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Rahnama M, Ghasemzadeh N, Latifi Z, Kheradmand F, Koukia FA, Sharun K, Golchin A. Menstrual Blood and Endometrial Mesenchymal Stem/Stromal Cells: A Frontier in Regenerative Medicine and Cancer Therapy. Eur J Pharmacol 2025:177726. [PMID: 40350020 DOI: 10.1016/j.ejphar.2025.177726] [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: 12/24/2024] [Revised: 05/08/2025] [Accepted: 05/09/2025] [Indexed: 05/14/2025]
Abstract
The acquisition of suitable stem cell sources is a significant issue in regenerative medicine. There has been considerable interest in utilizing mesenchymal stem cells (MSCs) derived from endometrial and menstrual blood as a promising resource of MSCs, owing to their unique biochemical properties and prospective use in clinical therapies. This population of stem cells has distinct characteristics in terms of immunophenotype, proliferation rate, and differentiation capacity. A notable characteristic of these stem cells is their capacity to develop into mesodermal lineages, highlighting their regenerative capability. Moreover, the presence of certain surface markers facilitates the augmentation of clonogenic endometrial MSCs. Their distinctive characteristics, along with their swift multiplication ability, underscore their significant promise for therapeutic applicability in regenerative medicine and cell-based treatments. Current investigations are examining possible usage of diverse stem cell resources in the treatment of inflammatory diseases and perhaps intractable illnesses like Parkinson's disease, utilizing their immunomodulatory properties. This review aims to analyze stem cell-related research that has utilized endometrial and menstrual blood-derived MSCs (enMSCs and MenSCs) with a special focus on their clinical application. We will explore the existing evidence about the therapeutic potential for these stem cells across many medical diseases and address the obstacles and prospective trajectories in this domain. Additionally, we will study the unique properties of enMSCs and MenSCs that make them promising candidates for regenerative medicine.
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Affiliation(s)
- Maryam Rahnama
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran; Department of Applied Cell Sciences, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Navid Ghasemzadeh
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran; Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Zeinab Latifi
- Department of Biochemistry, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Fatemeh Kheradmand
- Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Fariba Abbasi Koukia
- Department of Pathology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Khan Sharun
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India
| | - Ali Golchin
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran; Independent Researcher, Urmia, Iran.
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Kong T, Seo SK, Han YS, Seo WM, Kim B, Kim J, Cho YJ, Lee S, Kang KS. Primed Mesenchymal Stem Cells by IFN-γ and IL-1β Ameliorate Acute Respiratory Distress Syndrome through Enhancing Homing Effect and Immunomodulation. Biomol Ther (Seoul) 2025; 33:311-324. [PMID: 39973472 PMCID: PMC11893491 DOI: 10.4062/biomolther.2025.004] [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: 01/10/2025] [Revised: 02/04/2025] [Accepted: 02/05/2025] [Indexed: 02/21/2025] Open
Abstract
Acute Respiratory Distress Syndrome (ARDS) is a severe condition characterized by extensive lung inflammation and increased alveolar-capillary permeability, often triggered by infections or systemic inflammatory responses. Mesenchymal stem cells (MSCs)-based therapy holds promise for treating ARDS, as MSCs manifest immunomodulatory and regenerative properties that mitigate inflammation and enhance tissue repair. Primed MSCs, modified to augment specific functionalities, demonstrate superior therapeutic efficacy in targeted therapies compared to naive MSCs. This study explored the immunomodulatory potential of MSCs using mixed lymphocyte reaction (MLR) assays and co-culture experiments with M1/M2 macrophages. Additionally, RNA sequencing was employed to identify alterations in immune and inflammation-related factors in primed MSCs. The therapeutic effects of primed MSCs were assessed in an LPS-induced ARDS mouse model, and the underlying mechanisms were investigated through spatial transcriptomics analysis. The study revealed that MSCs primed with IFN-γ and IL-1β significantly enhanced the suppression of T cell activity compared to naive MSCs, concurrently inhibiting TNF-α while increasing IL-10 production in macrophages. Notably, combined treatment with these two cytokines resulted in a significant upregulation of immune and inflammation-regulating factors. Furthermore, our analyses elucidated the mechanisms behind the therapeutic effects of primed MSCs, including the inhibition of inflammatory cell infiltration in lung tissue, modulation of immune and inflammatory responses, and enhancement of elastin fiber formation. Signaling pathway analysis confirmed that efficacy could be enhanced by modulating NFκB and TNF-α signaling. In conclusion, in early-phase ARDS, primed MSCs displayed enhanced homing capabilities, improved lung function, and reduced inflammation.
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Affiliation(s)
- Taeho Kong
- Stem Cell and Regenerative Bioengineering Institute, Global R&D Center, Kangstem Biotech Co., Ltd., Seoul 08590, Republic of Korea
| | - Su Kyoung Seo
- Stem Cell and Regenerative Bioengineering Institute, Global R&D Center, Kangstem Biotech Co., Ltd., Seoul 08590, Republic of Korea
| | - Yong-Seok Han
- Stem Cell and Regenerative Bioengineering Institute, Global R&D Center, Kangstem Biotech Co., Ltd., Seoul 08590, Republic of Korea
| | - Woo Min Seo
- Stem Cell and Regenerative Bioengineering Institute, Global R&D Center, Kangstem Biotech Co., Ltd., Seoul 08590, Republic of Korea
| | - Bokyong Kim
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea
| | - Jieun Kim
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea
| | - Young-Jae Cho
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea
| | - Seunghee Lee
- Stem Cell and Regenerative Bioengineering Institute, Global R&D Center, Kangstem Biotech Co., Ltd., Seoul 08590, Republic of Korea
| | - Kyung-Sun Kang
- Stem Cell and Regenerative Bioengineering Institute, Global R&D Center, Kangstem Biotech Co., Ltd., Seoul 08590, Republic of Korea
- Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea
- Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea
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Chakraborty C, Bhattacharya M, Das A, Saha A. Regulation of miRNA in Cytokine Storm (CS) of COVID-19 and Other Viral Infection: An Exhaustive Review. Rev Med Virol 2025; 35:e70026. [PMID: 40032584 DOI: 10.1002/rmv.70026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Revised: 01/29/2025] [Accepted: 02/18/2025] [Indexed: 03/05/2025]
Abstract
In the initial stage of the COVID-19 pandemic, high case fatality was noted. The case fatality during this was associated with the cytokine storm (CS) or cytokine storm syndrome (CSS). Sometimes, virus infections are due to the excessive secretion of pro-inflammatory cytokines, leading to cytokine storms, which might be directed to ARDS, multi-organ failure, and death. However, it was noted that several miRNAs are involved in regulating cytokines during SARS-CoV-2 and other viruses such as IFNs, ILs, GM-CSF, TNF, etc. The article spotlighted several miRNAs involved in regulating cytokines associated with the cytokine storm caused by SARS-CoV-2 and other viruses (influenza virus, MERS-CoV, SARS-CoV, dengue virus). Targeting those miRNAs might help in the discovery of novel therapeutics, considering CS or CSS associated with different virus infections.
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Affiliation(s)
- Chiranjib Chakraborty
- Department of Biotechnology, School of Life Science and Biotechnology, Adamas University, Kolkata, India
| | | | - Arpita Das
- Department of Biotechnology, School of Life Science and Biotechnology, Adamas University, Kolkata, India
| | - Abinit Saha
- Deparment of Zoology, J.K. College, Purulia, India
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Nardo D, Maddox EG, Riley JL. Cell therapies for viral diseases: a new frontier. Semin Immunopathol 2025; 47:5. [PMID: 39747475 PMCID: PMC11695571 DOI: 10.1007/s00281-024-01031-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 12/10/2024] [Indexed: 01/04/2025]
Abstract
Despite advances in medicine and antimicrobial research, viral infections continue to pose a major threat to human health. While major strides have been made in generating vaccines and small molecules to combat emerging pathogens, new modalities of treatment are warranted in diseases where there is a lack of treatment options, or where treatment cannot fully eradicate pathogens, as in HIV infection. Cellular therapies, some of which are FDA approved for treating cancer, take advantage of our developing understanding of the immune system, and harness this knowledge to enhance, or direct, immune responses toward infectious agents. As with cancer, viruses that evade immunity, do so by avoiding immune recognition or by redirecting the cellular responses that would eradicate them. As such, infusing virus specific immune cells has the potential to improve patient outcomes and should be investigated as a potential tool in the arsenal to fight infection. The present manuscript summarizes key findings made using cellular therapies for the treatment of viral infections, focusing on the potential that these strategies might have in controlling disease.
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Affiliation(s)
- David Nardo
- Department of Microbiology and Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Emileigh G Maddox
- Department of Microbiology and Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - James L Riley
- Department of Microbiology and Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, 19104, USA.
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Tang J, Shi J, Han Z, Chen X. Application of Macrophage Subtype Analysis in Acute Lung Injury/Acute Respiratory Distress Syndrome. FRONT BIOSCI-LANDMRK 2024; 29:412. [PMID: 39735977 DOI: 10.31083/j.fbl2912412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Revised: 07/28/2024] [Accepted: 08/16/2024] [Indexed: 12/31/2024]
Abstract
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common critical illness. Supportive therapy is still the main strategy for ALI/ARDS. Macrophages are the predominant immune cells in the lungs and play a pivotal role in maintaining homeostasis, regulating metabolism, and facilitating tissue repair. During ALI/ARDS, these versatile cells undergo polarization into distinct subtypes with significant variations in transcriptional profiles, developmental trajectory, phenotype, and functionality. This review discusses developments in the analysis of alveolar macrophage subtypes in the study of ALI/ARDS, and the potential value of targeting new macrophage subtypes in the diagnosis, prognostic evaluation, and treatment of ALI/ARDS.
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Affiliation(s)
- Jiajia Tang
- Department of Pulmonary and Critical Care Medicine, The Sixth Medical Center of Chinese PLA General Hospital, 100048 Beijing, China
- School of Medicine, South China University of Technology, 510006 Guangzhou, Guangdong, China
| | - Jun Shi
- Department of Pulmonary and Critical Care Medicine, The Sixth Medical Center of Chinese PLA General Hospital, 100048 Beijing, China
- School of Medicine, South China University of Technology, 510006 Guangzhou, Guangdong, China
| | - Zhihai Han
- Department of Pulmonary and Critical Care Medicine, The Sixth Medical Center of Chinese PLA General Hospital, 100048 Beijing, China
- School of Medicine, South China University of Technology, 510006 Guangzhou, Guangdong, China
| | - Xuxin Chen
- Department of Pulmonary and Critical Care Medicine, The Sixth Medical Center of Chinese PLA General Hospital, 100048 Beijing, China
- School of Medicine, South China University of Technology, 510006 Guangzhou, Guangdong, China
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Hussen BM, Taheri M, Yashooa RK, Abdullah GH, Abdullah SR, Kheder RK, Mustafa SA. Revolutionizing medicine: recent developments and future prospects in stem-cell therapy. Int J Surg 2024; 110:8002-8024. [PMID: 39497543 PMCID: PMC11634165 DOI: 10.1097/js9.0000000000002109] [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: 04/04/2024] [Accepted: 09/27/2024] [Indexed: 12/13/2024]
Abstract
Stem-cell therapy is a revolutionary frontier in modern medicine, offering enormous capacity to transform the treatment landscape of numerous debilitating illnesses and injuries. This review examines the revolutionary frontier of treatments utilizing stem cells, highlighting the distinctive abilities of stem cells to undergo regeneration and specialized cell differentiation into a wide variety of phenotypes. This paper aims to guide researchers, physicians, and stakeholders through the intricate terrain of stem-cell therapy, examining the processes, applications, and challenges inherent in utilizing stem cells across diverse medical disciplines. The historical journey from foundational contributions in the late 19th and early 20th centuries to recent breakthroughs, including ESC isolation and iPSC discovery, has set the stage for monumental leaps in medical science. Stem cells' regenerative potential spans embryonic, adult, induced pluripotent, and perinatal stages, offering unprecedented therapeutic opportunities in cancer, neurodegenerative disorders, cardiovascular ailments, spinal cord injuries, diabetes, and tissue damage. However, difficulties, such as immunological rejection, tumorigenesis, and precise manipulation of stem-cell behavior, necessitate comprehensive exploration and innovative solutions. This manuscript summarizes recent biotechnological advancements, critical trial evaluations, and emerging technologies, providing a nuanced understanding of the triumphs, difficulties, and future trajectories in stem cell-based regenerative medicine. Future directions, including precision medicine integration, immune modulation strategies, advancements in gene-editing technologies, and bioengineering synergy, offer a roadmap in stem cell treatment. The focus on stem-cell therapy's potential highlights its significant influence on contemporary medicine and points to a future in which individualized regenerative therapies will alleviate various medical disorders.
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Affiliation(s)
- Bashdar M. Hussen
- Department of Biomedical Sciences, Cihan University-Erbil
- Department of Clinical Analysis, College of Pharmacy, Hawler Medical University, Erbil, Kurdistan Region, Iraq
| | - Mohammad Taheri
- Institute of Human Genetics, Jena University Hospital, Jena, Germany
| | - Raya Kh. Yashooa
- General Directorate of Scientific Research Center, Salahaddin University-Erbil
| | | | - Snur R. Abdullah
- Department of Medical Laboratory Science, College of Health sciences, Lebanese French University, Erbil, Kurdistan Region, Erbil, Iraq
| | - Ramiar Kamal Kheder
- Medical Laboratory Science Department, College of Science, University of Raparin, Rania, Sulaymaniyah, Iraq
- Department of Medical Analysis, Faculty of Applied Science, Tishk International University, Erbil, Iraq
| | - Suhad A. Mustafa
- General Directorate of Scientific Research Center, Salahaddin University-Erbil
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Zhidu S, Ying T, Rui J, Chao Z. Translational potential of mesenchymal stem cells in regenerative therapies for human diseases: challenges and opportunities. Stem Cell Res Ther 2024; 15:266. [PMID: 39183341 PMCID: PMC11346273 DOI: 10.1186/s13287-024-03885-z] [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: 05/17/2024] [Accepted: 08/14/2024] [Indexed: 08/27/2024] Open
Abstract
Advances in stem cell technology offer new possibilities for patients with untreated diseases and disorders. Stem cell-based therapy, which includes multipotent mesenchymal stem cells (MSCs), has recently become important in regenerative therapies. MSCs are multipotent progenitor cells that possess the ability to undergo in vitro self-renewal and differentiate into various mesenchymal lineages. MSCs have demonstrated promise in several areas, such as tissue regeneration, immunological modulation, anti-inflammatory qualities, and wound healing. Additionally, the development of specific guidelines and quality control methods that ultimately result in the therapeutic application of MSCs has been made easier by recent advancements in the study of MSC biology. This review discusses the latest clinical uses of MSCs obtained from the umbilical cord (UC), bone marrow (BM), or adipose tissue (AT) in treating various human diseases such as pulmonary dysfunctions, neurological disorders, endocrine/metabolic diseases, skin burns, cardiovascular conditions, and reproductive disorders. Additionally, this review offers comprehensive information regarding the clinical application of targeted therapies utilizing MSCs. It also presents and examines the concept of MSC tissue origin and its potential impact on the function of MSCs in downstream applications. The ultimate aim of this research is to facilitate translational research into clinical applications in regenerative therapies.
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Affiliation(s)
- Song Zhidu
- Department of Ophthalmology, the Second Hospital of Jilin University, No. 218, Ziqiang Street, Nanguan District, Changchun City, Jilin Province, China
| | - Tao Ying
- Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Jiang Rui
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Zhang Chao
- Department of Ophthalmology, the Second Hospital of Jilin University, No. 218, Ziqiang Street, Nanguan District, Changchun City, Jilin Province, China.
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Zheng Q, Li Y, Sheng G, Li L. The Value of Ursodeoxycholic Acid and Mesenchymal Stem Cells in the Treatment of Severe COVID-19. Microorganisms 2024; 12:1269. [PMID: 39065038 PMCID: PMC11279161 DOI: 10.3390/microorganisms12071269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 06/04/2024] [Accepted: 06/19/2024] [Indexed: 07/28/2024] Open
Abstract
Objective: The objective of this study was to evaluate the therapeutic efficacy of ursodeoxycholic acid (UDCA) and mesenchymal stem cells (MSCs) in patients with severe COVID-19. Methods: We included severe COVID-19 patients hospitalized at Shulan (Hangzhou) Hospital between December 2022 and June 2023. We used a logistic regression model to compare the use of UDCA and MSCs in the two distinct groups of improved and poor outcomes. It is noteworthy that the deterioration group encompassed instances of both death and abandonment of treatment. The receiver operating characteristic (ROC) curve was plotted to assess the performance of the model. The aim was to assess the therapeutic effect of UDCA and MSCs on the outcome of severe COVID-19 patients. Results: A total of 167 patients with severe COVID-19 were included in this study. The analysis revealed that out of 42 patients (25.1%), 17 patients (10.2%) had taken UDCA, and 17 patients (10.2%) had used MSCs. Following a multivariable logistic regression, the results indicated a negative association between UDCA treatment (OR = 0.38 (0.16-0.91), p = 0.029), MSCs treatment (OR = 0.21 (0.07-0.65), p = 0.007), and the risk of severe COVID-19 mortality. Additionally, age showed a positive association with the risk of mortality (OR = 1.03 (1.01-1.07), p = 0.025). Conclusions: UDCA and MSCs have shown potential in improving the prognosis of severe COVID-19 patients and could be considered as additional treatments for COVID-19 in the future.
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Affiliation(s)
- Qi Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China; (Q.Z.); (Y.L.)
| | - Yuetong Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China; (Q.Z.); (Y.L.)
| | - Guoping Sheng
- Department of Infectious Disease, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University, Shulan International Medical College, Hangzhou 310022, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou 310003, China; (Q.Z.); (Y.L.)
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Martínez-Muñoz ME, Payares-Herrera C, Lipperheide I, Malo de Molina R, Salcedo I, Alonso R, Martín-Donaire T, Sánchez R, Zafra R, García-Berciano M, Trisán-Alonso A, Pérez-Torres M, Ramos-Martínez A, Ussetti P, Rubio JJ, Avendaño-Solà C, Duarte RF. Mesenchymal stromal cell therapy for COVID-19 acute respiratory distress syndrome: a double-blind randomised controlled trial. Bone Marrow Transplant 2024; 59:777-784. [PMID: 38409332 DOI: 10.1038/s41409-024-02230-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 01/23/2024] [Accepted: 01/25/2024] [Indexed: 02/28/2024]
Abstract
Mesenchymal stromal cells (MSC) have immunomodulatory and tissue-regenerative properties and have shown promising results in acute respiratory distress syndrome (ARDS) of multiple causes, including COVID-19. We conducted a randomised (1:1), placebo-controlled, double-blind clinical trial to assess the efficacy and safety of one bone marrow-derived MSC infusion in twenty patients with moderate to severe ARDS caused by COVID-19. The primary endpoint (increase in PaO2/FiO2 ratio from baseline to day 7, MSC 83.3 versus placebo 57.6) was not statistically significant, although a clinical improvement at day 7 in the WHO scale was observed in MSC patients (5, 50% vs 0, 0%, p = 0.033). Median time to discontinuation of supplemental oxygen was also shorter in the experimental arm (14 versus 23 days, p = 0.007), resulting in a shorter hospital stay (17.5 versus 28 days, p = 0.042). No significant differences were observed for other efficacy or safety secondary endpoints. No infusion or treatment-related serious adverse events occurred during the one-year follow-up. This study did not meet the primary endpoint of PaO2/FiO2 increase by day 7, although it suggests that MSC are safe in COVID-19 ARDS and may accelerate patients' clinical recovery and hospital discharge. Larger studies are warranted to elucidate their role in ARDS and other inflammatory lung disorders.Trial Registration: EudraCT Number: 2020-002193-27, registered on July 14th, 2020, https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-002193-27/ES . NCT number: NCT04615429, registered on November 4th, 2020, https://clinicaltrials.gov/ct2/show/NCT04615429 .
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Affiliation(s)
- María E Martínez-Muñoz
- Department of Haematology and GMP Cellular Therapy Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
- Instituto de Investigación Sanitaria Puerta de Hierro Segovia Arana, Madrid, Spain
| | - Concepción Payares-Herrera
- Instituto de Investigación Sanitaria Puerta de Hierro Segovia Arana, Madrid, Spain
- Department of Clinical Pharmacology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - Inés Lipperheide
- Intensive Care Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - Rosa Malo de Molina
- Department of Pneumology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - Isabel Salcedo
- Department of Haematology and GMP Cellular Therapy Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
- Instituto de Investigación Sanitaria Puerta de Hierro Segovia Arana, Madrid, Spain
| | - Rosalía Alonso
- Instituto de Investigación Sanitaria Puerta de Hierro Segovia Arana, Madrid, Spain
| | - Trinidad Martín-Donaire
- Department of Haematology and GMP Cellular Therapy Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
- Instituto de Investigación Sanitaria Puerta de Hierro Segovia Arana, Madrid, Spain
| | - Rocío Sánchez
- Department of Haematology and GMP Cellular Therapy Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
- Instituto de Investigación Sanitaria Puerta de Hierro Segovia Arana, Madrid, Spain
| | - Rocío Zafra
- Department of Haematology and GMP Cellular Therapy Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
- Instituto de Investigación Sanitaria Puerta de Hierro Segovia Arana, Madrid, Spain
| | - Miguel García-Berciano
- Department of Haematology and GMP Cellular Therapy Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
- Instituto de Investigación Sanitaria Puerta de Hierro Segovia Arana, Madrid, Spain
| | - Andrea Trisán-Alonso
- Department of Pneumology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - Manuel Pérez-Torres
- Intensive Care Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - Antonio Ramos-Martínez
- Instituto de Investigación Sanitaria Puerta de Hierro Segovia Arana, Madrid, Spain
- Department of Internal Medicine and Infectious Diseases, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - Piedad Ussetti
- Instituto de Investigación Sanitaria Puerta de Hierro Segovia Arana, Madrid, Spain
- Department of Pneumology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - Juan J Rubio
- Intensive Care Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - Cristina Avendaño-Solà
- Instituto de Investigación Sanitaria Puerta de Hierro Segovia Arana, Madrid, Spain
- Department of Clinical Pharmacology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - Rafael F Duarte
- Department of Haematology and GMP Cellular Therapy Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain.
- Instituto de Investigación Sanitaria Puerta de Hierro Segovia Arana, Madrid, Spain.
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Shen J, Li J, Lei Y, Chen Z, Wu L, Lin C. Frontiers and hotspots evolution in cytokine storm: A bibliometric analysis from 2004 to 2022. Heliyon 2024; 10:e30955. [PMID: 38774317 PMCID: PMC11107250 DOI: 10.1016/j.heliyon.2024.e30955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 05/08/2024] [Accepted: 05/08/2024] [Indexed: 05/24/2024] Open
Abstract
Background As a fatal disease, cytokine storm has garnered research attention in recent years. Nonetheless, as the body of related studies expands, a thorough and impartial evaluation of the current status of research on cytokine storms remains absent. Consequently, this study aimed to thoroughly explore the research landscape and evolution of cytokine storm utilizing bibliometric and knowledge graph approaches. Methods Research articles and reviews centered on cytokine storms were retrieved from the Web of Science Core Collection database. For bibliometric analysis, tools such as Excel 365, CiteSpace, VOSviewer, and the Bibliometrix R package were utilized. Results This bibliometric analysis encompassed 6647 articles published between 2004 and 2022. The quantity of pertinent articles and citation frequency exhibited a yearly upward trend, with a sharp increase starting in 2020. Network analysis of collaborations reveals that the United States holds a dominant position in this area, boasting the largest publication count and leading institutions. Frontiers in Immunology ranks as the leading journal for the largest publication count in this area. Stephan A. Grupp, a prominent researcher in this area, has authored the largest publication count and has the second-highest citation frequency. Research trends and keyword evaluations show that the connection between cytokine storm and COVID-19, as well as cytokine storm treatment, are hot topics in research. Furthermore, research on cytokine storm and COVID-19 sits at the forefront in this area. Conclusion This study employed bibliometric analysis to create a visual representation of cytokine storm research, revealing current trends and burgeoning topics in this area for the first time. It will provide valuable insights, helping scholars pinpoint critical research areas and potential collaborators.
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Affiliation(s)
- Junyi Shen
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Jiaming Li
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Yuqi Lei
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Zhengrui Chen
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Lingling Wu
- Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Chunyan Lin
- Department of Teaching and Research Section of Internal Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
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Huang Q, Le Y, Li S, Bian Y. Signaling pathways and potential therapeutic targets in acute respiratory distress syndrome (ARDS). Respir Res 2024; 25:30. [PMID: 38218783 PMCID: PMC10788036 DOI: 10.1186/s12931-024-02678-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Accepted: 01/03/2024] [Indexed: 01/15/2024] Open
Abstract
Acute respiratory distress syndrome (ARDS) is a common condition associated with critically ill patients, characterized by bilateral chest radiographical opacities with refractory hypoxemia due to noncardiogenic pulmonary edema. Despite significant advances, the mortality of ARDS remains unacceptably high, and there are still no effective targeted pharmacotherapeutic agents. With the outbreak of coronavirus disease 19 worldwide, the mortality of ARDS has increased correspondingly. Comprehending the pathophysiology and the underlying molecular mechanisms of ARDS may thus be essential to developing effective therapeutic strategies and reducing mortality. To facilitate further understanding of its pathogenesis and exploring novel therapeutics, this review provides comprehensive information of ARDS from pathophysiology to molecular mechanisms and presents targeted therapeutics. We first describe the pathogenesis and pathophysiology of ARDS that involve dysregulated inflammation, alveolar-capillary barrier dysfunction, impaired alveolar fluid clearance and oxidative stress. Next, we summarize the molecular mechanisms and signaling pathways related to the above four aspects of ARDS pathophysiology, along with the latest research progress. Finally, we discuss the emerging therapeutic strategies that show exciting promise in ARDS, including several pharmacologic therapies, microRNA-based therapies and mesenchymal stromal cell therapies, highlighting the pathophysiological basis and the influences on signal transduction pathways for their use.
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Affiliation(s)
- Qianrui Huang
- Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095, Jie Fang Avenue, Wuhan, 430030, China
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jie Fang Avenue, Wuhan, 430030, China
| | - Yue Le
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjia Bridge, Hunan Road, Gu Lou District, Nanjing, 210009, China
| | - Shusheng Li
- Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095, Jie Fang Avenue, Wuhan, 430030, China.
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jie Fang Avenue, Wuhan, 430030, China.
| | - Yi Bian
- Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095, Jie Fang Avenue, Wuhan, 430030, China.
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jie Fang Avenue, Wuhan, 430030, China.
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12
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Hussain S, Songhua X, Aslam MU, Hussain F. Clinical predictions of COVID-19 patients using deep stacking neural networks. J Investig Med 2024; 72:112-127. [PMID: 37712431 DOI: 10.1177/10815589231201103] [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: 09/16/2023]
Abstract
The coronavirus disease 2019 (COVID-19) pandemic, which emerged in late 2019, has caused millions of infections and fatalities globally, disrupting various aspects of human society, including socioeconomic, political, and educational systems. One of the key challenges during the COVID-19 pandemic is accurately predicting the clinical development and outcome of the infected patients. In response, scientists and medical professionals globally have mobilized to develop prognostic strategies such as risk scores, biomarkers, and machine learning models to predict the clinical course and outcomes of COVID-19 patients. In this contribution, we deployed a mathematical approach called matrix factorization feature selection to select the most relevant features from the anonymized laboratory biomarkers and demographic data of COVID-19 patients. Based on these features, developed a model that leverages the deep stacking neural network (DSNN) to aid in clinical care by predicting patients' mortality risk. To gauge the performance of our suggested model, performed a comparative analysis with principal component analysis plus support vector machine, deep learning, and random forest, achieving outstanding performances. The DSNN model outperformed all the other models in terms of area under the curve (96.0%), F1-score (98.1%), recall (98.5%), accuracy (99.0%), precision (97.7%), specificity (97.0%), and maximum probability of correction decision (93.4%). Our model outperforms the clinical predictive models regarding patient mortality risk and classification in the literature. Therefore, we conclude that our robust model can help healthcare professionals to manage COVID-19 patients more effectively. We expect that early prediction of COVID-19 patients and preventive interventions can reduce the mortality risk of patients.
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Affiliation(s)
- Sajid Hussain
- School of Mathematics and Statistics XJTU, Xian, Shaanxi, China
| | - Xu Songhua
- School of Mathematics and Statistics XJTU, Xian, Shaanxi, China
| | | | - Fida Hussain
- School of Engineering and Sciences, Tecnologico de Monterrey, Monterrey, Nuevo León, Mexico
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13
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Zhang M, Xu G, Zhou X, Luo M, Ma N, Wang X, Wang Z, Tang H, Wang X, Li Y, Yuan X, Li Y. Mesenchymal stem cells ameliorate H9N2-induced acute lung injury by inhibiting caspase-3-GSDME-mediated pyroptosis of lung alveolar epithelial cells. Eur J Pharmacol 2023; 960:176148. [PMID: 37866742 DOI: 10.1016/j.ejphar.2023.176148] [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: 08/31/2023] [Revised: 10/19/2023] [Accepted: 10/20/2023] [Indexed: 10/24/2023]
Abstract
Influenza A virus infection mediates the host's excessive immune response, wherein caspase-3-GSDME-mediated pyroptosis of lung alveolar epithelial cells can contribute to inducing cytokine storm, leading to acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Numerous studies have shown that mesenchymal stem cells (MSCs) possess potent immunomodulatory abilities and can mitigate virus-induced cytokine storm and lung injury. However, the role of MSCs in lung pyroptosis remains poorly understood. In this study, we established an ALI model using a mouse-adapted strain of avian influenza virus H9N2 (MA01) and intervened by injecting appropriate bone marrow-derived mesenchymal stem cells (BMMSCs) into the mouse's trachea. The results obtained from animal experiments demonstrated that BMMSCs prevented and ameliorated ALI by inhibiting Caspase-3-GSDME-mediated pyroptosis of lung epithelial cells as well as hypercytokinemia. Similarly, corresponding results were observed in vitro, where BMMSCs and the lung epithelial cell line MLE-12 cells were co-cultured in a transwell compartment. Additionally, the caspase-3 inhibitor Z-DEVD-FMK could block MA01-induced GSDME activation. Furthermore, by combining RNA-Seq data with in vitro and in vivo results, we also discovered that MA01-induced pyroptosis is associated with the BAK/BAX-dependent mitochondrial apoptosis pathway. Notably, BMMSCs exhibit the ability to interfere with this signaling pathway. In conclusion, this study provides novel theoretical support for the utilization of BMMSCs in the treatment of ALI induced by influenza.
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Affiliation(s)
- Mengwei Zhang
- Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China; Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Guofeng Xu
- Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Xin Zhou
- Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China; Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Min Luo
- Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China; Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Ning Ma
- Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Xing Wang
- Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Zhibin Wang
- Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Hongmei Tang
- Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Xiaoyun Wang
- Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Yuejiao Li
- Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Xiefang Yuan
- Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Yuying Li
- Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China; Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China.
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14
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Derafsh E, Ebrahimzadeh F, Kahrizi MS, Kayedi M, Shojaei N, Rahimi S, Alesaeidi S, Ghafouri K. The therapeutic effects of mesenchymal stem cell (MSCs) exosomes in covid-19 disease; Focusing on dexamethasone therapy. Pathol Res Pract 2023; 251:154815. [PMID: 37797382 DOI: 10.1016/j.prp.2023.154815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Revised: 09/05/2023] [Accepted: 09/08/2023] [Indexed: 10/07/2023]
Abstract
The study of diseases, specifically their aetiologies, their step-by-step progressions (pathogenesis), and their impact on normal structure and function, is the focus of pathology, a branch of science and medicine. In therapeutic fields, it is critical to decrease significantly elevated levels of proinflammatory cytokines. The immunomodulatory drugs such as dexamethasone have been used in several of inflammatory diseases such as Covid-19. The use of dexamethasone alone or in combination with other drugs or method such as mesenchymal stem cell (MSC) is one of the most up-to-date discussions about Covid-19. In this review, we first examined the effects of dexamethasone as monotherapy on inflammatory cytokines and then examined studies that used combination therapy of dexamethasone and other drugs such as Baricitinib, Tofacitinib and tocilizumab. Also, therapeutic aspects of MSCs are examined in this review.
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Affiliation(s)
- Ehsan Derafsh
- Department of Basic Medical Science, Windsor University School of Medicine, Brighton's Estate, Cayton, Saint Kitts and Nevis
| | - Farnoosh Ebrahimzadeh
- Department of Internal Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, lran
| | | | - Mehrdad Kayedi
- Department of radiology. Shiraz university of medical sciences, Shiraz, iran
| | - Niloofar Shojaei
- School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Shiva Rahimi
- School of medicine,fasa university of medical sciences,Fasa, Iran
| | - Samira Alesaeidi
- Department of Internal medicine and rheumatology, ⁎Rheumatology Research Center⁎, Tehran University of Medical Sciences, Tehran, Iran.
| | - Kimia Ghafouri
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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15
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An N, Chen Z, Zhao P, Yin W. Extracellular Vesicles in Sepsis: Pathogenic Roles, Organ Damage, and Therapeutic Implications. Int J Med Sci 2023; 20:1722-1731. [PMID: 37928875 PMCID: PMC10620861 DOI: 10.7150/ijms.86832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 10/05/2023] [Indexed: 11/07/2023] Open
Abstract
Despite significant advances in anti-infective treatment and organ function support technology in recent years, the mortality rate of sepsis remains high. In addition to the high costs of sepsis treatment, the increasing consumption of medical resources also aggravates economic pressure and social burden. Extracellular vesicles (EVs) are membrane vesicles released from different types of activated or apoptotic cells to mediate intercellular communication, which can be detected in both human and animal body fluids. A growing body of researches suggest that EVs play an important role in the pathogenesis of sepsis. In this review, we summarize the predominant roles of EVs in various pathological processes during sepsis and its related organ dysfunction.
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Affiliation(s)
- Ni An
- Department of Emergency, Xijing Hospital, Air Force Medical University, Xi'an, China
| | - Zhe Chen
- University College London, London, UK
| | - Peng Zhao
- Department of Emergency, Xijing Hospital, Air Force Medical University, Xi'an, China
| | - Wen Yin
- Department of Emergency, Xijing Hospital, Air Force Medical University, Xi'an, China
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16
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Gonzaga A, Andreu E, Hernández-Blasco LM, Meseguer R, Al-Akioui-Sanz K, Soria-Juan B, Sanjuan-Gimenez JC, Ferreras C, Tejedo JR, Lopez-Lluch G, Goterris R, Maciá L, Sempere-Ortells JM, Hmadcha A, Borobia A, Vicario JL, Bonora A, Aguilar-Gallardo C, Poveda JL, Arbona C, Alenda C, Tarín F, Marco FM, Merino E, Jaime F, Ferreres J, Figueira JC, Cañada-Illana C, Querol S, Guerreiro M, Eguizabal C, Martín-Quirós A, Robles-Marhuenda Á, Pérez-Martínez A, Solano C, Soria B. Rationale for combined therapies in severe-to-critical COVID-19 patients. Front Immunol 2023; 14:1232472. [PMID: 37767093 PMCID: PMC10520558 DOI: 10.3389/fimmu.2023.1232472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 08/22/2023] [Indexed: 09/29/2023] Open
Abstract
An unprecedented global social and economic impact as well as a significant number of fatalities have been brought on by the coronavirus disease 2019 (COVID-19), produced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Acute SARS-CoV-2 infection can, in certain situations, cause immunological abnormalities, leading to an anomalous innate and adaptive immune response. While most patients only experience mild symptoms and recover without the need for mechanical ventilation, a substantial percentage of those who are affected develop severe respiratory illness, which can be fatal. The absence of effective therapies when disease progresses to a very severe condition coupled with the incomplete understanding of COVID-19's pathogenesis triggers the need to develop innovative therapeutic approaches for patients at high risk of mortality. As a result, we investigate the potential contribution of promising combinatorial cell therapy to prevent death in critical patients.
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Affiliation(s)
- Aitor Gonzaga
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Institute of Bioengineering, Miguel Hernández University, Elche, Spain
| | - Etelvina Andreu
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Applied Physics Department, Miguel Hernández University, Elche, Spain
| | | | - Rut Meseguer
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Clinic University Hospital, Fundación para la Investigación del Hospital Clínico de la Comunidad Valenciana (INCLIVA) Health Research Institute, Valencia, Spain
| | - Karima Al-Akioui-Sanz
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Hospital La Paz Institute for Health Research, IdiPAZ, University Hospital La Paz, Madrid, Spain
| | - Bárbara Soria-Juan
- Réseau Hospitalier Neuchâtelois, Hôpital Pourtalès, Neuchâtel, Switzerland
| | | | - Cristina Ferreras
- Hospital La Paz Institute for Health Research, IdiPAZ, University Hospital La Paz, Madrid, Spain
| | - Juan R. Tejedo
- Department of Molecular Biology and Biochemical Engineering, University Pablo de Olavide, Seville, Spain
- Biomedical Research Network for Diabetes and Related Metabolic Diseases-Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) of the Carlos III Health Institute (ISCIII), Madrid, Spain
| | - Guillermo Lopez-Lluch
- University Pablo de Olavide, Centro Andaluz de Biología del Desarrollo - Consejo Superior de Investigaciones Científicas (CABD-CSIC), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Sevilla, Spain
| | - Rosa Goterris
- Clinic University Hospital, Fundación para la Investigación del Hospital Clínico de la Comunidad Valenciana (INCLIVA) Health Research Institute, Valencia, Spain
| | - Loreto Maciá
- Nursing Department, University of Alicante, Alicante, Spain
| | - Jose M. Sempere-Ortells
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Biotechnology Department, University of Alicante, Alicante, Spain
| | - Abdelkrim Hmadcha
- Department of Molecular Biology and Biochemical Engineering, University Pablo de Olavide, Seville, Spain
- Biosanitary Research Institute (IIB-VIU), Valencian International University (VIU), Valencia, Spain
| | - Alberto Borobia
- Clinical Pharmacology Department, La Paz University Hospital, School of Medicine, Universidad Autónoma de Madrid, IdiPAz, Madrid, Spain
| | - Jose L. Vicario
- Transfusion Center of the Autonomous Community of Madrid, Madrid, Spain
| | - Ana Bonora
- Health Research Institute Hospital La Fe, Valencia, Spain
| | | | - Jose L. Poveda
- Health Research Institute Hospital La Fe, Valencia, Spain
| | - Cristina Arbona
- Valencian Community Blood Transfusion Center, Valencia, Spain
| | - Cristina Alenda
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
| | - Fabian Tarín
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
| | - Francisco M. Marco
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Immunology Department, Dr. Balmis General University Hospital, Alicante, Spain
| | - Esperanza Merino
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Department of Clinical Medicine, Miguel Hernández University, Elche, Spain
- Infectious Diseases Unit, Dr. Balmis General University Hospital, Alicante, Spain
| | - Francisco Jaime
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
| | - José Ferreres
- Intensive Care Service, Hospital Clinico Universitario, Fundación para la Investigación del Hospital Clínico de la Comunidad Valenciana (INCLIVA), Valencia, Spain
| | | | | | | | - Manuel Guerreiro
- Department of Hematology, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Cristina Eguizabal
- Research Unit, Basque Center for Blood Transfusion and Human Tissues, Galdakao, Spain
- Cell Therapy, Stem Cells and Tissues Group, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
| | | | | | - Antonio Pérez-Martínez
- Hospital La Paz Institute for Health Research, IdiPAZ, University Hospital La Paz, Madrid, Spain
- Department of Pediatrics, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain
| | - Carlos Solano
- Hematology Service, Hospital Clínico Universitario, Fundación para la Investigación del Hospital Clínico de la Comunidad Valenciana (INCLIVA), Valencia, Spain
| | - Bernat Soria
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Institute of Bioengineering, Miguel Hernández University, Elche, Spain
- Biomedical Research Network for Diabetes and Related Metabolic Diseases-Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) of the Carlos III Health Institute (ISCIII), Madrid, Spain
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17
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Yan C, Hu M, Dai R. Safety and efficacy of mesenchymal stem cells in COVID-19 patients: A systematic review and meta-analysis. Immun Inflamm Dis 2023; 11:e1000. [PMID: 37773722 PMCID: PMC10515507 DOI: 10.1002/iid3.1000] [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: 06/26/2023] [Revised: 08/03/2023] [Accepted: 08/22/2023] [Indexed: 10/01/2023] Open
Abstract
BACKGROUND Coronavirus disease-19 (COVID-19) is a zoonotic disease that has become a global pandemic. The fast evolution of the COVID-19 pandemic and persist problems make COVID-19 highly infectious; publicly accessible literature and other sources of information continue to expand in volume. The mesenchymal stem cells (MSCs) therapy efficacy for COVID-19 is debatable. OBJECTIVE This systematic review and meta-analysis (SRMA) aimed to evaluate the usefulness of MSCs in treating COVID-19. METHODS Relevant publications were retrieved from databases up to April 30, 2022. In the case of dichotomous data, the 95% confidence intervals (CIs) and pooled risk ratio (RR) were estimated with a random effects model (REM) or fixed effects model (FEM). The pooled mean difference (MD) and 95% CIs were calculated with REM or FEM in continuous data. In the outcomes, studies with insufficient or unusable data were reported descriptively. RESULTS A total of eight randomized controlled trials (RCTs) with 464 people were chosen for this SRMA. Relative to the control group, mortality was significantly lower in the MSCs group (RR: 0.66, 95% CI: 0.44, 0.99, Z = 2.01, p = .04); other secondary outcomes, such as the clinical symptom improvement rate improved in the MSCs group (RR: 1.44, 95% CI: 1.05, 1.99, Z = 2.24, p = .03), clinical symptom improvement time (MD: -4.01, 95% CI: -6.33, -1.68, Z = 3.38, p = .0007), C-reactive protein (CRP) (MD: -39.16, 95% CI: -44.39, -33.94, Z = 14.70, p < .00001) and days to hospital discharge (MD: -3.83, 95% CI: -6.19, -1.48, Z = 3.19, p = .001) reduced significantly in MSCs group. However, the adverse reaction incidence did not change significantly. CONCLUSIONS MSCs are a viable therapy option for COVID-19 because of their safety and potential efficacy. With no significant adverse effects, MSCs can reduce mortality, clinical symptom improvement time, and days to hospital discharge, improve clinical symptoms, and reduce inflammatory cytokines CRP in COVID-19. However, further high-quality clinical studies are required to confirm these results.
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Affiliation(s)
- Cai Yan
- Xiangtan Central HospitalDepartment of Infectious diseasesXiangtanHunan provincePeople's Republic of China
| | - Minjie Hu
- The First Affiliated Hospital, Department of Cardiothoracic Surgery, Hengyang Medical SchoolUniversity of South ChinaHengyangHunan provincePeople's Republic of China
| | - Rongjuan Dai
- The First Affiliated Hospital, Department of Infectious Diseases, Hengyang Medical SchoolUniversity of South ChinaHengyangHunan provincePeople's Republic of China
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18
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Laroye C, Gauthier M, Morello J, Charif N, Cannard VL, Bonnet C, Lozniewski A, Tchirkov A, De Isla N, Decot V, Reppel L, Bensoussan D. Scale-Up of Academic Mesenchymal Stromal Cell Production. J Clin Med 2023; 12:4414. [PMID: 37445448 DOI: 10.3390/jcm12134414] [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: 05/17/2023] [Revised: 06/26/2023] [Accepted: 06/28/2023] [Indexed: 07/15/2023] Open
Abstract
BACKGROUND Many clinical trials have reported the use of mesenchymal stromal cells (MSCs) following the indication of severe SARS-CoV-2 infection. However, in the COVID19 pandemic context, academic laboratories had to adapt a production process to obtain MSCs in a very short time. Production processes, especially freezing/thawing cycles, or culture medium have impacts on MSC properties. We evaluated the impact of an intermediate cryopreservation state during MSC culture to increase production yields. METHODS Seven Wharton's jelly (WJ)-MSC batches generated from seven different umbilical cords with only one cryopreservation step and 13 WJ-MSC batches produced with intermediate freezing were formed according to good manufacturing practices. The identity (phenotype and clonogenic capacities), safety (karyotype, telomerase activity, sterility, and donor qualification), and functionality (viability, mixed lymphocyte reaction) were analyzed. RESULTS No significant differences between MSC production processes were observed, except for the clonogenic capacity, which was decreased, although it always remained above our specifications. CONCLUSIONS Intermediate cryopreservation allows an increase in the production yield and has little impact on the basic characteristics of MSCs.
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Affiliation(s)
- Caroline Laroye
- CHRU Nancy, Cell Therapy and Tissue Bank Unit, MTInov Bioproduction and Biotherapy Integrator, F-54000 Nancy, France
- CNRS, IMoPA, Lorraine University, F-54000 Nancy, France
| | - Mélanie Gauthier
- CHRU Nancy, Cell Therapy and Tissue Bank Unit, MTInov Bioproduction and Biotherapy Integrator, F-54000 Nancy, France
- CNRS, IMoPA, Lorraine University, F-54000 Nancy, France
| | - Jessica Morello
- CHRU Nancy, Cell Therapy and Tissue Bank Unit, MTInov Bioproduction and Biotherapy Integrator, F-54000 Nancy, France
| | - Naceur Charif
- CNRS, IMoPA, Lorraine University, F-54000 Nancy, France
| | | | - Céline Bonnet
- CHRU Nancy, Genetics Laboratory, F-54000 Nancy, France
| | | | - Andrei Tchirkov
- CHRU Clermont-Ferrand, Medical Cytogenetics Laboratory, F-63003 Clermont-Ferrand, France
| | | | - Véronique Decot
- CHRU Nancy, Cell Therapy and Tissue Bank Unit, MTInov Bioproduction and Biotherapy Integrator, F-54000 Nancy, France
- CNRS, IMoPA, Lorraine University, F-54000 Nancy, France
| | - Loïc Reppel
- CHRU Nancy, Cell Therapy and Tissue Bank Unit, MTInov Bioproduction and Biotherapy Integrator, F-54000 Nancy, France
- CNRS, IMoPA, Lorraine University, F-54000 Nancy, France
| | - Danièle Bensoussan
- CHRU Nancy, Cell Therapy and Tissue Bank Unit, MTInov Bioproduction and Biotherapy Integrator, F-54000 Nancy, France
- CNRS, IMoPA, Lorraine University, F-54000 Nancy, France
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19
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Mattoli S, Schmidt M. Investigational Use of Mesenchymal Stem/Stromal Cells and Their Secretome as Add-On Therapy in Severe Respiratory Virus Infections: Challenges and Perspectives. Adv Ther 2023; 40:2626-2692. [PMID: 37069355 PMCID: PMC10109238 DOI: 10.1007/s12325-023-02507-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 03/24/2023] [Indexed: 04/19/2023]
Abstract
Serious manifestations of respiratory virus infections such as influenza and coronavirus disease 2019 (COVID-19) are associated with a dysregulated immune response and systemic inflammation. Treating the immunological/inflammatory dysfunction with glucocorticoids, Janus kinase inhibitors, and monoclonal antibodies against the interleukin-6 receptor has significantly reduced the risk of respiratory failure and death in hospitalized patients with severe COVID-19, but the proportion of those requiring invasive mechanical ventilation (IMV) and dying because of respiratory failure remains elevated. Treatment of severe influenza-associated pneumonia and acute respiratory distress syndrome (ARDS) with available immunomodulators and anti-inflammatory compounds is still not recommended. New therapies are therefore needed to reduce the use of IMV and the risk of death in hospitalized patients with rapidly increasing oxygen demand and systemic inflammation who do not respond to the current standard of care. This paper provides a critical assessment of the published clinical trials that have tested the investigational use of intravenously administered allogeneic mesenchymal stem/stromal cells (MSCs) and MSC-derived secretome with putative immunomodulatory/antiinflammatory/regenerative properties as add-on therapy to improve the outcome of these patients. Increased survival rates are reported in 5 of 12 placebo-controlled or open-label comparative trials involving patients with severe and critical COVID-19 and in the only study concerning patients with influenza-associated ARDS. Results are encouraging but inconclusive for the following reasons: small number of patients tested in each trial; differences in concomitant treatments and respiratory support; imbalances between study arms; differences in MSC source, MSC-derived product, dosing and starting time of the investigational therapy; insufficient/inappropriate reporting of clinical data. Solutions are proposed for improving the clinical development plan, with the aim of facilitating regulatory approval of the MSC-based investigational therapy for life-threatening respiratory virus infections in the future. Major issues are the absence of a biomarker predicting responsiveness to MSCs and MSC-derived secretome and the lack of pharmacoeconomic evaluations.
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Affiliation(s)
- Sabrina Mattoli
- Center of Expertise in Research and Innovation of the International Network for the Advancement of Viable and Applicable Innovations in Life Sciences (InAvail), InAvail at Rosental Nexxt, 4058 Basel, Switzerland
- Avail Biomedical Research Institute, 80539 Munich, Germany
| | - Matthias Schmidt
- Avail Biomedical Research Institute, 80539 Munich, Germany
- Discovery and Translational Research Center, 80539 Munich, Germany
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20
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Kandula UR, Wake AD. Effectiveness of RCTs Pooling Evidence on Mesenchymal Stem Cell (MSC) Therapeutic Applications During COVID-19 Epidemic: A Systematic Review. Biologics 2023; 17:85-112. [PMID: 37223116 PMCID: PMC10202141 DOI: 10.2147/btt.s404421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 05/09/2023] [Indexed: 05/25/2023]
Abstract
Background Global pandemic identified as coronavirus disease 2019 (COVID-19) has resulted in a variety of clinical symptoms, from asymptomatic carriers to those with severe acute respiratory distress syndrome (SARS) and moderate upper respiratory tract symptoms (URTS). This systematic review aimed to determine effectiveness of stem cell (SC) applications among COVID-19 patients. Methods Multiple databases of PubMed, EMBASE, Science Direct, Google Scholar, Scopus, Web of Science, and Cochrane Library were used. Studies were screened, chosen, and included in this systematic review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 flowchart diagram and PRISMA checklist. Included studies' quality was assessed employing Critical Appraisal Skills Programme (CASP) quality evaluation criteria for 14 randomized controlled trials (RCTs). Results Fourteen RCTs were performed between the years of 2020 to 2022, respectively, with a sample size n = 574 (treatment group (n = 318); control group (n = 256)) in multiple countries of Indonesia, Iran, Brazil, Turkey, China, Florida, UK, and France. The greatest sample size reported from China among 100 COVID-19 patients, while the lowest sample of 9 COVID-19 patients from Jakarta, Indonesia, and the patient's age ranges from 18 to 69 years. Studies applied to the type of SC were "Umbilical cord MSCs, MSCs secretome, MSCs, Placenta-derived MSCs, Human immature dental pulp SC, DW-MSC infusion, Wharton Jelly-derived MSCs". The injected therapeutic dose was 1 × 106 cells/kg, 1 × 107 cells/kg, 1 × 105 cells/kg, and 1 million cells/kg as per the evidence from the different studies. Studies focused on demographic variables, clinical symptoms, laboratory tests, Comorbidities, respiratory measures, concomitant therapies, Sequential Organ Failure Assessment score, mechanical ventilation, body mass index, adverse events, inflammatory markers, and PaO2/FiO2 ratio were all recorded as study characteristics. Conclusion Clinical evidence on MSC's therapeutic applications during COVID-19 pandemic has proven to be a promising therapy for COVID-19 patient recovery with no consequences and applied as a routine treatment for challenging ailments.
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Affiliation(s)
- Usha Rani Kandula
- Department of Clinical Nursing, College of Health Sciences, Arsi University, Asella, Ethiopia
| | - Addisu Dabi Wake
- Department of Clinical Nursing, College of Health Sciences, Arsi University, Asella, Ethiopia
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21
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Han L, Wu X, Wang O, Luan X, Velander WH, Aynardi M, Halstead ES, Bonavia AS, Jin R, Li G, Li Y, Wang Y, Dong C, Lei Y. Mesenchymal stromal cells and alpha-1 antitrypsin have a strong synergy in modulating inflammation and its resolution. Theranostics 2023; 13:2843-2862. [PMID: 37284443 PMCID: PMC10240832 DOI: 10.7150/thno.83942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 04/25/2023] [Indexed: 06/08/2023] Open
Abstract
Rationale: Trauma, surgery, and infection can cause severe inflammation. Both dysregulated inflammation intensity and duration can lead to significant tissue injuries, organ dysfunction, mortality, and morbidity. Anti-inflammatory drugs such as steroids and immunosuppressants can dampen inflammation intensity, but they derail inflammation resolution, compromise normal immunity, and have significant adverse effects. The natural inflammation regulator mesenchymal stromal cells (MSCs) have high therapeutic potential because of their unique capabilities to mitigate inflammation intensity, enhance normal immunity, and accelerate inflammation resolution and tissue healing. Furthermore, clinical studies have shown that MSCs are safe and effective. However, they are not potent enough, alone, to completely resolve severe inflammation and injuries. One approach to boost the potency of MSCs is to combine them with synergistic agents. We hypothesized that alpha-1 antitrypsin (A1AT), a plasma protein used clinically and has an excellent safety profile, was a promising candidate for synergism. Methods: This investigation examined the efficacy and synergy of MSCs and A1AT to mitigate inflammation and promote resolution, using in vitro inflammatory assay and in vivo mouse acute lung injury model. The in vitro assay measured cytokine releases, inflammatory pathways, reactive oxygen species (ROS), and neutrophil extracellular traps (NETs) production by neutrophils and phagocytosis in different immune cell lines. The in vivo model monitored inflammation resolution, tissue healing, and animal survival. Results: We found that the combination of MSCs and A1AT was much more effective than each component alone in i) modulating cytokine releases and inflammatory pathways, ii) inhibiting ROS and NETs production by neutrophils, iii) enhancing phagocytosis and, iv) promoting inflammation resolution, tissue healing, and animal survival. Conclusion: These results support the combined use of MSCs, and A1AT is a promising approach for managing severe, acute inflammation.
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Affiliation(s)
- Li Han
- Department of Biomedical Engineering, Pennsylvania State University; University Park, PA, 16802, USA
- Huck Institutes of the Life Sciences, Pennsylvania State University; University Park, PA, 16802, USA
| | - Xinran Wu
- Department of Biomedical Engineering, Pennsylvania State University; University Park, PA, 16802, USA
| | - Ou Wang
- Department of Chemical and Biomolecular Engineering, University of Nebraska-Lincoln; Lincoln, NE, 68588, USA
| | - Xiao Luan
- Biomedical Center of Qingdao University; Qingdao, Shandong, 266000, China
| | - William H. Velander
- Department of Chemical and Biomolecular Engineering, University of Nebraska-Lincoln; Lincoln, NE, 68588, USA
| | - Michael Aynardi
- Department of Orthopedics Surgery, Pennsylvania State University College of Medicine; Hershey, PA, 17033, USA
| | - E. Scott Halstead
- Division of Pediatric Critical Care Medicine, Department of Pediatrics, Pennsylvania State Milton S Hershey Medical Center; Hershey, PA, 17033, USA
| | - Anthony S. Bonavia
- Division of Critical Care Medicine, Department of Anesthesiology and Perioperative Medicine, Pennsylvania State Milton S Hershey Medical Center; Hershey, PA, 17033, USA
| | - Rong Jin
- Department of Neurosurgery, Pennsylvania State Milton S Hershey Medical Center; Hershey, PA, 17033, USA
| | - Guohong Li
- Department of Neurosurgery, Pennsylvania State Milton S Hershey Medical Center; Hershey, PA, 17033, USA
| | - Yulong Li
- Department of Emergency Medicine, University of Nebraska Medical Center; Omaha, NE, 68105, USA
| | - Yong Wang
- Department of Biomedical Engineering, Pennsylvania State University; University Park, PA, 16802, USA
| | - Cheng Dong
- Department of Biomedical Engineering, Pennsylvania State University; University Park, PA, 16802, USA
| | - Yuguo Lei
- Department of Biomedical Engineering, Pennsylvania State University; University Park, PA, 16802, USA
- Huck Institutes of the Life Sciences, Pennsylvania State University; University Park, PA, 16802, USA
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22
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Kim YE, Sung DK, Bang Y, Sung SI, Yang M, Ahn SY, Chang YS. SOCS3 Protein Mediates the Therapeutic Efficacy of Mesenchymal Stem Cells against Acute Lung Injury. Int J Mol Sci 2023; 24:ijms24098256. [PMID: 37175961 PMCID: PMC10179427 DOI: 10.3390/ijms24098256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 04/25/2023] [Accepted: 04/28/2023] [Indexed: 05/15/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have been studied as novel therapeutic agents because of their immunomodulatory properties in inflammatory diseases. The suppressor of cytokine signaling (SOCS) proteins are key regulators of the immune response and macrophage modulation. In the present study, we hypothesized that SOCS in MCSs might mediate macrophage modulation and tested this in a bacteria-induced acute lung injury (ALI) mouse model. The macrophage phenotype was observed in RAW264.7 alveolar macrophages exposed to lipopolysaccharide (LPS) in an in vitro model, and in the ALI mouse model induced by tracheal administration of Escherichia coli (1 × 107 CFU in 0.05mL PBS). In LPS-exposed RAW264.7 cells, the levels of markers of M1 macrophages, such as CD86 and pro-inflammatory cytokines (IL-1α, IL-1β, IL-6 and TNF-α), significantly increased, but they significantly reduced after MSC treatment. Meanwhile, the levels of markers of M2 macrophages, such as CD204 and anti-inflammatory cytokines (IL-4 and IL-10), increased after LPS exposure, and further significantly increased after MSC treatment. This regulatory effect of MSCs on M1/M2 macrophage polarization was significantly abolished by SOCS3 inhibition. In the E. coli-induced ALI model, tissue injury and inflammation in the mouse lung were significantly attenuated by the transplantation of MSCs, but not by SOCS3-inhibited MSCs. The regulatory effect of MSCs on M1/M2 macrophage polarization was observed in the lung injury model but was significantly abolished by SOCS3 inhibition. Taken together, our findings suggest that SOCS3 is an important mediator for macrophage modulation in anti-inflammatory properties of MSCs.
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Affiliation(s)
- Young Eun Kim
- Cell and Gene Therapy Institute, Samsung Medical Center, Seoul 06351, Republic of Korea
| | - Dong Kyung Sung
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| | - Yuna Bang
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
- Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Suwon 16419, Republic of Korea
| | - Se In Sung
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| | - Misun Yang
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| | - So Yoon Ahn
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| | - Yun Sil Chang
- Cell and Gene Therapy Institute, Samsung Medical Center, Seoul 06351, Republic of Korea
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 06351, Republic of Korea
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23
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Yudhawati R, Shimizu K. PGE2 Produced by Exogenous MSCs Promotes Immunoregulation in ARDS Induced by Highly Pathogenic Influenza A through Activation of the Wnt-β-Catenin Signaling Pathway. Int J Mol Sci 2023; 24:ijms24087299. [PMID: 37108459 PMCID: PMC10138595 DOI: 10.3390/ijms24087299] [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: 02/06/2023] [Revised: 04/12/2023] [Accepted: 04/13/2023] [Indexed: 04/29/2023] Open
Abstract
Acute respiratory distress syndrome is an acute respiratory failure caused by cytokine storms; highly pathogenic influenza A virus infection can induce cytokine storms. The innate immune response is vital in this cytokine storm, acting by activating the transcription factor NF-κB. Tissue injury releases a danger-associated molecular pattern that provides positive feedback for NF-κB activation. Exogenous mesenchymal stem cells can also modulate immune responses by producing potent immunosuppressive substances, such as prostaglandin E2. Prostaglandin E2 is a critical mediator that regulates various physiological and pathological processes through autocrine or paracrine mechanisms. Activation of prostaglandin E2 results in the accumulation of unphosphorylated β-catenin in the cytoplasm, which subsequently reaches the nucleus to inhibit the transcription factor NF-κB. The inhibition of NF-κB by β-catenin is a mechanism that reduces inflammation.
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Affiliation(s)
- Resti Yudhawati
- Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas Airlangga-Dr. Soetomo General Academic Hospital, Surabaya 60286, Indonesia
- Indonesia-Japan Collaborative Research Center for Emerging and Re-Emerging Infectious Diseases, Institute of Tropical Disease, Airlangga University, Surabaya 60286, Indonesia
| | - Kazufumi Shimizu
- Indonesia-Japan Collaborative Research Center for Emerging and Re-Emerging Infectious Diseases, Institute of Tropical Disease, Airlangga University, Surabaya 60286, Indonesia
- Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
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24
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Zielińska A, Eder P, Karczewski J, Szalata M, Hryhorowicz S, Wielgus K, Szalata M, Dobrowolska A, Atanasov AG, Słomski R, Souto EB. Tocilizumab-coated solid lipid nanoparticles loaded with cannabidiol as a novel drug delivery strategy for treating COVID-19: A review. Front Immunol 2023; 14:1147991. [PMID: 37033914 PMCID: PMC10073701 DOI: 10.3389/fimmu.2023.1147991] [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: 01/19/2023] [Accepted: 03/06/2023] [Indexed: 04/11/2023] Open
Abstract
Commonly used clinical strategies against coronavirus disease 19 (COVID-19), including the potential role of monoclonal antibodies for site-specific targeted drug delivery, are discussed here. Solid lipid nanoparticles (SLN) tailored with tocilizumab (TCZ) and loading cannabidiol (CBD) are proposed for the treatment of COVID-19 by oral route. TCZ, as a humanized IgG1 monoclonal antibody and an interleukin-6 (IL-6) receptor agonist, can attenuate cytokine storm in patients infected with SARS-CoV-2. CBD (an anti-inflammatory cannabinoid and TCZ agonist) alleviates anxiety, schizophrenia, and depression. CBD, obtained from Cannabis sativa L., is known to modulate gene expression and inflammation and also shows anti-cancer and anti-inflammatory properties. It has also been recognized to modulate angiotensin-converting enzyme II (ACE2) expression in SARS-CoV-2 target tissues. It has already been proven that immunosuppressive drugs targeting the IL-6 receptor may ameliorate lethal inflammatory responses in COVID-19 patients. TCZ, as an immunosuppressive drug, is mainly used to treat rheumatoid arthritis, although several attempts have been made to use it in the active hyperinflammatory phase of COVID-19, with promising outcomes. TCZ is currently administered intravenously. It this review, we discuss the potential advances on the use of SLN for oral administration of TCZ-tailored CBD-loaded SLN, as an innovative platform for managing SARS-CoV-2 and related infections.
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Affiliation(s)
| | - Piotr Eder
- Department of Gastroenterology, Dietetics, and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Jacek Karczewski
- Department of Environmental Medicine/Department of Gastroenterology, Human Nutrition and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Marlena Szalata
- Department of Biochemistry and Biotechnology, Poznań University of Life Sciences, Poznań, Poland
| | - Szymon Hryhorowicz
- Institute of Human Genetics, Polish Academy of Sciences Poznan, Poznan, Poland
| | - Karolina Wielgus
- Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Milena Szalata
- Department of Biotechnology, Institute of Natural Fibres and Medicinal Plants National Research Institute, Poznan, Poland
| | - Agnieszka Dobrowolska
- Department of Gastroenterology, Dietetics, and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Atanas G. Atanasov
- Institute of Genetics and Animal Biotechnology, Magdalenka, Poland
- Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria
- Department of Pharmacognosy, University of Vienna, Vienna, Austria
| | - Ryszard Słomski
- Institute of Human Genetics, Polish Academy of Sciences Poznan, Poznan, Poland
| | - Eliana B. Souto
- UCIBIO – Applied Molecular Biosciences Unit, MEDTECH, Laboratory of Pharmaceutical Technology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
- Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, Porto, Portugal
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25
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Khandelwal V, Sharma T, Gupta S, Singh S, Sharma MK, Parashar D, Kashyap VK. Stem cell therapy: a novel approach against emerging and re-emerging viral infections with special reference to SARS-CoV-2. Mol Biol Rep 2023; 50:2663-2683. [PMID: 36536185 PMCID: PMC9762873 DOI: 10.1007/s11033-022-07957-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Accepted: 09/17/2022] [Indexed: 12/23/2022]
Abstract
The past several decades have witnessed the emergence and re-emergence of many infectious viral agents, flaviviruses, influenza, filoviruses, alphaviruses, and coronaviruses since the advent of human deficiency virus (HIV). Some of them even become serious threats to public health and have raised major global health concerns. Several different medicinal compounds such as anti-viral, anti-malarial, and anti-inflammatory agents, are under investigation for the treatment of these viral diseases. These therapies are effective improving recovery rates and overall survival of patients but are unable to heal lung damage caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, there is a critical need to identify effective treatments to combat this unmet clinical need. Due to its antioxidant and immunomodulatory properties, stem cell therapy is considered a novel approach to regenerate damaged lungs and reduce inflammation. Stem cell therapy uses a heterogeneous subset of regenerative cells that can be harvested from various adult tissue types and is gaining popularity due to its prodigious regenerative potential as well as immunomodulatory and anti-inflammatory properties. These cells retain expression of cluster of differentiation markers (CD markers), interferon-stimulated gene (ISG), reduce expression of pro-inflammatory cytokines and, show a rapid proliferation rate, which makes them an attractive tool for cellular therapies and to treat various inflammatory and viral-induced injuries. By examining various clinical studies, this review demonstrates positive considerations for the implications of stem cell therapy and presents a necessary approach for treating virally induced infections in patients.
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Affiliation(s)
- Vishal Khandelwal
- Department of Biotechnology, GLA University, Mathura, Uttar Pradesh, 281406, India
| | - Tarubala Sharma
- Department of Biotechnology, GLA University, Mathura, Uttar Pradesh, 281406, India
| | - Saurabh Gupta
- Department of Biotechnology, GLA University, Mathura, Uttar Pradesh, 281406, India
| | - Shoorvir Singh
- Department of Biotechnology, GLA University, Mathura, Uttar Pradesh, 281406, India
| | - Manish Kumar Sharma
- Department of Microbiology, Dr. Ram Manohar Lohia Avadh University, Faizabad, Uttar Pradesh, 224001, India
| | - Deepak Parashar
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
| | - Vivek K Kashyap
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, USA. .,South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, USA.
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26
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Pooled evidence from preclinical and clinical studies for stem cell-based therapy in ARDS and COVID-19. Mol Cell Biochem 2022; 478:1487-1518. [PMID: 36394787 DOI: 10.1007/s11010-022-04601-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 10/24/2022] [Indexed: 11/18/2022]
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27
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Yudintceva N, Mikhailova N, Fedorov V, Samochernych K, Vinogradova T, Muraviov A, Shevtsov M. Mesenchymal Stem Cells and MSCs-Derived Extracellular Vesicles in Infectious Diseases: From Basic Research to Clinical Practice. Bioengineering (Basel) 2022; 9:662. [PMID: 36354573 PMCID: PMC9687734 DOI: 10.3390/bioengineering9110662] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 10/30/2022] [Accepted: 11/04/2022] [Indexed: 08/10/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are attractive in various fields of regenerative medicine due to their therapeutic potential and complex unique properties. Basic stem cell research and the global COVID-19 pandemic have given impetus to the development of cell therapy for infectious diseases. The aim of this review was to systematize scientific data on the applications of mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) in the combined treatment of infectious diseases. Application of MSCs and MSC-EVs in the treatment of infectious diseases has immunomodulatory, anti-inflammatory, and antibacterial effects, and also promotes the restoration of the epithelium and stimulates tissue regeneration. The use of MSC-EVs is a promising cell-free treatment strategy that allows solving the problems associated with the safety of cell therapy and increasing its effectiveness. In this review, experimental data and clinical trials based on MSCs and MSC-EVs for the treatment of infectious diseases are presented. MSCs and MSC-EVs can be a promising tool for the treatment of various infectious diseases, particularly in combination with antiviral drugs. Employment of MSC-derived EVs represents a more promising strategy for cell-free treatment, demonstrating a high therapeutic potential in preclinical studies.
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Affiliation(s)
- Natalia Yudintceva
- Institute of Cytology of the Russian Academy of Sciences (RAS), St. Petersburg 194064, Russia
- Personalized Medicine Centre, Almazov National Medical Research Centre, St. Petersburg 197341, Russia
| | - Natalia Mikhailova
- Institute of Cytology of the Russian Academy of Sciences (RAS), St. Petersburg 194064, Russia
| | - Viacheslav Fedorov
- Personalized Medicine Centre, Almazov National Medical Research Centre, St. Petersburg 197341, Russia
| | - Konstantin Samochernych
- Personalized Medicine Centre, Almazov National Medical Research Centre, St. Petersburg 197341, Russia
| | - Tatiana Vinogradova
- Saint-Petersburg State Research Institute of Phthisiopulmonology of the Ministry of Health of the Russian Federation, St. Petersburg 191036, Russia
| | - Alexandr Muraviov
- Saint-Petersburg State Research Institute of Phthisiopulmonology of the Ministry of Health of the Russian Federation, St. Petersburg 191036, Russia
| | - Maxim Shevtsov
- Institute of Cytology of the Russian Academy of Sciences (RAS), St. Petersburg 194064, Russia
- Personalized Medicine Centre, Almazov National Medical Research Centre, St. Petersburg 197341, Russia
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28
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Haddad F, Dokmak G, Karaman R. A Comprehensive Review on the Efficacy of Several Pharmacologic Agents for the Treatment of COVID-19. Life (Basel) 2022; 12:1758. [PMID: 36362912 PMCID: PMC9692303 DOI: 10.3390/life12111758] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 10/15/2022] [Accepted: 10/26/2022] [Indexed: 11/06/2022] Open
Abstract
SARS-CoV-2, the coronavirus disease-2019 (COVID-19), and the cause of the pandemic is extremely contagious among people and has spread around the world. Antivirals, immunomodulators, and other medications, such as antibiotics, stem cells, and plasma therapy, have all been utilized in the treatment of COVID-19. To better understand the clinical efficacy of these agents and to aid in the selection of effective COVID-19 therapies in various countries, this study reviewed the effectiveness of the various pharmacologic agents that have been used for COVID-19 therapy globally by summarizing the clinical outcomes that have been obtained from the clinical trials published on each drug related to COVID-19 infection. The Food and Drug Administration (FDA) has authorized the use of remdesivir, paxlovid, molnupiravir, baricitinib, tixagevimab-cilgavimab, and bebtelovimab for the management of COVID-19. On the other hand, most research advises against using chloroquine and hydroxychloroquine to treat COVID-19 patients because they are not beneficial. Although the FDA has given emergency use authorization for some monoclonal antibodies, including bamlanivimab, etesevimab, casirivimab, and imdevimab for managing COVID-19, they are not currently approved for use because the Omicron variant has significantly reduced their in vitro susceptibility. In this study, we also included a wide range of alternative therapy strategies that effectively treat COVID-19 patients, although further randomized studies are necessary to support and assess their applicability.
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Affiliation(s)
- Fatma Haddad
- Pharmaceutical Sciences Department, Faculty of Pharmacy, Al-Quds University, Jerusalem 9103401, Palestine
- Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, UK
| | - Ghadeer Dokmak
- Pharmaceutical Sciences Department, Faculty of Pharmacy, Al-Quds University, Jerusalem 9103401, Palestine
| | - Rafik Karaman
- Pharmaceutical Sciences Department, Faculty of Pharmacy, Al-Quds University, Jerusalem 9103401, Palestine
- Department of Sciences, University of Basilicata, 85100 Potenza, Italy
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29
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Remuzzi G, Schiaffino S, Santoro MG, FitzGerald GA, Melino G, Patrono C. Drugs for the prevention and treatment of COVID-19 and its complications: An update on what we learned in the past 2 years. Front Pharmacol 2022; 13:987816. [PMID: 36304162 PMCID: PMC9595217 DOI: 10.3389/fphar.2022.987816] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 09/12/2022] [Indexed: 12/15/2022] Open
Abstract
The COVID-19 Committee of the Lincei Academy has reviewed the scientific evidence supporting the efficacy and safety of existing and new drugs/biologics for the preventing and treating of COVID-19 and its complications. This position paper reports what we have learned in the field in the past 2 years. The focus was on, but not limited to, drugs and neutralizing monoclonal antibodies, anti-SARS-CoV-2 agents, anti-inflammatory and immunomodulatory drugs, complement inhibitors and anticoagulant agents. We also discuss the risks/benefit of using cell therapies on COVID-19 patients. The report summarizes the available evidence, which supports recommendations from health authorities and panels of experts regarding some drugs and biologics, and highlights drugs that are not recommended, or drugs for which there is insufficient evidence to recommend for or against their use. We also address the issue of the safety of drugs used to treat underlying concomitant conditions in COVID-19 patients. The investigators did an enormous amount of work very quickly to understand better the nature and pathophysiology of COVID-19. This expedited the development and repurposing of safe and effective therapeutic interventions, saving an impressive number of lives in the community as well as in hospitals.
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Affiliation(s)
- Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | | | - Maria Gabriella Santoro
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
- Institute of Translational Pharmacology, CNR, Rome, Italy
| | - Garret A. FitzGerald
- Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Philadelphia, Philadelphia, PA, United States
| | - Gennaro Melino
- Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Carlo Patrono
- Department of Pharmacology, Catholic University of the Sacred Heart, Rome, Italy
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30
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Quaglia M, Fanelli V, Merlotti G, Costamagna A, Deregibus MC, Marengo M, Balzani E, Brazzi L, Camussi G, Cantaluppi V. Dual Role of Extracellular Vesicles in Sepsis-Associated Kidney and Lung Injury. Biomedicines 2022; 10:biomedicines10102448. [PMID: 36289710 PMCID: PMC9598620 DOI: 10.3390/biomedicines10102448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 09/25/2022] [Accepted: 09/27/2022] [Indexed: 11/16/2022] Open
Abstract
Extracellular vesicles form a complex intercellular communication network, shuttling a variety of proteins, lipids, and nucleic acids, including regulatory RNAs, such as microRNAs. Transfer of these molecules to target cells allows for the modulation of sets of genes and mediates multiple paracrine and endocrine actions. EVs exert broad pro-inflammatory, pro-oxidant, and pro-apoptotic effects in sepsis, mediating microvascular dysfunction and multiple organ damage. This deleterious role is well documented in sepsis-associated acute kidney injury and acute respiratory distress syndrome. On the other hand, protective effects of stem cell-derived extracellular vesicles have been reported in experimental models of sepsis. Stem cell-derived extracellular vesicles recapitulate beneficial cytoprotective, regenerative, and immunomodulatory properties of parental cells and have shown therapeutic effects in experimental models of sepsis with kidney and lung involvement. Extracellular vesicles are also likely to play a role in deranged kidney-lung crosstalk, a hallmark of sepsis, and may be key to a better understanding of shared mechanisms underlying multiple organ dysfunction. In this review, we analyze the state-of-the-art knowledge on the dual role of EVs in sepsis-associated kidney/lung injury and repair. PubMed library was searched from inception to July 2022, using a combination of medical subject headings (MeSH) and keywords related to EVs, sepsis, acute kidney injury (AKI), acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). Key findings are summarized into two sections on detrimental and beneficial mechanisms of actions of EVs in kidney and lung injury, respectively. The role of EVs in kidney-lung crosstalk is then outlined. Efforts to expand knowledge on EVs may pave the way to employ them as prognostic biomarkers or therapeutic targets to prevent or reduce organ damage in sepsis.
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Affiliation(s)
- Marco Quaglia
- Nephrology and Kidney Transplantation Unit, Department of Translational Medicine, University of Piemonte Orientale (UPO), 28100 Novara, Italy
| | - Vito Fanelli
- Department of Anaesthesia, Critical Care and Emergency, Città della Salute e della Scienza Hospital, University of Torino, 10126 Torino, Italy
| | - Guido Merlotti
- Nephrology and Kidney Transplantation Unit, Department of Translational Medicine, University of Piemonte Orientale (UPO), 28100 Novara, Italy
| | - Andrea Costamagna
- Department of Anaesthesia, Critical Care and Emergency, Città della Salute e della Scienza Hospital, University of Torino, 10126 Torino, Italy
| | | | - Marita Marengo
- Nephrology and Dialysis Unit, ASL CN1, 12038 Savigliano, Italy
| | - Eleonora Balzani
- Department of Anaesthesia, Critical Care and Emergency, Città della Salute e della Scienza Hospital, University of Torino, 10126 Torino, Italy
| | - Luca Brazzi
- Department of Anaesthesia, Critical Care and Emergency, Città della Salute e della Scienza Hospital, University of Torino, 10126 Torino, Italy
| | - Giovanni Camussi
- Department of Medical Sciences, University of Torino, 10126 Torino, Italy
- Correspondence: (G.C.); (V.C.)
| | - Vincenzo Cantaluppi
- Nephrology and Kidney Transplantation Unit, Department of Translational Medicine, University of Piemonte Orientale (UPO), 28100 Novara, Italy
- Correspondence: (G.C.); (V.C.)
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Faizan MI, Chaudhuri R, Sagar S, Albogami S, Chaudhary N, Azmi I, Akhtar A, Ali SM, Kumar R, Iqbal J, Joshi MC, Kharya G, Seth P, Roy SS, Ahmad T. NSP4 and ORF9b of SARS-CoV-2 Induce Pro-Inflammatory Mitochondrial DNA Release in Inner Membrane-Derived Vesicles. Cells 2022; 11:cells11192969. [PMID: 36230930 PMCID: PMC9561960 DOI: 10.3390/cells11192969] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 09/13/2022] [Accepted: 09/13/2022] [Indexed: 12/05/2022] Open
Abstract
Circulating cell-free mitochondrial DNA (cf-mtDNA) has been found in the plasma of severely ill COVID-19 patients and is now known as a strong predictor of mortality. However, the underlying mechanism of mtDNA release is unexplored. Here, we show a novel mechanism of SARS-CoV-2-mediated pro-inflammatory/pro-apoptotic mtDNA release and a rational therapeutic stem cell-based approach to mitigate these effects. We systematically screened the effects of 29 SARS-CoV-2 proteins on mitochondrial damage and cell death and found that NSP4 and ORF9b caused extensive mitochondrial structural changes, outer membrane macropore formation, and the release of inner membrane vesicles loaded with mtDNA. The macropore-forming ability of NSP4 was mediated through its interaction with BCL2 antagonist/killer (BAK), whereas ORF9b was found to inhibit the anti-apoptotic member of the BCL2 family protein myeloid cell leukemia-1 (MCL1) and induce inner membrane vesicle formation containing mtDNA. Knockdown of BAK and/or overexpression of MCL1 significantly reversed SARS-CoV-2-mediated mitochondrial damage. Therapeutically, we engineered human mesenchymal stem cells (MSCs) with a simultaneous knockdown of BAK and overexpression of MCL1 (MSCshBAK+MCL1) and named these cells IMAT-MSCs (intercellular mitochondrial transfer-assisted therapeutic MSCs). Upon co-culture with SARS-CoV-2-infected or NSP4/ORF9b-transduced airway epithelial cells, IMAT-MSCs displayed functional intercellular mitochondrial transfer (IMT) via tunneling nanotubes (TNTs). The mitochondrial donation by IMAT-MSCs attenuated the pro-inflammatory and pro-apoptotic mtDNA release from co-cultured epithelial cells. Our findings thus provide a new mechanistic basis for SARS-CoV-2-induced cell death and a novel therapeutic approach to engineering MSCs for the treatment of COVID-19.
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Affiliation(s)
- Md Imam Faizan
- Multidisciplinary Centre for Advanced Research & Studies (MCARS), Jamia Millia Islamia, New Delhi 110025, India
| | - Rituparna Chaudhuri
- Molecular and Cellular Neuroscience, Neurovirology Section, National Brain Research Centre (NBRC), Gurugram 122052, India
| | - Shakti Sagar
- CSIR-Institute of Genomics and Integrative Biology, New Delhi 110007, India
| | - Sarah Albogami
- Department of Biotechnology, College of Science, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Nisha Chaudhary
- Multidisciplinary Centre for Advanced Research & Studies (MCARS), Jamia Millia Islamia, New Delhi 110025, India
| | - Iqbal Azmi
- Multidisciplinary Centre for Advanced Research & Studies (MCARS), Jamia Millia Islamia, New Delhi 110025, India
| | - Areej Akhtar
- Multidisciplinary Centre for Advanced Research & Studies (MCARS), Jamia Millia Islamia, New Delhi 110025, India
| | - Syed Mansoor Ali
- Department of Biotechnology, Jamia Millia Islamia, New Delhi 110025, India
| | - Rohit Kumar
- Department of Pulmonary Medicine and Sleep Disorders, Vardhman Mahavir Medical College, Safdarjung Hospital, New Delhi 10029, India
| | - Jawed Iqbal
- Multidisciplinary Centre for Advanced Research & Studies (MCARS), Jamia Millia Islamia, New Delhi 110025, India
| | - Mohan C. Joshi
- Multidisciplinary Centre for Advanced Research & Studies (MCARS), Jamia Millia Islamia, New Delhi 110025, India
| | - Gaurav Kharya
- Center for Bone Marrow Transplantation & Cellular Therapy Indraprastha Apollo Hospital, New Delhi 110076, India
| | - Pankaj Seth
- Molecular and Cellular Neuroscience, Neurovirology Section, National Brain Research Centre (NBRC), Gurugram 122052, India
| | - Soumya Sinha Roy
- CSIR-Institute of Genomics and Integrative Biology, New Delhi 110007, India
| | - Tanveer Ahmad
- Multidisciplinary Centre for Advanced Research & Studies (MCARS), Jamia Millia Islamia, New Delhi 110025, India
- Correspondence: ; Tel.: +91-9971525411
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32
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Regenerative mesenchymal stem c
ell‐derived
extracellular vesicles: A potential alternative to c
ell‐based
therapy in viral infection and disease damage control. WIREs Mech Dis 2022; 14:e1574. [DOI: 10.1002/wsbm.1574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 05/24/2022] [Indexed: 11/07/2022]
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Pathophysiology of Sepsis and Genesis of Septic Shock: The Critical Role of Mesenchymal Stem Cells (MSCs). Int J Mol Sci 2022; 23:ijms23169274. [PMID: 36012544 PMCID: PMC9409099 DOI: 10.3390/ijms23169274] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 08/14/2022] [Accepted: 08/15/2022] [Indexed: 11/17/2022] Open
Abstract
The treatment of sepsis and septic shock remains a major public health issue due to the associated morbidity and mortality. Despite an improvement in the understanding of the physiological and pathological mechanisms underlying its genesis and a growing number of studies exploring an even higher range of targeted therapies, no significant clinical progress has emerged in the past decade. In this context, mesenchymal stem cells (MSCs) appear more and more as an attractive approach for cell therapy both in experimental and clinical models. Pre-clinical data suggest a cornerstone role of these cells and their secretome in the control of the host immune response. Host-derived factors released from infected cells (i.e., alarmins, HMGB1, ATP, DNA) as well as pathogen-associated molecular patterns (e.g., LPS, peptidoglycans) can activate MSCs located in the parenchyma and around vessels to upregulate the expression of cytokines/chemokines and growth factors that influence, respectively, immune cell recruitment and stem cell mobilization. However, the way in which MSCs exert their beneficial effects in terms of survival and control of inflammation in septic states remains unclear. This review presents the interactions identified between MSCs and mediators of immunity and tissue repair in sepsis. We also propose paradigms related to the plausible roles of MSCs in the process of sepsis and septic shock. Finally, we offer a presentation of experimental and clinical studies and open the way to innovative avenues of research involving MSCs from a prognostic, diagnostic, and therapeutic point of view in sepsis.
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Aghayan HR, Salimian F, Abedini A, Fattah Ghazi S, Yunesian M, Alavi-Moghadam S, Makarem J, Majidzadeh-A K, Hatamkhani A, Moghri M, Danesh A, Haddad-Marandi MR, Sanati H, Abbasvandi F, Arjmand B, Azimi P, Ghavamzadeh A, Sarrami-Forooshani R. Human placenta-derived mesenchymal stem cells transplantation in patients with acute respiratory distress syndrome (ARDS) caused by COVID-19 (phase I clinical trial): safety profile assessment. Stem Cell Res Ther 2022; 13:365. [PMID: 35902979 PMCID: PMC9330663 DOI: 10.1186/s13287-022-02953-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 06/04/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND High morbidity and mortality rates of the COVID-19 pandemic have made it a global health priority. Acute respiratory distress syndrome (ARDS) is one of the most important causes of death in COVID-19 patients. Mesenchymal stem cells have been the subject of many clinical trials for the treatment of ARDS because of their immunomodulatory, anti-inflammatory, and regenerative potentials. The aim of this phase I clinical trial was the safety assessment of allogeneic placenta-derived mesenchymal stem cells (PL-MSCs) intravenous injection in patients with ARDS induced by COVID-19. METHODS We enrolled 20 patients suffering from ARDS caused by COVID-19 who had been admitted to the intensive care unit. PL-MSCs were isolated and propagated using a xeno-free/GMP compliant protocol. Each patient in the treatment group (N = 10) received standard treatment and a single dose of 1 × 106 cells/kg PL-MSCs intravenously. The control groups (N = 10) only received the standard treatment. Clinical signs and laboratory tests were evaluated in all participants at the baseline and during 28 days follow-ups. RESULTS No adverse events were observed in the PL-MSC group. Mean length of hospitalization, serum oxygen saturation, and other clinical and laboratory parameters were not significantly different in the two groups (p > 0.05). CONCLUSION Our results demonstrated that intravenous administration of PL-MSCs in patients with COVID-19 related ARDS is safe and feasible. Further studies whit higher cell doses and repeated injections are needed to evaluate the efficacy of this treatment modality. TRIAL REGISTRATION Iranian Registry of Clinical Trials (IRCT); IRCT20200621047859N4. Registered 1 March 2021, https://en.irct.ir/trial/52947 .
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Affiliation(s)
- Hamid Reza Aghayan
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Salimian
- ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, P.O. BOX: 15179/64311, Tehran, Iran
| | - Atefeh Abedini
- Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Samrand Fattah Ghazi
- Department of Anesthesiology and Critical Care, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Masud Yunesian
- Department of Environmental Health Engineering, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Sepideh Alavi-Moghadam
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Jalil Makarem
- Department of Anesthesiology and Critical Care, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Keivan Majidzadeh-A
- Genetics Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Ali Hatamkhani
- ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, P.O. BOX: 15179/64311, Tehran, Iran
| | - Maryam Moghri
- ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, P.O. BOX: 15179/64311, Tehran, Iran
| | - Abbas Danesh
- Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Haddad-Marandi
- ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, P.O. BOX: 15179/64311, Tehran, Iran
| | - Hassan Sanati
- ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, P.O. BOX: 15179/64311, Tehran, Iran
| | - Fereshteh Abbasvandi
- ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, P.O. BOX: 15179/64311, Tehran, Iran
| | - Babak Arjmand
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Pourya Azimi
- Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ardeshir Ghavamzadeh
- Cancer and Cell Therapy Research Center, Tehran University of Medical Sciences, Tehran, Iran.
| | - Ramin Sarrami-Forooshani
- ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, P.O. BOX: 15179/64311, Tehran, Iran.
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Sharma A, Kulkarni R, Sane H, Awad N, Bopardikar A, Joshi A, Baweja S, Joshi M, Vishwanathan C, Gokulchandran N, Badhe P, Khan M, Paranjape A, Kulkarni P, Methal AK. Phase 1 clinical trial for intravenous administration of mesenchymal stem cells derived from umbilical cord and placenta in patients with moderate COVID-19 virus pneumonia: results of stage 1 of the study. AMERICAN JOURNAL OF STEM CELLS 2022; 11:37-55. [PMID: 35873716 PMCID: PMC9301142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 06/10/2022] [Indexed: 06/15/2023]
Abstract
OBJECTIVE Mesenchymal stem cells can serve as a therapeutic option for COVID-19. Their immunomodulatory and anti-inflammatory properties can regulate the exaggerated inflammatory response and promote recovery of lung damage. METHOD Phase-1, single-centre open-label, prospective clinical trial was conducted to evaluate the safety and efficacy of intravenous administration of mesenchymal stem cells derived from umbilical cord and placenta in moderate COVID-19. The study was done in 2 stages with total 20 patients. Herein, the results of stage 1 including first 10 patients receiving 100 million cells on day 1 and 4 with a follow up of 6 months have been discussed. RESULTS No adverse events were recorded immediately after the administration of MSCs or on follow up. There was no deterioration observed in clinical, laboratory and radiological parameters. All symptoms of the study group resolved within 10 days. Levels of inflammatory biomarkers such as NLR, CRP, IL6, ferritin and D-dimer improved in all patients after intervention along with improved oxygenation demonstrated by improvement in the SpO2/FiO2 ratio and PaO2/FiO2 ratio. None of the patients progressed to severe stage. 9 out of 10 patients were discharged within 9 days of their admission. Improvements were noted in chest x-ray and chest CT scan scores at day 7 in most patients. No post-covid fibrosis was observed on chest CT 28 days after intervention and Chest X ray after 6 months of the intervention. CONCLUSION Administration of 100 million mesenchymal stem cells in combination with standard treatment was found to be safe and resulted in prevention of the cytokine storm, halting of the disease progression and acceleration of recovery in moderate COVID-19. This clinical trial has been registered with the Clinical Trial Registry- India (CTRI) as CTRI/2020/08/027043. http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=43175.
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Affiliation(s)
- Alok Sharma
- Department of Neurosurgery, LTMG Hospital and LTM Medical CollegeMumbai, Maharashtra, India
- Department of Medical Services and Clinical Research, NeuroGen Brain & Spine InstituteNavi Mumbai, Maharashtra, India
| | | | - Hemangi Sane
- Department of Research & Development, NeuroGen Brain & Spine InstituteNavi Mumbai, Maharashtra, India
| | - Nilkanth Awad
- Department of Pulmonary Medicine, LTMG Hospital and LTM Medical CollegeSion, Mumbai, Maharashtra, India
| | | | - Anagha Joshi
- Department of Radiology, LTMG Hospital and LTM Medical CollegeMumbai, Maharashtra, India
| | - Sujata Baweja
- Department of Microbiology, LTMG Hospital and LTM Medical CollegeMumbai, Maharashtra, India
| | - Mohan Joshi
- Dean, LTMG Hospital and LTM Medical CollegeMumbai, Maharashtra, India
| | | | - Nandini Gokulchandran
- Department of Medical Services and Clinical Research, NeuroGen Brain & Spine InstituteNavi Mumbai, Maharashtra, India
| | - Prerna Badhe
- Department of Regenerative Laboratory, NeuroGen Brain and Spine InstituteSeawoods, Navi Maharashtra, India
| | - Mazhar Khan
- Department of Neurosurgery, LTMG Hospital and LTM Medical CollegeMumbai, Maharashtra, India
| | - Amruta Paranjape
- Department of Research & Development, NeuroGen Brain & Spine InstituteNavi Mumbai, Maharashtra, India
| | - Pooja Kulkarni
- Department of Research & Development, NeuroGen Brain & Spine InstituteNavi Mumbai, Maharashtra, India
| | - Arjun K Methal
- Department of Research & Development, NeuroGen Brain & Spine InstituteNavi Mumbai, Maharashtra, India
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Abstract
The lung is the primary site of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced immunopathology whereby the virus enters the host cells by binding to angiotensin-converting enzyme 2 (ACE2). Sophisticated regeneration and repair programs exist in the lungs to replenish injured cell populations. However, known resident stem/progenitor cells have been demonstrated to express ACE2, raising a substantial concern regarding the long-term consequences of impaired lung regeneration after SARS-CoV-2 infection. Moreover, clinical treatments may also affect lung repair from antiviral drug candidates to mechanical ventilation. In this review, we highlight how SARS-CoV-2 disrupts a program that governs lung homeostasis. We also summarize the current efforts of targeted therapy and supportive treatments for COVID-19 patients. In addition, we discuss the pros and cons of cell therapy with mesenchymal stem cells or resident lung epithelial stem/progenitor cells in preventing post-acute sequelae of COVID-19. We propose that, in addition to symptomatic treatments being developed and applied in the clinic, targeting lung regeneration is also essential to restore lung homeostasis in COVID-19 patients.
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Affiliation(s)
- Fuxiaonan Zhao
- Department of Basic Medicine, Haihe Clinical School, Tianjin Medical University, Tianjin, China
| | - Qingwen Ma
- Department of Basic Medicine, Haihe Clinical School, Tianjin Medical University, Tianjin, China
| | - Qing Yue
- Department of Basic Medicine, Haihe Clinical School, Tianjin Medical University, Tianjin, China
| | - Huaiyong Chen
- Department of Basic Medicine, Haihe Clinical School, Tianjin Medical University, Tianjin, China
- Key Research Laboratory for Infectious Disease Prevention for State Administration of Traditional Chinese Medicine, Tianjin Institute of Respiratory Diseases, Tianjin Haihe Hospital, Tianjin, China
- Department of Basic Medicine, Haihe Hospital, Tianjin University, Tianjin, China
- Tianjin Key Laboratory of Lung Regenerative Medicine, Tianjin, China
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Yao W, Shi L, Zhang Y, Dong H, Zhang Y. Mesenchymal stem/stromal cell therapy for COVID-19 pneumonia: potential mechanisms, current clinical evidence, and future perspectives. Stem Cell Res Ther 2022; 13:124. [PMID: 35321737 PMCID: PMC8942612 DOI: 10.1186/s13287-022-02810-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 02/07/2022] [Indexed: 12/20/2022] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread into more than 200 countries and infected approximately 203 million people globally. COVID-19 is associated with high mortality and morbidity in some patients, and this disease still does not have effective treatments with reproducibly appreciable outcomes. One of the leading complications associated with COVID-19 is acute respiratory distress syndrome (ARDS); this is an anti-viral host inflammatory response, and it is usually caused by a cytokine storm syndrome which may lead to multi-organ failure and death. Currently, COVID-19 patients are treated with approaches that mostly fall into two major categories: immunomodulators, which promote the body's fight against viruses efficiently, and antivirals, which slow or stop viruses from multiplying. These treatments include a variety of novel therapies that are currently being tested in clinical trials, including serum, IL-6 antibody, and remdesivir; however, the outcomes of these therapies are not consistently appreciable and remain a subject of debate. Mesenchymal stem/stromal cells (MSCs), the multipotent stem cells that have previously been used to treat viral infections and various respiratory diseases such as ARDS exhibit immunomodulatory properties and can ameliorate tissue damage. Given that SARS-CoV-2 targets the immune system and causes tissue damage, it is presumable that MSCs are being explored to treat COVID-19 patients. This review summarizes the potential mechanisms of action of MSC therapy, progress of MSC, and its related products in clinical trials for COVID-19 therapy based on the outcomes of these clinical studies.
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Affiliation(s)
- Weiqi Yao
- Department of Hematology, Union Hospital, Tong Ji Medical College, Hua Zhong University of Science and Technology, Hubei, China
- State Industrial Base for Stem Cell Engineering Products, No. 12 Meiyuan Road, Tianjin, 300384, China
- Hubei Engineering Research Center for Human Stem Cell Preparation, Application and Resource Preservation, Wuhan, China
| | - Lei Shi
- Department of Infectious Diseases, Fifth Medical Center of Chinese, PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China
| | - Yun Zhang
- State Industrial Base for Stem Cell Engineering Products, No. 12 Meiyuan Road, Tianjin, 300384, China
- Tianjin Key Laboratory for Stem Cell and Regenerative Medicine, Tianjin, China
| | - Haibo Dong
- Hubei Engineering Research Center for Human Stem Cell Preparation, Application and Resource Preservation, Wuhan, China
- Wuhan Optics Valley VCANBIO Cell & Gene Technology Co., Ltd., Hubei, China
| | - Yu Zhang
- State Industrial Base for Stem Cell Engineering Products, No. 12 Meiyuan Road, Tianjin, 300384, China.
- Hubei Engineering Research Center for Human Stem Cell Preparation, Application and Resource Preservation, Wuhan, China.
- Tianjin Key Laboratory for Stem Cell and Regenerative Medicine, Tianjin, China.
- Tianjin Key Laboratory for Blood Cell Therapy Technology, Tianjin, China.
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38
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Rebelatto CLK, Senegaglia AC, Franck CL, Daga DR, Shigunov P, Stimamiglio MA, Marsaro DB, Schaidt B, Micosky A, de Azambuja AP, Leitão CA, Petterle RR, Jamur VR, Vaz IM, Mallmann AP, Carraro Junior H, Ditzel E, Brofman PRS, Correa A. Safety and long-term improvement of mesenchymal stromal cell infusion in critically COVID-19 patients: a randomized clinical trial. Stem Cell Res Ther 2022; 13:122. [PMID: 35313959 PMCID: PMC8935270 DOI: 10.1186/s13287-022-02796-1] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Accepted: 02/20/2022] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND COVID-19 is a multisystem disease that presents acute and persistent symptoms, the postacute sequelae (PASC). Long-term symptoms may be due to consequences from organ or tissue injury caused by SARS-CoV-2, associated clotting or inflammatory processes during acute COVID-19. Various strategies are being chosen by clinicians to prevent severe cases of COVID-19; however, a single treatment would not be efficient in treating such a complex disease. Mesenchymal stromal cells (MSCs) are known for their immunomodulatory properties and regeneration ability; therefore, they are a promising tool for treating disorders involving immune dysregulation and extensive tissue damage, as is the case with COVID-19. This study aimed to assess the safety and explore the long-term efficacy of three intravenous doses of UC-MSCs (umbilical cord MSCs) as an adjunctive therapy in the recovery and postacute sequelae reduction caused by COVID-19. To our knowledge, this is one of the few reports that presents the longest follow-up after MSC treatment in COVID-19 patients. METHODS This was a phase I/II, prospective, single-center, randomized, double-blind, placebo-controlled clinical trial. Seventeen patients diagnosed with COVID-19 who require intensive care surveillance and invasive mechanical ventilation-critically ill patients-were included. The patient infusion was three doses of 5 × 105 cells/kg UC-MSCs, with a dosing interval of 48 h (n = 11) or placebo (n = 6). The evaluations consisted of a clinical assessment, viral load, laboratory testing, including blood count, serologic, biochemical, cell subpopulation, cytokines and CT scan. RESULTS The results revealed that in the UC-MSC group, there was a reduction in the levels of ferritin, IL-6 and MCP1-CCL2 on the fourteen day. In the second month, a decrease in the levels of reactive C-protein, D-dimer and neutrophils and an increase in the numbers of TCD3, TCD4 and NK lymphocytes were observed. A decrease in extension of lung damage was observed at the fourth month. The improvement in all these parameters was maintained until the end of patient follow-up. CONCLUSIONS UC-MSCs infusion is safe and can play an important role as an adjunctive therapy, both in the early stages, preventing severe complications and in the chronic phase with postacute sequelae reduction in critically ill COVID-19 patients. Trial registration Brazilian Registry of Clinical Trials (ReBEC), UTN code-U1111-1254-9819. Registered 31 October 2020-Retrospectively registered, https://ensaiosclinicos.gov.br/rg/RBR-3fz9yr.
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Affiliation(s)
- Carmen Lúcia Kuniyoshi Rebelatto
- Core for Cell Technology, School of Medicine, Pontifícia Universidade Católica Do Paraná, 1155 Imaculada Conceição Street, Prado Velho, Curitiba, PR, 80215-901, Brazil.
- Complexo Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, PR, Brazil.
- National Institute of Science and Technology for Regenerative Medicine, INCT-REGENERA, Rio de Janeiro, Brazil.
| | - Alexandra Cristina Senegaglia
- Core for Cell Technology, School of Medicine, Pontifícia Universidade Católica Do Paraná, 1155 Imaculada Conceição Street, Prado Velho, Curitiba, PR, 80215-901, Brazil
- Complexo Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, PR, Brazil
- National Institute of Science and Technology for Regenerative Medicine, INCT-REGENERA, Rio de Janeiro, Brazil
| | | | - Debora Regina Daga
- Core for Cell Technology, School of Medicine, Pontifícia Universidade Católica Do Paraná, 1155 Imaculada Conceição Street, Prado Velho, Curitiba, PR, 80215-901, Brazil
- National Institute of Science and Technology for Regenerative Medicine, INCT-REGENERA, Rio de Janeiro, Brazil
| | - Patrícia Shigunov
- National Institute of Science and Technology for Regenerative Medicine, INCT-REGENERA, Rio de Janeiro, Brazil
- Laboratory of Basic Biology of Stem Cells, Carlos Chagas Institute, Fiocruz-Paraná, Curitiba, PR, Brazil
| | - Marco Augusto Stimamiglio
- National Institute of Science and Technology for Regenerative Medicine, INCT-REGENERA, Rio de Janeiro, Brazil
- Laboratory of Basic Biology of Stem Cells, Carlos Chagas Institute, Fiocruz-Paraná, Curitiba, PR, Brazil
| | - Daniela Boscaro Marsaro
- Core for Cell Technology, School of Medicine, Pontifícia Universidade Católica Do Paraná, 1155 Imaculada Conceição Street, Prado Velho, Curitiba, PR, 80215-901, Brazil
- National Institute of Science and Technology for Regenerative Medicine, INCT-REGENERA, Rio de Janeiro, Brazil
| | - Bruna Schaidt
- Core for Cell Technology, School of Medicine, Pontifícia Universidade Católica Do Paraná, 1155 Imaculada Conceição Street, Prado Velho, Curitiba, PR, 80215-901, Brazil
| | - Andressa Micosky
- Core for Cell Technology, School of Medicine, Pontifícia Universidade Católica Do Paraná, 1155 Imaculada Conceição Street, Prado Velho, Curitiba, PR, 80215-901, Brazil
| | | | | | | | - Valderez Ravaglio Jamur
- Core for Cell Technology, School of Medicine, Pontifícia Universidade Católica Do Paraná, 1155 Imaculada Conceição Street, Prado Velho, Curitiba, PR, 80215-901, Brazil
| | - Isadora May Vaz
- Core for Cell Technology, School of Medicine, Pontifícia Universidade Católica Do Paraná, 1155 Imaculada Conceição Street, Prado Velho, Curitiba, PR, 80215-901, Brazil
| | | | | | | | - Paulo Roberto Slud Brofman
- Core for Cell Technology, School of Medicine, Pontifícia Universidade Católica Do Paraná, 1155 Imaculada Conceição Street, Prado Velho, Curitiba, PR, 80215-901, Brazil
- National Institute of Science and Technology for Regenerative Medicine, INCT-REGENERA, Rio de Janeiro, Brazil
| | - Alejandro Correa
- National Institute of Science and Technology for Regenerative Medicine, INCT-REGENERA, Rio de Janeiro, Brazil
- Laboratory of Basic Biology of Stem Cells, Carlos Chagas Institute, Fiocruz-Paraná, Curitiba, PR, Brazil
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Subhalakshmi RT, Balamurugan SAA, Sasikala S. Deep learning based fusion model for COVID-19 diagnosis and classification using computed tomography images. CONCURRENT ENGINEERING, RESEARCH, AND APPLICATIONS 2022; 30:116-127. [PMID: 35382156 PMCID: PMC8968394 DOI: 10.1177/1063293x211021435] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
Recently, the COVID-19 pandemic becomes increased in a drastic way, with the availability of a limited quantity of rapid testing kits. Therefore, automated COVID-19 diagnosis models are essential to identify the existence of disease from radiological images. Earlier studies have focused on the development of Artificial Intelligence (AI) techniques using X-ray images on COVID-19 diagnosis. This paper aims to develop a Deep Learning Based MultiModal Fusion technique called DLMMF for COVID-19 diagnosis and classification from Computed Tomography (CT) images. The proposed DLMMF model operates on three main processes namely Weiner Filtering (WF) based pre-processing, feature extraction and classification. The proposed model incorporates the fusion of deep features using VGG16 and Inception v4 models. Finally, Gaussian Naïve Bayes (GNB) based classifier is applied for identifying and classifying the test CT images into distinct class labels. The experimental validation of the DLMMF model takes place using open-source COVID-CT dataset, which comprises a total of 760 CT images. The experimental outcome defined the superior performance with the maximum sensitivity of 96.53%, specificity of 95.81%, accuracy of 96.81% and F-score of 96.73%.
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Affiliation(s)
- RT Subhalakshmi
- Department of Information Technology, Sethu Institute of Technology, Virudhunagar, Tamil Nadu, India
| | - S Appavu alias Balamurugan
- Department of Computer Science, Central University of Tamil Nadu, Thiruvarur, Tamil Nadu, India
- S Appavu alias Balamurugan, Department of Computer Science, Central University of Tamil Nadu, Thiruvarur – 610 005, Tamilnadu, India.
| | - S Sasikala
- Department of Computer Science and Engineering, Velammal College of Engineering and Technology, Madurai, Tamil Nadu, India
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Kebria MM, Milan PB, Peyravian N, Kiani J, Khatibi S, Mozafari M. Stem cell therapy for COVID-19 pneumonia. MOLECULAR BIOMEDICINE 2022; 3:6. [PMID: 35174448 PMCID: PMC8850486 DOI: 10.1186/s43556-021-00067-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Accepted: 12/22/2021] [Indexed: 12/11/2022] Open
Abstract
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus is a highly contagious microorganism, and despite substantial investigation, no progress has been achieved in treating post-COVID complications. However, the virus has made various mutations and has spread around the world. Researchers have tried different treatments to reduce the side effects of the COVID-19 symptoms. One of the most common and effective treatments now used is steroid therapy to reduce the complications of this disease. Long-term steroid therapy for chronic inflammation following COVID-19 is harmful and increases the risk of secondary infection, and effective treatment remains challenging owing to fibrosis and severe inflammation and infection. Sometimes our immune system can severely damage ourselves in disease. In the past, many researchers have conducted various studies on the immunomodulatory properties of stem cells. This property of stem cells led them to modulate the immune system of autoimmune diseases like diabetes, multiple sclerosis, and Parkinson's. Because of their immunomodulatory properties, stem cell-based therapy employing mesenchymal or hematopoietic stem cells may be a viable alternative treatment option in some patients. By priming the immune system and providing cytokines, chemokines, and growth factors, stem cells can be employed to build a long-term regenerative and protective response. This review addresses the latest trends and rapid progress in stem cell treatment for Acute Respiratory Distress Syndrome (ARDS) following COVID-19.
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Affiliation(s)
- Maziar Malekzadeh Kebria
- Cellular and Molecular Research Centre, Iran University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Peiman Brouki Milan
- Cellular and Molecular Research Centre, Iran University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Noshad Peyravian
- Cellular and Molecular Research Centre, Iran University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Jafar Kiani
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
- Present Address: Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Soheil Khatibi
- Babol University of Medical Sciences, Infection Diseases Centre, Mazandaran, Iran
| | - Masoud Mozafari
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
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Henriques-Pons A, Beghini DG, Silva VDS, Iwao Horita S, da Silva FAB. Pulmonary Mesenchymal Stem Cells in Mild Cases of COVID-19 Are Dedicated to Proliferation; In Severe Cases, They Control Inflammation, Make Cell Dispersion, and Tissue Regeneration. Front Immunol 2022; 12:780900. [PMID: 35095855 PMCID: PMC8793136 DOI: 10.3389/fimmu.2021.780900] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 12/17/2021] [Indexed: 12/29/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent adult stem cells present in virtually all tissues; they have potent self-renewal capacity and differentiate into multiple cell types. For many reasons, these cells are a promising therapeutic alternative to treat patients with severe COVID-19 and pulmonary post-COVID sequelae. These cells are not only essential for tissue regeneration; they can also alter the pulmonary environment through the paracrine secretion of several mediators. They can control or promote inflammation, induce other stem cells differentiation, restrain the virus load, and much more. In this work, we performed single-cell RNA-seq data analysis of MSCs in bronchoalveolar lavage samples from control individuals and COVID-19 patients with mild and severe clinical conditions. When we compared samples from mild cases with control individuals, most genes transcriptionally upregulated in COVID-19 were involved in cell proliferation. However, a new set of genes with distinct biological functions was upregulated when we compared severely affected with mild COVID-19 patients. In this analysis, the cells upregulated genes related to cell dispersion/migration and induced the γ-activated sequence (GAS) genes, probably triggered by IFNGR1 and IFNGR2. Then, IRF-1 was upregulated, one of the GAS target genes, leading to the interferon-stimulated response (ISR) and the overexpression of many signature target genes. The MSCs also upregulated genes involved in the mesenchymal-epithelial transition, virus control, cell chemotaxis, and used the cytoplasmic RNA danger sensors RIG-1, MDA5, and PKR. In a non-comparative analysis, we observed that MSCs from severe cases do not express many NF-κB upstream receptors, such as Toll-like (TLRs) TLR-3, -7, and -8; tumor necrosis factor (TNFR1 or TNFR2), RANK, CD40, and IL-1R1. Indeed, many NF-κB inhibitors were upregulated, including PPP2CB, OPTN, NFKBIA, and FHL2, suggesting that MSCs do not play a role in the "cytokine storm" observed. Therefore, lung MSCs in COVID-19 sense immune danger and act protectively in concert with the pulmonary environment, confirming their therapeutic potential in cell-based therapy for COVID-19. The transcription of MSCs senescence markers is discussed.
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Affiliation(s)
- Andrea Henriques-Pons
- Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Rio de Janeiro, Brazil
| | - Daniela Gois Beghini
- Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Rio de Janeiro, Brazil
| | | | - Samuel Iwao Horita
- Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Rio de Janeiro, Brazil
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Karakaş N, Üçüncüoğlu S, Uludağ D, Karaoğlan BS, Shah K, Öztürk G. Mesenchymal Stem Cell-Based COVID-19 Therapy: Bioengineering Perspectives. Cells 2022; 11:465. [PMID: 35159275 PMCID: PMC8834073 DOI: 10.3390/cells11030465] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/18/2021] [Accepted: 12/22/2021] [Indexed: 02/06/2023] Open
Abstract
The novel pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). Mesenchymal stem cells (MSCs) are currently utilized in clinics for pulmonary inflammatory diseases, including acute respiratory distress syndrome and acute lung injury. Given that MSCs offer a promising treatment against COVID-19, they are being used against COVID-19 in more than 70 clinical trials with promising findings. Genetically engineered MSCs offer promising therapeutic options in pulmonary diseases. However, their potential has not been explored yet. In this review, we provide perspectives on the functionally modified MSCs that can be developed and harnessed for COVID-19 therapy. Options to manage the SARS-CoV-2 infection and its variants using various bioengineering tools to increase the therapeutic efficacy of MSCs are highlighted.
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Affiliation(s)
- Nihal Karakaş
- Department of Medical Biology, School of Medicine, İstanbul Medipol University, İstanbul 34810, Turkey
- Regenerative and Restorative Medicine Research Center (REMER), Institute for Health Sciences and Technologies (SABITA), İstanbul Medipol University, İstanbul 34810, Turkey; (S.Ü.); (D.U.); (B.S.K.); (G.Ö.)
| | - Süleyman Üçüncüoğlu
- Regenerative and Restorative Medicine Research Center (REMER), Institute for Health Sciences and Technologies (SABITA), İstanbul Medipol University, İstanbul 34810, Turkey; (S.Ü.); (D.U.); (B.S.K.); (G.Ö.)
- Department of Biophysics, International School of Medicine, İstanbul Medipol University, İstanbul 34810, Turkey
| | - Damla Uludağ
- Regenerative and Restorative Medicine Research Center (REMER), Institute for Health Sciences and Technologies (SABITA), İstanbul Medipol University, İstanbul 34810, Turkey; (S.Ü.); (D.U.); (B.S.K.); (G.Ö.)
- Graduate School for Health Sciences, Medical Biology and Genetics Program, İstanbul Medipol University, İstanbul 34810, Turkey
| | - Birnur Sinem Karaoğlan
- Regenerative and Restorative Medicine Research Center (REMER), Institute for Health Sciences and Technologies (SABITA), İstanbul Medipol University, İstanbul 34810, Turkey; (S.Ü.); (D.U.); (B.S.K.); (G.Ö.)
| | - Khalid Shah
- Center for Stem Cell and Translational Immunotherapies, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02114, USA;
| | - Gürkan Öztürk
- Regenerative and Restorative Medicine Research Center (REMER), Institute for Health Sciences and Technologies (SABITA), İstanbul Medipol University, İstanbul 34810, Turkey; (S.Ü.); (D.U.); (B.S.K.); (G.Ö.)
- Department of Physiology, International School of Medicine, İstanbul Medipol University, İstanbul 34810, Turkey
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Wu Z, Zhang R, Liu D, Liu X, Zhang J, Zhang Z, Chen S, He W, Li Y, Xu Y, Liu X. Acute Respiratory Distress Syndrome Caused by Human Adenovirus in Adults: A Prospective Observational Study in Guangdong, China. Front Med (Lausanne) 2022; 8:791163. [PMID: 35155471 PMCID: PMC8829445 DOI: 10.3389/fmed.2021.791163] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 12/23/2021] [Indexed: 12/12/2022] Open
Abstract
BackgroundViral causes of acute respiratory distress syndrome (ARDS) are mostly limited to influenza. However, adenovirus has been emerging as a cause of ARDS with a high mortality rate and described in adults are rare.MethodsWe conducted a prospective, single-center observational study of viral pneumonia with ARDS and confirmed adenovirus-associated ARDS in adults at our quaternary referral institution between March 2019 and June 2020. We prospectively analyzed clinical characteristics, laboratory test results, radiological characteristics, viral load from nasopharyngeal swabs and endotracheal aspirates, treatments, and outcomes for the study participants.ResultsThe study enrolled 143 ARDS patients, including 47 patients with viral pneumonia-related ARDS, among which there were 14 adenovirus-associated ARDS patients, which accounted for 29.79% of the viral pneumonia-related ARDS cases. Among the adenovirus-associated ARDS patients, 78.57% were men with a mean age of 54.93 ± 19.04 years, younger than that of the non-adenovirus associated ARDS patients. Adenovirus-associated ARDS patients had no specific clinical characteristics, but they presented with decrease in the number of CD3+CD4+ T cells and higher serum creatinine during the early stage. The viral load and the positivity rate in the lower respiratory tract were higher than that of the upper respiratory tract in the patients with adenovirus-associated ARDS. All patients required invasive mechanical ventilation treatment. The average time from shortness of breath to the application of invasive ventilation was 24 h. Ten patients (71.43%) complicated by acute kidney injury, while 13 patients (71.43%) in the non-adenovirus associated ARDS group (P = 0.045). Additionally, 85.71% of the 14 adenovirus-associated ARDS patients survived. No significant differences were detected between the two groups regarding duration of ventilation, length of ICU stay and mortality.ConclusionAdenovirus infection is an important cause of virus-related ARDS. The positivity rate of adenovirus infection in lower respiratory tract secretions was higher than that in upper respiratory tract secretions in these patients. Age, lower CD3+CD4+ T cells, and high serum creatinine may be were associated with adenovirus induce ARDS in adults required mechanical ventilation. Early identification and intervention to prevent disease progression are essential for reducing the mortality rate in these patients.
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Jawahar M, Prassanna J, Ravi V, Anbarasi LJ, Jasmine SG, Manikandan R, Sekaran R, Kannan S. Computer-aided diagnosis of COVID-19 from chest X-ray images using histogram-oriented gradient features and Random Forest classifier. MULTIMEDIA TOOLS AND APPLICATIONS 2022; 81:40451-40468. [PMID: 35572385 PMCID: PMC9090123 DOI: 10.1007/s11042-022-13183-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 01/30/2022] [Accepted: 04/28/2022] [Indexed: 05/13/2023]
Abstract
The decision-making process is very crucial in healthcare, which includes quick diagnostic methods to monitor and prevent the COVID-19 pandemic disease from spreading. Computed tomography (CT) is a diagnostic tool used by radiologists to treat COVID patients. COVID x-ray images have inherent texture variations and similarity to other diseases like pneumonia. Manually diagnosing COVID X-ray images is a tedious and challenging process. Extracting the discriminant features and fine-tuning the classifiers using low-resolution images with a limited COVID x-ray dataset is a major challenge in computer aided diagnosis. The present work addresses this issue by proposing and implementing Histogram Oriented Gradient (HOG) features trained with an optimized Random Forest (RF) classifier. The proposed HOG feature extraction method is evaluated with Gray-Level Co-Occurrence Matrix (GLCM) and Hu moments. Results confirm that HOG is found to reflect the local description of edges effectively and provide excellent structural features to discriminate COVID and non-COVID when compared to the other feature extraction techniques. The performance of the RF is compared with other classifiers such as Linear Regression (LR), Linear Discriminant Analysis (LDA), K-nearest neighbor (kNN), Classification and Regression Trees (CART), Random Forest (RF), Support Vector Machine (SVM), and Multi-layer perceptron neural network (MLP). Experimental results show that the highest classification accuracy (99. 73%) is achieved using HOG trained by using the Random Forest (RF) classifier. The proposed work has provided promising results to assist radiologists/physicians in automatic COVID diagnosis using X-ray images.
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Affiliation(s)
- Malathy Jawahar
- Leather Process Technology Division, CSIR-Central Leather Research Institute, Adyar, Chennai, 600020 India
| | - J. Prassanna
- School of Computer Science and Engineering, Vellore Institute of Technology, 600 127 Chennai, India
| | - Vinayakumar Ravi
- Center for Artificial Intelligence, Prince Mohammad Bin Fahd University, Khobar, Saudi Arabia
| | - L. Jani Anbarasi
- School of Computer Science and Engineering, Vellore Institute of Technology, 600 127 Chennai, India
| | - S. Graceline Jasmine
- School of Computer Science and Engineering, Vellore Institute of Technology, 600 127 Chennai, India
| | - R. Manikandan
- School of Computing, SASTRA Deemed University, Thanjavur, India
| | - Ramesh Sekaran
- Department of Information Technology, Velgapudi Ramakrishna Siddhartha Engineering College, Vijayawada, India
| | - Suthendran Kannan
- Department of Information Technology, Kalasalingam Academy of Research and Education, Srivilliputhur, India
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Taechangam N, Kol A, Arzi B, Borjesson DL. Multipotent Stromal Cells and Viral Interaction: Current Implications for Therapy. Stem Cell Rev Rep 2022; 18:214-227. [PMID: 34347271 PMCID: PMC8335712 DOI: 10.1007/s12015-021-10224-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/19/2021] [Indexed: 12/29/2022]
Abstract
Multipotent stromal cells (MSCs) are widely utilized in therapy for their immunomodulatory properties, but their usage in infectious viral diseases is less explored. This review aimed to collate the current novel use of MSCs in virus-associated conditions, including MSC's susceptibility to virus infection, antiviral properties of MSCs and their effects on cell-based immune response and implementation of MSC therapy in animal models and human clinical trials of viral diseases. Recent discoveries shed lights on MSC's capability in suppressing viral replication and augmenting clearance through enhancement of antiviral immunity. MSC therapy may maintain a crucial balance between aiding pathogen clearance and suppressing hyperactive immune response.
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Affiliation(s)
- Nopmanee Taechangam
- Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, CA USA
| | - Amir Kol
- Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, CA USA
| | - Boaz Arzi
- Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, Davis, CA USA
| | - Dori L. Borjesson
- Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, CA USA
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Gupta SD, Nandy M, Song DG, Pan CH. Present therapeutic and diagnostic approaches for SARS-CoV-2 infection. COMPUTATIONAL APPROACHES FOR NOVEL THERAPEUTIC AND DIAGNOSTIC DESIGNING TO MITIGATE SARS-COV-2 INFECTION 2022. [PMCID: PMC9300475 DOI: 10.1016/b978-0-323-91172-6.00025-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The novel Coronavirus (nCoV), severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2), has shaken the whole world and posed significant challenges to the global healthcare system for more than a year. The scientific community across the globe is trying to combat this virus by developing a safe vaccine that can provide long-term immunity against the virus. The other means of overcoming its pathogenicity is to treat the infected people with available drugs and/or novel therapeutic strategies. The available drugs were previously designed to combat viral infections and come with tested safety. This appears to be the most practical approach as a quick response to the highly infectious pandemic with high morbidity and mortality. Although many repurposed drugs like favipiravir and hydroxychloroquine have been tried, they have been proven toxic and/or less efficacious. This has led the world to find urgent therapeutic interventions (traditional and novel), to help decrease the severity of COVID-19 infection and aim towards recovery. This chapter of the book will discuss the most up-to-date published data with respect to prevention and treatment of COVID-19 infection. Diagnosis also plays an important part in controlling the pandemic caused by the virus. A cheap, accurate and fast identification test for the virus is the need of the hour. This chapter will also throw light on the various diagnostic procedures available for the identification of SARS-CoV-2, till date, along with their advantages and disadvantages.
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Masterson CH, Ceccato A, Artigas A, Dos Santos C, Rocco PR, Rolandsson Enes S, Weiss DJ, McAuley D, Matthay MA, English K, Curley GF, Laffey JG. Mesenchymal stem/stromal cell-based therapies for severe viral pneumonia: therapeutic potential and challenges. Intensive Care Med Exp 2021; 9:61. [PMID: 34970706 PMCID: PMC8718182 DOI: 10.1186/s40635-021-00424-5] [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: 10/11/2021] [Accepted: 11/21/2021] [Indexed: 12/15/2022] Open
Abstract
Severe viral pneumonia is a significant cause of morbidity and mortality globally, whether due to outbreaks of endemic viruses, periodic viral epidemics, or the rarer but devastating global viral pandemics. While limited anti-viral therapies exist, there is a paucity of direct therapies to directly attenuate viral pneumonia-induced lung injury, and management therefore remains largely supportive. Mesenchymal stromal/stem cells (MSCs) are receiving considerable attention as a cytotherapeutic for viral pneumonia. Several properties of MSCs position them as a promising therapeutic strategy for viral pneumonia-induced lung injury as demonstrated in pre-clinical studies in relevant models. More recently, early phase clinical studies have demonstrated a reassuring safety profile of these cells. These investigations have taken on an added importance and urgency during the COVID-19 pandemic, with multiple trials in progress across the globe. In parallel with clinical translation, strategies are being investigated to enhance the therapeutic potential of these cells in vivo, with different MSC tissue sources, specific cellular products including cell-free options, and strategies to ‘licence’ or ‘pre-activate’ these cells, all being explored. This review will assess the therapeutic potential of MSC-based therapies for severe viral pneumonia. It will describe the aetiology and epidemiology of severe viral pneumonia, describe current therapeutic approaches, and examine the data suggesting therapeutic potential of MSCs for severe viral pneumonia in pre-clinical and clinical studies. The challenges and opportunities for MSC-based therapies will then be considered.
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Affiliation(s)
- C H Masterson
- Anaesthesia, School of Medicine, National University of Ireland, Galway, Ireland.,Regenerative Medicine Institute, National University of Ireland, Galway, Ireland
| | - A Ceccato
- Intensive Care Unit, Hospital Universitari Sagrat Cor, Barcelona, Spain.,CIBER de Enfermedades Respiratorias (CIBERES), Sabbadell, Spain
| | - A Artigas
- CIBER de Enfermedades Respiratorias (CIBERES), Sabbadell, Spain.,Critical Center, Corporacion Sanitaria Universitaria Parc Tauli, Autonomous University of Barcelona, Sabadell, Spain
| | - C Dos Santos
- Keenan Center for Biomedical Research, St. Michael's Hospital, Bond St, Toronto, Canada.,Interdepartmental Division of Critical Care Medicine and Institutes of Medical Sciences, University of Toronto, Toronto, Canada
| | - P R Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.,National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil
| | - S Rolandsson Enes
- Department of Experimental Medical Science, Faculty of Medicine, Lund University, Lund, Sweden
| | - D J Weiss
- Department of Medicine, University of Vermont College of Medicine, Burlington, VT, 05405, USA
| | - D McAuley
- Regional Intensive Care Unit, Royal Victoria Hospital, Belfast, UK.,Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK
| | - M A Matthay
- Department of Medicine and Anesthesia, University of California, San Francisco, CA, USA.,Cardiovascular Research Institute, University of California, San Francisco, CA, USA
| | - K English
- Department of Biology, Maynooth University, Maynooth, Co. Kildare, Ireland.,Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Co. Kildare, Ireland
| | - G F Curley
- Anaesthesia, School of Medicine, Royal College of Surgeons in Ireland, Dublin 9, Ireland
| | - J G Laffey
- Anaesthesia, School of Medicine, National University of Ireland, Galway, Ireland. .,Regenerative Medicine Institute, National University of Ireland, Galway, Ireland. .,Department of Anaesthesia and Intensive Care Medicine, Galway University Hospitals, Saolta University Hospital Group, Galway, Ireland.
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Zheng ZX. Stem cell therapy: A promising treatment for COVID-19. World J Clin Cases 2021; 9:11148-11155. [PMID: 35071545 PMCID: PMC8717529 DOI: 10.12998/wjcc.v9.i36.11148] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 05/12/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
Novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. SARS-CoV-2 is an RNA virus and has a glycosylated spike (S) protein used for genome encoding. COVID-19 can lead to a cytokine storm and patients usually have early respiratory signs and further secondary infections, which can be fatal. COVID-19 has entered an emergency phase, but there are still no specific effective drugs for this disease. Mesenchymal stem cells (MSCs) are multipotent stromal cells, which cause antiapoptosis and can repair damaged epithelial cells. Many clinical trials have proved that MSC therapy could be a potential feasible therapy for COVID-19 patients, especially those with acute respiratory distress syndrome, without serious adverse events or toxicities. However, more studies are needed in the future, in order to confirm the effect of this therapy.
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Affiliation(s)
- Zhi-Xue Zheng
- Department of General Surgery, Beijing Jishuitan Hospital, Beijing 100035, China
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Ardalan M, Chodari L, Zununi Vahed S, Hosseiniyan Khatibi SM, Eftekhari A, Davaran S, Cucchiarini M, Roshangar L, Ahmadian E. Stem cell-derived biofactors fight against coronavirus infection. World J Stem Cells 2021; 13:1813-1825. [PMID: 35069984 PMCID: PMC8727231 DOI: 10.4252/wjsc.v13.i12.1813] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 04/12/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023] Open
Abstract
Despite various treatment protocols and newly recognized therapeutics, there are no effective treatment approaches against coronavirus disease. New therapeutic strategies including the use of stem cells-derived secretome as a cell-free therapy have been recommended for patients with critical illness. The pro-regenerative, pro-angiogenic, anti-inflammatory, anti-apoptotic, immunomodulatory, and trophic properties of stem cells-derived secretome, extracellular vesicles (EVs), and bioactive factors have made them suitable candidates for respiratory tract regeneration in coronavirus disease 2019 (COVID-19) patients. EVs including microvesicles and exosomes can be applied for communication at the intercellular level due to their abilities in the long-distance transfer of biological messages such as mRNAs, growth factors, transcription factors, microRNAs, and cytokines, and therefore, simulate the specifications of the parent cell, influencing target cells upon internalization and/or binding. EVs exhibit both anti-inflammatory and tolerogenic immune responses by regulation of proliferation, polarization, activation, and migration of different immune cells. Due to effective immunomodulatory and high safety including a minimum risk of immunogenicity and tumorigenicity, mesenchymal stem cell (MSC)-EVs are more preferable to MSC-based therapies. Thus, as an endogenous repair and inflammation-reducing agent, MSC-EVs could be used against COVID-19 induced morbidity and mortality after further mechanistic and preclinical/clinical investigations. This review is focused on the therapeutic perspective of the secretome of stem cells in alleviating the cytokine storm and organ injury in COVID-19 patients.
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Affiliation(s)
- Mohammadreza Ardalan
- Kidney Research Center, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran
| | - Leila Chodari
- Physiology Department, Faculty of Medicine, Urmia University of Medical Sciences, Urmia 5715799313, Iran
| | - Sepideh Zununi Vahed
- Kidney Research Center, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran
| | | | - Aziz Eftekhari
- Department of Toxicology, Maragheh University of Medical Sciences, Maragheh 3453554, Iran
| | - Soodabeh Davaran
- Department of Medicinal Chemistry, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran
| | - Magali Cucchiarini
- Center of Experimental Orthopaedics, Saarland University Medical Center, Homburg D-66421, Germany
| | - Leila Roshangar
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran
| | - Elham Ahmadian
- Kidney Research Center, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran.
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Shi L, Yuan X, Yao W, Wang S, Zhang C, Zhang B, Song J, Huang L, Xu Z, Fu JL, Li Y, Xu R, Li TT, Dong J, Cai J, Li G, Xie Y, Shi M, Li Y, Zhang Y, Xie WF, Wang FS. Human mesenchymal stem cells treatment for severe COVID-19: 1-year follow-up results of a randomized, double-blind, placebo-controlled trial. EBioMedicine 2021; 75:103789. [PMID: 34963099 PMCID: PMC8709782 DOI: 10.1016/j.ebiom.2021.103789] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 12/15/2021] [Accepted: 12/16/2021] [Indexed: 02/07/2023] Open
Abstract
Background The long-term consequences of human umbilical cord-derived mesenchymal stem cell (UC-MSC) treatment for COVID-19 patients are yet to be reported. This study assessed the 1-year outcomes in patients with severe COVID-19, who were recruited in our previous UC-MSC clinical trial. Methods In this prospective, longitudinal, cohort study, 100 patients enrolled in our phase 2 trial were prospectively followed up at 3-month intervals for 1 year to evaluate the long-term safety and effectiveness of UC-MSC treatment. The primary endpoint was an altered proportion of whole-lung lesion volumes measured by high-resolution CT. Other imaging outcomes, 6 min walking distance (6-MWD), lung function, plasma biomarkers, and adverse events were also recorded and analyzed. This trial was registered with ClinicalTrials.gov (NCT04288102). Findings MSC administration improved in whole-lung lesion volume compared with the placebo with a difference of −10.8% (95% CI: −20.7%, −1.5%, p = 0.030) on day 10. MSC also reduced the proportion of solid component lesion volume compared with the placebo at each follow-up point. More interestingly, 17.9% (10/56) of patients in the MSC group had normal CT images at month 12, but none in the placebo group (p = 0.013). The incidence of symptoms was lower in the MSC group than in the placebo group at each follow-up time. Neutralizing antibodies were all positive, with a similar median inhibition rate (61.6% vs. 67.6%) in both groups at month 12. No difference in adverse events at the 1-year follow-up and tumor markers at month 12 were observed between the two groups. Interpretation UC-MSC administration achieves a long-term benefit in the recovery of lung lesions and symptoms in COVID-19 patients. Funding The National Key R&D Program of China, the Innovation Groups of the National Natural Science Foundation of China, and the National Science and Technology Major Project.
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Affiliation(s)
- Lei Shi
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, No.100 Western 4th Ring Road, Beijing 100039, China; Wuhan Huoshenshan Hospital, Wuhan, China
| | - Xin Yuan
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, No.100 Western 4th Ring Road, Beijing 100039, China; Wuhan Huoshenshan Hospital, Wuhan, China
| | - Weiqi Yao
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; National Industrial Base for Stem Cell Engineering Products, Tianjin, China
| | - Siyu Wang
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, No.100 Western 4th Ring Road, Beijing 100039, China
| | - Chao Zhang
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, No.100 Western 4th Ring Road, Beijing 100039, China; Wuhan Huoshenshan Hospital, Wuhan, China
| | - Bo Zhang
- Department of Infectious Disease, General Hospital of Central Theater Command, Wuhan, China
| | - Jinwen Song
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, No.100 Western 4th Ring Road, Beijing 100039, China; Wuhan Huoshenshan Hospital, Wuhan, China
| | - Lei Huang
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, No.100 Western 4th Ring Road, Beijing 100039, China; Wuhan Huoshenshan Hospital, Wuhan, China
| | - Zhe Xu
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, No.100 Western 4th Ring Road, Beijing 100039, China; Wuhan Huoshenshan Hospital, Wuhan, China
| | - Jun-Liang Fu
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, No.100 Western 4th Ring Road, Beijing 100039, China; Wuhan Huoshenshan Hospital, Wuhan, China
| | - Yuanyuan Li
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, No.100 Western 4th Ring Road, Beijing 100039, China
| | - Ruonan Xu
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, No.100 Western 4th Ring Road, Beijing 100039, China
| | - Tian-Tian Li
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, No.100 Western 4th Ring Road, Beijing 100039, China; The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Jinghui Dong
- Department of Radiology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Jianming Cai
- Department of Radiology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Genshi Li
- Wuhan Kingmed Center for Clinical Laboratory Co., Ltd., Wuhan, China
| | - Yunbo Xie
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, No.100 Western 4th Ring Road, Beijing 100039, China
| | - Ming Shi
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, No.100 Western 4th Ring Road, Beijing 100039, China
| | - Yonggang Li
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, No.100 Western 4th Ring Road, Beijing 100039, China
| | - Yu Zhang
- National Industrial Base for Stem Cell Engineering Products, Tianjin, China; VCANBIO Cell&Gene Engineering Corp., Ltd., Tianjin, China
| | - Wei-Fen Xie
- Department of Gastroenterology, Changzheng Hospital, Naval Medical University, 415 Fengyang Road, Shanghai, 200003, China; Optical Valley Branch of Maternal and Child Hospital of Hubei Province, Wuhan, China.
| | - Fu-Sheng Wang
- Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, No.100 Western 4th Ring Road, Beijing 100039, China; Wuhan Huoshenshan Hospital, Wuhan, China.
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