022] Open
Abstract
The emergence of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) at the end of 2019 in Hubei province China, is now the cause of a global pandemic present in over 150 countries. COVID-19 is a respiratory illness with most subjects presenting with fever, cough and shortness of breath. In a subset of patients, COVID-19 progresses to hypoxic respiratory failure and acute respiratory distress syndrome (ARDS), both of which are mediated by widespread inflammation and a dysregulated immune response. Mesenchymal stem cells (MSCs), multipotent stromal cells that mediate immunomodulation and regeneration, could be of potential benefit to a subset of COVID-19 subjects with acute respiratory failure. In this review, we discuss key features of the current COVID-19 outbreak, and the rationale for MSC-based therapy in this setting, as well as the limitations associated with this therapeutic approach.
Collapse
Affiliation(s)
- Nisha Durand
- Laboratory Medicine and Pathology and Center for Regenerative Medicine, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Jorge Mallea
- Department of Medicine, Division of Allergy, Pulmonary and Sleep Medicine, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Abba C Zubair
- Laboratory Medicine and Pathology and Center for Regenerative Medicine, Mayo Clinic, Jacksonville, FL, 32224, USA.
| |
Collapse
|
|
34
|
Lin F, Ichim TE, Pingle S, Jones LD, Kesari S, Ashili S. Mesenchymal stem cells as living anti-inflammatory therapy for COVID-19 related acute respiratory distress syndrome. World J Stem Cells 2020; 12:1067-1079. [PMID: 33178392 PMCID: PMC7596438 DOI: 10.4252/wjsc.v12.i10.1067] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 08/13/2020] [Accepted: 09/14/2020] [Indexed: 02/06/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19), a pandemic disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), is growing at an exponential rate worldwide. Manifestations of this disease are heterogeneous; however, advanced cases often exhibit various acute respiratory distress syndrome-like symptoms, systemic inflammatory reactions, coagulopathy, and organ involvements. A common theme in advanced COVID-19 is unrestrained immune activation, classically referred to as a “cytokine storm”, as well as deficiencies in immune regulatory mechanisms such as T regulatory cells. While mesenchymal stem cells (MSCs) themselves are objects of cytokine regulation, they can secrete cytokines to modulate immune cells by inducing anti-inflammatory regulatory Treg cells, macrophages and neutrophils; and by reducing the activation of T and B cells, dendritic and nature killer cells. Consequently, they have therapeutic potential for treating severe cases of COVID-19. Here we discuss the unique ability of MSCs, to act as a “living anti-inflammatory”, which can “rebalance” the cytokine/immune responses to restore equilibrium. We also discuss current MSC trials and present different concepts for optimization of MSC therapy in patients with COVID-19 acute respiratory distress syndrome.
Collapse
Affiliation(s)
- Feng Lin
- Research and Development, CureScience, San Diego, CA 92121, United States
| | - Thomas E Ichim
- Research and Development, CureScience, San Diego, CA 92121, United States
| | - Sandeep Pingle
- Research and Development, CureScience, San Diego, CA 92121, United States
| | - Lawrence D Jones
- Research and Development, CureScience, San Diego, CA 92121, United States
| | - Santosh Kesari
- Cancer Center, John Wayne Cancer Institute and Pacific Neuroscience Institute at Providence Saint John's Health Center, Santa Monica, CA 90404, United States
| | - Shashaanka Ashili
- Research and Development, CureScience, San Diego, CA 92121, United States
| |
Collapse
|
|
35
|
Kavianpour M, Saleh M, Verdi J. The role of mesenchymal stromal cells in immune modulation of COVID-19: focus on cytokine storm. Stem Cell Res Ther 2020; 11:404. [PMID: 32948252 PMCID: PMC7499002 DOI: 10.1186/s13287-020-01849-7] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 06/30/2020] [Accepted: 07/23/2020] [Indexed: 12/11/2022] Open
Abstract
The outbreak of coronavirus disease 2019 (COVID-19) pandemic is quickly spreading all over the world. This virus, which is called SARS-CoV-2, has infected tens of thousands of people. Based on symptoms, the pathogenesis of acute respiratory illness is responsible for highly homogenous coronaviruses as well as other pathogens. Evidence suggests that high inflammation rates, oxidation, and overwhelming immune response probably contribute to pathology of COVID-19. COVID-19 causes cytokine storm, which subsequently leads to acute respiratory distress syndrome (ARDS), often ending up in the death of patients. Mesenchymal stem cells (MSCs) are multipotential stem cells that are recognized via self-renewal capacity, generation of clonal populations, and multilineage differentiation. MSCs are present in nearly all tissues of the body, playing an essential role in repair and generation of tissues. Furthermore, MSCs have broad immunoregulatory properties through the interaction of immune cells in both innate and adaptive immune systems, leading to immunosuppression of many effector activities. MSCs can reduce the cytokine storm produced by coronavirus infection. In a number of studies, the administration of these cells has been beneficial for COVID-19 patients. Also, MSCs may be able to improve pulmonary fibrosis and lung function. In this review, we will review the newest research findings regarding MSC-based immunomodulation in patients with COVID-19.
Collapse
Affiliation(s)
- Maria Kavianpour
- Department of Tissue Engineering and Applied Cell Sciences, Faculty of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Cell-Based Therapies Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahshid Saleh
- Department of Tissue Engineering and Applied Cell Sciences, Faculty of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Javad Verdi
- Department of Tissue Engineering and Applied Cell Sciences, Faculty of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
36
|
Chen XY, Chen YY, Lin W, Chien CW, Chen CH, Wen YC, Hsiao TC, Chuang HC. Effects of Human Umbilical Cord-Derived Mesenchymal Stem Cells on the Acute Cigarette Smoke-Induced Pulmonary Inflammation Model. Front Physiol 2020; 11:962. [PMID: 32903481 PMCID: PMC7434987 DOI: 10.3389/fphys.2020.00962] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 07/15/2020] [Indexed: 12/27/2022] Open
Abstract
Cigarette smoke (CS) has been reported to induce oxidative stress and inflammatory process in the lungs. However, the role of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in the regulation of pulmonary inflammation remains unclear. The objective of this study is to investigate the effects of hUC-MSCs on lung inflammation in the acute CS-induced pulmonary inflammation animal model. Eight-week-old male C57BL/6 mice were intravenously administered 3 × 106, 1 × 107, and 3 × 107 cells/kg of hUC-MSCs as well as normal saline alone (control) after 3 days of CS exposure. Mice exposed to high-efficiency particulate air (HEPA)-filtered room air served as the CS control group. High-dose (3 × 107 cells/kg) hUC-MSC administration significantly decreased tumor necrosis factor (TNF)-α in the bronchoalveolar lavage fluid (BALF) of CS-exposed mice (p < 0.05). The chemokine (CXC motif) ligand 1/keratinocyte chemoattractant (CXCL1/KC) in BALF were significantly reduced by low-dose (3 × 106 cells/kg) and high-dose (3 × 107 cells/kg) hUC-MSC (p < 0.05). Medium-dose hUC-MSC administration decreased interleukin (IL)-1β in lung of mice, and TNF-α and caspase-3 were decreased in the lung of CS-exposed mice by medium- and high-dose MSC (p < 0.05). Low-dose hUC-MSCs significantly elevated serum CXCL1/KC and IL-1β in CS-exposed mice (p < 0.05). Our results suggest that high-dose hUC-MSCs reduced pulmonary inflammation and had antiapoptotic effects in acute pulmonary inflammation.
Collapse
Affiliation(s)
- Xiao-Yue Chen
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yi-Ying Chen
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Willie Lin
- Meridigen Biotech Co. Ltd., Taipei, Taiwan
| | | | | | | | - Ta-Chih Hsiao
- Graduate Institute of Environmental Engineering, National Taiwan University, Taipei, Taiwan
| | - Hsiao-Chi Chuang
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.,Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| |
Collapse
|
|
37
|
Masterson CH, Murphy EJ, Gonzalez H, Major I, McCarthy SD, O'Toole D, Laffey JG, Rowan NJ. Purified β-glucans from the Shiitake mushroom ameliorates antibiotic-resistant Klebsiella pneumoniae-induced pulmonary sepsis. Lett Appl Microbiol 2020; 71:405-412. [PMID: 32706908 DOI: 10.1111/lam.13358] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 06/26/2020] [Accepted: 07/16/2020] [Indexed: 12/14/2022]
Abstract
Bacterial infection remains the main cause of acute respiratory distress syndrome and is a leading cause of death and disability in critically ill patients. Here we report on the use of purified β-glucan (lentinan) extracts from Lentinus edodes (Shiitake) mushroom that can reduce infection by a multidrug-resistant clinical isolate of Klebsiella pneumoniae in a rodent pneumonia model, likely through immunomodulation. Adult male Sprague-Dawley rats were subjected to intra-tracheal administration of K. pneumoniae to induce pulmonary sepsis and randomized to three groups; vehicle control (Vehicle, n = 12), commercial lentinan (CL, n = 8) or in-house extracted lentinan (IHL, n = 8) were administered intravenously 1 h postinfection. Physiological parameters and blood gas analysis were measured, bacterial counts from bronchoalveolar-lavage (BAL) were determined, along with differential staining of white cells and measurement of protein concentration in BAL 48 h after pneumonia induction. Use of IHL extract significantly decreased BAL CFU counts. Both CL and IHL extractions reduced protein concentration in BAL. Use of IHL resulted in an improvement in physiological parameters compared to controls and CL. In conclusion, administration of lentinan to treat sepsis-induced lung injury appears safe and effective and may exert its effects in an immunomodulatory manner.
Collapse
Affiliation(s)
- C H Masterson
- Lung Biology Group, National University of Ireland, Galway, Ireland
| | - E J Murphy
- Bioscience Research Institute, Athlone Institute of Technology, Athlone, Ireland
| | - H Gonzalez
- Lung Biology Group, National University of Ireland, Galway, Ireland
| | - I Major
- Materials Research Institute, Athlone Institute of Technology, Athlone, Ireland
| | - S D McCarthy
- Lung Biology Group, National University of Ireland, Galway, Ireland
| | - D O'Toole
- Lung Biology Group, National University of Ireland, Galway, Ireland
| | - J G Laffey
- Lung Biology Group, National University of Ireland, Galway, Ireland.,Anesthesia and Intensive Care Medicine, University Hospital Galway, Galway, Ireland
| | - N J Rowan
- Centre for Disinfection, Sterilisation and Biosecurity, Athlone Institute of Technology, Athlone, Ireland
| |
Collapse
|
|
38
|
Byrnes D, Masterson CH, Artigas A, Laffey JG. Mesenchymal Stem/Stromal Cells Therapy for Sepsis and Acute Respiratory Distress Syndrome. Semin Respir Crit Care Med 2020; 42:20-39. [PMID: 32767301 DOI: 10.1055/s-0040-1713422] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Sepsis and acute respiratory distress syndrome (ARDS) constitute devastating conditions with high morbidity and mortality. Sepsis results from abnormal host immune response, with evidence for both pro- and anti-inflammatory activation present from the earliest phases. The "proinflammatory" response predominates initially causing host injury, with later-phase sepsis characterized by immune cell hypofunction and opportunistic superinfection. ARDS is characterized by inflammation and disruption of the alveolar-capillary membrane leading to injury and lung dysfunction. Sepsis is the most common cause of ARDS. Approximately 20% of deaths worldwide in 2017 were due to sepsis, while ARDS occurs in over 10% of all intensive care unit patients and results in a mortality of 30 to 45%. Given the fact that sepsis and ARDS share some-but not all-underlying pathophysiologic injury mechanisms, the lack of specific therapies, and their frequent coexistence in the critically ill, it makes sense to consider therapies for both conditions together. In this article, we will focus on the therapeutic potential of mesenchymal stem/stromal cells (MSCs). MSCs are available from several tissues, including bone marrow, umbilical cord, and adipose tissue. Allogeneic administration is feasible, an important advantage for acute conditions like sepsis or ARDS. They possess diverse mechanisms of action of relevance to sepsis and ARDS, including direct and indirect antibacterial actions, potent effects on the innate and adaptive response, and pro-reparative effects. MSCs can be preactivated thereby potentiating their effects, while the use of their extracellular vesicles can avoid whole cell administration. While early-phase clinical trials suggest safety, considerable challenges exist in moving forward to phase III efficacy studies, and to implementation as a therapy should they prove effective.
Collapse
Affiliation(s)
- Declan Byrnes
- Department of Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland.,Regenerative Medicine Institute (REMEDI), CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Galway, Ireland
| | - Claire H Masterson
- Department of Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland.,Regenerative Medicine Institute (REMEDI), CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Galway, Ireland
| | - Antonio Artigas
- Critical Care Center, Corporació Sanitaria Parc Tauli, CIBER Enfermedades Respiratorias, Autonomous University of Barcelona, Sabadell, Spain
| | - John G Laffey
- Department of Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland.,Regenerative Medicine Institute (REMEDI), CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Galway, Ireland.,Department of Anaesthesia, SAOLTA University Health Group, Galway University Hospitals, Galway, Ireland
| |
Collapse
|
|
39
|
Evans KV, Lee J. Alveolar wars: The rise of in vitro models to understand human lung alveolar maintenance, regeneration, and disease. Stem Cells Transl Med 2020; 9:867-881. [PMID: 32272001 PMCID: PMC7381809 DOI: 10.1002/sctm.19-0433] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 02/14/2020] [Accepted: 03/10/2020] [Indexed: 12/25/2022] Open
Abstract
Diseases such as idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and bronchopulmonary dysplasia injure the gas-exchanging alveoli of the human lung. Animal studies have indicated that dysregulation of alveolar cells, including alveolar type II stem/progenitor cells, is implicated in disease pathogenesis. Due to mouse-human differences, there has been a desperate need to develop human-relevant lung models that can more closely recapitulate the human lung during homeostasis, injury repair, and disease. Here we discuss how current single-cell RNA sequencing studies have increased knowledge of the cellular and molecular composition of human lung alveoli, including the identification of molecular heterogeneity, cellular diversity, and previously unknown cell types, some of which arise specifically during disease. For functional analysis of alveolar cells, in vitro human alveolar organoids established from human pluripotent stem cells, embryonic progenitors, and adult tissue from both healthy and diseased lungs have modeled aspects of the cellular and molecular features of alveolar epithelium. Drawbacks of such systems are highlighted, along with possible solutions. Organoid-on-a-chip and ex vivo systems including precision-cut lung slices can complement organoid studies by providing further cellular and structural complexity of lung tissues, and have been shown to be invaluable models of human lung disease, while the production of acellular and synthetic scaffolds hold promise in lung transplant efforts. Further improvements to such systems will increase understanding of the underlying biology of human alveolar stem/progenitor cells, and could lead to future therapeutic or pharmacological intervention in patients suffering from end-stage lung diseases.
Collapse
Affiliation(s)
- Kelly V. Evans
- Wellcome – MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical CentreUniversity of CambridgeCambridgeUK
- Department of Physiology, Development and NeuroscienceUniversity of CambridgeCambridgeUK
| | - Joo‐Hyeon Lee
- Wellcome – MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical CentreUniversity of CambridgeCambridgeUK
- Department of Physiology, Development and NeuroscienceUniversity of CambridgeCambridgeUK
| |
Collapse
|
|
40
|
Kim SY, Joglekar MV, Hardikar AA, Phan TH, Khanal D, Tharkar P, Limantoro C, Johnson J, Kalionis B, Chrzanowski W. Placenta Stem/Stromal Cell-Derived Extracellular Vesicles for Potential Use in Lung Repair. Proteomics 2020; 19:e1800166. [PMID: 31318160 DOI: 10.1002/pmic.201800166] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 06/26/2019] [Indexed: 12/28/2022]
Abstract
Many acute and chronic lung injuries are incurable and rank as the fourth leading cause of death globally. While stem cell treatment for lung injuries is a promising approach, there is growing evidence that the therapeutic efficacy of stem cells originates from secreted extracellular vesicles (EVs). Consequently, EVs are emerging as next-generation therapeutics. While EVs are extensively researched for diagnostic applications, their therapeutic potential to promote tissue repair is not fully elucidated. By housing and delivering tissue-repairing cargo, EVs refine the cellular microenvironment, modulate inflammation, and ultimately repair injury. Here, the potential use of EVs derived from two placental mesenchymal stem/stromal cell (MSC) lines is presented; a chorionic MSC line (CMSC29) and a decidual MSC cell line (DMSC23) for applications in lung diseases. Functional analyses using in vitro models of injury demonstrate that these EVs have a role in ameliorating injuries caused to lung cells. It is also shown that EVs promote repair of lung epithelial cells. This study is fundamental to advancing the field of EVs and to unlock the full potential of EVs in regenerative medicine.
Collapse
Affiliation(s)
- Sally Yunsun Kim
- Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, New South Wales, 2006, Australia.,Nano Institute, The University of Sydney, New South Wales, 2006, Australia
| | - Mugdha V Joglekar
- Islet Biology and Diabetes Group, National Health and Medical Research Council Clinical Trials Center, Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, 2050, Australia
| | - Anandwardhan A Hardikar
- Islet Biology and Diabetes Group, National Health and Medical Research Council Clinical Trials Center, Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, 2050, Australia
| | - Thanh Huyen Phan
- Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, New South Wales, 2006, Australia.,Nano Institute, The University of Sydney, New South Wales, 2006, Australia
| | - Dipesh Khanal
- Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, New South Wales, 2006, Australia.,Nano Institute, The University of Sydney, New South Wales, 2006, Australia
| | - Priyanka Tharkar
- Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, New South Wales, 2006, Australia.,Nano Institute, The University of Sydney, New South Wales, 2006, Australia
| | - Christina Limantoro
- Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, New South Wales, 2006, Australia.,Nano Institute, The University of Sydney, New South Wales, 2006, Australia
| | - Jancy Johnson
- Department of Maternal fetal Medicine, Royal Women's Hospital, Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Bill Kalionis
- Department of Maternal fetal Medicine, Royal Women's Hospital, Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Wojciech Chrzanowski
- Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, New South Wales, 2006, Australia.,Nano Institute, The University of Sydney, New South Wales, 2006, Australia
| |
Collapse
|
|
41
|
Human Umbilical Cord Mesenchymal Stromal Cells Attenuate Systemic Sepsis in Part by Enhancing Peritoneal Macrophage Bacterial Killing via Heme Oxygenase-1 Induction in Rats. Anesthesiology 2020; 132:140-154. [PMID: 31764154 DOI: 10.1097/aln.0000000000003018] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Mesenchymal stromal cells have therapeutic potential in sepsis, but the mechanism of action is unclear. We tested the effects, dose-response, and mechanisms of action of cryopreserved, xenogeneic-free human umbilical cord mesenchymal stromal cells in a rat model of fecal peritonitis, and examined the role of heme oxygenase-1 in protection. METHODS Separate in vivo experiments evaluated mesenchymal stromal cells in fecal sepsis, established dose response (2, 5, and 10 million cells/kg), and the role of heme oxygenase-1 in mediating human umbilical cord-derived mesenchymal stromal/stem cell effects. Ex vivo studies utilized pharmacologic blockers and small inhibitory RNAs to evaluate mechanisms of mesenchymal stromal cell enhanced function in (rodent, healthy and septic human) macrophages. RESULTS Human umbilical cord mesenchymal stromal cells reduced injury and increased survival (from 48%, 12 of 25 to 88%, 14 of 16, P = 0.0033) in fecal sepsis, with dose response studies demonstrating that 10 million cells/kg was the most effective dose. Mesenchymal stromal cells reduced bacterial load and peritoneal leukocyte infiltration (from 9.9 ± 3.1 × 10/ml to 6.2 ± 1.8 × 10/ml, N = 8 to 10 per group, P < 0.0001), and increased heme oxygenase-1 expression in peritoneal macrophages, liver, and spleen. Heme oxygenase-1 blockade abolished the effects of mesenchymal stromal cells (N = 7 or 8 per group). Mesenchymal stromal cells also increased heme oxygenase-1 expression in macrophages from healthy donors and septic patients. Direct ex vivo upregulation of macrophage heme oxygenase-1 enhanced macrophage function (phagocytosis, reactive oxygen species production, bacterial killing). Blockade of lipoxin A4 production in mesenchymal stromal cells, and of prostaglandin E2 synthesis in mesenchymal stromal cell/macrophage cocultures, prevented upregulation of heme oxygenase-1 in macrophages (from 9.6 ± 5.5-fold to 2.3 ± 1.3 and 2.4 ± 2.3 respectively, P = 0.004). Knockdown of heme oxygenase-1 production in macrophages ablated mesenchymal stromal cell enhancement of macrophage phagocytosis. CONCLUSIONS Human umbilical cord mesenchymal stromal cells attenuate systemic sepsis by enhancing peritoneal macrophage bacterial killing, mediated partly via upregulation of peritoneal macrophage heme oxygenase-1. Lipoxin A4 and prostaglandin E2 play key roles in the mesenchymal stromal cell and macrophage interaction.
Collapse
|
|
42
|
Lanzoni G, Linetsky E, Correa D, Alvarez RA, Marttos A, Hirani K, Cayetano SM, Castro JG, Paidas MJ, Efantis Potter J, Xu X, Glassberg M, Tan J, Patel AN, Goldstein B, Kenyon NS, Baidal D, Alejandro R, Vianna R, Ruiz P, Caplan AI, Ricordi C. Umbilical Cord-derived Mesenchymal Stem Cells for COVID-19 Patients with Acute Respiratory Distress Syndrome (ARDS). CELLR4-- REPAIR, REPLACEMENT, REGENERATION, & REPROGRAMMING 2020; 8. [PMID: 34164564 DOI: 10.32113/cellr4_20204_2839] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The coronavirus SARS-CoV-2 is cause of a global pandemic of a pneumonia-like disease termed Coronavirus Disease 2019 (COVID-19). COVID-19 presents a high mortality rate, estimated at 3.4%. More than 1 out of 4 hospitalized COVID-19 patients require admission to an Intensive Care Unit (ICU) for respiratory support, and a large proportion of these ICU-COVID-19 patients, between 17% and 46%, have died. In these patients COVID-19 infection causes an inflammatory response in the lungs that can progress to inflammation with cytokine storm, Acute Lung Injury (ALI), Acute Respiratory Distress Syndrome (ARDS), thromboembolic events, disseminated intravascular coagulation, organ failure, and death. Mesenchymal Stem Cells (MSCs) are potent immunomodulatory cells that recognize sites of injury, limit effector T cell reactions, and positively modulate regulatory cell populations. MSCs also stimulate local tissue regeneration via paracrine effects inducing angiogenic, anti-fibrotic and remodeling responses. MSCs can be derived in large number from the Umbilical Cord (UC). UC-MSCs, utilized in the allogeneic setting, have demonstrated safety and efficacy in clinical trials for a number of disease conditions including inflammatory and immune-based diseases. UC-MSCs have been shown to inhibit inflammation and fibrosis in the lungs and have been utilized to treat patients with severe COVID-19 in pilot, uncontrolled clinical trials, that reported promising results. UC-MSCs processed at our facility have been authorized by the FDA for clinical trials in patients with an Alzheimer's Disease, and in patients with Type 1 Diabetes (T1D). We hypothesize that UC-MSC will also exert beneficial therapeutic effects in COVID-19 patients with cytokine storm and ARDS. We propose an early phase controlled, randomized clinical trial in COVID-19 patients with ALI/ARDS. Subjects in the treatment group will be treated with two doses of UC-MSC (l00 × 106 cells). The first dose will be infused within 24 hours following study enrollment. A second dose will be administered 72 ± 6 hours after the first infusion. Subject in the control group will receive infusion of vehicle (DPBS supplemented with 1% HSA and 70 U/kg unfractionated Heparin, delivered IV) following the same timeline. Subjects will be evaluated daily during the first 6 days, then at 14, 28, 60, and 90 days following enrollment (see Schedule of Assessment for time window details). Safety will be determined by adverse events (AEs) and serious adverse events (SAEs) during the follow-up period. Efficacy will be defined by clinical outcomes, as well as a variety of pulmonary, biochemical and immunological tests. Success of the current study will provide a framework for larger controlled, randomized clinical trials and a means of accelerating a possible solution for this urgent but unmet medical need. The proposed early phase clinical trial will be performed at the University of Miami (UM), in the facilities of the Diabetes Research Institute (DRI), UHealth Intensive Care Unit (ICU) and the Clinical Translational Research Site (CTRS) at the University of Miami Miller School of Medicine and at the Jackson Memorial Hospital (JMH).
Collapse
Affiliation(s)
- G Lanzoni
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - E Linetsky
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - D Correa
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Orthopedics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - R A Alvarez
- University of Miami Health System and Jackson Health System, Miami, FL, USA.,Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - A Marttos
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.,University of Miami Health System and Jackson Health System, Miami, FL, USA
| | - K Hirani
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - S Messinger Cayetano
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA.,Department Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL, USA
| | - J G Castro
- University of Miami Health System and Jackson Health System, Miami, FL, USA.,Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - M J Paidas
- University of Miami Health System and Jackson Health System, Miami, FL, USA.,Department of Obstetrics, Gynecology and Reproductive Sciences, University of Miami Miller School of Medicine, Miami, FL, USA
| | - J Efantis Potter
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Miami Miller School of Medicine, Miami, FL, USA
| | - X Xu
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - M Glassberg
- Department of Medicine, University of Arizona College of Medicine, Phoenix, AZ, USA
| | - J Tan
- Organ Transplant Institute, Fuzhou General Hospital, Xiamen University, Fuzhou, China
| | - A N Patel
- Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, USA.,HCA Research Institute, Nashville, TN, USA
| | - B Goldstein
- Department of Head and Neck Surgery and Communication Sciences, Duke University, Durham, NC, USA
| | - N S Kenyon
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - D Baidal
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - R Alejandro
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - R Vianna
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.,University of Miami Health System and Jackson Health System, Miami, FL, USA.,Miami Transplant Institute, Jackson Health System, Miami, FL, USA
| | - P Ruiz
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.,University of Miami Health System and Jackson Health System, Miami, FL, USA.,Miami Transplant Institute, Jackson Health System, Miami, FL, USA
| | - A I Caplan
- Department of Medicine, University of Arizona College of Medicine, Phoenix, AZ, USA
| | - C Ricordi
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.,University of Miami Health System and Jackson Health System, Miami, FL, USA
| |
Collapse
|
|
43
|
Extracellular Vesicles from Interferon-γ-primed Human Umbilical Cord Mesenchymal Stromal Cells Reduce Escherichia coli-induced Acute Lung Injury in Rats. Anesthesiology 2020; 130:778-790. [PMID: 30870158 DOI: 10.1097/aln.0000000000002655] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Human umbilical cord mesenchymal stromal cells possess considerable therapeutic promise for acute respiratory distress syndrome. Umbilical cord mesenchymal stromal cells may exert therapeutic effects via extracellular vesicles, while priming umbilical cord mesenchymal stromal cells may further enhance their effect. The authors investigated whether interferon-γ-primed umbilical cord mesenchymal stromal cells would generate mesenchymal stromal cell-derived extracellular vesicles with enhanced effects in Escherichia coli (E. coli) pneumonia. METHODS In a university laboratory, anesthetized adult male Sprague-Dawley rats (n = 8 to 18 per group) underwent intrapulmonary E. coli instillation (5 × 10 colony forming units per kilogram), and were randomized to receive (a) primed mesenchymal stromal cell-derived extracellular vesicles, (b) naïve mesenchymal stromal cell-derived extracellular vesicles (both 100 million mesenchymal stromal cell-derived extracellular vesicles per kilogram), or (c) vehicle. Injury severity and bacterial load were assessed at 48 h. In vitro studies assessed the potential for primed and naïve mesenchymal stromal cell-derived extracellular vesicles to enhance macrophage bacterial phagocytosis and killing. RESULTS Survival increased with primed (10 of 11 [91%]) and naïve (8 of 8 [100%]) mesenchymal stromal cell-derived extracellular vesicles compared with vehicle (12 of 18 [66.7%], P = 0.038). Primed-but not naïve-mesenchymal stromal cell-derived extracellular vesicles reduced alveolar-arterial oxygen gradient (422 ± 104, 536 ± 58, 523 ± 68 mm Hg, respectively; P = 0.008), reduced alveolar protein leak (0.7 ± 0.3, 1.4 ± 0.4, 1.5 ± 0.7 mg/ml, respectively; P = 0.003), increased lung mononuclear phagocytes (23.2 ± 6.3, 21.7 ± 5, 16.7 ± 5 respectively; P = 0.025), and reduced alveolar tumor necrosis factor alpha concentrations (29 ± 14.5, 35 ± 12.3, 47.2 ± 6.3 pg/ml, respectively; P = 0.026) compared with vehicle. Primed-but not naïve-mesenchymal stromal cell-derived extracellular vesicles enhanced endothelial nitric oxide synthase production in the injured lung (endothelial nitric oxide synthase/β-actin = 0.77 ± 0.34, 0.25 ± 0.29, 0.21 ± 0.33, respectively; P = 0.005). Both primed and naïve mesenchymal stromal cell-derived extracellular vesicles enhanced E. coli phagocytosis and bacterial killing in human acute monocytic leukemia cell line (THP-1) in vitro (36.9 ± 4, 13.3 ± 8, 0.1 ± 0.01%, respectively; P = 0.0004) compared with vehicle. CONCLUSIONS Extracellular vesicles from interferon-γ-primed human umbilical cord mesenchymal stromal cells more effectively attenuated E. coli-induced lung injury compared with extracellular vesicles from naïve mesenchymal stromal cells, potentially via enhanced macrophage phagocytosis and killing of E. coli.
Collapse
|
|
44
|
Horie S, Gaynard S, Murphy M, Barry F, Scully M, O'Toole D, Laffey JG. Cytokine pre-activation of cryopreserved xenogeneic-free human mesenchymal stromal cells enhances resolution and repair following ventilator-induced lung injury potentially via a KGF-dependent mechanism. Intensive Care Med Exp 2020; 8:8. [PMID: 32025852 PMCID: PMC7002627 DOI: 10.1186/s40635-020-0295-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Accepted: 01/20/2020] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Human mesenchymal stem/stromal cells (hMSCs) represent a promising therapeutic strategy for ventilator-induced lung injury (VILI) and acute respiratory distress syndrome. Translational challenges include restoring hMSC efficacy following cryopreservation, developing effective xenogeneic-free (XF) hMSCs and establishing true therapeutic potential at a clinically relevant time point of administration. We wished to determine whether cytokine pre-activation of cryopreserved, bone marrow-derived XF-hMSCs would enhance their capacity to facilitate injury resolution following VILI and elucidate mechanisms of action. METHODS Initially, in vitro studies examined the potential for the secretome from cytokine pre-activated XF-hMSCs to attenuate pulmonary epithelial injury induced by cyclic mechanical stretch. Later, anaesthetised rats underwent VILI and, 6 h following injury, were randomized to receive 1 × 107 XF-hMSC/kg that were (i) naive fresh, (ii) naive cryopreserved, (iii) cytokine pre-activated fresh or (iv) cytokine pre-activated cryopreserved, while control animals received (v) vehicle. The extent of injury resolution was measured at 24 h after injury. Finally, the role of keratinocyte growth factor (KGF) in mediating the effect of pre-activated XF-hMSCs was determined in a pulmonary epithelial wound repair model. RESULTS Pre-activation enhanced the capacity of the XF-hMSC secretome to decrease stretch-induced pulmonary epithelial inflammation and injury. Both pre-activated fresh and cryopreserved XF-hMSCs enhanced resolution of injury following VILI, restoring oxygenation, improving lung compliance, reducing lung leak and improving resolution of lung structural injury. Finally, the secretome of pre-activated XF-hMSCs enhanced epithelial wound repair, in part via a KGF-dependent mechanism. CONCLUSIONS Cytokine pre-activation enhanced the capacity of cryopreserved, XF-hMSCs to promote injury resolution following VILI, potentially via a KGF-dependent mechanism.
Collapse
Affiliation(s)
- Shahd Horie
- Anaesthesia, School of Medicine, National University of Ireland, Galway, Ireland
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Galway, Ireland
| | - Sean Gaynard
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Galway, Ireland
| | - Mary Murphy
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Galway, Ireland
- Medicine, School of Medicine, National University of Ireland, Galway, Ireland
| | - Frank Barry
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Galway, Ireland
- Medicine, School of Medicine, National University of Ireland, Galway, Ireland
| | - Michael Scully
- Anaesthesia, School of Medicine, National University of Ireland, Galway, Ireland
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Galway, Ireland
| | - Daniel O'Toole
- Anaesthesia, School of Medicine, National University of Ireland, Galway, Ireland
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Galway, Ireland
| | - John G Laffey
- Anaesthesia, School of Medicine, National University of Ireland, Galway, Ireland.
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Galway, Ireland.
- Department of Anaesthesia, Galway University Hospitals, Saolta University Health Group, Galway, Ireland.
| |
Collapse
|
|
45
|
Kong D, Liu X, Li X, Hu J, Li X, Xiao J, Dai Y, He M, Liu X, Jiang Y, Cui R, Zhang L, Wang J, Li A, Wang F, Zhang Y, Xiao J, Wang W, Zheng C. Mesenchymal stem cells significantly improved treatment effects of Linezolid on severe pneumonia in a rabbit model. Biosci Rep 2019; 39:BSR20182455. [PMID: 31484796 PMCID: PMC6746999 DOI: 10.1042/bsr20182455] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2018] [Revised: 08/19/2019] [Accepted: 09/03/2019] [Indexed: 12/13/2022] Open
Abstract
The present study aimed to investigate whether co-administration of mesenchymal stromal cells (MSC) and linezolid (LZD) into a rabbit model of methicillin-resistant Staphylococcus aureus (MRSA)-infected pneumonia would bring a synergistic therapeutic effect. Human umbilical cord-derived MSCs (hUMSCs) were isolated and characterized. A rabbit model of pneumonia was constructed by delivering 1 × 1010 CFU MRSA via a bronchoscope into the basal segment of lower lobe of right lung. Through analyzing vital sign, pulmonary auscultation, SpO2, chest imaging, bronchoscopic manifestations, pathology, neutrophil percentage, and inflammatory factors, we verified that a rabbit model of MRSA-induced pneumonia was successfully constructed. Individual treatment with LZD (50 mg/kg for two times/day) resulted in improvement of body weight, chest imaging, bronchoscopic manifestations, histological parameters, and IL-10 concentration in plasma (P<0.01), decreasing pulmonary auscultation, and reduction of IL-8, IL-6, CRP, and TNF-α concentrations in plasma (P<0.01) compared with the pneumonia model group at 48 and 168 h. Compared with LZD group, co-administration of hUMSCs (1 × 106/kg for two times at 6 and 72 h after MRSA instillation) and LZD further increased the body weight (P<0.05). The changes we observed from chest imaging, bronchoscopic manifestations and pathology revealed that co-administration of hUMSCs and LZD reduced lung inflammation more significantly than that of LZD group. The plasma levels of IL-8, IL-6, CRP, and TNF-α in combined group decreased dramatically compared with the LZD group (P<0.05). In conclusion, hUMSCs administration significantly improved therapeutic effects of LZD on pneumonia resulted from MRSA infection in a rabbit model.
Collapse
Affiliation(s)
- Dexiao Kong
- Department of hematology of the Second Hospital, Institute of Biotherapy for Hematological Malignancies, Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, Shandong Province, China
- Department of Hematology, Zhaoyuan Sorting-Yingcheng Hospital, Second Hospital of Shandong University, Yantai, Shandong Province, China
| | - Xia Liu
- Department of Respiratory Intervention, Qilu Children's Hospital of Shandong University, Jinan, Shandong Province, China
| | - Xiaomei Li
- Cancer Center, The Second Hospital of Shandong University, Jinan, Shandong Province, China
| | - Jianting Hu
- Shandong Pharmaceutical Academy, Shandong Provincial Key Laboratory of Chemical Drugs, Jinan, Shandong Province, China
| | - Xiaoyan Li
- Department of hematology of the Second Hospital, Institute of Biotherapy for Hematological Malignancies, Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, Shandong Province, China
| | - Juan Xiao
- Department of hematology of the Second Hospital, Institute of Biotherapy for Hematological Malignancies, Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, Shandong Province, China
| | - Yibo Dai
- Department of hematology of the Second Hospital, Institute of Biotherapy for Hematological Malignancies, Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, Shandong Province, China
| | - Mingming He
- Department of hematology of the Second Hospital, Institute of Biotherapy for Hematological Malignancies, Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, Shandong Province, China
| | - Xiaoli Liu
- Department of hematology of the Second Hospital, Institute of Biotherapy for Hematological Malignancies, Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, Shandong Province, China
- Department of Hematology, Zhaoyuan Sorting-Yingcheng Hospital, Second Hospital of Shandong University, Yantai, Shandong Province, China
| | - Yang Jiang
- Department of hematology of the Second Hospital, Institute of Biotherapy for Hematological Malignancies, Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, Shandong Province, China
- Department of Hematology, Zhaoyuan Sorting-Yingcheng Hospital, Second Hospital of Shandong University, Yantai, Shandong Province, China
| | - Ruodi Cui
- Department of Radiology, Qilu Children's Hospital of Shandong University, Jinan, Shandong Province, China
| | - Lihong Zhang
- Department of Pathology, Qilu Children's Hospital of Shandong University, Jinan, Shandong Province, China
| | - Juandong Wang
- Department of hematology of the Second Hospital, Institute of Biotherapy for Hematological Malignancies, Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, Shandong Province, China
- Department of Hematology, Zhaoyuan Sorting-Yingcheng Hospital, Second Hospital of Shandong University, Yantai, Shandong Province, China
| | - Ai Li
- Department of hematology of the Second Hospital, Institute of Biotherapy for Hematological Malignancies, Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, Shandong Province, China
- Department of Hematology, Zhaoyuan Sorting-Yingcheng Hospital, Second Hospital of Shandong University, Yantai, Shandong Province, China
| | - Fang Wang
- Clinical Laboratory, The Second Hospital of Shandong University, Jinan, Shandong Province, China
| | - Yuan Zhang
- Center of Evidence-Based Medicine, The Second Hospital of Shandong University, Jinan, Shandong Province, China
| | - Juan Xiao
- Center of Evidence-Based Medicine, The Second Hospital of Shandong University, Jinan, Shandong Province, China
| | - Wei Wang
- Department of Respiratory Medicine, The Second Hospital of Shandong University, Jinan, Shandong Province, China
| | - Chengyun Zheng
- Department of hematology of the Second Hospital, Institute of Biotherapy for Hematological Malignancies, Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, Shandong Province, China
- Department of Hematology, Zhaoyuan Sorting-Yingcheng Hospital, Second Hospital of Shandong University, Yantai, Shandong Province, China
| |
Collapse
|
|
46
|
Hoogduijn MJ, Lombardo E. Mesenchymal Stromal Cells Anno 2019: Dawn of the Therapeutic Era? Concise Review. Stem Cells Transl Med 2019; 8:1126-1134. [PMID: 31282113 PMCID: PMC6811696 DOI: 10.1002/sctm.19-0073] [Citation(s) in RCA: 105] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 06/17/2019] [Indexed: 12/11/2022] Open
Abstract
2018 was the year of the first marketing authorization of an allogeneic stem cell therapy by the European Medicines Agency. The authorization concerns the use of allogeneic adipose tissue-derived mesenchymal stromal cells (MSCs) for treatment of complex perianal fistulas in Crohn's disease. This is a breakthrough in the field of MSC therapy. The last few years have, furthermore, seen some breakthroughs in the investigations into the mechanisms of action of MSC therapy. Although the therapeutic effects of MSCs have largely been attributed to their secretion of immunomodulatory and regenerative factors, it has now become clear that some of the effects are mediated through host phagocytic cells that clear administered MSCs and in the process adapt an immunoregulatory and regeneration supporting function. The increased interest in therapeutic use of MSCs and the ongoing elucidation of the mechanisms of action of MSCs are promising indicators that 2019 may be the dawn of the therapeutic era of MSCs and that there will be revived interest in research to more efficient, practical, and sustainable MSC-based therapies. Stem Cells Translational Medicine 2019;8:1126-1134.
Collapse
Affiliation(s)
- Martin J Hoogduijn
- Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | | |
Collapse
|
|
47
|
Jerkic M, Masterson C, Ormesher L, Gagnon S, Goyal S, Rabani R, Otulakowski G, Zhang H, Kavanagh BP, Laffey JG. Overexpression of IL-10 Enhances the Efficacy of Human Umbilical-Cord-Derived Mesenchymal Stromal Cells in E. coli Pneumosepsis. J Clin Med 2019; 8:jcm8060847. [PMID: 31200579 PMCID: PMC6616885 DOI: 10.3390/jcm8060847] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 06/06/2019] [Accepted: 06/09/2019] [Indexed: 12/18/2022] Open
Abstract
Enhancing the immunomodulatory effects of mesenchymal stromal cells (MSCs) may increase their effects in sepsis. We tested the potential for overexpression of Interleukin-10 (IL-10) in human umbilical cord (UC) MSCs to increase MSC efficacy in Escherichia coli (E. coli) pneumosepsis and to enhance human macrophage function. Pneumonia was induced in rats by intratracheal instillation of E. coli ((2.0–3.0) × 109 Colony forming units (CFU)/kg). One hour later, animals were randomized to receive (a) vehicle; (b) naïve UC-MSCs; or (c) IL-10 overexpressing UC-MSCs (1 × 107 cells/kg). Lung injury severity, cellular infiltration, and E. coli colony counts were assessed after 48 h. The effects and mechanisms of action of IL-10 UC-MSCs on macrophage function in septic rodents and in humans were subsequently assessed. Survival increased with IL-10 (9/11 (82%)) and naïve (11/12 (91%)) UC-MSCs compared to vehicle (9/15 (60%, p = 0.03). IL-10 UC-MSCs—but not naïve UC-MSCs—significantly decreased the alveolar arterial gradient (455 ± 93 and 520 ± 81, mmHg, respectively) compared to that of vehicle animals (544 ± 52, p = 0.02). Lung tissue bacterial counts were significantly increased in vehicle- and naïve-UC-MSC-treated animals but were not different from sham animals in those treated with IL-10 overexpressing UC-MSCs. IL-10 (but not naïve) UC-MSCs decreased alveolar neutrophils and increased alveolar macrophage percentages compared to vehicle. IL-10 UC-MSCs decreased structural lung injury compared to naïve UC-MSC or vehicle therapy. Alveolar macrophages from IL-10-UC-MSC-treated rats and from human volunteers demonstrated enhanced phagocytic capacity. This was mediated via increased macrophage hemeoxygenase-1, an effect blocked by prostaglandin E2 and lipoxygenase A4 blockade. IL-10 overexpression in UC-MSCs enhanced their effects in E. coli pneumosepsis and increased macrophage function. IL-10 UC-MSCs similarly enhanced human macrophage function, illustrating their therapeutic potential for infection-induced acute respiratory distress syndrome (ARDS).
Collapse
Affiliation(s)
- Mirjana Jerkic
- St. Michael's Hospital, Keenan Research Centre for Biomedical Science, University of Toronto, Toronto, ON M5B 1T8, Canada.
| | - Claire Masterson
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, Biomedical Sciences Building, National University of Ireland Galway, Galway H91 TK33, Ireland.
| | - Lindsay Ormesher
- St. Michael's Hospital, Keenan Research Centre for Biomedical Science, University of Toronto, Toronto, ON M5B 1T8, Canada.
| | - Stéphane Gagnon
- St. Michael's Hospital, Keenan Research Centre for Biomedical Science, University of Toronto, Toronto, ON M5B 1T8, Canada.
| | - Sakshi Goyal
- St. Michael's Hospital, Keenan Research Centre for Biomedical Science, University of Toronto, Toronto, ON M5B 1T8, Canada.
| | - Razieh Rabani
- St. Michael's Hospital, Keenan Research Centre for Biomedical Science, University of Toronto, Toronto, ON M5B 1T8, Canada.
| | - Gail Otulakowski
- Department of Critical Care Medicine, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
| | - Haibo Zhang
- St. Michael's Hospital, Keenan Research Centre for Biomedical Science, University of Toronto, Toronto, ON M5B 1T8, Canada.
| | - Brian P Kavanagh
- Department of Critical Care Medicine, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
- Departments of Anesthesia, Physiology and Interdepartmental Division of Critical Care, University of Toronto, ON M5G 1E2, Canada.
| | - John G Laffey
- Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, Biomedical Sciences Building, National University of Ireland Galway, Galway H91 TK33, Ireland.
- Departments of Anesthesia, Physiology and Interdepartmental Division of Critical Care, University of Toronto, ON M5G 1E2, Canada.
- Anaesthesia, School of Medicine, National University of Ireland, Galway, H91 TK33, Ireland.
| |
Collapse
|
|
48
|
Wang H, Ji Z. Inhibition of p53 alleviates prostate cell apoptosis in Escherichia coli‑induced bacterial prostatitis. Mol Med Rep 2019; 20:895-902. [PMID: 31173258 DOI: 10.3892/mmr.2019.10354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Accepted: 12/21/2018] [Indexed: 11/05/2022] Open
Abstract
Previous studies demonstrated that uropathogenic Escherichia coli infection contributes to human bacterial prostatitis. Apoptosis of prostate epithelial cells is closely associated with the progression of bacterial prostatitis. The aim of the present study was to investigate the effect of cellular tumor antigen p53 (p53) on the apoptosis of bacterial prostatitis cells. The prostate epithelial RWPE‑1 cell line was infected with Escherichia coli, and treated cells and the culture supernatant were obtained at specific time points. The cell apoptosis rates, protein and mRNA of p53 were detected in the different treatment groups. Flow cytometry and terminal deoxynucleotidyl‑transferase‑mediated dUTP nick end labeling assays were used for the detection of cell apoptosis, and cell proliferation was determined by a Cell Counting Kit‑8 assay. The expression of p53 was inhibited by small interfering (si)RNA, and its mRNA and protein were detected. An ELISA was used for detecting cytokines in the culture supernatant. The result demonstrated that Escherichia coli infection led to an increase in prostate epithelial cell apoptosis (P<0.05), and resulted in increases of interleukin (IL)‑4, IL‑6 and IL‑8, and decrease in IL‑10. p53, apoptosis regulator BAX (Bax), caspase‑9 and Caspase‑3 expression were upregulated upon Escherichia coli exposure (P<0.05). Following transfection with p53 siRNA, the promotion of cell apoptosis induced by Escherichia coli infection was decreased, and the p53 and Bax protein expression were additionally decreased. Therefore, it was suggested that Escherichia coli increases cell apoptosis in bacterial prostatitis by activating the death receptor pathway involving p53. Inhibition of p53 alleviated prostate cell apoptosis induced by Escherichia coli.
Collapse
Affiliation(s)
- Hai Wang
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing 100730, P.R. China
| | - Zhigang Ji
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing 100730, P.R. China
| |
Collapse
|
|
49
|
The authors reply. Crit Care Med 2019. [PMID: 28622234 DOI: 10.1097/ccm.0000000000002480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
|
|
50
|
Human Mesenchymal Stem/Stromal Cells From Human Umbilical Cord Ameliorate Acute Respiratory Distress Syndrome in Rats: Factors to Consider. Crit Care Med 2019. [PMID: 28622233 DOI: 10.1097/ccm.0000000000002401] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
|