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Soundara Pandi SP, Winter H, Smith MR, Harkin K, Bojdo J. Preclinical Retinal Disease Models: Applications in Drug Development and Translational Research. Pharmaceuticals (Basel) 2025; 18:293. [PMID: 40143072 PMCID: PMC11944893 DOI: 10.3390/ph18030293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Revised: 02/10/2025] [Accepted: 02/18/2025] [Indexed: 03/28/2025] Open
Abstract
Retinal models play a pivotal role in translational drug development, bridging preclinical research and therapeutic applications for both ocular and systemic diseases. This review highlights the retina as an ideal organ for studying advanced therapies, thanks to its immune privilege, vascular and neuronal networks, accessibility, and advanced imaging capabilities. Preclinical retinal disease models offer unparalleled insights into inflammation, angiogenesis, fibrosis, and hypoxia, utilizing clinically translatable bioimaging tools like fundoscopy, optical coherence tomography, confocal scanning laser ophthalmoscopy, fluorescein angiography, optokinetic tracking, and electroretinography. These models have driven innovations in anti-inflammatory, anti-angiogenic, and neuroprotective strategies, with broader implications for systemic diseases such as rheumatoid arthritis, Alzheimer's, and fibrosis-related conditions. By emphasizing the integration of the 3Rs principles and novel imaging modalities, this review highlights how retinal research not only enhances therapeutic precision but also minimizes ethical concerns, paving the way for more predictive and human-relevant approaches in drug development.
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Affiliation(s)
| | - Hanagh Winter
- Medinect Bioservices Ltd., Belfast BT7 1NF, UK; (S.P.S.P.); (H.W.); (M.R.S.); (K.H.)
| | - Madeleine R. Smith
- Medinect Bioservices Ltd., Belfast BT7 1NF, UK; (S.P.S.P.); (H.W.); (M.R.S.); (K.H.)
| | - Kevin Harkin
- Medinect Bioservices Ltd., Belfast BT7 1NF, UK; (S.P.S.P.); (H.W.); (M.R.S.); (K.H.)
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast BT9 7BL, UK
| | - James Bojdo
- Medinect Bioservices Ltd., Belfast BT7 1NF, UK; (S.P.S.P.); (H.W.); (M.R.S.); (K.H.)
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2
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Hazrati A, Mirarefin SMJ, Malekpour K, Rahimi A, Khosrojerdi A, Rasouli A, Akrami S, Soudi S. Mesenchymal stem cell application in pulmonary disease treatment with emphasis on their interaction with lung-resident immune cells. Front Immunol 2024; 15:1469696. [PMID: 39582867 PMCID: PMC11581898 DOI: 10.3389/fimmu.2024.1469696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 10/01/2024] [Indexed: 11/26/2024] Open
Abstract
Due to the vital importance of the lungs, lung-related diseases and their control are very important. Severe inflammatory responses mediated by immune cells were among the leading causes of lung tissue pathology and damage during the COVID-19 pandemic. In addition, uncontrolled immune cell responses can lead to lung tissue damage in other infectious and non-infectious diseases. It is essential to control immune responses in a way that leads to homeostasis. Immunosuppressive drugs only suppress inflammatory responses and do not affect the homeostasis of reactions. The therapeutic application of mesenchymal stem cells (MSCs), in addition to restoring immune homeostasis, can promote the regeneration of lung tissue through the production of growth factors and differentiation into lung-related cells. However, the communication between MSCs and immune cells after treatment of pulmonary diseases is essential, and investigating this can help develop a clinical perspective. Different studies in the clinical phase showed that MSCs can reverse fibrosis, increase regeneration, promote airway remodeling, and reduce damage to lung tissue. The proliferation and differentiation potential of MSCs is one of the mechanisms of their therapeutic effects. Furthermore, they can secrete exosomes that affect the function of lung cells and immune cells and change their function. Another important mechanism is that MSCs reduce harmful inflammatory responses through communication with innate and adaptive immune cells, which leads to a shift of the immune system toward regulatory and hemostatic responses.
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Affiliation(s)
- Ali Hazrati
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Kosar Malekpour
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Arezou Rahimi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Arezou Khosrojerdi
- Infectious Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Ashkan Rasouli
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Susan Akrami
- Department of Microbiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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Kim SD, Kang SA, Mun SJ, Yu HS, Roh HJ, Cho KS. SCGB1C1 Plays a Critical Role in Suppression of Allergic Airway Inflammation through the Induction of Regulatory T Cell Expansion. Int J Mol Sci 2024; 25:6282. [PMID: 38892470 PMCID: PMC11173076 DOI: 10.3390/ijms25116282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 05/27/2024] [Accepted: 06/03/2024] [Indexed: 06/21/2024] Open
Abstract
The nanosized vesicles secreted from various cell types into the surrounding extracellular space are called extracellular vesicles (EVs). Although mesenchymal stem cell-derived EVs are known to have immunomodulatory effects in asthmatic mice, the role of identified pulmonary genes in the suppression of allergic airway inflammation remains to be elucidated. Moreover, the major genes responsible for immune regulation in allergic airway diseases have not been well documented. This study aims to evaluate the immunomodulatory effects of secretoglobin family 1C member 1 (SCGB1C1) on asthmatic mouse models. C57BL/6 mice were sensitized to ovalbumin (OVA) using intraperitoneal injection and were intranasally challenged with OVA. To evaluate the effect of SCGB1C1 on allergic airway inflammation, 5 μg/50 μL of SCGB1C1 was administrated intranasally before an OVA challenge. We evaluated airway hyperresponsiveness (AHR), total inflammatory cells, eosinophils in the bronchoalveolar lavage fluid (BALF), lung histology, serum immunoglobulin (Ig), the cytokine profiles of BALF and lung-draining lymph nodes (LLN), and the T cell populations in LLNs. The intranasal administration of SCGB1C1 significantly inhibited AHR, the presence of eosinophils in BALF, eosinophilic inflammation, goblet cell hyperplasia in the lung, and serum total and allergen-specific IgE. SCGB1C1 treatment significantly decreased the expression of interleukin (IL)-5 in the BALF and IL-4 in the LLN, but significantly increased the expression of IL-10 and transforming growth factor (TGF)-β in the BALF. Furthermore, SCGB1C1 treatment notably increased the populations of CD4+CD25+Foxp3+ regulatory T cells (Tregs) in asthmatic mice. The intranasal administration of SCGB1C1 provides a significant reduction in allergic airway inflammation and improvement of lung function through the induction of Treg expansion. Therefore, SCGB1C1 may be the major regulator responsible for suppressing allergic airway inflammation.
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Affiliation(s)
- Sung-Dong Kim
- Department of Otorhinolaryngology, Pusan National University Hospital, Busan 49241, Republic of Korea;
| | - Shin-Ae Kang
- Department of Parasitology and Tropical Medicine, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea; (S.-A.K.); (H.-S.Y.)
| | - Sue-Jean Mun
- Department of Otorhinolaryngology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea; (S.-J.M.); (H.-J.R.)
| | - Hak-Sun Yu
- Department of Parasitology and Tropical Medicine, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea; (S.-A.K.); (H.-S.Y.)
| | - Hwan-Jung Roh
- Department of Otorhinolaryngology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea; (S.-J.M.); (H.-J.R.)
| | - Kyu-Sup Cho
- Department of Otorhinolaryngology, Pusan National University Hospital, Busan 49241, Republic of Korea;
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Barrett JG, MacDonald ES. Use of Biologics and Stem Cells in the Treatment of Other Inflammatory Diseases in the Horse. Vet Clin North Am Equine Pract 2023; 39:553-563. [PMID: 37607855 DOI: 10.1016/j.cveq.2023.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/24/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are powerful immunomodulatory cells that act via multiple mechanisms to coordinate, inhibit, and control the cells of the immune system. MSCs act as rescuers for various damaged or degenerated cells of the body via (1) cytokines, growth factors, and signaling molecules; (2) extracellular vesicle (exosome) signaling; and (3) direct donation of mitochondria. Several studies evaluating the efficacy of MSCs have used MSCs grown using xenogeneic media, which may reduce or eliminate efficacy. Although more research is needed to optimize the anti-inflammatory potential of MSCs, there is ample evidence that MSC therapeutics are worthy of further development.
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Affiliation(s)
- Jennifer G Barrett
- Marion duPont Scott Equine Medical Center, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Leesburg, VA, USA.
| | - Elizabeth S MacDonald
- Marion duPont Scott Equine Medical Center, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Leesburg, VA, USA
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Peng YQ, Deng XH, Xu ZB, Wu ZC, Fu QL. Mesenchymal stromal cells and their small extracellular vesicles in allergic diseases: From immunomodulation to therapy. Eur J Immunol 2023; 53:e2149510. [PMID: 37572379 DOI: 10.1002/eji.202149510] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 06/09/2023] [Accepted: 08/10/2023] [Indexed: 08/14/2023]
Abstract
Mesenchymal stromal cells (MSCs) have long been considered a potential tool for treatment of allergic inflammatory diseases, owing to their immunomodulatory characteristics. In recent decades, the medical utility of MSCs has been evaluated both in vitro and in vivo, providing a foundation for therapeutic applications. However, the existing limitations of MSC therapy indicate the necessity for novel therapies. Notably, small extracellular vesicles (sEV) derived from MSCs have emerged rapidly as candidates instead of their parental cells. The acquisition of abundant and scalable MSC-sEV is an obstacle for clinical applications. The potential application of MSC-sEV in allergic diseases has attracted increasing attention from researchers. By carrying biological microRNAs or active proteins, MSC-sEV can modulate the function of various innate and adaptive immune cells. In this review, we summarise the recent advances in the immunomodulatory properties of MSCs in allergic diseases, the cellular sources of MSC-sEV, and the methods for obtaining high-quality human MSC-sEV. In addition, we discuss the immunoregulatory capacity of MSCs and MSC-sEV for the treatment of asthma, atopic dermatitis, and allergic rhinitis, with a special emphasis on their immunoregulatory effects and the underlying mechanisms of immune cell modulation.
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Affiliation(s)
- Ya-Qi Peng
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Department of Otolaryngology-Head and Neck Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Xiao-Hui Deng
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, China
| | - Zhi-Bin Xu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zi-Cong Wu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qing-Ling Fu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, China
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6
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Serretiello E, Ballini A, Smimmo A, Acunzo M, Raimo M, Cantore S, Di Domenico M. Extracellular Vesicles as a Translational Approach for the Treatment of COVID-19 Disease: An Updated Overview. Viruses 2023; 15:1976. [PMID: 37896755 PMCID: PMC10611252 DOI: 10.3390/v15101976] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 09/18/2023] [Accepted: 09/21/2023] [Indexed: 10/29/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic in the years 2020-2022. With a high prevalence, an easy route of transmission, and a long incubation time, SARS-CoV-2 spread quickly and affected public health and socioeconomic conditions. Several points need to be elucidated about its mechanisms of infection, in particular, its capability to evade the immune system and escape from neutralizing antibodies. Extracellular vesicles (EVs) are phospholipid bilayer-delimited particles that are involved in cell-to-cell communication; they contain biological information such as miRNAs, proteins, nucleic acids, and viral components. Abundantly released from biological fluids, their dimensions are highly variable, which are used to divide them into exosomes (40 to 150 nm), microvesicles (40 to 10,000 nm), and apoptotic bodies (100-5000 nm). EVs are involved in many physiological and pathological processes. In this article, we report the latest evidence about EVs' roles in viral infections, focusing on the dual role of exosomes in promoting and inhibiting SARS-CoV-2 infection. The involvement of mesenchymal stromal/stem cells (MSCs) and MSC-derived EVs in COVID-19 treatment, such as the use of translational exosomes as a diagnostical/therapeutic approach, is also investigated. These elucidations could be useful to better direct the discovery of future diagnostical tools and new exosome-derived COVID-19 biomarkers, which can help achieve optimal therapeutic interventions and implement future vaccine strategies.
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Affiliation(s)
- Enrica Serretiello
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (E.S.); (A.S.); (M.A.); (M.R.); (S.C.); (M.D.D.)
| | - Andrea Ballini
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (E.S.); (A.S.); (M.A.); (M.R.); (S.C.); (M.D.D.)
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy
| | - Annafrancesca Smimmo
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (E.S.); (A.S.); (M.A.); (M.R.); (S.C.); (M.D.D.)
| | - Marina Acunzo
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (E.S.); (A.S.); (M.A.); (M.R.); (S.C.); (M.D.D.)
| | - Mariarosaria Raimo
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (E.S.); (A.S.); (M.A.); (M.R.); (S.C.); (M.D.D.)
| | - Stefania Cantore
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (E.S.); (A.S.); (M.A.); (M.R.); (S.C.); (M.D.D.)
| | - Marina Di Domenico
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (E.S.); (A.S.); (M.A.); (M.R.); (S.C.); (M.D.D.)
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Rafiyan M, Sadeghmousavi S, Akbarzadeh M, Rezaei N. Experimental animal models of chronic inflammation. CURRENT RESEARCH IN IMMUNOLOGY 2023; 4:100063. [PMID: 37334102 PMCID: PMC10276141 DOI: 10.1016/j.crimmu.2023.100063] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 05/24/2023] [Accepted: 05/31/2023] [Indexed: 06/20/2023] Open
Abstract
Inflammation is a general term for a wide variety of both physiological and pathophysiological processes in the body which primarily prevents the body from diseases and helps to remove dead tissues. It has a crucial part in the body immune system. Tissue damage can recruit inflammatory cells and cytokines and induce inflammation. Inflammation can be classified as acute, sub-acute, and chronic. If it remained unresolved and lasted for prolonged periods, it would be considered as chronic inflammation (CI), which consequently exacerbates tissue damage in different organs. CI is the main pathophysiological cause of many disorders such as obesity, diabetes, arthritis, myocardial infarction, and cancer. Thus, it is critical to investigate different mechanisms involved in CI to understand its processes and to find proper anti-inflammatory therapeutic approaches for it. Animal models are one of the most useful tools for study about different diseases and mechanisms in the body, and are important in pharmacological studies to find proper treatments. In this study, we discussed the various experimental animal models that have been used to recreate CI which can help us to enhance the understanding of CI mechanisms in human and contribute to the development of potent new therapies.
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Affiliation(s)
- Mahdi Rafiyan
- Animal Model Integrated Network (AMIN), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Shaghayegh Sadeghmousavi
- Animal Model Integrated Network (AMIN), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Milad Akbarzadeh
- Animal Model Integrated Network (AMIN), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
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8
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Gholami M, Ghorban K, Sadeghi M, Dadmanesh M, Rouzbahani NH, Dehnavi S. Mesenchymal stem cells and allergic airway inflammation; a therapeutic approach to induce immunoregulatory responses. Int Immunopharmacol 2023; 120:110367. [PMID: 37230032 DOI: 10.1016/j.intimp.2023.110367] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 05/07/2023] [Accepted: 05/18/2023] [Indexed: 05/27/2023]
Abstract
Allergic airway inflammations are among the essential disorders worldwide that are already considered a significant concern. Mesenchymal stem cells (MSCs) are stromal cells with regenerative potential and immunomodulatory characteristics and are widely administered for tissue repair as an immunoregulatory agent in different inflammatory diseases. The current review summarized primary studies conducted to evaluate the therapeutic potential of MSCs for allergic airway disorders. In this case, modulation of airway pathologic inflammation and infiltration of inflammatory cells were examined, and modulation of the Th1/Th2 cellular balance and humoral responses. Also, the effects of MSCs on the Th17/Treg ratio and inducing Treg immunoregulatory responses along with macrophage and dendritic cell function were evaluated.
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Affiliation(s)
- Mohammad Gholami
- Infectious Diseases Research Center, Aja University of Medical Sciences, Tehran, Iran; Department of Medical Microbiology, Faculty of Medicine, Aja University of Medical Sciences, Tehran, Iran
| | - Khodayar Ghorban
- Department of Immunology, Faculty of Medicine, Aja University of Medical Sciences, Tehran, Iran
| | - Mahvash Sadeghi
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Maryam Dadmanesh
- Infectious Diseases Research Center, Aja University of Medical Sciences, Tehran, Iran; Department of Infectious Diseases, School Of Medicine, Aja University of Medical Sciences, Tehran, Iran
| | - Negin Hosseini Rouzbahani
- Infectious Diseases Research Center, Aja University of Medical Sciences, Tehran, Iran; Department of Immunology, Faculty of Medicine, Aja University of Medical Sciences, Tehran, Iran
| | - Sajad Dehnavi
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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9
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Adamič N, Vengust M. Regenerative medicine in lung diseases: A systematic review. Front Vet Sci 2023; 10:1115708. [PMID: 36733636 PMCID: PMC9887049 DOI: 10.3389/fvets.2023.1115708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 01/02/2023] [Indexed: 01/18/2023] Open
Abstract
Regenerative medicine has opened the door to the exploration of new therapeutic methods for the treatment of various diseases, especially those associated with local or general disregulation of the immune system. In pulmonary diseases, new therapeutic strategies have emerged that are aimed at restoring functional lung tissue rather than alleviating symptoms. These strategies focus on tissue regeneration using stem cells and/or their derivatives or replacement of dysfunctional tissue using biomedical engineering. Animal health can directly benefit from regenerative therapy strategies and also serve as a translational experimental model for human disease. Several clinical trials have been conducted to evaluate the effects of cellular treatment on inflammatory lung disease in animals. Data reported to date show several beneficial effects in ex vivo and in vivo models; however, our understanding of the mechanisms that regenerative therapies exert on diseased tissues remains incomplete.
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Intratracheal administration of mesenchymal stem cells modulates lung macrophage polarization and exerts anti-asthmatic effects. Sci Rep 2022; 12:11728. [PMID: 35821386 PMCID: PMC9276742 DOI: 10.1038/s41598-022-14846-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 06/13/2022] [Indexed: 12/24/2022] Open
Abstract
Mesenchymal stem cells (MSCs) possess immunomodulatory properties that have therapeutic potential for the treatment of inflammatory diseases. This study investigates the effects of direct MSC administration on asthmatic airways. Umbilical cord MSCs (ucMSCs) were intratracheally administered to six-week-old female BALB/c mice sensitized and challenged with ovalbumin; airway hyperresponsiveness (AHR), analyses of airway inflammatory cells, lung histology, flow cytometry, and quantitative real-time PCR were performed. Furthermore, ex vivo and in vitro experiments were performed to assess the effects of ucMSC on M2 activation. Intratracheally administered ucMSCs decreased degree of airway resistance and the number of inflammatory cells such as T helper 2 (Th2) cells, type 2 innate lymphoid cells (ILC2), and macrophages in the murine asthma model. Particularly, MHCII and CD86 expression diminished in dendritic cells and alveolar macrophages (AMs) following ucMSC treatment. SiglecF+CD11c+CD11b- AMs show a negative correlation with type II inflammatory cells including Th2 cells, ILC2, and eosinophils in asthmatic mice and were restored following intratracheal ucMSCs treatment. In addition, ucMSCs decreased the macrophage polarization to M2, particularly M2a. The expression levels of markers associated with M2 polarization and Th2 inflammation were also decreased. ucMSC reduced Il-12 and Tnfa expression as well as that of M2 markers such as Cd206 and Retnla ex vivo. Furthermore, the in vitro study using IL-4 treated macrophages confirmed that both direct and indirect MSC treatment significantly reduced the expression of Il-5 and Il-13. In conclusion, ucMSCs appear to suppress type II inflammation by regulating lung macrophages via soluble mediators.
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Lee DG, Lee YJ, Park SH, Park HR, Kang H, Kim JE. Preventive Effects of a Human Hematopoietic Mesenchymal Stem Cell (hHMSC) Therapy in Ovalbumin-Induced Food Allergy. Biomedicines 2022; 10:biomedicines10020511. [PMID: 35203718 PMCID: PMC8962321 DOI: 10.3390/biomedicines10020511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 02/02/2022] [Accepted: 02/17/2022] [Indexed: 11/23/2022] Open
Abstract
No effective therapeutic strategies have been developed against food allergies. Immunomodulation during early infant period could prevent the development of food allergies. We investigated the preventive effects of human hematopoietic mesenchymal stem cells (hHMSCs) in mice with ovalbumin (OVA)-induced food allergy. BALB/c mice with OVA-induced food allergy were divided into 3 groups, and each group was treated with hHMSCs or hHMSC culture medium (hHMSC-CM) or saline. Ear thickness, allergy score, rectal temperature, and diarrhea occurrence were checked. Total IgE, OVA-specific IgE, and mucosal mast cell protease-1 (mMCP-1) were measured by ELISA. Other allergic parameters were analyzed using histology specimens, RT-PCR, and flow cytometry. Treatment with hHMSCs or hHMSC-CM significantly suppressed the frequency of anaphylactic response and rectal temperature decline, reduced diarrhea, total IgE, OVA-specific IgE, and mMCP-1. While the treatment decreased the level of Th2 cytokines, it enhanced IL-10 and TGF-β1 mRNA. Exposure to hHMSC or hHMSC-CM did not generate regulatory T cells, but reduced mast cells. The immunomodulatory effect on the Th2 cytokines was greater in hHMSC-CM than in hHMSCs. hHMSC treatment may be a promising preventive intervention against food allergy. Further studies are needed to elucidate the key substances released from hHMSC to induce immune tolerance.
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12
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Shan L, Liu S, Zhang Q, Zhou Q, Shang Y. Human bone marrow-mesenchymal stem cell-derived exosomal microRNA-188 reduces bronchial smooth muscle cell proliferation in asthma through suppressing the JARID2/Wnt/β-catenin axis. Cell Cycle 2022; 21:352-367. [PMID: 34974799 PMCID: PMC8855860 DOI: 10.1080/15384101.2021.2020432] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
The functions of exosomes in allergic diseases including asthma have aroused increasing concerns. This paper focuses on the effects of exosomes derived from human bone marrow-mesenchymal stem cells (hBM-MSCs) on the proliferation of bronchial smooth muscle cells in asthma and the mechanism involved. Exosomes were extracted from hBM-MSCs and identified. Human BSMCs were induced with transforming growth factor (TGF)-β1 to mimic an asthma-like condition in vitro and then treated with exosomes. A mouse model with asthma was induced by ovalbumin (OVA) and treated with exosomes for in vivo study. The hBM-MSC-derived exosomes significantly reduced the abnormal proliferation and migration of TGF-β1-treated BSMCs. microRNA (miR)-188 was the most enriched miRNA in exosomes according the microarray analysis, and JARID2 was identified as a mRNA target of miR-188. Either downregulation of miR-188 or upregulation of JARID2 blocked the protective effects of exosomes on BSMCs. JARID2 activated the Wnt/β-catenin signaling pathway. In the asthmatic mice, hBM-MSC-derived exosomes reduced inflammatory cell infiltration, mucus production, and collagen deposition in mouse lung tissues. In conclusion, this study suggestes that hBM-MSC-derived exosomes suppress proliferation of BSMCs and lung injury in asthmatic mice through the miR-188/JARID2/Wnt/β-catenin axis. This study may provide novel insights into asthma management.
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Affiliation(s)
- Lishen Shan
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, P.R. China
| | - Si Liu
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, P.R. China
| | - Qinzhen Zhang
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, P.R. China
| | - Qianlan Zhou
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, P.R. China
| | - Yunxiao Shang
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, P.R. China,CONTACT Yunxiao Shang Department of Pediatrics, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Heping District, Shenyang110004, Liaoning, P.R. China
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13
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Adamič N, Prpar Mihevc S, Blagus R, Kramarič P, Krapež U, Majdič G, Viel L, Hoffman AM, Bienzle D, Vengust M. Effect of intrabronchial administration of autologous adipose-derived mesenchymal stem cells on severe equine asthma. Stem Cell Res Ther 2022; 13:23. [PMID: 35063028 PMCID: PMC8777441 DOI: 10.1186/s13287-022-02704-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 01/04/2022] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Severe equine asthma (SEA) is a common chronic respiratory disease and a significant health and well-being problem in horses. Current therapeutic strategies improve pulmonary function and clinical signs in some horses, but in the long-term, return to full athletic function appears to be rare. The aim of this study was to assess the safety and the effect of intrabronchial administration of adipose-derived mesenchymal stem cells (AD-MSC) on pulmonary inflammatory and clinical parameters in horses with SEA. METHODS This was a randomized controlled trial. Twenty adult horses diagnosed with SEA were randomly divided into two groups (n = 10), and treated either with a single intrabronchial application of autologous AD-MSC or oral dexamethasone for three weeks. A targeted clinical examination with determination of clinical score, maximal change in pleural pressure during the breathing cycle, and an endoscopic examination of the airways were performed at baseline and three weeks after treatment. Bronchoalveolar lavage fluid was analyzed cytologically, and IL-1β, IL-4, IL-8, IL-17, TNFα and IFNγ mRNA and protein concentrations were measured at baseline and three weeks. The horses were then monitored over one year for recurrence of SEA. A non-inferiority analysis and a linear mixed-effects model were performed to assess differences between treatments. RESULTS The non-inferiority of AD-MSC treatment was not established. However, AD-MSC administration significantly ameliorated the clinical score (P = 0.01), decreased the expression of IL-17 mRNA (P = 0.05) and IL-1β (P ≤ 0.001), IL-4 (P ≤ 0.001), TNFα (P = 0.02) protein levels, and had a positive long-term effect on SEA-associated clinical signs (P = 0.02). CONCLUSIONS Intrabronchial administration of AD-MSC had limited short-term anti-inflammatory effects but improved the clinical signs of SEA at one year.
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Affiliation(s)
- Neža Adamič
- Veterinary Faculty, University of Ljubljana, 1000, Ljubljana, Slovenia
| | | | - Rok Blagus
- Institute for Biostatistics and Medical Informatics, Faculty of Medicine, University of Ljubljana, 1000, Ljubljana, Slovenia
| | - Petra Kramarič
- Veterinary Faculty, University of Ljubljana, 1000, Ljubljana, Slovenia
| | - Uroš Krapež
- Veterinary Faculty, University of Ljubljana, 1000, Ljubljana, Slovenia
| | - Gregor Majdič
- Veterinary Faculty, University of Ljubljana, 1000, Ljubljana, Slovenia
| | - Laurent Viel
- Clinical Studies, University of Guelph, Guelph, ON, Canada
| | - Andrew M Hoffman
- School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Dorothee Bienzle
- Department of Pathobiology, University of Guelph, Guelph, ON, Canada
| | - Modest Vengust
- Veterinary Faculty, University of Ljubljana, 1000, Ljubljana, Slovenia.
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14
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Caplan AI. Mesenchymal stem cells and COVID-19: the process of discovery and of translation. BIOMATERIALS TRANSLATIONAL 2021; 2:307-311. [PMID: 35837414 PMCID: PMC9255802 DOI: 10.12336/biomatertransl.2021.04.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 10/19/2021] [Accepted: 11/16/2021] [Indexed: 01/17/2023]
Abstract
Mesenchymal stem cells were developed as a cell-based therapeutic in the 1990's. The translation of culture expanded mesenchymal stem cells from a basic science focus into a modern therapeutic has taken 30 years. The current state of the basic science information argues that mesenchymal stem cells may be curative for coronavirus disease 2019 (COVID-19). Indeed, early small-scale clinical trials have shown positive results. The issue raised is how to assemble the resources to get this cell-based therapy approved for clinical use. The technology is complex, the COVID-19 viral infections are life threatening, the cost is high, but human life is precious. What will it take to perfect this potentially curative technology?
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15
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Intranasally Administered Extracellular Vesicles from Adipose Stem Cells Have Immunomodulatory Effects in a Mouse Model of Asthma. Stem Cells Int 2021; 2021:6686625. [PMID: 34899920 PMCID: PMC8664544 DOI: 10.1155/2021/6686625] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 06/02/2021] [Accepted: 07/14/2021] [Indexed: 12/27/2022] Open
Abstract
Asthma is a chronic eosinophilic airway disease characterized by type 2 helper T cell-driven inflammation. Adipose stem cells (ASCs) and the ASC culture supernatant are known to improve allergic airway inflammation; however, the immunomodulatory effects of ASC-derived extracellular vesicles (EVs) on allergic airway diseases remain unclear. Thus, we assessed the effects of ASC-derived EVs on allergic airway inflammation in a mouse model of asthma. EVs were isolated from the culture supernatant of murine ASCs and characterized. Six-week-old female C57BL/6 mice were sensitized to ovalbumin (OVA) by intraperitoneal injection and challenged intranasally with OVA. Before the OVA challenge, 10 μg/50 μl of ASC-derived EVs was administered intranasally to the experimental group. ASC-derived EVs significantly attenuated airway hyperresponsiveness (AHR) in asthmatic mice (p = 0.023). ASC-derived EVs resulted in a remarkable reduction of the total number of inflammatory cells (p = 0.005) and eosinophils (p = 0.023) in the bronchoalveolar lavage fluid (BALF), the degree of eosinophilic lung inflammation (p < 0.001), and the serum total and OVA-specific immunoglobulin (Ig)E (p = 0.048 and p = 0.001) and total IgG1 (p < 0.001). Interleukin- (IL-) 4 was significantly inhibited with ASC-derived EV pretreatment in the BALF and lung draining lymph nodes (LLNs) (p = 0.040 and p = 0.011). Furthermore, ASC-derived EV administration resulted in a significant increase of the regulatory T cell (Treg) populations in LLNs. ASC-derived EVs alleviated AHR and allergic airway inflammation caused by the induction of Treg expansion in a mouse model of asthma. There seems to be a role for ASC-derived EVs as a modifier in allergic airway disease.
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16
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Pelizzo G, Silvestro S, Avanzini MA, Zuccotti G, Mazzon E, Calcaterra V. Mesenchymal Stromal Cells for the Treatment of Interstitial Lung Disease in Children: A Look from Pediatric and Pediatric Surgeon Viewpoints. Cells 2021; 10:3270. [PMID: 34943779 PMCID: PMC8699409 DOI: 10.3390/cells10123270] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/11/2021] [Accepted: 11/21/2021] [Indexed: 12/16/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) have been proposed as a potential therapy to treat congenital and acquired lung diseases. Due to their tissue-regenerative, anti-fibrotic, and immunomodulatory properties, MSCs combined with other therapy or alone could be considered as a new approach for repair and regeneration of the lung during disease progression and/or after post- surgical injury. Children interstitial lung disease (chILD) represent highly heterogeneous rare respiratory diseases, with a wild range of age of onset and disease expression. The chILD is characterized by inflammatory and fibrotic changes of the pulmonary parenchyma, leading to gas exchange impairment and chronic respiratory failure associated with high morbidity and mortality. The therapeutic strategy is mainly based on the use of corticosteroids, hydroxychloroquine, azithromycin, and supportive care; however, the efficacy is variable, and their long-term use is associated with severe toxicity. The role of MSCs as treatment has been proposed in clinical and pre-clinical studies. In this narrative review, we report on the currently available on MSCs treatment as therapeutical strategy in chILD. The progress into the therapy of respiratory disease in children is mandatory to ameliorate the prognosis and to prevent the progression in adult age. Cell therapy may be a future therapy from both a pediatric and pediatric surgeon's point of view.
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Affiliation(s)
- Gloria Pelizzo
- Pediatric Surgery Department, Children’s Hospital “Vittore Buzzi”, 20154 Milano, Italy
- Department of Biomedical and Clinical Sciences-L. Sacco, University of Milan, 20157 Milan, Italy;
| | - Serena Silvestro
- IRCCS Centro Neurolesi “Bonino-Pulejo”, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy; (S.S.); (E.M.)
| | - Maria Antonietta Avanzini
- Cell Factory, Pediatric Hematology Oncology Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy;
| | - Gianvincenzo Zuccotti
- Department of Biomedical and Clinical Sciences-L. Sacco, University of Milan, 20157 Milan, Italy;
- Department of Pediatrics, Children’s Hospital “Vittore Buzzi”, 20154 Milano, Italy;
| | - Emanuela Mazzon
- IRCCS Centro Neurolesi “Bonino-Pulejo”, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy; (S.S.); (E.M.)
| | - Valeria Calcaterra
- Department of Pediatrics, Children’s Hospital “Vittore Buzzi”, 20154 Milano, Italy;
- Pediatrics and Adolescentology Unit, Department of Internal Medicine, University of Pavia, 27100 Pavia, Italy
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17
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Kim EY, Kim HS, Hong KS, Chung HM, Park SP, Noh G. Mesenchymal stem/stromal cell therapy in atopic dermatitis and chronic urticaria: immunological and clinical viewpoints. Stem Cell Res Ther 2021; 12:539. [PMID: 34635172 PMCID: PMC8503727 DOI: 10.1186/s13287-021-02583-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 08/30/2021] [Indexed: 12/29/2022] Open
Abstract
Allergic diseases are immune-mediated diseases. Allergies share a common immunopathogenesis, with specific differences according to the specific disease. Mesenchymal stem/stromal cells (MSCs) have been applied to people suffering from allergic and many other diseases. In this review, the immunologic roles of MSCs are systemically reviewed according to disease immunopathogenesis from a clinical viewpoint. MSCs seem to be a promising therapeutic modality not only as symptomatic treatments but also as causative and even preventive treatments for allergic diseases, including atopic dermatitis and chronic urticaria.
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Affiliation(s)
| | - Hyuk Soon Kim
- Department of Biomedical Sciences, College of Natural Science, The Graduate School of Dong-A University, Busan, Korea.,Department of Health Sciences, The Graduate School of Dong-A University, Busan, Korea
| | | | - Hyung-Min Chung
- Miraecellbio Co., Ltd., Seoul, Korea.,Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul, Korea
| | - Se-Pill Park
- Miraecellbio Co., Ltd., Seoul, Korea. .,Faculty of Biotechnology, College of Applied Life Sciences, Jeju National University, Jeju, 63243, Korea.
| | - Geunwoong Noh
- Department of Allergy, Allergy and Clinical Immunology Center, Cheju Halla General Hospital, Doreongno 65, Jeju-si, 63127, Jeju Special Self-Governing Province, Korea.
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18
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Wang M, Zhou T, Zhang Z, Liu H, Zheng Z, Xie H. Current therapeutic strategies for respiratory diseases using mesenchymal stem cells. MedComm (Beijing) 2021; 2:351-380. [PMID: 34766151 PMCID: PMC8554668 DOI: 10.1002/mco2.74] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 03/15/2021] [Accepted: 03/18/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stromal/stem cells (MSCs) have a great potential to proliferate, undergo multi-directional differentiation, and exert immunoregulatory effects. There is already much enthusiasm for their therapeutic potentials for respiratory inflammatory diseases. Although the mechanism of MSCs-based therapy has been well explored, only a few articles have summarized the key advances in this field. We hereby provide a review over the latest progresses made on the MSCs-based therapies for four types of inflammatory respiratory diseases, including idiopathic pulmonary fibrosis, acute respiratory distress syndrome, chronic obstructive pulmonary disease, and asthma, and the uncovery of their underlying mechanisms from the perspective of biological characteristics and functions. Furthermore, we have also discussed the advantages and disadvantages of the MSCs-based therapies and prospects for their optimization.
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Affiliation(s)
- Ming‐yao Wang
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Ting‐yue Zhou
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Zhi‐dong Zhang
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Hao‐yang Liu
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Zhi‐yao Zheng
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Hui‐qi Xie
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
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19
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Shin JW, Ryu S, Ham J, Jung K, Lee S, Chung DH, Kang HR, Kim HY. Mesenchymal Stem Cells Suppress Severe Asthma by Directly Regulating Th2 Cells and Type 2 Innate Lymphoid Cells. Mol Cells 2021; 44:580-590. [PMID: 34462397 PMCID: PMC8424137 DOI: 10.14348/molcells.2021.0101] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/25/2021] [Accepted: 05/27/2021] [Indexed: 12/19/2022] Open
Abstract
Patients with severe asthma have unmet clinical needs for effective and safe therapies. One possibility may be mesenchymal stem cell (MSC) therapy, which can improve asthma in murine models. However, it remains unclear how MSCs exert their beneficial effects in asthma. Here, we examined the effect of human umbilical cord blood-derived MSCs (hUC-MSC) on two mouse models of severe asthma, namely, Alternaria alternata-induced and house dust mite (HDM)/diesel exhaust particle (DEP)-induced asthma. hUC-MSC treatment attenuated lung type 2 (Th2 and type 2 innate lymphoid cell) inflammation in both models. However, these effects were only observed with particular treatment routes and timings. In vitro co-culture showed that hUC-MSC directly downregulated the interleukin (IL)-5 and IL-13 production of differentiated mouse Th2 cells and peripheral blood mononuclear cells from asthma patients. Thus, these results showed that hUC-MSC treatment can ameliorate asthma by suppressing the asthmogenic cytokine production of effector cells. However, the successful clinical application of MSCs in the future is likely to require careful optimization of the route, dosage, and timing.
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Affiliation(s)
- Jae Woo Shin
- Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Seungwon Ryu
- Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Jongho Ham
- Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Keehoon Jung
- Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Korea
- Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul 03080, Korea
| | - Sangho Lee
- Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Korea
- Biomedical Institute for Convergence at SKKU, Sungkyunkwan University, Suwon 16419, Korea
| | - Doo Hyun Chung
- Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Korea
- Laboratory of Immune Regulation, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Hye-Ryun Kang
- Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul 03080, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Hye Young Kim
- Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
- Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul 03080, Korea
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20
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Moradinasab S, Pourbagheri-Sigaroodi A, Zafari P, Ghaffari SH, Bashash D. Mesenchymal stromal/stem cells (MSCs) and MSC-derived extracellular vesicles in COVID-19-induced ARDS: Mechanisms of action, research progress, challenges, and opportunities. Int Immunopharmacol 2021; 97:107694. [PMID: 33932694 PMCID: PMC8079337 DOI: 10.1016/j.intimp.2021.107694] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/11/2021] [Accepted: 04/17/2021] [Indexed: 02/06/2023]
Abstract
In late 2019, a novel coronavirus (SARS-CoV-2) emerged in Wuhan city, Hubei province, China. Rapidly escalated into a worldwide pandemic, it has caused an unprecedented and devastating situation on the global public health and society economy. The severity of recent coronavirus disease, abbreviated to COVID-19, seems to be mostly associated with the patients' immune response. In this vein, mesenchymal stromal/stem cells (MSCs) have been suggested as a worth-considering option against COVID-19 as their therapeutic properties are mainly displayed in immunomodulation and anti-inflammatory effects. Indeed, administration of MSCs can attenuate cytokine storm and enhance alveolar fluid clearance, endothelial recovery, and anti-fibrotic regeneration. Despite advantages attributed to MSCs application in lung injuries, there are still several issues __foremost probability of malignant transformation and incidence of MSCs-related coagulopathy__ which should be resolved for the successful application of MSC therapy in COVID-19. In the present study, we review the historical evidence of successful use of MSCs and MSC-derived extracellular vesicles (EVs) in the treatment of acute respiratory distress syndrome (ARDS). We also take a look at MSCs mechanisms of action in the treatment of viral infections, and then through studying both the dark and bright sides of this approach, we provide a thorough discussion if MSC therapy might be a promising therapeutic approach in COVID-19 patients.
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Affiliation(s)
- Susan Moradinasab
- Iranian Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Parisa Zafari
- Department of Immunology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Seyed H Ghaffari
- Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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21
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Abstract
Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by progressive lung scarring due to unknown injurious stimuli ultimately leading to respiratory failure. Diagnosis is complex and requires a combination of clinical, laboratory, radiological, and histological investigations, along with exclusion of known causes of lung fibrosis. The current understanding of the disease etiology suggests an interaction between genetic factors and epigenetic alterations in susceptible, older individuals. Prognosis is dismal and current treatment options include anti-fibrotic agents that only slow down disease progression and carry considerable side effects that hamper patients' quality of life. Therefore, the need for new, more effective treatments, alone or in combination with existing pharmacotherapy, is sorely needed. Regenerative medicine, the potential use of cell therapies to treat destructive diseases that cause architectural distortion to the target organ, has also emerged as an alternative therapeutic for lung diseases with unfavorable prognosis such as IPF. Mesenchymal stem cells (MSCs) and type II alveolar epithelial cells (AEC2s) have been used and their safety has been demonstrated. In the case of MSCs, both homogenic and allogeneic sources have been used and both are considered viable options without immunosuppressive therapy, taking into consideration the absence of immunogenicity and HLA response. AEC2s have been used in one trial with promising results but their use requires a deceased donor and immunosuppressive pre-treatment. In this review, we briefly summarize the current state of knowledge regarding the pathogenesis of IPF, and the background and rationale for using MSCs or AEC2s as potential treatment options. We list and describe the clinical trials completed to date and provide a comparison of their methods and results as well as a possible way forward.
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22
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Cequier A, Sanz C, Rodellar C, Barrachina L. The Usefulness of Mesenchymal Stem Cells beyond the Musculoskeletal System in Horses. Animals (Basel) 2021; 11:ani11040931. [PMID: 33805967 PMCID: PMC8064371 DOI: 10.3390/ani11040931] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 03/21/2021] [Accepted: 03/22/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary The main target of mesenchymal stem cell therapy in horses has long been the locomotor system, because these athletic animals commonly suffer from tendon and joint lesions. Originally, mesenchymal stem cells were thought to act by just differentiating into the cells of the injured tissue. However, these cells are also able to regulate and stimulate the body’s own repair mechanisms, opening the door to many applications in inflammatory and immune-mediated disorders in both animals and humans. In horses, beyond their traditional application in the musculoskeletal system, these cells have been studied for ophthalmologic pathologies such as corneal ulcers or immune-mediated processes, and for reproductive disorders such as endometritis/endometrosis. Their potential has been explored for equine pathologies very similar to those affecting people, such as asthma, metabolic syndrome, aberrant wound healing, or endotoxemia, as well as for equine-specific pathologies such as laminitis. Current evidence is still preliminary, and further research is needed to clarify different aspects, although research performed so far shows the promising potential of mesenchymal stem cells to treat a wide variety of equine pathologies, some of which are analogous to human disorders. Therefore, advancements in this path will be beneficial for both animals and people. Abstract The differentiation ability of mesenchymal stem cells (MSCs) initially raised interest for treating musculoskeletal injuries in horses, but MSC paracrine activity has widened their scope for inflammatory and immune-mediated pathologies in both equine and human medicine. Furthermore, the similar etiopathogenesis of some diseases in both species has advanced the concept of “One Medicine, One Health”. This article reviews the current knowledge on the use of MSCs for equine pathologies beyond the locomotor system, highlighting the value of the horse as translational model. Ophthalmologic and reproductive disorders are among the most studied for MSC application. Equine asthma, equine metabolic syndrome, and endotoxemia have been less explored but offer an interesting scenario for human translation. The use of MSCs in wounds also provides a potential model for humans because of the healing particularities in both species. High-burden equine-specific pathologies such as laminitis have been suggested to benefit from MSC-therapy, and MSC application in challenging disorders such as neurologic conditions has been proposed. The available data are preliminary, however, and require further development to translate results into the clinic. Nevertheless, current evidence indicates a significant potential of equine MSCs to enlarge their range of application, with particular interest in pathologies analogous to human conditions.
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Affiliation(s)
- Alina Cequier
- Laboratorio de Genética Bioquímica LAGENBIO—Instituto de Investigación Sanitaria de Aragón (IIS)—Instituto Agroalimentario de Aragón (IA2), Universidad de Zaragoza, C/Miguel Servet, 177, 50013 Zaragoza, Spain; (A.C.); (C.R.)
| | - Carmen Sanz
- Servicio de Cirugía y Medicina Equina, Hospital Veterinario, Universidad de Zaragoza, C/Miguel Servet, 177, 50013 Zaragoza, Spain;
| | - Clementina Rodellar
- Laboratorio de Genética Bioquímica LAGENBIO—Instituto de Investigación Sanitaria de Aragón (IIS)—Instituto Agroalimentario de Aragón (IA2), Universidad de Zaragoza, C/Miguel Servet, 177, 50013 Zaragoza, Spain; (A.C.); (C.R.)
| | - Laura Barrachina
- Laboratorio de Genética Bioquímica LAGENBIO—Instituto de Investigación Sanitaria de Aragón (IIS)—Instituto Agroalimentario de Aragón (IA2), Universidad de Zaragoza, C/Miguel Servet, 177, 50013 Zaragoza, Spain; (A.C.); (C.R.)
- Servicio de Cirugía y Medicina Equina, Hospital Veterinario, Universidad de Zaragoza, C/Miguel Servet, 177, 50013 Zaragoza, Spain;
- Correspondence:
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23
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Tynecka M, Moniuszko M, Eljaszewicz A. Old Friends with Unexploited Perspectives: Current Advances in Mesenchymal Stem Cell-Based Therapies in Asthma. Stem Cell Rev Rep 2021; 17:1323-1342. [PMID: 33649900 PMCID: PMC7919631 DOI: 10.1007/s12015-021-10137-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/10/2021] [Indexed: 02/07/2023]
Abstract
Mesenchymal stem cells (MSCs) have a great regenerative and immunomodulatory potential that was successfully tested in numerous pre-clinical and clinical studies of various degenerative, hematological and inflammatory disorders. Over the last few decades, substantial immunoregulatory effects of MSC treatment were widely observed in different experimental models of asthma. Therefore, it is tempting to speculate that stem cell-based treatment could become an attractive means to better suppress asthmatic airway inflammation, especially in subjects resistant to currently available anti-inflammatory therapies. In this review, we discuss mechanisms accounting for potent immunosuppressive properties of MSCs and the rationale for their use in asthma. We describe in detail an intriguing interplay between MSCs and other crucial players in the immune system as well as lung microenvironment. Finally, we reveal the potential of MSCs in maintaining airway epithelial integrity and alleviating lung remodeling.
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Affiliation(s)
- Marlena Tynecka
- Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, ul. Waszyngtona 13, 15-269, Białystok, Poland
| | - Marcin Moniuszko
- Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, ul. Waszyngtona 13, 15-269, Białystok, Poland.
- Department of Allergology and Internal Medicine, Medical University of Bialystok, ul. M. Skłodowskiej-Curie 24A, Białystok, 15-276, Poland.
| | - Andrzej Eljaszewicz
- Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, ul. Waszyngtona 13, 15-269, Białystok, Poland.
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24
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Gugjoo MB, Hussain S, Amarpal, Shah RA, Dhama K. Mesenchymal Stem Cell-Mediated Immuno-Modulatory and Anti- Inflammatory Mechanisms in Immune and Allergic Disorders. ACTA ACUST UNITED AC 2020; 14:3-14. [PMID: 32000656 PMCID: PMC7509741 DOI: 10.2174/1872213x14666200130100236] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 01/25/2020] [Accepted: 01/25/2020] [Indexed: 02/06/2023]
Abstract
Background: Mesenchymal Stem Cells (MSCs) are present in almost all the tissues of the body and act as the backbone of the internal tissue homeostasis. Among their various characteristic features, immuno-modulatory and/ anti-inflammatory properties play an important role in therapeutics. Objective: The current topic focuses on the characterization and immuno-modulatory and/ anti-inflammatory properties of MSCs. To present and discuss the current status of MSCs immuno-modulatory properties. Methods: Available literature on MSCs properties and patents have been detailed, critically interpreted, and discussed based upon available literature. The main focus has been on their characteristic immuno-modulatory and anti-inflammatory properties though some of the basic characterization markers have also been detailed. The databases searched for the literature include PubMed, Med Line, PubMed Central, Science Direct and a few other scientific databases. Results: MSCs are present in a very limited concentration in the tissues, and as such their culture expansion becomes imperative. MSCs immuno-modulatory and anti-inflammatory roles are achieved through direct cell-cell contact and / by the release of certain factors. Such properties are controlled by micro-environment upon which currently very limited control can be exerted. Besides, further insights in the xeno-protein free culture media as against the fetal bovine serum is required. Conclusion: MSCs have been well-isolated, cultured and characterized from numerous tissues of the body. The majority of the studies have shown MSCs as immuno-compromised with immunomodulatory and / or anti-inflammatory properties except some of the latest studies that have failed to achieve the desired results and thus, demand further research. Further research is required in the area to translate the results into clinical application.
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Affiliation(s)
- Mudasir B Gugjoo
- Division of Veterinary Clinical Complex, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST, Shuhama, Srinagar-190006, Jammu and Kashmir, India
| | - Shahid Hussain
- Division of Veterinary Clinical Complex, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST, Shuhama, Srinagar-190006, Jammu and Kashmir, India
| | - Amarpal
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, 243 122, Uttar Pradesh, India
| | - Riaz A Shah
- Divison of Animal Biotechnology, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST, Shuhama, Srinagar-190006, Jammu and Kashmir, India
| | - Kuldeep Dhama
- Division of Pathology, ICARIndian Veterinary Research Institute, Izatnagar, Bareilly, 243 122, Uttar Pradesh, India
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25
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Kan XL, Pan XH, Zhao J, He J, Cai XM, Pang RQ, Zhu XQ, Cao XB, Ruan GP. Effect and mechanism of human umbilical cord mesenchymal stem cells in treating allergic rhinitis in mice. Sci Rep 2020; 10:19295. [PMID: 33168885 PMCID: PMC7652838 DOI: 10.1038/s41598-020-76343-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 10/27/2020] [Indexed: 12/17/2022] Open
Abstract
A model of allergic rhinitis (AR) in BALB/c mice was established and evaluated to provide experimental subjects for further research. Preparation of human umbilical cord mesenchymal stem cells (hUCMSCs), including isolation, expansion culture, passaging, cryopreservation, and preparation of cell suspensions, provided materials for experimental research and clinical treatment. The mouse AR model was established by ovalbumin (OVA) intraperitoneal injection and the nasal stimulation induction method, and the model had a good effect and high repeatability. GFP-labeled hUCMSCs had good effects and were stable cells that could be used for tracking in animals. Transplantation of hUCMSCs by intraperitoneal and tail vein injections had a specific effect on the AR model of mice, and tail vein injection had a better effect. Tracking of hUCMSCs in vivo showed that the three groups of mice had the greatest number of hUCMSCs in the nose at week 2. The mouse AR model was used to evaluate the efficacy of hUCMSC transplantation via multiple methods for AR. The distribution of hUCMSCs in vivo was tracked by detecting green fluorescent protein (GFP), and the treatment mechanism of hUCMSCs was elucidated. This study provides technical methods and a theoretical basis for the clinical application of hUCMSCs.
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Affiliation(s)
- Xiao-Li Kan
- Kunming Key Laboratory of Stem Cell and Regenerative Medicine, 920th Hospital of the PLA Joint Logistics Support Force, Kunming, 650032, Yunnan, China.,Stem Cell and Immune Cell Biomedical Techniques and Integrated Engineering Laboratory of State and Regions, Kunming, Yunnan, China.,Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming, Yunnan, China
| | - Xing-Hua Pan
- Kunming Key Laboratory of Stem Cell and Regenerative Medicine, 920th Hospital of the PLA Joint Logistics Support Force, Kunming, 650032, Yunnan, China.,Stem Cell and Immune Cell Biomedical Techniques and Integrated Engineering Laboratory of State and Regions, Kunming, Yunnan, China.,Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming, Yunnan, China
| | - Jing Zhao
- Kunming Key Laboratory of Stem Cell and Regenerative Medicine, 920th Hospital of the PLA Joint Logistics Support Force, Kunming, 650032, Yunnan, China.,Stem Cell and Immune Cell Biomedical Techniques and Integrated Engineering Laboratory of State and Regions, Kunming, Yunnan, China.,Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming, Yunnan, China
| | - Jie He
- Kunming Key Laboratory of Stem Cell and Regenerative Medicine, 920th Hospital of the PLA Joint Logistics Support Force, Kunming, 650032, Yunnan, China.,Stem Cell and Immune Cell Biomedical Techniques and Integrated Engineering Laboratory of State and Regions, Kunming, Yunnan, China.,Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming, Yunnan, China
| | - Xue-Min Cai
- Kunming Key Laboratory of Stem Cell and Regenerative Medicine, 920th Hospital of the PLA Joint Logistics Support Force, Kunming, 650032, Yunnan, China.,Stem Cell and Immune Cell Biomedical Techniques and Integrated Engineering Laboratory of State and Regions, Kunming, Yunnan, China.,Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming, Yunnan, China
| | - Rong-Qing Pang
- Kunming Key Laboratory of Stem Cell and Regenerative Medicine, 920th Hospital of the PLA Joint Logistics Support Force, Kunming, 650032, Yunnan, China.,Stem Cell and Immune Cell Biomedical Techniques and Integrated Engineering Laboratory of State and Regions, Kunming, Yunnan, China.,Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming, Yunnan, China
| | - Xiang-Qing Zhu
- Kunming Key Laboratory of Stem Cell and Regenerative Medicine, 920th Hospital of the PLA Joint Logistics Support Force, Kunming, 650032, Yunnan, China.,Stem Cell and Immune Cell Biomedical Techniques and Integrated Engineering Laboratory of State and Regions, Kunming, Yunnan, China.,Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming, Yunnan, China
| | - Xian-Bao Cao
- Department of Otorhinolaryngology, Kunming First People's Hospital, Kunming, Yunnan, China.
| | - Guang-Ping Ruan
- Kunming Key Laboratory of Stem Cell and Regenerative Medicine, 920th Hospital of the PLA Joint Logistics Support Force, Kunming, 650032, Yunnan, China. .,Stem Cell and Immune Cell Biomedical Techniques and Integrated Engineering Laboratory of State and Regions, Kunming, Yunnan, China. .,Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming, Yunnan, China.
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Mirershadi F, Ahmadi M, Rezabakhsh A, Rajabi H, Rahbarghazi R, Keyhanmanesh R. Unraveling the therapeutic effects of mesenchymal stem cells in asthma. Stem Cell Res Ther 2020; 11:400. [PMID: 32933587 PMCID: PMC7493154 DOI: 10.1186/s13287-020-01921-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 08/27/2020] [Accepted: 09/02/2020] [Indexed: 12/13/2022] Open
Abstract
Asthma is a chronic inflammatory disease associated with airway hyper-responsiveness, chronic inflammatory response, and excessive structural remodeling. The current therapeutic strategies in asthmatic patients are based on controlling the activity of type 2 T helper lymphocytes in the pulmonary tissue. However, most of the available therapies are symptomatic and expensive and with diverse side outcomes in which the interruption of these modalities contributes to the relapse of asthmatic symptoms. Up to date, different reports highlighted the advantages and beneficial outcomes regarding the transplantation of different stem cell sources, and relevant products from for the diseases' alleviation and restoration of injured sites. However, efforts to better understand by which these cells elicit therapeutic effects are already underway. The precise understanding of these mechanisms will help us to translate stem cells into the clinical setting. In this review article, we described current knowledge and future perspectives related to the therapeutic application of stem cell-based therapy in animal models of asthma, with emphasis on the underlying therapeutic mechanisms.
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Affiliation(s)
- Fatemeh Mirershadi
- Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Daneshgah St, Tabriz, 51666-14766, Iran.,Department of Physiology, Ardabil Branch, Islamic Azad University, Ardabil, Iran
| | - Mahdi Ahmadi
- Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Daneshgah St, Tabriz, 51666-14766, Iran.,Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aysa Rezabakhsh
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hadi Rajabi
- Koc University Research Center for Translational Medicine (KUTTAM), Koc University School of Medicine, Istanbul, Turkey.,Department of Pulmonary Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. .,Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Daneshgah St, Tabriz, 51548-53431, Iran.
| | - Rana Keyhanmanesh
- Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Daneshgah St, Tabriz, 51666-14766, Iran. .,Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. .,Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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27
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Halim NSS, Ch'ng ES, Kardia E, Ali SA, Radzi R, Yahaya BH. Aerosolised Mesenchymal Stem Cells Expressing Angiopoietin-1 Enhances Airway Repair. Stem Cell Rev Rep 2020; 15:112-125. [PMID: 30178289 DOI: 10.1007/s12015-018-9844-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND The aim of this study was to investigate the effects of MSCs and MSC-expressing ANGPT1 (MSC-pANGPT1) treatment via aerosolisation in alleviating the asthma-related airway inflammation in the rabbit model. METHODS Rabbits were sensitised and challenged with both intraperitoneal injection and inhalation of ovalbumin (Ova). MSCs and MSC-pANGPT1 cells were aerosolised into rabbit lungs using the MicroSprayer® Aerosolizer Model IA-1B 48 h after injury. The post mortem was performed 3 days following cell delivery. Histopathological assessments of the lung tissues and inflammatory response were quantitatively scored following treatments. RESULT(S) Administration of aerosolised MSCs and MSC-pANGPT1 were significantly reduced inflammation of the airways (p < 0.001), as reflected by improved of structural changes such as thickness of the basement membrane, epithelium, mucosa and sub-mucosa regions. The airway inflammation score of both treatment groups revealed a significant reduction of inflammation and granulocyte infiltration at the peribronchiale and perivascular regions (p < 0.05). Administration of aerosolised MSCs alone was resulted in significant reduction in the levels of pro-inflammatory genes (IL-4 and TGF-β) while treatment with aerosolised MSC-pANGPT1 led to further reduction of various pro-inflammatory genes to the base-line values (IL4, TNF, MMP9 and TGF-β). Treatment with both aerosolised MSCs and MSC-pANGPT1 cells was also alleviated the number of airway inflammatory cells in the bronchoalveolar lavage (BAL) fluid and goblet cell hyperplasia. CONCLUSION(S) Our findings suggest that treatment with MSCs alone attenuated airway inflammation and structural changes of the airway. Treatment with MSC-pANGPT1 provided an additional effect in reducing the expression levels of various pro-inflammatory genes. Both of these treatment enhancing airway repair and therefore may provide a basis for the development of an innovative approach for the treatment and prevention of airway inflammatory diseases.
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Affiliation(s)
- N S S Halim
- Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, 13200, Bertam, Penang, Malaysia
| | - E S Ch'ng
- Oncological and Radiological Science Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, 13200, Bertam, Penang, Malaysia
| | - E Kardia
- Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, 13200, Bertam, Penang, Malaysia
| | - S A Ali
- Oncological and Radiological Science Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, 13200, Bertam, Penang, Malaysia
| | - R Radzi
- Animal Research Facilities, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, 13200 Bertam, Penang, Malaysia
| | - B H Yahaya
- Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, 13200, Bertam, Penang, Malaysia.
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28
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Cell-Based Therapeutic Approaches for Cystic Fibrosis. Int J Mol Sci 2020; 21:ijms21155219. [PMID: 32718005 PMCID: PMC7432606 DOI: 10.3390/ijms21155219] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/20/2020] [Accepted: 07/20/2020] [Indexed: 01/01/2023] Open
Abstract
Cystic Fibrosis (CF) is a chronic autosomal recessive disease caused by defects in the cystic fibrosis transmembrane conductance regulator gene (CFTR). Cystic Fibrosis affects multiple organs but progressive remodeling of the airways, mucus accumulation, and chronic inflammation in the lung, result in lung disease as the major cause of morbidity and mortality. While advances in management of CF symptoms have increased the life expectancy of this devastating disease, and there is tremendous excitement about the potential of new agents targeting the CFTR molecule itself, there is still no curative treatment. With the recent advances in the identification of endogenous airway progenitor cells and in directed differentiation of pluripotent cell sources, cell-based therapeutic approaches for CF have become a plausible treatment method with the potential to ultimately cure the disease. In this review, we highlight the current state of cell therapy in the CF field focusing on the relevant autologous and allogeneic cell populations under investigation and the challenges associated with their use. In addition, we present advances in induced pluripotent stem (iPS) cell approaches and emerging new genetic engineering methods, which have the capacity to overcome the current limitations hindering cell therapy approaches.
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29
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Screening and Functional Pathway Analysis of Pulmonary Genes Associated with Suppression of Allergic Airway Inflammation by Adipose Stem Cell-Derived Extracellular Vesicles. Stem Cells Int 2020; 2020:5684250. [PMID: 32676117 PMCID: PMC7336241 DOI: 10.1155/2020/5684250] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 05/19/2020] [Accepted: 06/02/2020] [Indexed: 12/26/2022] Open
Abstract
Background Although mesenchymal stem cell- (MSC-) derived extracellular vesicles (EVs) are as effective as MSCs in the suppression of allergic airway inflammation, few studies have explored the molecular mechanisms of MSC-derived EVs in allergic airway diseases. The objective of this study was to evaluate differentially expressed genes (DEGs) in the lung associated with the suppression of allergic airway inflammation using adipose stem cell- (ASC-) derived EVs. Methods C57BL/6 mice were sensitized to ovalbumin (OVA) by intraperitoneal injection and challenged intranasally with OVA. To evaluate the effect of ASC-derived EVs on allergic airway inflammation, 10 μg/50 μL of EVs were administered intranasally prior to OVA challenge. Lung tissues were removed and DEGs were compared pairwise among the three groups. DEG profiles and hierarchical clustering of the identified genes were analyzed to evaluate changes in gene expression. Real-time PCR was performed to determine the expression levels of genes upregulated after treatment with ASC-derived EVs. Enrichment analysis based on the Gene Ontology (GO) database and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were also performed to further identify the function of DEGs. Results Expression of paraoxonase 1 (PON1), brain-expressed X-linked 2 (Bex2), insulin-like growth factor binding protein 6 (Igfbp6), formyl peptide receptor 1 (Fpr1), and secretoglobin family 1C member 1 (Scgb1c1) was significantly increased in asthmatic mice following treatment with ASC-derived EVs. GO enrichment and KEGG pathway analysis showed that these genes were strongly associated with immune system processes and their regulation, cellular processes, single-organism processes, and biological regulation. Conclusion These results suggest that the DEGs identified in this study (PON1, Bex2, Igfbp6, Fpr1, and Scgb1c1) may be involved in the amelioration of allergic airway inflammation by ASC-derived EVs.
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30
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Hur J, Kang JY, Kim YK, Lee SY, Jeon S, Kim Y, Jung CK, Rhee CK. Evaluation of Human MSCs Treatment Frequency on Airway Inflammation in a Mouse Model of Acute Asthma. J Korean Med Sci 2020; 35:e188. [PMID: 32537953 PMCID: PMC7295606 DOI: 10.3346/jkms.2020.35.e188] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 04/16/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Studies in experimental models of allergic asthma have shown that mesenchymal stem cells (MSCs) have therapeutic potential for T-helper 2 (TH2) cell-mediated inflammation. However, the mechanisms underlying these therapeutic effects are not fully understood and their safety has not been confirmed. METHODS Using a mouse model of experimental allergic asthma, we investigated the efficacy of human adipose-derived mesenchymal stem cells (hADSCs) or human bone marrow-derived mesenchymal stem cells (hBMSCs) according to treatment frequency and timing. RESULTS Ovalbumin (OVA)-sensitized and -challenged mice exhibited airway hyperresponsiveness (AHR), airway inflammation, and significant increases in TH2 cytokine levels. Both double and single human mesenchymal stem cell (hMSC) treatments significantly decreased AHR and bronchoalveolar lavage fluid counts. In addition, single treatment with hMSCs showed significant attenuation of allergic airway inflammation. However, double treatment with hMSCs during OVA -sensitization and -challenge further increased inflammatory cell infiltration, and TH2 cytokine levels. CONCLUSION The results of treatment with hADSCs or hBMSCs suppresses AHR and airway inflammation. However, double hMSC treatment significantly induces eosinophilic airway inflammation and lung histological changes. Therefore, double hMSC treatment is ineffective against asthma and single injection frequency appears to be more important for the treatment of asthma. These results suggest that hMSC therapy can be used for treatment of asthma patients but that it should be used carefully.
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Affiliation(s)
- Jung Hur
- Division of Allergy and Pulmonary Medicine, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ji Young Kang
- Division of Allergy and Pulmonary Medicine, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Young Kyoon Kim
- Division of Allergy and Pulmonary Medicine, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sook Young Lee
- Division of Allergy and Pulmonary Medicine, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sora Jeon
- Department of Hospital Pathology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Yourha Kim
- Department of Hospital Pathology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Chan Kwon Jung
- Department of Hospital Pathology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
| | - Chin Kook Rhee
- Division of Allergy and Pulmonary Medicine, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
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31
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Yen BL, Yen ML, Wang LT, Liu KJ, Sytwu HK. Current status of mesenchymal stem cell therapy for immune/inflammatory lung disorders: Gleaning insights for possible use in COVID-19. Stem Cells Transl Med 2020; 9:1163-1173. [PMID: 32526079 PMCID: PMC7300965 DOI: 10.1002/sctm.20-0186] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 05/18/2020] [Accepted: 05/24/2020] [Indexed: 01/08/2023] Open
Abstract
The broad immunomodulatory properties of human mesenchymal stem cells (MSCs) have allowed for wide application in regenerative medicine as well as immune/inflammatory diseases, including unmatched allogeneic use. The novel coronavirus disease COVID‐19 has unleashed a pandemic in record time accompanied by an alarming mortality rate mainly due to pulmonary injury and acute respiratory distress syndrome. Because there are no effective preventive or curative therapies currently, MSC therapy (MSCT) has emerged as a possible candidate despite the lack of preclinical data of MSCs for COVID‐19. Interestingly, MSCT preclinical data specifically on immune/inflammatory disorders of the lungs were among the earliest to be reported in 2003, with the first clinical use of MSCT for graft‐vs‐host disease reported in 2004. Since these first reports, preclinical data showing beneficial effects of MSC immunomodulation have accumulated substantially, and as a consequence, over a third of MSCT clinical trials now target immune/inflammatory diseases. There is much preclinical evidence for MSCT in noninfectious—including chronic obstructive pulmonary disease, asthma, and idiopathic pulmonary fibrosis—as well as infectious bacterial immune/inflammatory lung disorders, with data generally demonstrating therapeutic effects; however, for infectious viral pulmonary conditions, the preclinical evidence is more scarce with some inconsistent outcomes. In this article, we review the mechanistic evidence for clinical use of MSCs in pulmonary immune/inflammatory disorders, and survey the ongoing clinical trials—including for COVID‐19—of MSCT for these diseases, with some perspectives and comment on MSCT for COVID‐19.
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Affiliation(s)
- B Linju Yen
- Regenerative Medicine Research Group, Institute of Cellular & System Medicine, National Health Research Institutes (NHRI), Zhunan, Taiwan
| | - Men-Luh Yen
- Department of Obstetrics/Gynecology, National Taiwan University (NTU) Hospital & College of Medicine, NTU, Taipei, Taiwan
| | - Li-Tzu Wang
- Department of Obstetrics/Gynecology, National Taiwan University (NTU) Hospital & College of Medicine, NTU, Taipei, Taiwan
| | - Ko-Jiunn Liu
- National Institute of Cancer Research, NHRI, Tainan, Taiwan
| | - Huey-Kang Sytwu
- National Institute of Infectious Diseases & Vaccinology, NHRI, Zhunan, Taiwan.,Department & Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan
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Akkoç T, Genç D. Asthma immunotherapy and treatment approaches with mesenchymal stem cells. Immunotherapy 2020; 12:665-674. [PMID: 32489107 DOI: 10.2217/imt-2019-0194] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Asthma is a chronic inflammatory disease of the airways where exaggerated T helper 2 immune responses and inflammatory mediators play a role. Current asthma treatment options can effectively suppress symptoms and control the inflammatory process; however, cannot modulate the dysregulated immune response. Allergen-specific immunotherapy is one of the effective treatments capable of disease modification. Injecting allergens under the skin in allergen-specific immunotherapy can reduce asthma and improve the sensitivity of the lungs, however, has a risk of severe reactions. Mesenchymal stem cells have immunoregulatory activity with their soluble mediators and contact dependent manner. In this review, we focus on the current treatment strategies with mesenchymal stem cells in asthma as a new therapeutic tool and compare those with immunotherapy.
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Affiliation(s)
- Tunç Akkoç
- Department of Pediatric Allergy & Immunology, Faculty of Medicine, Marmara University, Istanbul, Turkey
| | - Deniz Genç
- Department of Pediatric Health & Diseases, Faculty of Health Sciences, Muğla Sıtkı Koçman University, Muğla, Turkey
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33
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Wang ZN, Su RN, Yang BY, Yang KX, Yang LF, Yan Y, Chen ZG. Potential Role of Cellular Senescence in Asthma. Front Cell Dev Biol 2020; 8:59. [PMID: 32117985 PMCID: PMC7026390 DOI: 10.3389/fcell.2020.00059] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 01/22/2020] [Indexed: 12/18/2022] Open
Abstract
Cellular senescence is a complicated process featured by irreversible cell cycle arrest and senescence-associated secreted phenotype (SASP), resulting in accumulation of senescent cells, and low-grade inflammation. Cellular senescence not only occurs during the natural aging of normal cells, but also can be accelerated by various pathological factors. Cumulative studies have shown the role of cellular senescence in the pathogenesis of chronic lung diseases including chronic obstructive pulmonary diseases (COPD) and idiopathic pulmonary fibrosis (IPF) by promoting airway inflammation and airway remodeling. Recently, great interest has been raised in the involvement of cellular senescence in asthma. Limited but valuable data has indicated accelerating cellular senescence in asthma. This review will compile current findings regarding the underlying relationship between cellular senescence and asthma, mainly through discussing the potential mechanisms of cellular senescence in asthma, the impact of senescent cells on the pathobiology of asthma, and the efficiency and feasibility of using anti-aging therapies in asthmatic patients.
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Affiliation(s)
- Zhao-Ni Wang
- Department of Pediatrics, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Ruo-Nan Su
- Department of Pediatrics, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Bi-Yuan Yang
- Department of Pediatrics, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ke-Xin Yang
- Department of Pediatrics, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Li-Fen Yang
- Department of Pediatrics, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yan Yan
- Guangdong Provincial Key Laboratory of Biomedical Imaging, Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China.,Center for Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
| | - Zhuang-Gui Chen
- Department of Pediatrics, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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MacDonald ES, Barrett JG. The Potential of Mesenchymal Stem Cells to Treat Systemic Inflammation in Horses. Front Vet Sci 2020; 6:507. [PMID: 32039250 PMCID: PMC6985200 DOI: 10.3389/fvets.2019.00507] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 12/20/2019] [Indexed: 12/13/2022] Open
Abstract
One hallmark of mesenchymal stem cells (MSCs) is the ability to differentiate into multiple tissue types which assists in tissue regeneration. Another hallmark of MSCs is their potent anti-inflammatory and immunomodulatory properties and the potential to treat inflammatory, immune-mediated, and ischemic conditions. In equine practice, MSCs have shown efficacy in the treatment of musculoskeletal disorders such as tendinopathy, meniscal tears and cartilage injury. However, there are many equine disease processes and conditions that may benefit from the immunomodulatory properties of MSCs. Examples include conditions associated with overwhelming acute inflammatory response such as systemic inflammatory response syndrome to chronic diseases characterized by a prolonged low level of inflammation such as equine asthma and recurrent uveitis. For the acute inflammatory response processes, there is often high morbidity and mortality with no effective immunomodulatory treatment to prevent the overwhelming synthesis of proinflammatory mediators. For chronic inflammatory disease processes, frequently long-term corticosteroid treatment is the therapeutic mainstay, with serious potential complications. Thus, there is an unmet need for alternative anti-inflammatory treatments for both acute and chronic illnesses in horses. While MSCs show promise for such conditions, much research is needed before a clinically safe and effective treatment will be available. Optimal MSC tissue source, patient vs. donor source (autologous vs. allogeneic) and cell growth conditions need to be determined for each problem. For immediate use, allogeneic MSC treatments is preferable, but immune tolerance and adequate safety require further study. MSC collection and cryopreservation from horses before they are injured or ill, whether from umbilical cord tissue, bone marrow or adipose might become more widespread. Once these fundamental approaches to treating specific diseases with MSCs are determined, the route of administration, dose and timing of administration also need to be studied. To provide a framework for development of MSC immunomodulatory treatments, this article reviews the current understanding of equine MSC anti-inflammatory and immunomodulatory properties and proposes how MSC therapy may be further developed to treat acute onset systemic inflammatory processes and chronic inflammatory diseases.
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Affiliation(s)
- Elizabeth S MacDonald
- Marion duPont Scott Equine Medical Center, Virginia Maryland College of Veterinary Medicine, Virginia Tech, Leesburg, VA, United States
| | - Jennifer G Barrett
- Marion duPont Scott Equine Medical Center, Virginia Maryland College of Veterinary Medicine, Virginia Tech, Leesburg, VA, United States
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Li H, Tian Y, Xie L, Liu X, Huang Z, Su W. Mesenchymal stem cells in allergic diseases: Current status. Allergol Int 2020; 69:35-45. [PMID: 31445840 DOI: 10.1016/j.alit.2019.08.001] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 07/17/2019] [Accepted: 07/24/2019] [Indexed: 12/13/2022] Open
Abstract
Allergic diseases, which include asthma, allergic skin diseases, allergic rhinitis and allergic conjunctivitis, have already garnered worldwide public health attention over recent decades. Mesenchymal stem cells (MSCs) have gradually emerged as a potential method for treating allergic diseases due to their immunosuppressive characteristics, tissue repair ability and secretion of various biological factors. This potential of MSC-based therapy has been confirmed in clinical and preclinical studies, which report the therapeutic benefits of MSCs for various allergic diseases and explore the antiallergic mechanisms. In this review, we focus on the discoveries and biological mechanisms of MSCs as a therapeutic tool in allergic diseases. We discuss the challenges of conducting MSC studies as well as future directions.
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Abstract
Asthma is an important allergic lower-airway disease in cats affecting approximately 1% to 5% of the pet cat population. New diagnostics are being developed to help better differentiate asthma from other lower-airway diseases and improve monitoring. In addition, new treatments are being developed to help in refractory cases or in those cases in which traditional therapeutics are contraindicated. This article discusses potential pitfalls in the diagnosis of asthma. In addition, current literature investigating new diagnostic tests and therapies for feline asthma is reviewed.
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Affiliation(s)
- Julie E Trzil
- IndyVet Emergency and Specialty Hospital, 5425 Victory Drive, Indianapolis, IN 46203, USA.
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MSCs exosomal miR-1470 promotes the differentiation of CD4 +CD25 +FOXP3 + Tregs in asthmatic patients by inducing the expression of P27KIP1. Int Immunopharmacol 2019; 77:105981. [PMID: 31685437 DOI: 10.1016/j.intimp.2019.105981] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 10/02/2019] [Accepted: 10/13/2019] [Indexed: 01/15/2023]
Abstract
Exosomes derived from Mesenchymal Stem Cells (MSCs) possesses similar immunomodulatory effect as MSCs. It had been suggested that MSCs exosomes contain higher level of miR-1470 compared to exosomes derived from fibroblast. Here, we show that MSCs exosomal miR-1470 can elevate the proportion of CD4+CD25+FOXP3+ regulatory T cells (Tregs) in asthmatic patients. Moreover, mechanistic studies revealed that miR-1470 can promote the upregulation of P27KIP1 by directly targeting the 3' region of c-Jun mRNA. Furthermore, miR-1470 mimic transfection could significantly upregulate the proportion of CD4+CD25+FOXP3+ Tregs in CD4+ T cells. P27KIP1 knockdown via siRNA silencing significantly inhibited the proportion of CD4+CD25+FOXP3+ Tregs with over-expression of miR-1470, which indicates that miR-1470 induces the differentiation of CD4+CD25+FOXP3+ Tregs through P27KIP1.
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Emukah C, Dittmar E, Naqvi R, Martinez J, Corral A, Moreira A, Moreira A. Mesenchymal stromal cell conditioned media for lung disease: a systematic review and meta-analysis of preclinical studies. Respir Res 2019; 20:239. [PMID: 31666086 PMCID: PMC6822429 DOI: 10.1186/s12931-019-1212-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 10/10/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Inflammation plays an important role in the pathogenesis of many lung diseases. Preclinical studies suggest that mesenchymal stromal cell (MSC) conditioned media (CdM) can attenuate inflammation. Our aim was threefold: (1) summarize the existing animal literature evaluating CdM as a therapeutic agent for pediatric/adult lung disease, (2) quantify the effects of CdM on inflammation, and (3) compare inflammatory effects of CdM to MSCs. METHODS Adhering to the Systematic Review Protocol for Animal Intervention Studies, a systematic search of English articles was performed in five databases. Meta-analysis and meta-regression were performed to generate random effect size using standardized mean difference (SMD). RESULTS A total of 10 studies met inclusion. Lung diseases included bronchopulmonary dysplasia, asthma, pulmonary hypertension, and acute respiratory distress syndrome. CdM decreased inflammatory cells (1.02 SMD, 95% CI 0.86, 1.18) and cytokines (0.71 SMD, 95% CI 0.59, 0.84). The strongest effect for inflammatory cells was in bronchopulmonary dysplasia (3.74 SMD, 95% CI 3.13, 4.36) while pulmonary hypertension had the greatest reduction in inflammatory cytokine expression (1.44 SMD, 95% CI 1.18, 1.71). Overall, CdM and MSCs had similar anti-inflammatory effects. CONCLUSIONS In this meta-analysis of animal models recapitulating lung disease, CdM improved inflammation and had an effect size comparable to MSCs. While these findings are encouraging, the risk of bias and heterogeneity limited the strength of our findings.
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Affiliation(s)
- Chimobi Emukah
- Department of Pediatrics, Division of Neonatology, University of Texas Health-San Antonio, San Antonio, Texas, 78229-3900, USA
| | - Evan Dittmar
- Department of Pediatrics, Division of Neonatology, University of Texas Health-San Antonio, San Antonio, Texas, 78229-3900, USA
| | - Rija Naqvi
- Department of Pediatrics, Division of Neonatology, University of Texas Health-San Antonio, San Antonio, Texas, 78229-3900, USA
| | - John Martinez
- Department of Pediatrics, Division of Neonatology, University of Texas Health-San Antonio, San Antonio, Texas, 78229-3900, USA
| | - Alexis Corral
- Department of Pediatrics, Division of Neonatology, University of Texas Health-San Antonio, San Antonio, Texas, 78229-3900, USA
| | - Axel Moreira
- Department of Pediatrics, Texas Children's Hospital, Houston, Texas, USA
| | - Alvaro Moreira
- Department of Pediatrics, Division of Neonatology, University of Texas Health-San Antonio, San Antonio, Texas, 78229-3900, USA.
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Lin SC, Liou YM, Ling TY, Chuang YH, Chiang BL. Placenta-Derived Mesenchymal Stem Cells Reduce the Interleukin-5 Level Experimentally in Children with Asthma. Int J Med Sci 2019; 16:1430-1438. [PMID: 31673233 PMCID: PMC6818200 DOI: 10.7150/ijms.33590] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 06/21/2019] [Indexed: 12/20/2022] Open
Abstract
Background: Mesenchymal stem cells (MSCs) have been investigated as a new treatment option for various diseases in recent years. However, the role of placenta-derived MSCs in children with asthma remains unclear. We assessed the effect of placenta-derived MSCs on T cell immune responses and cytokine IL-5 levels according to cultures in children with and without asthma. Study design: We enrolled children with and without asthma and recorded asthma symptom scores in the asthma group. Blood samples from children were collected to isolate peripheral blood mononuclear cells (PBMCs) and determine the total IgE level. The PBMCs were cultured in vitro with or without MSCs after stimulation with human anti-CD3 and anti-CD28 antibodies (0.5 μg/mL) to evaluate the effect of placenta-derived MSCs. Flow cytometry was performed to detect the activation and proliferation of CD4+ and CD8+ T cells. Pre- and post-culture IL-5 levels were measured in all samples. Results: The percentages of activation and proliferation among CD4+ and CD8+ T cells after coculture with MSCs were significantly lower in the asthma group (P < 0.05). IL-5 levels differed significantly between the PBMC culture and PBMC + MSC (P+S) coculture in the asthma group (P < 0.05). IL-5 levels differed significantly between the PBMC culture and P+S coculture in both the lower (P < 0.05) and higher (P < 0.0005) IgE asthma subgroups. IL-5 levels were also decreased in children with all severities of asthma (P < 0.05). Conclusions: Placenta-derived MSCs exerted an anti-IL-5 effect and reduced the IL-5 level in culture in different subgroups of children with asthma.
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Affiliation(s)
- Sheng-Chieh Lin
- Department of Pediatrics, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan
- Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yih-Mei Liou
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Thai-Yen Ling
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ya-Hui Chuang
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Laboratory Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Bor-Luen Chiang
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
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Genç D, Zibandeh N, Nain E, Arığ Ü, Göker K, Aydıner E, Akkoç T. IFN-γ stimulation of dental follicle mesenchymal stem cells modulates immune response of CD4 + T lymphocytes in Der p1 + asthmatic patients in vitro. Allergol Immunopathol (Madr) 2019; 47:467-476. [PMID: 30826066 DOI: 10.1016/j.aller.2018.12.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 12/22/2018] [Accepted: 12/29/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND House dust mite (Dermataphagoides pteronyssinus) is a widespread risk factor in the development of asthma. CD4+ T lymphocytes have an important role in the pathogenesis of allergic asthma by polarizing to Th2 cells. OBJECTIVE We aimed to evaluate the immunoregulatory effects of dental follicle mesenchymal stem cells with and without IFN-γ stimulation on peripheral blood mononuclear cells of house dust mite sensitive asthmatic patients, and compared those with Dexamethasone as a systemic steroid. MATERIAL AND METHODS PBMC of asthmatic patients and healthy individuals separately cultured with or without DF-MSCs in the presence and absence of IFN-γ or Der p1 or Dexamethasone for 72h. CD4+ T proliferation, cell viability, CD4+CD25+FoxP3+ Treg cell frequency and cytokine profiles of PBMC were evaluated via flow cytometry. RESULTS DF-MSCs suppressed proliferation of CD4+ T lymphocytes (pCDmix<0.01, pDerp1<0.01, pIFN<0.005) by increasing the number of FoxP3 expressing CD4+CD25+ T regulatory cells (pCDmix<0.005, pDerp1<0.01, pIFN<0.001) and suppressed lymphocyte apoptosis (pCDmix<0.05, pDerp1<0.05, pIFN<0.05), while Dexamethasone increased the apoptosis and decreased Treg cell frequency in asthmatic patients. IFN-γ stimulation increased the suppressive effect of DF-MSCs and also enhanced the frequency of FoxP3 expressing CD4+CD25+ T regulatory cells. The cytokine levels were regulated by DF-MSCs by reducing IL-4 cytokine levels (pCDmix<0.01, pDerp1<0.05, pIFN<0.05) and upregulating IFN-γ levels (pCDmix<0.01, pDerp1<0.05, pIFN<0.005) in asthmatic patients. CONCLUSION IFN-γ stimulated DF-MSCs were found to have a high modulatory effect on CD4+ T cell responses, while Dexamethasone had an apoptotic effect on CD4+ T cells in asthmatic patients. DF-MSCs may be a new cell-based therapy option for allergic diseases including asthma.
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Laing AG, Riffo-Vasquez Y, Sharif-Paghaleh E, Lombardi G, Sharpe PT. Immune modulation by apoptotic dental pulp stem cells in vivo. Immunotherapy 2019; 10:201-211. [PMID: 29370720 DOI: 10.2217/imt-2017-0117] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs) show considerable promise as a cellular immunotherapy for the treatment of a number of autoimmune and inflammatory disorders. However, the precise physiologically and therapeutically relevant mechanism(s) by which MSCs mediate immune modulation remains elusive. Dental pulp stem cells are a readily available source of MSCs that have been reported to show similar immune modulation in vitro as bone marrow MSCs. To test their potential in vivo, we used a clinically relevant humanized mouse model of GvHD in which only human T cells engraft. In this model, we found no effects on either T-cell proliferation, T-cell phenotype or disease progression. To determine if this lack of efficacy was related to a failure of engraftment or persistence of the cells, we used viability dependent radioactive cell tracking and showed that no cells were detectable after 24-h postinjection. Given the apparent failure of MSC to survive following intravenous injection, we hypothesized that their apoptosis may account for the widely reported therapeutic effect in numerous experimental models in vivo. To address this, we employed a well-established model of allergic airway inflammation to compare the efficacy of live and apoptotic MSCs in a fully immunocompetent model. In this model, both live and apoptotic dental pulp MSCs induced a robust immune suppressive reaction that was substantially greater with apoptotic cells. We propose that the mechanism of immune modulation following systemic application of MSCs is a result of cell entrapment and apoptosis occurring in the lungs.
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Affiliation(s)
- Adam G Laing
- MRC Centre for Transplantation, King's College London, London, UK, SE1 9RT.,Centre for Craniofacial & Regenerative Biology, King's College London, London, UK, SE1 9RT
| | - Yanira Riffo-Vasquez
- Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, SE1 9NH, UK
| | | | - Giovanna Lombardi
- MRC Centre for Transplantation, King's College London, London, UK, SE1 9RT
| | - Paul T Sharpe
- MRC Centre for Transplantation, King's College London, London, UK, SE1 9RT.,Centre for Craniofacial & Regenerative Biology, King's College London, London, UK, SE1 9RT
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Lange-Consiglio A, Stucchi L, Zucca E, Lavoie JP, Cremonesi F, Ferrucci F. Insights into animal models for cell-based therapies in translational studies of lung diseases: Is the horse with naturally occurring asthma the right choice? Cytotherapy 2019; 21:525-534. [PMID: 30929991 DOI: 10.1016/j.jcyt.2019.02.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 02/21/2019] [Accepted: 02/25/2019] [Indexed: 12/15/2022]
Abstract
Human asthma is a widespread disease associated with chronic inflammation of the airways, leading to loss of quality of life, disability and death. Corticosteroid administration is the mainstream treatment for asthmatic patients. Corticosteroids reduce airway obstruction and improve quality of life, although symptoms persist despite treatment in many patients. Moreover, available therapies failed to reverse the lung pathology present in asthma. Animal models, mostly rats and mice, in which the disease is experimentally induced, have been studied to identify new therapeutic targets for human asthma. Alternative animal models could include horses in which naturally occurring asthma could represent an important step to test therapies, potentially designed around mouse studies, before being translated to human testing. Horses naturally suffer from asthma, which has striking parallels with human asthma. Severe equine asthma (SEA) is characterized by reversible bronchospasms and neutrophil accumulation in the lungs immunologically mediated mainly by Th2. Moreover, the pulmonary remodelling that occurs in SEA closely resembles that of human asthma, making the equine model unique for investigation of tissue repair and new therapies. Cell therapy, consisting on mesenchymal stromal cells (MSCs) and derivatives (conditioned medium and extracellular vesicles), could represent a novel therapeutic contribution for tissue regeneration. Cell therapy may prove advantageous over conventional therapy in that it may repair or regenerate the site of injury and reduce the reaction to allergens, rather than simply modulating the inflammatory process.
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Affiliation(s)
- Anna Lange-Consiglio
- Department of Veterinary Medicine, Università degli Studi di Milano, Milano, Italy; Reproduction Unit, Centro Clinico-Veterinario e Zootecnico Sperimentale di Ateneo, Università degli Studi di Milano, Lodi, Italy.
| | - Luca Stucchi
- Equine Medicine Unit, Department of Health, Animal Science and Food Safety, Università degli Studi di Milano, Milano, Italy
| | - Enrica Zucca
- Equine Medicine Unit, Department of Health, Animal Science and Food Safety, Università degli Studi di Milano, Milano, Italy
| | - Jean Pierre Lavoie
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Université de Montréal, St-Hyacinthe, QC, Canada
| | - Fausto Cremonesi
- Department of Veterinary Medicine, Università degli Studi di Milano, Milano, Italy; Reproduction Unit, Centro Clinico-Veterinario e Zootecnico Sperimentale di Ateneo, Università degli Studi di Milano, Lodi, Italy
| | - Francesco Ferrucci
- Equine Medicine Unit, Department of Health, Animal Science and Food Safety, Università degli Studi di Milano, Milano, Italy
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Zhong H, Fan XL, Fang SB, Lin YD, Wen W, Fu QL. Human pluripotent stem cell-derived mesenchymal stem cells prevent chronic allergic airway inflammation via TGF-β1-Smad2/Smad3 signaling pathway in mice. Mol Immunol 2019; 109:51-57. [PMID: 30852246 DOI: 10.1016/j.molimm.2019.02.017] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2018] [Revised: 01/10/2019] [Accepted: 02/20/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND Asthma is a chronic disease involving inflamed airways, which were previously demonstrated, can be modulated by the mesenchymal stem cells derived from induced pluripotent stem cells (iPSC-MSCs). However, the long-term effects of iPSC-MSCs in inflamed airways are still unidentified. This study investigated the long-term effects and potential mechanisms involved in the immunomodulatory effects of iPSC-MSCs in the chronic mouse asthma model. METHODS Both human iPSC-MSCs and bone marrow (BM)-MSCs were transplanted into the long-term ovalbumin-induced mice before sensitization phase or during the challenge phase. Airway hyper-respnsiveness measurement, immunohistochemistry and ELISA were employed to assess the effects of MSCs. In addition, Smad2/3 levels were assessed by western blot analysis to investigate the possible mechanism involved. RESULTS The systemic administration of human iPSC-MSCs before the challenge protected the mice from the characters of the chronic allergic airway inflammation, in particular improving the airway remodeling and preventing fibrosis. In addition, the TGF-β1/Smad pathway was identified involved in the immunomodulatory effects of iPSC-MSCs on chronic allergic airway inflammation. CONCLUSIONS The study demonstrated that iPSC-MSCs are capable of preventing chronic allergic airway inflammation over a prolonged period, which further proved the iPSC-MSC therapeutic potential for allergic airway inflammation in a clinical scenario.
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Affiliation(s)
- Hua Zhong
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Xing-Liang Fan
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Centre for Stem Cell Clinical Research and Application, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Shu-Bin Fang
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Yong-Dong Lin
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Weiping Wen
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Qing-Ling Fu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; Centre for Stem Cell Clinical Research and Application, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
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Ebrahim N, Mandour YMH, Farid AS, Nafie E, Mohamed AZ, Safwat M, Taha R, Sabry D, Sorour SM, Refae A. Adipose Tissue-Derived Mesenchymal Stem Cell Modulates the Immune Response of Allergic Rhinitis in a Rat Model. Int J Mol Sci 2019; 20:E873. [PMID: 30781605 PMCID: PMC6412869 DOI: 10.3390/ijms20040873] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 02/13/2019] [Accepted: 02/14/2019] [Indexed: 12/19/2022] Open
Abstract
This study was designed to investigate the potential effects and underlying mechanism of adipose tissue-derived mesenchymal stem cells (MSCs) on allergic inflammation compared to Montelukast as an antileukotriene drug in a rat model of allergic rhinitis (AR). The effect of MSCs was evaluated in albino rats that were randomly divided into four (control, AR, AR + Montelukast, and AR + MSCs) groups. Rats of AR group were sensitized by ovalbumin (OVA) and then challenged with daily nasal drops of OVA diluted in sterile physiological saline (50 μL/nostril, 100 mg/mL, 10% OVA) from day 15 to day 21 of treatment with/without Montelukast (1 h before each challenge) or MSCs I/P injection (1 × 10⁶ MCSs; weekly for three constitutive weeks). Both Montelukast and MSCs treatment started from day 15 of the experiment. At the end of the 5th week, blood samples were collected from all rats for immunological assays, histological, and molecular biology examinations. Both oral Montelukast and intraperitoneal injection of MSCs significantly reduced allergic symptoms and OVA-specific immunoglobulin E (IgE), IgG1, IgG2a and histamine as well as increasing prostaglandin E2 (PGE2). Further analysis revealed that induction of nasal innate cytokines, such as interleukin (IL)-4 and TNF-α; and chemokines, such as CCL11 and vascular cell adhesion molecule-1 (VCAM-1), were suppressed; and transforming growth factor-β (TGF-β) was up-regulated in Montelukast and MSCs-treated groups with superior effect to MSCs, which explained their underlying mechanism. In addition, the adipose tissue-derived MSCs-treated group had more restoring effects on nasal mucosa structure demonstrated by electron microscopical examination.
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Affiliation(s)
- Nesrine Ebrahim
- Department of Histology and Cell Biology, Benha University, Benha, Qalyubia 13518, Egypt.
- Stem Cell Unit, Benha University, Benha, Qalyubia 13518, Egypt.
| | | | - Ayman Samir Farid
- Department of Clinical Pathology, Faculty of Veterinary Medicine, Benha University, Moshtohor, Toukh, Qalyubia 13736, Egypt.
| | - Ebtesam Nafie
- Zoology Department, Faculty of Science, Benha University, Benha 13518, Egypt.
| | - Amira Zaky Mohamed
- Department of Microbiology, Faculty of Science, Tanta University, Tanta 31527, Egypt.
| | - Miriam Safwat
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo 11562, Egypt.
| | - Radwa Taha
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo 11562, Egypt.
| | - Dina Sabry
- Department of Medical Biochemistry, Faculty of Medicine, Cairo University, Cairo 11562, Egypt.
- Molecular Biology and Stem Cell Unit, Faculty of Medicine, Cairo University, Cairo 11562, Egypt.
| | - Safwa M Sorour
- Department of Clinical Pharmacology, Faculty of Medicine, Benha University, Benha, Qalyubia 13518, Egypt.
| | - Ahmed Refae
- Department of Otorhinolaryngology, Faculty of Medicine, Benha University, Benha, Qalyubia 13518, Egypt.
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Zhang LB, He M. Effect of mesenchymal stromal (stem) cell (MSC) transplantation in asthmatic animal models: A systematic review and meta-analysis. Pulm Pharmacol Ther 2018; 54:39-52. [PMID: 30496803 DOI: 10.1016/j.pupt.2018.11.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2018] [Revised: 07/17/2018] [Accepted: 11/25/2018] [Indexed: 12/18/2022]
Abstract
BACKGROUND Over the years, mesenchymal stromal (stem) cells (MSCs) have been pre-clinically applied in the treatment of variety kinds of diseases including asthma and chronic lung diseases. Aim of the current study was to systematically review and to conduct meta-analysis on the published studies of MSC treatment in asthma animal models. METHODS Publications on the MSC and asthma treatment was thoroughly searched in the electronic databases. Statistical analysis was then performed using the Comprehensive Meta-Analysis software (Version 3). Effect of MSC therapy on asthma model was assessed by Hedges's g with 95% confidence intervals (95% CIs). Random effect model was used due to the heterogeneity between the studies. RESULTS Meta-analysis of the 32 included studies showed that MSC transplantation was significantly in favor of attenuating lung injury and remodeling (Hedges's g = -9.104 ± 0.951 with 95% CI: -10.969 ∼ -7.240, P < 0.001) and airway inflammation (Hedges's g = -4.146 ± 0.688 with 95% CI: -5.495 ∼ -2.797, P < 0.001). The mechanism of MSC therapy in asthma seems to be regulating the balance of Th1 cytokine and Th2 cytokines (IFN-γ: Hedges's g = 4.779 ± 1.408 with 95% CI: 1.099-2.725, P < 0.001; IL-4: Hedges's g = -10.781 ± 1.062 with 95% CI: -12.863 ∼ -8.699, P < 0.001; IL-5: Hedges's g = -10.537 ± 1.269 with 95% CI: -13.025 ∼ -8.050, P < 0.001; IL-13: Hedges's g = -6.773 ± 0.788 with 95% CI: -8.318 ∼ -5.229, P < 0.001). CONCLUSION Findings of the current systemic review suggested a potential role for MSCs in asthma treatment although it is still challenging in clinical practice. The mechanisms of MSCs in pre-clinical asthma treatment may be associated with attenuating airway inflammation through regulating Th1 and Th2 cytokines.
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Affiliation(s)
- Li-Bo Zhang
- Department of Respiratory Medicine, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Min He
- Department of Respiratory Medicine, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China.
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Rosenberg JT, Yuan X, Helsper SN, Bagdasarian FA, Ma T, Grant SC. Effects of labeling human mesenchymal stem cells with superparamagnetic iron oxides on cellular functions and magnetic resonance contrast in hypoxic environments and long-term monitoring. Brain Circ 2018; 4:133-138. [PMID: 30450421 PMCID: PMC6187941 DOI: 10.4103/bc.bc_18_18] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Revised: 08/27/2018] [Accepted: 09/10/2018] [Indexed: 01/25/2023] Open
Abstract
Ischemia, which involves decreased blood flow to a region and a corresponding deprivation of oxygen and nutrients, can be induced as a consequence of stroke or heart attack. A prevalent disease that affects many individuals worldwide, ischemic stroke results in functional and cognitive impairments, as neural cells in the brain receive inadequate nourishment and encounter inflammation and various other detrimental toxic factors that lead to their death. Given the scarce treatments for this disease in the clinic such as the administration of tissue plasminogen activator, which is only effective in a limited time window after the occurrence of stroke, it will be necessary to develop new strategies to ameliorate or prevent stroke-induced brain damage. Cell-based therapies appear to be a promising solution for treating ischemic stroke and many other ischemia-associated and neurodegenerative maladies. Particularly, human mesenchymal stem cells (hMSCs) are of interest for cell transplantation in stroke, given their multipotency, accessibility, and reparative abilities. To determine the fate and survival of hMSC, which will be imperative for successful transplantation therapies, these cells may be monitored using magnetic resonance imaging and transfected with superparamagnetic iron oxide (SPIO), a contrast agent that facilitates the detection of these hMSCs. This review encompasses pertinent research and findings to reveal the effects of SPIO on hMSC functions in the context of transplantation in ischemic environments and over extended time periods. This paper is a review article. Referred literature in this paper has been listed in the references section. The data sets supporting the conclusions of this article are available online by searching various databases, including PubMed. Some original points in this article come from the laboratory practice in our research center and the authors' experiences.
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Affiliation(s)
- Jens T Rosenberg
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Tallahassee, Florida, USA.,The National High Magnetic Field Laboratory, CIMAR, Florida State University, Tallahassee, Florida, USA
| | - Xuegang Yuan
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Tallahassee, Florida, USA
| | - Shannon N Helsper
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Tallahassee, Florida, USA.,The National High Magnetic Field Laboratory, CIMAR, Florida State University, Tallahassee, Florida, USA
| | - F Andrew Bagdasarian
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Tallahassee, Florida, USA.,The National High Magnetic Field Laboratory, CIMAR, Florida State University, Tallahassee, Florida, USA
| | - Teng Ma
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Tallahassee, Florida, USA
| | - Samuel C Grant
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Tallahassee, Florida, USA.,The National High Magnetic Field Laboratory, CIMAR, Florida State University, Tallahassee, Florida, USA
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Cobalt Chloride Enhances the Anti-Inflammatory Potency of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells through the ERK-HIF-1 α-MicroRNA-146a-Mediated Signaling Pathway. Stem Cells Int 2018; 2018:4978763. [PMID: 30254683 PMCID: PMC6145052 DOI: 10.1155/2018/4978763] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Revised: 05/17/2018] [Accepted: 07/25/2018] [Indexed: 12/25/2022] Open
Abstract
Human mesenchymal stem cells (hMSCs), including human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs), which have high proliferation capacity and immunomodulatory properties, are considered to be a good candidate for cell-based therapies. hMSCs show enhanced therapeutic effects via paracrine secretion or cell-to-cell contact that modulates inflammatory or immune reactions. Here, treatment with cobalt chloride (CoCl2) was more effective than naïve hUCB-MSCs in suppressing inflammatory responses in a coculture system with phytohemagglutinin- (PHA-) activated human peripheral blood mononuclear cells (hPBMCs). Furthermore, the effect of CoCl2 is exerted by promoting the expression of anti-inflammatory mediators (e.g., PGE2) and inhibiting that of inflammatory cytokines (e.g., TNF-α and IFN-γ). Treatment of hUCB-MSCs with CoCl2 leads to increased expression of microRNA- (miR-) 146a, which was reported to modulate anti-inflammatory responses. Hypoxia-inducible factor- (HIF-) 1α silencing and ERK inhibition abolished CoCl2-induced miR-146a expression, suggesting that ERK and HIF-1α signals are required for CoCl2-induced miR-146a expression in hUCB-MSCs. These data suggest that treatment with CoCl2 enhances the immunosuppressive capacity of hUCB-MSCs through the ERK-HIF-1α-miR-146a-mediated signaling pathway. Furthermore, pretreatment of transplanted MSCs with CoCl2 can suppress lung inflammation more than naïve MSCs can in a mouse model of asthma. These findings suggest that CoCl2 may improve the therapeutic effects of hUCB-MSCs for the treatment of inflammatory diseases.
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Mohammadian M, Sadeghipour HR, Jahromi GP, Jafari M, Nejad AK, Khamse S, Boskabady MH. Simvastatin and bone marrow-derived mesenchymal stem cells (BMSCs) affects serum IgE and lung cytokines levels in sensitized mice. Cytokine 2018; 113:83-88. [PMID: 29914792 DOI: 10.1016/j.cyto.2018.06.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 05/31/2018] [Accepted: 06/11/2018] [Indexed: 01/31/2023]
Abstract
INTRODUCTION The effects of bone marrow-derived mesenchymal stem cells (BMSCs) and simvastatin combination therapy on serum total and specific IgE levels and lung IL-13 and TGF-β levels in sensitized mouse were examined. MATERIAL AND METHODS Control (n = 5), Sensitized (S), (n = 5), S + BMSC (n = 6), S + simvastatin (n = 6) and S + BMSC + simvastatin (n = 4) groups of BALB/c mice were studied. Mice were sensitized by ovalbumin. Sensitized mice were treated with a single intravenous injection of BMSCs (1 × 106) or daily intraperitoneal injection of simvastatin (40 mg/kg) or both BMSCs and simvastatin on the last week of challenge. Serum total and ovalbumin specific IgE levels as well as IL-13 and TGF-β levels in broncho-alveolar lavage (BAL) fluid were evaluated. RESULTS Serum total and specific IgE levels as well as lung IL-13 and TGF-β levels were significantly increased in S group compared to control group (P < 0.001 for all cases). Treatment with BMSCs, simvastatin and their combination significantly decreased serum total and specific IgE levels (P < 0.05 to P < 0.01). However, IL-13 and TGF-β levels were significantly decreased by BMSCs and BMSC + simvastatin combination therapy (P < 0.05 for all cases). The effect of simvastatin and BMSCs combination therapy on serum specific IgE levels as well as lung IL-13 and TGF-β levels were significantly higher than the effect of BMSCs and simvastatin alone (P < 0.001 for IL-13 and P < 0.01 for other cases). CONCLUSIONS Simvastatin and BMSCs combination therapy affects serum IgE as well as lung IL-13 and TGFβ levels more than BMSC therapy and simvastatin therapy alone which may be due to increased BMSCs migration into the lung tissue.
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Affiliation(s)
- Maryam Mohammadian
- Department of Physiology, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Hamid Reza Sadeghipour
- Department of Physiology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Gila Pirzad Jahromi
- Neuroscience Research Centre, Baqiyatallah University of Medical Sciences, Tehran
| | - Mahvash Jafari
- Department of Biochemistry, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Amir Kavian Nejad
- Department of Emergency Medical Services, Faculty of Nursing and Midwifery, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Safoura Khamse
- Department of Physiology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Boskabady
- Neurogenic Inflammation Research Center and Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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49
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Tzouvelekis A, Toonkel R, Karampitsakos T, Medapalli K, Ninou I, Aidinis V, Bouros D, Glassberg MK. Mesenchymal Stem Cells for the Treatment of Idiopathic Pulmonary Fibrosis. Front Med (Lausanne) 2018; 5:142. [PMID: 29868594 PMCID: PMC5962715 DOI: 10.3389/fmed.2018.00142] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 04/25/2018] [Indexed: 12/24/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is an inexorably progressive lung disease of unknown origin. Prognosis is poor, with limited treatment options available, and the median survival remains just 3-5 years. Despite the use of pirfenidone and nintedanib for the treatment of IPF, curative therapies remain elusive and mortality remains high. Regenerative medicine and the use of cell-based therapies has recently emerged as a potential option for various diseases. Promising results of preclinical studies using mesenchymal stem cells (MSCs) suggest that they may represent a potential therapeutic option for the treatment of chronic lung diseases including IPF. Encouraging results of Phase 1 studies of MSCs various have reduced safety concerns. Nonetheless, there is still a pressing need for exploratory biomarkers and interval end-points in the context of MSCs investigation. This review intends to summarize the current state of knowledge for stem cells in the experimental and clinical setting of IPF, present important safety and efficacy issues, highlight future challenges and address the need for large, multicenter clinical trials coupled with realistic end-points, including biomarkers, to assess treatment efficacy.
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Affiliation(s)
- Argyrios Tzouvelekis
- First Academic Respiratory Department, Sotiria General Hospital for Thoracic Diseases, University of Athens, Athens, Greece.,Division of Immunology, Alexander Fleming Biomedical Sciences Research Center, Athens, Greece
| | - Rebecca Toonkel
- Department of Medicine, Florida International University Herbert Wertheim College of Medicine, Miami, FL, United States
| | - Theodoros Karampitsakos
- First Academic Respiratory Department, Sotiria General Hospital for Thoracic Diseases, University of Athens, Athens, Greece
| | - Kantha Medapalli
- Department of Medicine, Florida International University Herbert Wertheim College of Medicine, Miami, FL, United States.,Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Ioanna Ninou
- Division of Immunology, Alexander Fleming Biomedical Sciences Research Center, Athens, Greece
| | - Vasilis Aidinis
- Division of Immunology, Alexander Fleming Biomedical Sciences Research Center, Athens, Greece.,Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Demosthenes Bouros
- First Academic Respiratory Department, Sotiria General Hospital for Thoracic Diseases, University of Athens, Athens, Greece
| | - Marilyn K Glassberg
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States.,Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States
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50
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Sutton MT, Fletcher D, Episalla N, Auster L, Kaur S, Gwin MC, Folz M, Velasquez D, Roy V, van Heeckeren R, Lennon DP, Caplan AI, Bonfield TL. Mesenchymal Stem Cell Soluble Mediators and Cystic Fibrosis. ACTA ACUST UNITED AC 2017; 7. [PMID: 29291140 DOI: 10.4172/2157-7633.1000400] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Human Mesenchymal stem cells (hMSCs) secrete products (supernatants) that are anti-inflammatory and antimicrobial. We have previously shown that hMSCs decrease inflammation and Pseudomonas aeruginosa infection in the in vivo murine model of Cystic Fibrosis (CF). Cystic Fibrosis (CF) is a genetic disease in which pulmonary infection and inflammation becomes the major cause of morbidity and mortality. Our studies focus on determining how MSCs contribute to improved outcomes in the CF mouse model centering on how the MSCs impact the inflammatory response to pathogenic organisms. We hypothesize that MSCs secrete products that are anti-inflammatory in scenarios of chronic pulmonary infections using the murine model of infection and inflammation with a specific interest in Pseudomonas aeruginosa (gram negative). Further, our studies will identify whether the MSCs are impacting this inflammatory response through the regulation of peroxisome proliferator activator receptor gamma (PPARγ) which aides in decreasing inflammation.
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Affiliation(s)
- Morgan T Sutton
- Department of Pediatrics, Case Western Reserve University, Cleveland Ohio 44106-4948.,National Center of Regenerative Medicine, Case Western Reserve University, Cleveland Ohio 44106-4948.,School of Medicine, Case Western Reserve University, Cleveland Ohio 44106-4948.,School of Engineering, Case Western Reserve University, Cleveland Ohio 44106-4948.,Hathaway Brown School, Shaker Heights Ohio 44122.,Summer Programs in Undergraduate Research, Department of Pediatrics, Rainbow Babies and Children's Hospital, Cleveland Ohio 44106-4948
| | - David Fletcher
- Department of Pediatrics, Case Western Reserve University, Cleveland Ohio 44106-4948
| | - Nicole Episalla
- Department of Pediatrics, Case Western Reserve University, Cleveland Ohio 44106-4948.,Department of Biology, Case Western Reserve University, Cleveland Ohio 44106-4948
| | - Lauren Auster
- Department of Pediatrics, Case Western Reserve University, Cleveland Ohio 44106-4948.,Department of Biology, Case Western Reserve University, Cleveland Ohio 44106-4948
| | - Sukhmani Kaur
- Department of Pediatrics, Case Western Reserve University, Cleveland Ohio 44106-4948.,Hathaway Brown School, Shaker Heights Ohio 44122
| | - Mary Chandler Gwin
- Department of Pediatrics, Case Western Reserve University, Cleveland Ohio 44106-4948.,Summer Programs in Undergraduate Research, Department of Pediatrics, Rainbow Babies and Children's Hospital, Cleveland Ohio 44106-4948
| | - Michael Folz
- School of Engineering, Case Western Reserve University, Cleveland Ohio 44106-4948
| | - Dante Velasquez
- Department of Pediatrics, Case Western Reserve University, Cleveland Ohio 44106-4948.,National Center of Regenerative Medicine, Case Western Reserve University, Cleveland Ohio 44106-4948
| | - Varun Roy
- Department of Pediatrics, Case Western Reserve University, Cleveland Ohio 44106-4948.,School of Medicine, Case Western Reserve University, Cleveland Ohio 44106-4948
| | - Rolf van Heeckeren
- Department of Pediatrics, Case Western Reserve University, Cleveland Ohio 44106-4948
| | - Donald P Lennon
- Department of Biology, Case Western Reserve University, Cleveland Ohio 44106-4948.,Skeletal Research Center, Case Western Reserve University, Cleveland Ohio 44106-4948
| | - Arnold I Caplan
- Department of Biology, Case Western Reserve University, Cleveland Ohio 44106-4948.,Skeletal Research Center, Case Western Reserve University, Cleveland Ohio 44106-4948
| | - Tracey L Bonfield
- Department of Pediatrics, Case Western Reserve University, Cleveland Ohio 44106-4948.,National Center of Regenerative Medicine, Case Western Reserve University, Cleveland Ohio 44106-4948.,School of Medicine, Case Western Reserve University, Cleveland Ohio 44106-4948.,Skeletal Research Center, Case Western Reserve University, Cleveland Ohio 44106-4948
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