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Bonfield TL, Lazarus HM. Human mesenchymal stem cell therapy: Potential advances for reducing cystic fibrosis infection and organ inflammation. Best Pract Res Clin Haematol 2025; 38:101602. [PMID: 40274338 DOI: 10.1016/j.beha.2025.101602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 02/11/2025] [Accepted: 03/04/2025] [Indexed: 04/26/2025]
Abstract
Innovation in cystic fibrosis (CF) supportive care, including implementing new antimicrobial agents, improved physiotherapy, and highly effective modulators therapy, has advanced patient survival into the 4th and 5th decades of life. However, even with these remarkable improvements in therapy, CF patients continue to suffer from pulmonary infection and other visceral organ complications associated with long-term deficient cystic fibrosis transmembrane conductance regulator (CFTR) expression. Human mesenchymal stem cells (MSCs) have been utilized in tissue engineering based upon their capacity to provide structural components of mesenchymal tissues. An alternative role of MSCs, however is their versatile utilization as cell-based infusion powerhouses due to the unique capacity to deliver milieu specific soluble biologic factors, promoting immune supportive antimicrobial and anti-inflammatory potency. MSCs derived from umbilical cord blood, bone marrow, adipose and other tissues can be expanded in ex vivo using good manufacturing procedure facilities for a safe, unique therapeutic to reduce and limit CF infection and facilitate the resolution of multi-organ inflammation. In our efforts, we conducted extensive preclinical development and validation of an allogeneic derived bone marrow derived MSC product in preparation for a clinical trial in CF. In this process, potency models were developed to ensure the functional capacity of the MSC product to provide clinical benefit. In vitro, murine in vivo and patient tissue ex vivo potency models were utilized to follow MSC anti-infective and anti-inflammatory potency associated with the CFTR deficient environment. We showed in our "First in CF" clinical trial that the allogeneic MSCs obtained from healthy volunteer bone marrow samples were safe. The advent of improved CF care measures and exciting new small molecules has changed the survival and morbidity phenotype of patients with CF, however, there are CF patients who cannot tolerate or have genotypes that are non-responsive to modulators. Additionally, even with the small molecule therapy, CF patients are living longer, but without genetic correction, with the CF disease manifestation aggravated by the continuance of pre-existing CFTR-associated clinical issues such as ongoing inflammation. MSCs secrete bio-active factors that enhance and protect tissue function and can promote "self-immune" regulation. These properties can provide therapeutic support for the traditional and changing face of CF disease clinical complications. Further, MSC-derived bio-active factors can directly mitigate colonizing pathogens' survival by producing antimicrobial peptides (AMPs) which change the pathogen surface and increase host recognition, elimination, and sensitivity to antibiotics. Herein, we review the potential of MSC therapeutics for treating many facets of CF, emphasizing the potential for providing great additive therapeutics for managing morbidity and quality of life.
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Affiliation(s)
- Tracey L Bonfield
- Genetics and Genome Sciences, National Center for Regenerative Medicine, Pediatrics and Pathology, Case Western Reserve University, Cleveland, Ohio, 44106, USA.
| | - Hillard M Lazarus
- Department of Medicine, Hematology and National Center for Regenerative Medicine, Case Western Reserve University, Cleveland, Ohio, 44106, USA
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Lai S, Guo Z. Stem cell therapies for chronic obstructive pulmonary disease: mesenchymal stem cells as a promising treatment option. Stem Cell Res Ther 2024; 15:312. [PMID: 39300523 DOI: 10.1186/s13287-024-03940-9] [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: 04/28/2024] [Accepted: 09/16/2024] [Indexed: 09/22/2024] Open
Abstract
Chronic obstructive pulmonary disease(COPD) is an inflammatory disease characterized by the progressive and irreversible structural and functional damage of lung tissue. Although COPD is a significant global disease burden, the available treatments only ameliorate the symptoms, but cannot reverse lung damage. Researchers in regenerative medicine have examined the use of stem cell transplantation for treatment of COPD and other diseases because these cells have the potential for unlimited self-renewal and the ability to undergo directed differentiation. Stem cells are typically classified as embryonic stem cells, induced pluripotent stem cells, and adult stem cells (which includes mesenchymal stem cells [MSCs]), each with its own advantages and disadvantages regarding applications in regenerative medicine. Although the heterogeneity and susceptibility to senescence of MSCs make them require careful consideration for clinical applications. However, the low tumourigenicity and minimal ethical concerns of MSCs make them appear to be excellent candidates. This review summarizes the characteristics of various stem cell types and describes their therapeutic potential in the treatment of COPD, with a particular emphasis on MSCs. We aim to facilitate subsequent in-depth research and preclinical applications of MSCs by providing a comprehensive overview.
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Affiliation(s)
- Sumei Lai
- Stem Cell Laboratory, Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China.
| | - Zhifeng Guo
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
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Hu J, Wang N, Jiang Y, Li Y, Qin B, Wang Z, Gao L. BMSCs promote alveolar epithelial cell autophagy to reduce pulmonary fibrosis by inhibiting core fucosylation modifications. Stem Cells 2024; 42:809-820. [PMID: 38982795 DOI: 10.1093/stmcls/sxae044] [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: 01/21/2024] [Accepted: 06/06/2024] [Indexed: 07/11/2024]
Abstract
BACKGROUND Idiopathic pulmonary fibrosis (PF) is a chronic progressive interstitial lung disease characterized by alveolar epithelial cell (AEC) injury and fibroblast activation. Inadequate autophagy in AECs may result from the activation of several signaling pathways following AEC injury, with glycoproteins serving as key receptor proteins. The core fucosylation (CF) modification in glycoproteins is crucial. Mesenchymal stem cells derived from bone marrow (BMSCs) have the ability to regenerate damaged tissue and treat PF. This study aimed to elucidate the relationship and mechanism of interaction between BMSCs, CF modification, and autophagy in PF. METHODS C57BL/6 male mice, AEC-specific FUT8 conditional knockout (CKO) mice, and MLE12 cells were administered bleomycin (BLM), FUT8 siRNA, and mouse BMSCs, respectively. Experimental techniques including tissue staining, Western blotting, immunofluorescence, autophagic flux detection, and flow cytometry were used in this study. RESULTS First, we found that autophagy was inhibited while FUT8 expression was elevated in PF mice and BLM-induced AEC injury models. Subsequently, CKO mice and MLE12 cells transfected with FUT8 siRNA were used to demonstrate that inhibition of CF modification induces autophagy in AECs and mitigates PF. Finally, mouse BMSCs were used to demonstrate that they alleviate the detrimental autophagy of AECs by inhibiting CF modification and decreasing PF. CONCLUSIONS Suppression of CF modification enhanced the suppression of AEC autophagy and reduced PF in mice. Additionally, through the prevention of CF modification, BMSCs can assist AECs deficient in autophagy and partially alleviate PF.
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Affiliation(s)
- Jinying Hu
- Department of Respiratory Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, People's Republic of China
| | - Nan Wang
- Department of Respiratory Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, People's Republic of China
| | - Yu Jiang
- Department of Respiratory Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, People's Republic of China
| | - Yina Li
- Department of Respiratory Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, People's Republic of China
| | - Biaojie Qin
- Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, People's Republic of China
| | - Zhongzhen Wang
- Department of Cardiology, Institute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, People's Republic of China
| | - Lili Gao
- Department of Respiratory Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, People's Republic of China
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Wei S, Li M, Wang Q, Zhao Y, Du F, Chen Y, Deng S, Shen J, Wu K, Yang J, Sun Y, Gu L, Li X, Li W, Chen M, Ling X, Yu L, Xiao Z, Dong L, Wu X. Mesenchymal Stromal Cells: New Generation Treatment of Inflammatory Bowel Disease. J Inflamm Res 2024; 17:3307-3334. [PMID: 38800593 PMCID: PMC11128225 DOI: 10.2147/jir.s458103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 05/09/2024] [Indexed: 05/29/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract, which has a high recurrence rate and is incurable due to a lack of effective treatment. Mesenchymal stromal cells (MSCs) are a class of pluripotent stem cells that have recently received a lot of attention due to their strong self-renewal ability and immunomodulatory effects, and a large number of experimental and clinical models have confirmed the positive therapeutic effect of MSCs on IBD. In preclinical studies, MSC treatment for IBD relies on MSCs paracrine effects, cell-to-cell contact, and its mediated mitochondrial transfer for immune regulation. It also plays a therapeutic role in restoring the intestinal mucosal barrier through the homing effect, regulation of the intestinal microbiome, and repair of intestinal epithelial cells. In the latest clinical trials, the safety and efficacy of MSCs in the treatment of IBD have been confirmed by transfusion of autologous or allogeneic bone marrow, umbilical cord, and adipose MSCs, as well as their derived extracellular vesicles. However, regarding the stable and effective clinical use of MSCs, several concerns emerge, including the cell sources, clinical management (dose, route and frequency of administration, and pretreatment of MSCs) and adverse reactions. This article comprehensively summarizes the effects and mechanisms of MSCs in the treatment of IBD and its advantages over conventional drugs, as well as the latest clinical trial progress of MSCs in the treatment of IBD. The current challenges and future directions are also discussed. This review would add knowledge into the understanding of IBD treatment by applying MSCs.
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Affiliation(s)
- Shulin Wei
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Mingxing Li
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Qin Wang
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Yueshui Zhao
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Fukuan Du
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Yu Chen
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Shuai Deng
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Jing Shen
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Ke Wu
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Jiayue Yang
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Yuhong Sun
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Li Gu
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Xiaobing Li
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Wanping Li
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Meijuan Chen
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Xiao Ling
- Department of Obstetrics, Luzhou Maternal & Child Health Hospital (Luzhou Second People’s Hospital), Luzhou, Sichuan, 646100, People’s Republic of China
| | - Lei Yu
- Department of Obstetrics, Luzhou Maternal & Child Health Hospital (Luzhou Second People’s Hospital), Luzhou, Sichuan, 646100, People’s Republic of China
| | - Zhangang Xiao
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Lishu Dong
- Department of Obstetrics, Luzhou Maternal & Child Health Hospital (Luzhou Second People’s Hospital), Luzhou, Sichuan, 646100, People’s Republic of China
| | - Xu Wu
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
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Vizoso FJ, Costa LA, Eiro N. New era of mesenchymal stem cell-based medicine: basis, challenges and prospects. Rev Clin Esp 2023; 223:619-628. [PMID: 38000623 DOI: 10.1016/j.rceng.2023.11.002] [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: 09/21/2023] [Accepted: 10/25/2023] [Indexed: 11/26/2023]
Abstract
Stem cells of mesenchymal origin (MSC) arouse special interest due to their regenerative, anti-inflammatory, anti-apoptotic, anti-oxidative stress, antitumor or antimicrobial properties. However, its implementation in the clinic runs into drawbacks of cell therapy (immunological incompatibility, tumor formation, possible transmission of infections, entry into cellular senescence, difficult evaluation of safety, dose and potency; complex storage conditions, high economic cost or impractical clinical use). Considering that the positive effects of MSC are due, to a large extent, to the paracrine effects mediated by the set of substances they secrete (growth factors, cytokines, chemokines or microvesicles), the in vitro obtaining of these biological products makes possible a medicine cell-free regenerative therapy without the drawbacks of cell therapy. However, this new therapeutic innovation implies challenges, such as the recognition of the biological heterogeneity of MSC and the optimization and standardization of their secretome.
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Affiliation(s)
- F J Vizoso
- Unidad de Investigación, Fundación Hospital de Jove, Gijón, Spain; Servicio de Cirugía, Fundación Hospital de Jove, Gijón, Spain.
| | - L A Costa
- Unidad de Investigación, Fundación Hospital de Jove, Gijón, Spain
| | - N Eiro
- Unidad de Investigación, Fundación Hospital de Jove, Gijón, Spain.
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Jiménez MF, Gómez-Hernández MT, Villarón EM, López-Parra M, Sánchez-Guijo F. Autologous mesenchymal stromal cells embedded with Tissucol Duo ® for prevention of air leak after anatomical lung resection: results of a prospective phase I/II clinical trial with long-term follow-up. Stem Cell Res Ther 2023; 14:313. [PMID: 37904229 PMCID: PMC10617222 DOI: 10.1186/s13287-023-03545-8] [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: 12/14/2022] [Accepted: 10/25/2023] [Indexed: 11/01/2023] Open
Abstract
BACKGROUND Prolonged air leak (PAL) is the most frequent complication after pulmonary resection. Several measures have been described to prevent the occurrence of PAL in high-risk patients, however, the potential role of mesenchymal stem cells (MSCs) applied in the parenchymal suture line to prevent postoperative air leak in this setting has not been fully addressed. OBJECTIVE To analyse the feasibility, safety and potential clinical efficacy of the implantation of autologous MSCs embedded in Tissucol Duo® as a prophylactic alternative to prevent postoperative prolonged air leak after pulmonary resection in high-risk patients. STUDY DESIGN Phase I/II single-arm prospective clinical trial. METHODS Six patients with high risk of PAL undergoing elective pulmonary resection were included. Autologous bone marrow-derived MSCs were expanded at our Good Manufacturing Practice (GMP) Facility and implanted (embedded in a Tissucol Duo® carrier) in the parenchymal suture line during pulmonary resection surgery. Patients were monitored in the early postoperative period and evaluated for possible complications or adverse reactions. In addition, all patients were followed-up to 5 years for clinical outcomes. RESULTS The median age of patients included was 66 years (range: 55-70 years), and male/female ratio was 5/1. Autologous MSCs were expanded in five cases, in one case MSCs expansion was insufficient. There were no adverse effects related to cell implantation. Regarding efficacy, median air leak duration was 0 days (range: 0-2 days). The incidence of PAL was nil. Radiologically, only one patient presented pneumothorax in the chest X-ray at discharge. No adverse effects related to the procedure were recorded during the follow-up. CONCLUSIONS The use of autologous MSCs for prevention of PAL in patients with high risk of PAL is feasible, safe and potentially effective. TRIAL REGISTRATION NO EudraCT: 2013-000535-27. CLINICALTRIALS gov idenfier: NCT02045745.
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Affiliation(s)
- Marcelo F Jiménez
- Service of Thoracic Surgery, Salamanca University Hospital, 37007, Salamanca, Spain
- Salamanca Institute of Biomedical Research (IBSAL), Salamanca, Spain
- University of Salamanca, Salamanca, Spain
| | - María Teresa Gómez-Hernández
- Service of Thoracic Surgery, Salamanca University Hospital, 37007, Salamanca, Spain.
- Salamanca Institute of Biomedical Research (IBSAL), Salamanca, Spain.
- University of Salamanca, Salamanca, Spain.
| | - Eva M Villarón
- Cell Therapy Area & Hematology Department, Salamanca University Hospital, Salamanca, Spain
- Network Centre for Regenerative Medicine and Cellular Therapy of Castilla y León, Salamanca, Spain
| | - Miriam López-Parra
- Cell Therapy Area & Hematology Department, Salamanca University Hospital, Salamanca, Spain
- Salamanca Institute of Biomedical Research (IBSAL), Salamanca, Spain
- Network Centre for Regenerative Medicine and Cellular Therapy of Castilla y León, Salamanca, Spain
| | - Fermín Sánchez-Guijo
- Cell Therapy Area & Hematology Department, Salamanca University Hospital, Salamanca, Spain
- Salamanca Institute of Biomedical Research (IBSAL), Salamanca, Spain
- University of Salamanca, Salamanca, Spain
- Network Centre for Regenerative Medicine and Cellular Therapy of Castilla y León, Salamanca, Spain
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Martínez-Zarco BA, Jiménez-García MG, Tirado R, Ambrosio J, Hernández-Mendoza L. [Mesenchymal stem cells: Therapeutic option in ARDS, COPD, and COVID-19 patients]. REVISTA ALERGIA MÉXICO 2023; 70:89-101. [PMID: 37566772 DOI: 10.29262/ram.v70i1.1149] [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: 07/15/2022] [Accepted: 03/30/2023] [Indexed: 08/13/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD) and COVID-19 have as a common characteristic the inflammatory lesion of the lung epithelium. The therapeutic options are associated with opportunistic infections, a hyperglycemic state, and adrenal involvement. Therefore, the search for new treatment strategies that reduce inflammation, and promote re-epithelialization of damaged tissue is very important. This work describes the relevant pathophysiological characteristics of these diseases and evaluates recent findings on the immunomodulatory, anti-inflammatory and regenerative effect of mesenchymal stem cells (MSC) and their therapeutic use. In Pubmed we selected the most relevant studies on the subject, published between 2003 and 2022 following the PRISMA guide. We conclude that MSCs are an important therapeutic option for regenerative treatment in COPD, ARDS, and COVID-19, because of their ability to differentiate into type II pneumocytes and maintain the size and function of lung tissue by replacing dead or damaged cells.
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Affiliation(s)
| | | | - Rocío Tirado
- Doctor en Ciencias Biomédicas, Departamento de Microbiología y Parasitología.Universidad Nacional Autónoma de México, Facultad de Medicina, Laboratorio de Biología del Citoesqueleto y Virología, Ciudad de México
| | - Javier Ambrosio
- Doctor en Ciencias Biomédicas, Departamento de Microbiología y Parasitología.Universidad Nacional Autónoma de México, Facultad de Medicina, Laboratorio de Biología del Citoesqueleto y Virología, Ciudad de México
| | - Lilian Hernández-Mendoza
- Doctor en Ciencias Biomédicas, Departamento de Microbiología y Parasitología.Universidad Nacional Autónoma de México, Facultad de Medicina, Laboratorio de Biología del Citoesqueleto y Virología, Ciudad de México.
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Miceli V, Zito G, Bulati M, Gallo A, Busà R, Iannolo G, Conaldi PG. Different priming strategies improve distinct therapeutic capabilities of mesenchymal stromal/stem cells: Potential implications for their clinical use. World J Stem Cells 2023; 15:400-420. [PMID: 37342218 PMCID: PMC10277962 DOI: 10.4252/wjsc.v15.i5.400] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 03/07/2023] [Accepted: 04/17/2023] [Indexed: 05/26/2023] Open
Abstract
Mesenchymal stromal/stem cells (MSCs) have shown significant therapeutic potential, and have therefore been extensively investigated in preclinical studies of regenerative medicine. However, while MSCs have been shown to be safe as a cellular treatment, they have usually been therapeutically ineffective in human diseases. In fact, in many clinical trials it has been shown that MSCs have moderate or poor efficacy. This inefficacy appears to be ascribable primarily to the heterogeneity of MSCs. Recently, specific priming strategies have been used to improve the therapeutic properties of MSCs. In this review, we explore the literature on the principal priming approaches used to enhance the preclinical inefficacy of MSCs. We found that different priming strategies have been used to direct the therapeutic effects of MSCs toward specific pathological processes. Particularly, while hypoxic priming can be used primarily for the treatment of acute diseases, inflammatory cytokines can be used mainly to prime MSCs in order to treat chronic immune-related disorders. The shift in approach from regeneration to inflammation implies, in MSCs, a shift in the production of functional factors that stimulate regenerative or anti-inflammatory pathways. The opportunity to fine-tune the therapeutic properties of MSCs through different priming strategies could conceivably pave the way for optimizing their therapeutic potential.
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Affiliation(s)
- Vitale Miceli
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy.
| | - Giovanni Zito
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
| | - Matteo Bulati
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
| | - Alessia Gallo
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
| | - Rosalia Busà
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
| | - Gioacchin Iannolo
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
| | - Pier Giulio Conaldi
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
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Helissey C, Cavallero S, Guitard N, Théry H, Chargari C, François S. Revolutionizing Radiotoxicity Management with Mesenchymal Stem Cells and Their Derivatives: A Focus on Radiation-Induced Cystitis. Int J Mol Sci 2023; 24:ijms24109068. [PMID: 37240415 DOI: 10.3390/ijms24109068] [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: 04/16/2023] [Revised: 05/02/2023] [Accepted: 05/17/2023] [Indexed: 05/28/2023] Open
Abstract
Although radiation therapy plays a crucial role in cancer treatment, and techniques have improved continuously, irradiation induces side effects in healthy tissue. Radiation cystitis is a potential complication following the therapeutic irradiation of pelvic cancers and negatively impacts patients' quality of life (QoL). To date, no effective treatment is available, and this toxicity remains a therapeutic challenge. In recent times, stem cell-based therapy, particularly the use of mesenchymal stem cells (MSC), has gained attention in tissue repair and regeneration due to their easy accessibility and their ability to differentiate into several tissue types, modulate the immune system and secrete substances that help nearby cells grow and heal. In this review, we will summarize the pathophysiological mechanisms of radiation-induced injury to normal tissues, including radiation cystitis (RC). We will then discuss the therapeutic potential and limitations of MSCs and their derivatives, including packaged conditioned media and extracellular vesicles, in the management of radiotoxicity and RC.
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Affiliation(s)
- Carole Helissey
- Clinical Unit Research, HIA Bégin, 69 Avenu de Paris, 94160 Saint-Mandé, France
- Department of Radiation Biological Effects, French Armed Forces Biomedical Research Institute, Place Général Valérie André, 91220 Brétigny-sur-Orge, France
| | - Sophie Cavallero
- Department of Radiation Biological Effects, French Armed Forces Biomedical Research Institute, Place Général Valérie André, 91220 Brétigny-sur-Orge, France
| | - Nathalie Guitard
- Department of Radiation Biological Effects, French Armed Forces Biomedical Research Institute, Place Général Valérie André, 91220 Brétigny-sur-Orge, France
| | - Hélène Théry
- Department of Radiation Biological Effects, French Armed Forces Biomedical Research Institute, Place Général Valérie André, 91220 Brétigny-sur-Orge, France
| | - Cyrus Chargari
- Department of Radiation Biological Effects, French Armed Forces Biomedical Research Institute, Place Général Valérie André, 91220 Brétigny-sur-Orge, France
- Department of Radiation Oncology, Pitié Salpêtrière University Hospital, 47-83 Bd de l'Hôpital, 75013 Paris, France
| | - Sabine François
- Department of Radiation Biological Effects, French Armed Forces Biomedical Research Institute, Place Général Valérie André, 91220 Brétigny-sur-Orge, France
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Wu J, Ma Y, Chen Y. Extracellular vesicles and COPD: foe or friend? J Nanobiotechnology 2023; 21:147. [PMID: 37147634 PMCID: PMC10161449 DOI: 10.1186/s12951-023-01911-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Accepted: 04/25/2023] [Indexed: 05/07/2023] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory airway disease characterized by progressive airflow limitation. The complex biological processes of COPD include protein hydrolysis tissue remodeling, innate immune inflammation, disturbed host-pathogen response, abnormal cellular phenotype conversion, and cellular senescence. Extracellular vesicles (EVs) (including apoptotic vesicles, microvesicles and exosomes), are released by almost all cell types and can be found in a variety of body fluids including blood, sputum and urine. EVs are key mediators in cell-cell communication and can be used by using their bioactive substances (DNA, RNA, miRNA, proteins and other metabolites) to enable cells in adjacent and distant tissues to perform a wide variety of functions, which in turn affect the physiological and pathological functions of the body. Thus, EVs is expected to play an important role in the pathogenesis of COPD, which in turn affects its acute exacerbations and may serve as a diagnostic marker for it. Furthermore, recent therapeutic approaches and advances have introduced EVs into the treatment of COPD, such as the modification of EVs into novel drug delivery vehicles. Here, we discuss the role of EVs from cells of different origins in the pathogenesis of COPD and explore their possible use as biomarkers in diagnosis, and finally describe their role in therapy and future prospects for their application. Graphical Abstract.
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Affiliation(s)
- Jiankang Wu
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China
| | - Yiming Ma
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China.
| | - Yan Chen
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China.
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11
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Areny-Balagueró A, Solé-Porta A, Camprubí-Rimblas M, Campaña-Duel E, Ceccato A, Roig A, Closa D, Artigas A. Bioengineered extracellular vesicles: future of precision medicine for sepsis. Intensive Care Med Exp 2023; 11:11. [PMID: 36894763 PMCID: PMC9998145 DOI: 10.1186/s40635-023-00491-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 01/01/2023] [Indexed: 03/11/2023] Open
Abstract
Sepsis is a syndromic response to infection and is frequently a final common pathway to death from many infectious diseases worldwide. The complexity and high heterogeneity of sepsis hinder the possibility to treat all patients with the same protocol, requiring personalized management. The versatility of extracellular vesicles (EVs) and their contribution to sepsis progression bring along promises for one-to-one tailoring sepsis treatment and diagnosis. In this article, we critically review the endogenous role of EVs in sepsis progression and how current advancements have improved EVs-based therapies toward their translational future clinical application, with innovative strategies to enhance EVs effect. More complex approaches, including hybrid and fully synthetic nanocarriers that mimic EVs, are also discussed. Several pre-clinical and clinical studies are examined through the review to offer a general outlook of the current and future perspectives of EV-based sepsis diagnosis and treatment.
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Affiliation(s)
- Aina Areny-Balagueró
- Institut d’Investigació i Innovació Parc Taulí (I3PT), Parc Taulí Hospital Universitari, 08208 Sabadell, Spain
- Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
| | - Anna Solé-Porta
- Institut de Ciència de Materials de Barcelona, ICMAB-CSIC, Campus UAB, 08193 Bellaterra, Spain
| | - Marta Camprubí-Rimblas
- Institut d’Investigació i Innovació Parc Taulí (I3PT), Parc Taulí Hospital Universitari, 08208 Sabadell, Spain
- Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
- Present Address: Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias, CIBERES-Instituto De Salud Carlos III, 28029 Madrid, Spain
| | - Elena Campaña-Duel
- Institut d’Investigació i Innovació Parc Taulí (I3PT), Parc Taulí Hospital Universitari, 08208 Sabadell, Spain
| | - Adrián Ceccato
- Institut d’Investigació i Innovació Parc Taulí (I3PT), Parc Taulí Hospital Universitari, 08208 Sabadell, Spain
- Present Address: Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias, CIBERES-Instituto De Salud Carlos III, 28029 Madrid, Spain
| | - Anna Roig
- Institut de Ciència de Materials de Barcelona, ICMAB-CSIC, Campus UAB, 08193 Bellaterra, Spain
| | - Daniel Closa
- Institut d’Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (IIBB-CSIC), 08036 Barcelona, Spain
| | - Antonio Artigas
- Institut d’Investigació i Innovació Parc Taulí (I3PT), Parc Taulí Hospital Universitari, 08208 Sabadell, Spain
- Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
- Present Address: Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias, CIBERES-Instituto De Salud Carlos III, 28029 Madrid, Spain
- Servei de Medicina Intensiva, Corporació Sanitària i Universitària Parc Taulí, 08208 Sabadell, Spain
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12
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Bonfield TL, Sutton MT, Fletcher DR, Reese-Koc J, Roesch EA, Lazarus HM, Chmiel JF, Caplan AI. Human Mesenchymal Stem Cell (hMSC) Donor Potency Selection for the "First in Cystic Fibrosis" Phase I Clinical Trial (CEASE-CF). Pharmaceuticals (Basel) 2023; 16:220. [PMID: 37259368 PMCID: PMC9960767 DOI: 10.3390/ph16020220] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 01/15/2023] [Accepted: 01/16/2023] [Indexed: 08/27/2023] Open
Abstract
Human Mesenchymal Stem Cell (hMSC) immunotherapy has been shown to provide both anti-inflammatory and anti-microbial effectiveness in a variety of diseases. The clinical potency of hMSCs is based upon an initial direct hMSC effect on the pro-inflammatory and anti-microbial pathophysiology as well as sustained potency through orchestrating the host immunity to optimize the resolution of infection and tissue damage. Cystic fibrosis (CF) patients suffer from a lung disease characterized by excessive inflammation and chronic infection as well as a variety of other systemic anomalies associated with the consequences of abnormal cystic fibrosis transmembrane conductance regulator (CFTR) function. The application of hMSC immunotherapy to the CF clinical armamentarium is important even in the era of modulators when patients with an established disease still need anti-inflammatory and anti-microbial therapies. Additionally, people with CF mutations not addressed by current modulator resources need anti-inflammation and anti-infection management. Furthermore, hMSCs possess dynamic therapeutic properties, but the potency of their products is highly variable with respect to their anti-inflammatory and anti-microbial effects. Due to the variability of hMSC products, we utilized standardized in vitro and in vivo models to select hMSC donor preparations with the greatest potential for clinical efficacy. The models that were used recapitulate many of the pathophysiologic outcomes associated with CF. We applied this strategy in pursuit of identifying the optimal donor to utilize for the "First in CF" Phase I clinical trial of hMSCs as an immunotherapy and anti-microbial therapy for people with cystic fibrosis. The hMSCs screened in this study demonstrated significant diversity in antimicrobial and anti-inflammatory function using models which mimic some aspects of CF infection and inflammation. However, the variability in activity between in vitro potency and in vivo effectiveness continues to be refined. Future studies require and in-depth pursuit of hMSC molecular signatures that ultimately predict the capacity of hMSCs to function in the clinical setting.
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Affiliation(s)
- Tracey L. Bonfield
- Department of Genetics and Genome Sciences, National Center Regenerative Medicine and Pediatrics, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, BRB 822, Cleveland, OH 444106, USA
- National Center for Regenerative Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 444106, USA
- Department of Pediatric Pulmonary, Rainbow Babies and Children’s Hospital, Cleveland, OH 44106, USA
| | - Morgan T. Sutton
- Department of Genetics and Genome Sciences, National Center Regenerative Medicine and Pediatrics, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, BRB 822, Cleveland, OH 444106, USA
- National Center for Regenerative Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 444106, USA
- Department of Pediatric Pulmonary, Rainbow Babies and Children’s Hospital, Cleveland, OH 44106, USA
- Saint Jude Children’s Research Hospital, Graduate School of Biomedical Sciences, Memphis, TN 38105, USA
| | - David R. Fletcher
- Department of Genetics and Genome Sciences, National Center Regenerative Medicine and Pediatrics, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, BRB 822, Cleveland, OH 444106, USA
- Department of Pediatric Pulmonary, Rainbow Babies and Children’s Hospital, Cleveland, OH 44106, USA
| | - Jane Reese-Koc
- National Center for Regenerative Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 444106, USA
- University Hospitals Seidman Cancer Center, Cleveland, OH 44106, USA
| | - Erica A. Roesch
- Department of Pediatric Pulmonary, Rainbow Babies and Children’s Hospital, Cleveland, OH 44106, USA
| | - Hillard M. Lazarus
- National Center for Regenerative Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 444106, USA
- University Hospitals Seidman Cancer Center, Cleveland, OH 44106, USA
| | - James F. Chmiel
- Department of Pediatrics, Riley Hospital for Children at IU Health, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Arnold I. Caplan
- National Center for Regenerative Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 444106, USA
- Skeletal Research Center, Department of Biology, Case Western Reserve University, Cleveland, OH 44106, USA
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13
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Mesenchyme Stem Cell-Derived Conditioned Medium as a Potential Therapeutic Tool in Idiopathic Pulmonary Fibrosis. Biomedicines 2022; 10:biomedicines10092298. [PMID: 36140399 PMCID: PMC9496127 DOI: 10.3390/biomedicines10092298] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 09/04/2022] [Accepted: 09/14/2022] [Indexed: 11/17/2022] Open
Abstract
Mesenchyme Stem Cells (MSCs) are the most used types of stem cells in regenerative medicine. Regenerative medicine is a rapidly emerging medicine section that creates new methods to regrow, restore, and replace diseased and damaged tissues, organs, and cells. Scholars have shown a positive correlation between MSCs-based therapies and successful treatment of diseases like cardiac ischemia, cartilage problems, bone diseases, diabetes, and even neurological disorders. Although MSCs have several varying features that make them unique, their immuno-regulatory effects in tissue repair emerge from their secretion of paracrine growth factors, exosomes, and cytokines. These cells secrete a secretome, which has regenerative and reparative properties that lead to injury amelioration, immune modulation, or fibrosis reduction. Recent studies have shown that the administration MCSs derived conditioned medium (MSCs-CM) in acute doses in humans is safe and well-tolerated. Studies from animal models and human clinical trials have also shown that they are efficacious tools in regenerative medicine. In this review, we will explore the therapeutic potential of MSCs-CM in pulmonary fibrosis, with further insight into the treatment of Idiopathic Pulmonary Fibrosis (IPF).
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14
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Dhar R, Mukherjee S, Mukerjee N, Mukherjee D, Devi A, Ashraf GM, Alserihi RF, Tayeb HH, Hashem AM, Alexiou A, Thorate N. Interrelation between extracellular vesicles miRNAs with chronic lung diseases. J Cell Physiol 2022; 237:4021-4036. [PMID: 36063496 DOI: 10.1002/jcp.30867] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/18/2022] [Accepted: 08/22/2022] [Indexed: 11/07/2022]
Abstract
Extracellular vehicles (EVs) are nanoscale lipid bilayer vesicles that carry biologically active biomolecule cargos like proteins, lipids, and nucleic acids (DNA, RNA) outside of the cell. Blood (serum/plasma), urine, and bronchoalveolar lavage fluid are all examples of biofluids from which they may be collected. EVs play a vital role in intracellular communication. The molecular signature of EVs largely depends on the parental cell's status. EVs are classified into two groups, (1) exosomes (originated by endogenous route) and (2) microvesicles (originated from the plasma membrane, also known as ectosomes). The quantity and types of EV cargo vary during normal conditions compared to pathological conditions (chronic inflammatory lung diseases or lung cancer). Consequently, EVs contain novel biomarkers that differ based on the cell type of origin and during lung diseases. Small RNAs (e.g., microRNAs) are transported by EVs, which is one of the most rapidly evolving research areas in the field of EVs biology. EV-mediated cargos transport small RNAs that can result in reprograming the target/recipient cells. Multiple chronic inflammatory lung illnesses, such as chronic obstructive pulmonary disease, asthma, pulmonary hypertension, pulmonary fibrosis, cystic fibrosis, acute lung injury, and lung cancer, have been demonstrated to be regulated by EV. In this review, we will consolidate the current knowledge and literature on the novel role of EVs and their small RNAs concerning chronic lung diseases (CLDs). Additionally, we will also provide better insight into the clinical and translational impact of mesenchymal stem cells-derived EVs as novel therapeutic agents in treating CLDs.
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Affiliation(s)
- Rajib Dhar
- Cancer and Stem Cell Biology Laboratory, Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India
| | - Sayantanee Mukherjee
- Centre for Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham University, Kochi, Kerala, India
| | - Nobendu Mukerjee
- Department of Microbiology, Ramakrishna Mission Vivekananda Centenary College, Kolkata, West Bengal, India.,Department of Health Sciences, Novel Global Community Educational Foundation, Hebersham, Australia
| | | | - Arikketh Devi
- Cancer and Stem Cell Biology Laboratory, Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India
| | - Ghulam Md Ashraf
- Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.,Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Raed F Alserihi
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.,Hematology Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.,Nanomedicine Unit, Center of Innovation in Personalized Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Hossam H Tayeb
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.,Nanomedicine Unit, Center of Innovation in Personalized Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.,King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Anwar M Hashem
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.,Vaccines and Immunotherapy Unit, King Fahad Medical Research Center, Jeddah, Saudi Arabia
| | - Athanasios Alexiou
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, Australia
| | - Nanasaheb Thorate
- Division of Medical Sciences, Nuffield Department of Women's & Reproductive Health, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
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15
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Shimoyama K, Tsuchiya T, Watanabe H, Ergalad A, Iwatake M, Miyazaki T, Hashimoto Y, Hsu YI, Hatachi G, Matsumoto K, Ishii M, Mizoguchi S, Doi R, Tomoshige K, Yamaoka T, Nagayasu T. Donor and Recipient Adipose-Derived Mesenchymal Stem Cell Therapy for Rat Lung Transplantation. Transplant Proc 2022; 54:1998-2007. [PMID: 36041932 DOI: 10.1016/j.transproceed.2022.05.038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 05/03/2022] [Accepted: 05/22/2022] [Indexed: 10/15/2022]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are beginning to be proven as immunosuppressant in the field of organ transplantation. However, the effects of MSC origin (donor or recipient) on immunosuppression are not clear. Hence, we investigated the effects of recipient and donor adipose-derived MSCs (ADMSCs) on immunosuppression in a rat lung transplantation model. METHODS Subjects were divided into no treatment, tacrolimus administration, recipient ADMSC administration, donor ADMSC administration, and mixed donor and recipient ADMSC administration groups. ADMSC-administered groups were also treated with tacrolimus. Histologic study, immunofluorescence, immunohistochemistry, enzyme-linked immunosorbent assay, and polymerase chain reaction were used for various analyses. RESULTS Fluorescently labeled ADMSCs were predominant in the grafted donor lung, but not in the recipient lung, on day 5. On day 7, the pathologic rejection grades of the grafted donor lung were significantly lower in the ADMSC-administered groups (P < .05) and did not differ among these groups. Although serum hepatocyte growth factor and vascular endothelial growth factor levels did not differ among the groups, interleukin 10 level was slightly higher in the ADMSC-administered groups. The numbers of infiltrating regulatory T cells in the grafted lung were significantly higher in the ADMSC-administered groups (P < .05) but did not differ with cell origin. Transcriptional analysis suggested interleukin 6 suppression to be the main overlapping immunosuppressive mechanism, regardless of origin. Therefore, a donor or recipient origin may not influence the immunosuppressive efficacy of ADMSCs in our rat lung transplantation model. CONCLUSIONS Collectively, the results indicate that allogenic ADMSCs, regardless of their origin, may exert similar immunosuppressive effects in clinical organ transplantation.
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Affiliation(s)
- Koichiro Shimoyama
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Medical-Engineering Hybrid Professional Development Center, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tomoshi Tsuchiya
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Division of Nucleic Acid Drug Development, Research Institute for Science and Technology, Tokyo University of Science, Chiba, Japan.
| | - Hironosuke Watanabe
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Abdelmotagaly Ergalad
- Center for Preclinical Surgical and Interventional Research, Texas Heart Institute, Houston, Texas
| | - Mayumi Iwatake
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Takuro Miyazaki
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Yasumasa Hashimoto
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Medical-Engineering Hybrid Professional Development Center, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Yu-I Hsu
- Department of Biomedical Engineering, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan
| | - Go Hatachi
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Keitaro Matsumoto
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Medical-Engineering Hybrid Professional Development Center, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Mitsutoshi Ishii
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Medical-Engineering Hybrid Professional Development Center, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Satoshi Mizoguchi
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Medical-Engineering Hybrid Professional Development Center, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Ryoichiro Doi
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Koichi Tomoshige
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tetsuji Yamaoka
- Department of Biomedical Engineering, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan
| | - Takeshi Nagayasu
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Medical-Engineering Hybrid Professional Development Center, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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16
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Che Z, Ye Z, Zhang X, Lin B, Yang W, Liang Y, Zeng J. Mesenchymal stem/stromal cells in the pathogenesis and regenerative therapy of inflammatory bowel diseases. Front Immunol 2022; 13:952071. [PMID: 35990688 PMCID: PMC9386516 DOI: 10.3389/fimmu.2022.952071] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 07/12/2022] [Indexed: 12/02/2022] Open
Abstract
Inflammatory bowel diseases (IBDs) represent a group of chronic inflammatory disorders of the gastrointestinal (GI) tract including ulcerative colitis (UC), Crohn’s disease (CD), and unclassified IBDs. The pathogenesis of IBDs is related to genetic susceptibility, environmental factors, and dysbiosis that can lead to the dysfunction of immune responses and dysregulated homeostasis of local mucosal tissues characterized by severe inflammatory responses and tissue damage in GI tract. To date, extensive studies have indicated that IBDs cannot be completely cured and easy to relapse, thus prompting researchers to find novel and more effective therapeutics for this disease. Due to their potent multipotent differentiation and immunomodulatory capabilities, mesenchymal stem/stromal cells (MSCs) not only play an important role in regulating immune and tissue homeostasis but also display potent therapeutic effects on various inflammatory diseases, including IBDs, in both preclinical and clinical studies. In this review, we present a comprehensive overview on the pathological mechanisms, the currently available therapeutics, particularly, the potential application of MSCs-based regenerative therapy for IBDs.
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Affiliation(s)
- Zhengping Che
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
- Department of Pathology, Dongguan Hospital Affiliated to Jinan University, Binhaiwan Central Hospital of Dongguan, Dongguan, China
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Ziyu Ye
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Xueying Zhang
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Bihua Lin
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
- Key Laboratory of Medical Bioactive Molecular Research for Department of Education of Guangdong Province, School of Basic Medicine, Guangdong Medical University, Dongguan, China
- Collaborative Innovation Center for Antitumor Active Substance Research and Development, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Guangdong Medical University, Zhanjiang, China
| | - Weiqing Yang
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Yanfang Liang
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
- Department of Pathology, Dongguan Hospital Affiliated to Jinan University, Binhaiwan Central Hospital of Dongguan, Dongguan, China
- *Correspondence: Jincheng Zeng, ; Yanfang Liang,
| | - Jincheng Zeng
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
- Key Laboratory of Medical Bioactive Molecular Research for Department of Education of Guangdong Province, School of Basic Medicine, Guangdong Medical University, Dongguan, China
- Collaborative Innovation Center for Antitumor Active Substance Research and Development, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Guangdong Medical University, Zhanjiang, China
- Dongguan Metabolite Analysis Engineering Technology Center of Cells for Medical Use, Guangdong Xinghai Institute of Cell, Dongguan, China
- *Correspondence: Jincheng Zeng, ; Yanfang Liang,
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17
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Calzetta L, Aiello M, Frizzelli A, Camardelli F, Cazzola M, Rogliani P, Chetta A. Stem Cell-Based Regenerative Therapy and Derived Products in COPD: A Systematic Review and Meta-Analysis. Cells 2022; 11:cells11111797. [PMID: 35681492 PMCID: PMC9180461 DOI: 10.3390/cells11111797] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 05/25/2022] [Accepted: 05/27/2022] [Indexed: 11/25/2022] Open
Abstract
COPD is an incurable disorder, characterized by a progressive alveolar tissue destruction and defective mechanisms of repair and defense leading to emphysema. Currently, treatment for COPD is exclusively symptomatic; therefore, stem cell-based therapies represent a promising therapeutic approach to regenerate damaged structures of the respiratory system and restore lung function. The aim of this study was to provide a quantitative synthesis of the efficacy profile of stem cell-based regenerative therapies and derived products in COPD patients. A systematic review and meta-analysis was performed according to PRISMA-P. Data from 371 COPD patients were extracted from 11 studies. Active treatments elicited a strong tendency towards significance in FEV1 improvement (+71 mL 95% CI -2−145; p = 0.056) and significantly increased 6MWT (52 m 95% CI 18−87; p < 0.05) vs. baseline or control. Active treatments did not reduce the risk of hospitalization due to acute exacerbations (RR 0.77 95% CI 0.40−1.49; p > 0.05). This study suggests that stem cell-based regenerative therapies and derived products may be effective to treat COPD patients, but the current evidence comes from small clinical trials. Large and well-designed randomized controlled trials are needed to really quantify the beneficial impact of stem cell-based regenerative therapy and derived products in COPD.
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Affiliation(s)
- Luigino Calzetta
- Respiratory Disease and Lung Function Unit, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (M.A.); (A.F.); (A.C.)
- Correspondence:
| | - Marina Aiello
- Respiratory Disease and Lung Function Unit, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (M.A.); (A.F.); (A.C.)
| | - Annalisa Frizzelli
- Respiratory Disease and Lung Function Unit, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (M.A.); (A.F.); (A.C.)
| | - Francesca Camardelli
- Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy; (F.C.); (M.C.); (P.R.)
| | - Mario Cazzola
- Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy; (F.C.); (M.C.); (P.R.)
| | - Paola Rogliani
- Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy; (F.C.); (M.C.); (P.R.)
| | - Alfredo Chetta
- Respiratory Disease and Lung Function Unit, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (M.A.); (A.F.); (A.C.)
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18
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Filidou E, Kandilogiannakis L, Tarapatzi G, Spathakis M, Steiropoulos P, Mikroulis D, Arvanitidis K, Paspaliaris V, Kolios G. Anti-Inflammatory and Anti-Fibrotic Effect of Immortalized Mesenchymal-Stem-Cell-Derived Conditioned Medium on Human Lung Myofibroblasts and Epithelial Cells. Int J Mol Sci 2022; 23:ijms23094570. [PMID: 35562961 PMCID: PMC9102072 DOI: 10.3390/ijms23094570] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 04/18/2022] [Accepted: 04/19/2022] [Indexed: 12/13/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is caused by progressive lung tissue impairment due to extended chronic fibrosis, and it has no known effective treatment. The use of conditioned media (CM) from an immortalized human adipose mesenchymal stem cell line could be a promising therapeutic strategy, as it can reduce both fibrotic and inflammatory responses. We aimed to investigate the anti-inflammatory and anti-fibrotic effect of CM on human pulmonary subepithelial myofibroblasts (hPSM) and on A549 pulmonary epithelial cells, treated with pro-inflammatory or pro-fibrotic mediators. CM inhibited the proinflammatory cytokine-induced mRNA and protein production of various chemokines in both hPSMs and A549 cells. It also downregulated the mRNA expression of IL-1α, but upregulated IL-1β and IL-6 mRNA production in both cell types. CM downregulated the pro-fibrotic-induced mRNA expression of collagen Type III and the migration rate of hPSMs, but upregulated fibronectin mRNA production and the total protein collagen secretion. CM's direct effect on the chemotaxis and cell recruitment of immune-associated cells, and its indirect effect on fibrosis through the significant decrease in the migration capacity of hPSMs, makes it a plausible candidate for further development towards a therapeutic treatment for IPF.
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Affiliation(s)
- Eirini Filidou
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.F.); (L.K.); (G.T.); (M.S.); (K.A.); (G.K.)
| | - Leonidas Kandilogiannakis
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.F.); (L.K.); (G.T.); (M.S.); (K.A.); (G.K.)
| | - Gesthimani Tarapatzi
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.F.); (L.K.); (G.T.); (M.S.); (K.A.); (G.K.)
| | - Michail Spathakis
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.F.); (L.K.); (G.T.); (M.S.); (K.A.); (G.K.)
| | - Paschalis Steiropoulos
- Department of Pneumonology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece;
| | - Dimitrios Mikroulis
- Department of Cardiac Surgery, Democritus University of Thrace, University Hospital of Alexandroupolis, 68100 Alexandroupolis, Greece;
| | - Konstantinos Arvanitidis
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.F.); (L.K.); (G.T.); (M.S.); (K.A.); (G.K.)
| | - Vasilis Paspaliaris
- Vasilis Paspaliaris, Tithon Biotech Inc., 11440 West Bernardo Court, Suite 300, San Diego, CA 92127, USA
- Correspondence: ; Tel./Fax: +1-88-8780-2639
| | - George Kolios
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (E.F.); (L.K.); (G.T.); (M.S.); (K.A.); (G.K.)
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19
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Inhaled Placental Mesenchymal Stromal Cell Secretome from Two- and Three-Dimensional Cell Cultures Promotes Survival and Regeneration in Acute Lung Injury Model in Mice. Int J Mol Sci 2022; 23:ijms23073417. [PMID: 35408778 PMCID: PMC8998959 DOI: 10.3390/ijms23073417] [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: 01/10/2022] [Revised: 03/16/2022] [Accepted: 03/17/2022] [Indexed: 02/06/2023] Open
Abstract
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is a common clinical problem, leading to significant morbidity and mortality, and no effective pharmacotherapy exists. The problem of ARDS causing mortality became more apparent during the COVID-19 pandemic. Biotherapeutic products containing multipotent mesenchymal stromal cell (MMSC) secretome may provide a new therapeutic paradigm for human healthcare due to their immunomodulating and regenerative abilities. The content and regenerative capacity of the secretome depends on cell origin and type of cultivation (two- or three-dimensional (2D/3D)). In this study, we investigated the proteomic profile of the secretome from 2D- and 3D-cultured placental MMSC and lung fibroblasts (LFBs) and the effect of inhalation of freeze-dried secretome on survival, lung inflammation, lung tissue regeneration, fibrin deposition in a lethal ALI model in mice. We found that three inhaled administrations of freeze-dried secretome from 2D- and 3D-cultured placental MMSC and LFB protected mice from death, restored the histological structure of damaged lungs, and decreased fibrin deposition. At the same time, 3D MMSC secretome exhibited a more pronounced trend in lung recovery than 2D MMSC and LFB-derived secretome in some measures. Taking together, these studies show that inhalation of cell secretome may also be considered as a potential therapy for the management of ARDS in patients suffering from severe pneumonia, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), however, their effectiveness requires further investigation.
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20
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Mou K, Chan SMH, Brassington K, Dobric A, De Luca SN, Seow HJ, Selemidis S, Bozinovski S, Vlahos R. Influenza A Virus-Driven Airway Inflammation may be Dissociated From Limb Muscle Atrophy in Cigarette Smoke-Exposed Mice. Front Pharmacol 2022; 13:859146. [PMID: 35370652 PMCID: PMC8971713 DOI: 10.3389/fphar.2022.859146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 02/17/2022] [Indexed: 11/28/2022] Open
Abstract
Limb muscle dysfunction is a hallmark of Chronic Obstructive Pulmonary Disease (COPD) which is further worsened following a viral-induced acute exacerbation of COPD (AECOPD). An amplified airway inflammation underlies the aggravated respiratory symptoms seen during AECOPD, however, its contributory role to limb muscle dysfunction is unclear. The present study examined the impact of influenza A virus (IAV)-induced exacerbation on hind limb muscle parameters. Airway inflammation was established in male BALB/c mice by exposure to cigarette smoke (CS) for 8 weeks. Exacerbation was then induced via inoculation with IAV, and various lung and muscle parameters were assessed on day 3 (peak of airway inflammation) and day 10 (resolution phase) post-infection. IAV infection exacerbated CS-induced airway inflammation as evidenced by further increases in immune cell counts within bronchoalveolar lavage fluid. Despite no significant impact on muscle mass, IAV exacerbation worsened the force-generating capacity of the tibialis anterior (TA) muscle. Protein oxidation and myogenic disruption was observed in the TA following CS exposure, however, IAV exacerbation did not augment these detrimental processes. To further explore the contributory role of airway inflammation on myogenic signaling, cultured myotubes were exposed to conditioned medium (CM) derived from bronchial epithelial cells stimulated with polyinosinic:polycytidylic acid and cigarette smoke extract (CSE). Despite an amplified inflammatory response in the lung epithelial cells, the CM derived from these cells did not potentiate myogenic disruption in the C2C12 myotubes. In conclusion, our data suggest that certain parameters of limb muscle dysfunction seen during viral-induced AECOPD may be independent of airway inflammation.
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21
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Exo-D-Mapps Attenuates Production of Inflammatory Cytokines and Promoted Generation of Immunosuppressive Phenotype in Peripheral Blood Mononuclear Cells. SERBIAN JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2022. [DOI: 10.2478/sjecr-2019-0045] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Mesenchymal stem cells (MSCs) produce immunomodulatory factors that regulate production of cytokines and chemokines in immune cells affecting their functional properties. Administration of MSCs-sourced secretome, including MSC-derived conditioned medium (MSC-CM) and MSC-derived exosomes (MSC-Exos), showed beneficial effects similar to those observed after transplantation of MSCs. Due to their nano-size dimension, MSC-Exos easily penetrate through the tissue and in paracrine and endocrine manner, may deliver MSC-sourced factors to the target immune cells modulating their function. MSCs derived from amniotic fluid (AF-MSCs) had superior cell biological properties than MSCs derived from bone marrow. We recently developed “Exosomes Derived Multiple Allogeneic Proteins Paracrine Signaling (Exo-d-MAPPS)”, a biological product in which the activity is based on AF-MSC-derived Exos capable to deliver immunomodulatory molecules and growth factors to the target cells. Herewith, we analyzed immunosuppressive capacity of Exo-d-MAPPS against human peripheral blood mononuclear cells (pbMNCs) and demonstrated that Exo-d-MAPPS efficiently suppressed generation of inflammatory phenotype in activated pbMNCs. Exo-d-MAPPS attenuated production of inflammatory cytokines and promoted generation of immunosuppressive phenotype in Lipopolysaccharide-primed pbMNCs. Exo-d-MAPPS treatment reduced expansion of inflammatory Th1 and Th17 cells and promoted generation of immunosuppressive T regulatory cells in the population of Concanavalin A-primed pbMNCs. Similarly, Exod-MAPPS treatment suppressed pro-inflammatory and promoted anti-inflammatory properties of α-GalCer-primed pbMNCs. In summing up, due to its capacity for suppression of activated pbMNCs, Exo-d-MAPPS should be further explored in animal models of acute and chronic inflammatory diseases as a potentially new remedy for the attenuation of detrimental immune response.
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22
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Miceli V, Bertani A. Mesenchymal Stromal/Stem Cells and Their Products as a Therapeutic Tool to Advance Lung Transplantation. Cells 2022; 11:826. [PMID: 35269448 PMCID: PMC8909054 DOI: 10.3390/cells11050826] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 02/18/2022] [Accepted: 02/25/2022] [Indexed: 02/07/2023] Open
Abstract
Lung transplantation (LTx) has become the gold standard treatment for end-stage respiratory failure. Recently, extended lung donor criteria have been applied to decrease the mortality rate of patients on the waiting list. Moreover, ex vivo lung perfusion (EVLP) has been used to improve the number/quality of previously unacceptable lungs. Despite the above-mentioned progress, the morbidity/mortality of LTx remains high compared to other solid organ transplants. Lungs are particularly susceptible to ischemia-reperfusion injury, which can lead to graft dysfunction. Therefore, the success of LTx is related to the quality/function of the graft, and EVLP represents an opportunity to protect/regenerate the lungs before transplantation. Increasing evidence supports the use of mesenchymal stromal/stem cells (MSCs) as a therapeutic strategy to improve EVLP. The therapeutic properties of MSC are partially mediated by secreted factors. Hence, the strategy of lung perfusion with MSCs and/or their products pave the way for a new innovative approach that further increases the potential for the use of EVLP. This article provides an overview of experimental, preclinical and clinical studies supporting the application of MSCs to improve EVLP, the ultimate goal being efficient organ reconditioning in order to expand the donor lung pool and to improve transplant outcomes.
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Affiliation(s)
- Vitale Miceli
- Research Department, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), 90127 Palermo, Italy
| | - Alessandro Bertani
- Thoracic Surgery and Lung Transplantation Unit, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy
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23
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Keyhanmanesh R, Khodamoradi F, Rahbarghazi R, Rahbarghazi A, Rezaie J, Ahmadi M, Salimi L, Delkhosh A. Intra-tracheal delivery of mesenchymal stem cell-conditioned medium ameliorates pathological changes by inhibiting apoptosis in asthmatic rats. Mol Biol Rep 2022; 49:3721-3728. [PMID: 35118570 DOI: 10.1007/s11033-022-07212-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 01/27/2022] [Indexed: 11/26/2022]
Abstract
BACKGROUND Asthma, an inflammatory illness of the lungs, remains the most common long-term disease amongst children. This study tried to elaborate the status of apoptosis in asthmatic pulmonary niche after the application of rat mesenchymal stem cells (MSC-CM)-derived secretome. METHODS AND RESULTS Here, we randomly allocated male Wistar rats into three groups (n = 8); Control animals were intratracheally given 50 μl vehicle. In control-matched sensitized rats, 50 μl normal saline was used. In the last group, 50 μl MSC-CM was applied. Two-week post-administration, transcription of T-bet, GATA-3, Bax, Bcl-2 and Caspase-3 was measured by gene expression analysis. Pathological injuries were monitored using H&E staining. The BALF level of TNF-α was measured using ELISA assay. In asthmatic rats received MSC-CM, the expression of T-bet was increased while the level of GATA-3 decreased compared to the S group (p < 0.05). Levels of BALF TNF-α were suppressed in asthmatic niche after MSC-CM administration (p < 0.05). Compared to the asthmatic group, MSC-CM had potential to alter the expression of apoptosis-related genes in which the expression of Bax and Caspase 3 was decreased and the expression of pro-survival factor, Bcl-2 increased (p < 0.05). CONCLUSION Our data notified the potency of direct administration of MSC-CM in the alleviation of airway inflammation, presumably by down regulating apoptotic death in pulmonary niche.
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Affiliation(s)
- Rana Keyhanmanesh
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Khodamoradi
- Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Afshin Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jafar Rezaie
- Solid Tumor Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Mahdi Ahmadi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Leila Salimi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aref Delkhosh
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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24
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Balzanelli MG, Distratis P, Lazzaro R, D’Ettorre E, Nico A, Inchingolo F, Dipalma G, Tomassone D, Serlenga EM, Dalagni G, Ballini A, Nguyen KCD, Isacco CG. New Translational Trends in Personalized Medicine: Autologous Peripheral Blood Stem Cells and Plasma for COVID-19 Patient. J Pers Med 2022; 12:85. [PMID: 35055400 PMCID: PMC8778886 DOI: 10.3390/jpm12010085] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 12/29/2021] [Accepted: 01/04/2022] [Indexed: 02/04/2023] Open
Abstract
The COVID-19 pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), still remains a severe threat. At the time of writing this paper, the second infectious wave has caused more than 280,000 deaths all over the world. Italy was one of the first countries involved, with more than 200,000 people reported as infected and 30,000 deaths. There are no specific treatments for COVID-19 and the vaccine still remains somehow inconclusive. The world health community is trying to define and share therapeutic protocols in early and advanced clinical stages. However, numbers remain critical with a serious disease rate of 14%, ending with sepsis, acute respiratory distress syndrome (ARDS), multiple organ failure (MOF) and vascular and thromboembolic findings. The mortality rate was estimated within 2-3%, and more than double that for individuals over 65 years old; almost one patient in three dies in the Intensive Care Unit (ICU). Efforts for effective solutions are underway with multiple lines of investigations, and health authorities have reported success treating infected patients with donated plasma from survivors of the illness, the proposed benefit being protective antibodies formed by the survivors. Plasma transfusion, blood and stem cells, either autologous or allograft transplantation, are not novel therapies, and in this short paper, we propose therapeutic autologous plasma and peripheral blood stem cells as a possible treatment for fulminant COVID-19 infection.
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Affiliation(s)
- Mario Giosuè Balzanelli
- SET-118, Department of Pre-Hospital and Emergency, SG Giuseppe Moscati Hospital, 74010 Taranto, Italy; (M.G.B.); (P.D.); (R.L.)
| | - Pietro Distratis
- SET-118, Department of Pre-Hospital and Emergency, SG Giuseppe Moscati Hospital, 74010 Taranto, Italy; (M.G.B.); (P.D.); (R.L.)
| | - Rita Lazzaro
- SET-118, Department of Pre-Hospital and Emergency, SG Giuseppe Moscati Hospital, 74010 Taranto, Italy; (M.G.B.); (P.D.); (R.L.)
| | - Ernesto D’Ettorre
- Department of Pneumology, SG Giuseppe Moscati Hospital, 74010 Taranto, Italy; (E.D.); (A.N.); (G.D.)
| | - Andrea Nico
- Department of Pneumology, SG Giuseppe Moscati Hospital, 74010 Taranto, Italy; (E.D.); (A.N.); (G.D.)
| | - Francesco Inchingolo
- Department of Interdisciplinary Medicine, School of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (F.I.); (G.D.)
| | - Gianna Dipalma
- Department of Interdisciplinary Medicine, School of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (F.I.); (G.D.)
| | - Diego Tomassone
- Foundation of Physics Research Center, Celico, 87100 Cosenza, Italy;
| | | | - Giancarlo Dalagni
- Department of Pneumology, SG Giuseppe Moscati Hospital, 74010 Taranto, Italy; (E.D.); (A.N.); (G.D.)
| | - Andrea Ballini
- School of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
| | | | - Ciro Gargiulo Isacco
- SET-118, Department of Pre-Hospital and Emergency, SG Giuseppe Moscati Hospital, 74010 Taranto, Italy; (M.G.B.); (P.D.); (R.L.)
- American Stem Cells Hospital, Ho Chi Minh 70000, Vietnam;
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25
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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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26
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Filidou E, Kandilogiannakis L, Tarapatzi G, Su C, Po ENF, Paspaliaris V, Kolios G. Conditioned medium from a human adipose-derived stem cell line ameliorates inflammation and fibrosis in a lung experimental model of idiopathic pulmonary fibrosis. Life Sci 2021; 287:120123. [PMID: 34748761 DOI: 10.1016/j.lfs.2021.120123] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 10/31/2021] [Accepted: 11/02/2021] [Indexed: 12/19/2022]
Abstract
Idiopathic pulmonary fibrosis is a chronic, progressive parenchymal lung disease that results in fibrogenesis and the conditioned medium from adipose-derived mesenchymal stem cells (CM-ADSCs) has been shown to be efficacious in pulmonary fibrosis animal models. The aim of the present study is to evaluate the effect of CM-ADSCs on lung inflammation and fibrosis in a Bleomycin (BLM)-induced pulmonary fibrosis model. CM-ADSCs safety and toxicity were evaluated in Sprague Dawley rats and no adverse effects were observed. Six-week-old female C57BL/6J mice were employed in the BLM-induced pulmonary fibrosis model and were divided into four groups: Group 1 (Sham): animals were kept without BLM and treatment, Group 2 (Control): BLM with vehicle DMEM, Group 3: 10 μg/kg CM-ADSCs and Group 4: 100 μg/kg CM-ADSCs. Body weight, fibrosis and inflammation histological analyses, mRNA and protein pro-inflammatory cytokine, and total hydroxyproline content calculation were performed in all groups upon sacrifice. The 100 μg/kg CM-ADSCs showed a significant increase in mean body weight compared to Controls. CM-ADSCs doses resulted in the amelioration of fibrosis, as seen by Masson's Trichrome-staining, Ashcroft scoring, and Sirius red-staining. Compared to Controls, inflammation was also significantly reduced in CM-ADSCs-treated mice, with reduced F4/80 macrophage antigen staining, TNF-α mRNA and IL-6 and IL-10 protein levels. Total hydroxyproline content was found significantly reduced in both groups of CM-ADSCs-treated mice. Overall, our study shows that the CM-ADSCs is safe and efficient against pulmonary fibrosis, as it significantly reduced inflammation and fibrosis, with the larger dose of 100 μg/kg CM-ADSCs being the most efficient one.
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Affiliation(s)
- Eirini Filidou
- Lab of Pharmacology, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | | | - Gesthimani Tarapatzi
- Lab of Pharmacology, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Colin Su
- Tithon Biotech Inc, San Diego, CA 92127, USA
| | | | | | - George Kolios
- Lab of Pharmacology, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece.
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27
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Esquivel-Ruiz S, González-Rodríguez P, Lorente JA, Pérez-Vizcaíno F, Herrero R, Moreno L. Extracellular Vesicles and Alveolar Epithelial-Capillary Barrier Disruption in Acute Respiratory Distress Syndrome: Pathophysiological Role and Therapeutic Potential. Front Physiol 2021; 12:752287. [PMID: 34887773 PMCID: PMC8650589 DOI: 10.3389/fphys.2021.752287] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 09/27/2021] [Indexed: 12/11/2022] Open
Abstract
Extracellular vesicles (EVs) mediate intercellular communication by transferring genetic material, proteins and organelles between different cells types in both health and disease. Recent evidence suggests that these vesicles, more than simply diagnostic markers, are key mediators of the pathophysiology of acute respiratory distress syndrome (ARDS) and other lung diseases. In this review, we will discuss the contribution of EVs released by pulmonary structural cells (alveolar epithelial and endothelial cells) and immune cells in these diseases, with particular attention to their ability to modulate inflammation and alveolar-capillary barrier disruption, a hallmark of ARDS. EVs also offer a unique opportunity to develop new therapeutics for the treatment of ARDS. Evidences supporting the ability of stem cell-derived EVs to attenuate the lung injury and ongoing strategies to improve their therapeutic potential are also discussed.
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Affiliation(s)
- Sergio Esquivel-Ruiz
- Department of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.,Ciber de Enfermedades Respiratorias (CIBERES), Madrid, Spain
| | - Paloma González-Rodríguez
- Ciber de Enfermedades Respiratorias (CIBERES), Madrid, Spain.,Department of Critical Care, Hospital Universitario de Getafe, Madrid, Spain
| | - José A Lorente
- Ciber de Enfermedades Respiratorias (CIBERES), Madrid, Spain.,Department of Critical Care, Hospital Universitario de Getafe, Madrid, Spain.,Clinical Section, School of Medicine, European University of Madrid, Madrid, Spain
| | - Francisco Pérez-Vizcaíno
- Department of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.,Ciber de Enfermedades Respiratorias (CIBERES), Madrid, Spain
| | - Raquel Herrero
- Ciber de Enfermedades Respiratorias (CIBERES), Madrid, Spain.,Department of Critical Care, Hospital Universitario de Getafe, Madrid, Spain
| | - Laura Moreno
- Department of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.,Ciber de Enfermedades Respiratorias (CIBERES), Madrid, Spain
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28
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Antimicrobial and Regenerative Effects of Placental Multipotent Mesenchymal Stromal Cell Secretome-Based Chitosan Gel on Infected Burns in Rats. Pharmaceuticals (Basel) 2021; 14:ph14121263. [PMID: 34959663 PMCID: PMC8707738 DOI: 10.3390/ph14121263] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 12/01/2021] [Accepted: 12/01/2021] [Indexed: 01/08/2023] Open
Abstract
Background: There is a need for better strategies to promote burn wound healing and prevent infection. The aim of our study was to develop an easy-to-use placental multipotent mesenchymal stromal cell (MMSC) secretome-based chitosan hydrogel (MSC-Ch-gel) and estimate its antimicrobial and regenerative activity in Staphylococcus aureus-infected burn wounds in rats. Methods: Proteomic studies of the MMSC secretome revealed proteins involved in regeneration, angiogenesis, and defence responses. The MMSC secretome was collected from cultured cells and mixed with water-soluble chitosan to prepare the placental MSC-Ch-gel, which was stored in liquid phase at 4 °C. The wounds of rats with established II-IIIa-degree burns were then infected with S. aureus and externally covered with the MSC-Ch-gel. Three additional rat groups were treated with medical Vaseline oil, the antiseptic drug Miramistin®, or the drug Bepanthen® Plus. Skin wound samples were collected 4 and 8 days after burning for further microbiological and histological analysis. Blood samples were also collected for biochemical analysis. Results: Application of the MSC-Ch-gel cleared the wound of microorganisms (S. aureus wasn’t detected in the washings from the burned areas), decreased inflammation, enhanced re-epithelialisation, and promoted the formation of well-vascularised granulation tissue. Conclusions: MSC-Ch-gel effectively promotes infected wound healing in rats with third-degree burns. Gel preparation can be easily implemented into clinical practice.
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Rodrigues SDO, da Cunha CMC, Soares GMV, Silva PL, Silva AR, Gonçalves-de-Albuquerque CF. Mechanisms, Pathophysiology and Currently Proposed Treatments of Chronic Obstructive Pulmonary Disease. Pharmaceuticals (Basel) 2021; 14:979. [PMID: 34681202 PMCID: PMC8539950 DOI: 10.3390/ph14100979] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 08/13/2021] [Accepted: 08/28/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is one of the leading global causes of morbidity and mortality. A hallmark of COPD is progressive airflow obstruction primarily caused by cigarette smoke (CS). CS exposure causes an imbalance favoring pro- over antioxidants (oxidative stress), leading to transcription factor activation and increased expression of inflammatory mediators and proteases. Different cell types, including macrophages, epithelial cells, neutrophils, and T lymphocytes, contribute to COPD pathophysiology. Alteration in cell functions results in the generation of an oxidative and inflammatory microenvironment, which contributes to disease progression. Current treatments include inhaled corticosteroids and bronchodilator therapy. However, these therapies do not effectively halt disease progression. Due to the complexity of its pathophysiology, and the risk of exacerbating symptoms with existing therapies, other specific and effective treatment options are required. Therapies directly or indirectly targeting the oxidative imbalance may be promising alternatives. This review briefly discusses COPD pathophysiology, and provides an update on the development and clinical testing of novel COPD treatments.
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Affiliation(s)
- Sarah de Oliveira Rodrigues
- Laboratório de Imunofarmacologia, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro 21040-900, Brazil;
- Laboratório de Imunofarmacologia, Departamento de Bioquímica, Instituto Biomédico, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro 20211-010, Brazil; (C.M.C.d.C.); (G.M.V.S.)
- Programa de Pós-Graduação em Ciências e Biotecnologia, Universidade Federal Fluminense, Rio de Janeiro 24020-140, Brazil
| | - Carolina Medina Coeli da Cunha
- Laboratório de Imunofarmacologia, Departamento de Bioquímica, Instituto Biomédico, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro 20211-010, Brazil; (C.M.C.d.C.); (G.M.V.S.)
| | - Giovanna Martins Valladão Soares
- Laboratório de Imunofarmacologia, Departamento de Bioquímica, Instituto Biomédico, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro 20211-010, Brazil; (C.M.C.d.C.); (G.M.V.S.)
| | - Pedro Leme Silva
- Laboratório de Investigação Pulmonar, Carlos Chagas Filho, Instituto de Biofísica, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil;
| | - Adriana Ribeiro Silva
- Laboratório de Imunofarmacologia, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro 21040-900, Brazil;
- Programa de Pós-Graduação em Ciências e Biotecnologia, Universidade Federal Fluminense, Rio de Janeiro 24020-140, Brazil
- Programa de Pós-Graduação em Biologia Celular e Molecular, Instituto Oswaldo Cruz (FIOCRUZ), Rio de Janeiro 21040-900, Brazil
| | - Cassiano Felippe Gonçalves-de-Albuquerque
- Laboratório de Imunofarmacologia, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro 21040-900, Brazil;
- Laboratório de Imunofarmacologia, Departamento de Bioquímica, Instituto Biomédico, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro 20211-010, Brazil; (C.M.C.d.C.); (G.M.V.S.)
- Programa de Pós-Graduação em Ciências e Biotecnologia, Universidade Federal Fluminense, Rio de Janeiro 24020-140, Brazil
- Programa de Pós-Graduação em Biologia Molecular e Celular, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro 20210-010, Brazil
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Laurent A, Abdel-Sayed P, Hirt-Burri N, Scaletta C, Michetti M, de Buys Roessingh A, Raffoul W, Applegate LA. Evolution of Diploid Progenitor Lung Cell Applications: From Optimized Biotechnological Substrates to Potential Active Pharmaceutical Ingredients in Respiratory Tract Regenerative Medicine. Cells 2021; 10:2526. [PMID: 34685505 PMCID: PMC8533713 DOI: 10.3390/cells10102526] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 09/14/2021] [Accepted: 09/21/2021] [Indexed: 02/06/2023] Open
Abstract
The objective of this review is to describe the evolution of lung tissue-derived diploid progenitor cell applications, ranging from historical biotechnological substrate functions for vaccine production and testing to current investigations around potential therapeutic use in respiratory tract regenerative medicine. Such cell types (e.g., MRC-5 or WI-38 sources) were extensively studied since the 1960s and have been continuously used over five decades as safe and sustainable industrial vaccine substrates. Recent research and development efforts around diploid progenitor lung cells (e.g., FE002-Lu or Walvax-2 sources) consist in qualification for potential use as optimal and renewed vaccine production substrates and, alternatively, for potential therapeutic applications in respiratory tract regenerative medicine. Potentially effective, safe, and sustainable cell therapy approaches for the management of inflammatory lung diseases or affections and related symptoms (e.g., COVID-19 patients and burn patient severe inhalation syndrome) using local homologous allogeneic cell-based or cell-derived product administrations are considered. Overall, lung tissue-derived progenitor cells isolated and produced under good manufacturing practices (GMP) may be used with high versatility. They can either act as key industrial platforms optimally conforming to specific pharmacopoeial requirements or as active pharmaceutical ingredients (API) for potentially effective promotion of lung tissue repair or regeneration.
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Affiliation(s)
- Alexis Laurent
- Regenerative Therapy Unit, Lausanne University Hospital, University of Lausanne, CH-1066 Épalinges, Switzerland; (A.L.); (P.A.-S.); (N.H.-B.); (C.S.); (M.M.)
- TEC-PHARMA SA, Manufacturing Department, CH-1038 Bercher, Switzerland
- LAM Biotechnologies SA, Manufacturing Department, CH-1066 Épalinges, Switzerland
| | - Philippe Abdel-Sayed
- Regenerative Therapy Unit, Lausanne University Hospital, University of Lausanne, CH-1066 Épalinges, Switzerland; (A.L.); (P.A.-S.); (N.H.-B.); (C.S.); (M.M.)
| | - Nathalie Hirt-Burri
- Regenerative Therapy Unit, Lausanne University Hospital, University of Lausanne, CH-1066 Épalinges, Switzerland; (A.L.); (P.A.-S.); (N.H.-B.); (C.S.); (M.M.)
| | - Corinne Scaletta
- Regenerative Therapy Unit, Lausanne University Hospital, University of Lausanne, CH-1066 Épalinges, Switzerland; (A.L.); (P.A.-S.); (N.H.-B.); (C.S.); (M.M.)
| | - Murielle Michetti
- Regenerative Therapy Unit, Lausanne University Hospital, University of Lausanne, CH-1066 Épalinges, Switzerland; (A.L.); (P.A.-S.); (N.H.-B.); (C.S.); (M.M.)
| | - Anthony de Buys Roessingh
- Children and Adolescent Surgery Service, Lausanne University Hospital, University of Lausanne, CH-1011 Lausanne, Switzerland;
- Romand Burn Center, Lausanne University Hospital, University of Lausanne, CH-1011 Lausanne, Switzerland;
| | - Wassim Raffoul
- Romand Burn Center, Lausanne University Hospital, University of Lausanne, CH-1011 Lausanne, Switzerland;
- Plastic, Reconstructive, and Hand Surgery Service, Lausanne University Hospital, University of Lausanne, CH-1011 Lausanne, Switzerland
| | - Lee Ann Applegate
- Regenerative Therapy Unit, Lausanne University Hospital, University of Lausanne, CH-1066 Épalinges, Switzerland; (A.L.); (P.A.-S.); (N.H.-B.); (C.S.); (M.M.)
- Romand Burn Center, Lausanne University Hospital, University of Lausanne, CH-1011 Lausanne, Switzerland;
- Center for Applied Biotechnology and Molecular Medicine, University of Zurich, CH-8057 Zurich, Switzerland
- Oxford OSCAR Suzhou Center, Oxford University, Suzhou 215123, China
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Potential Therapeutic Effect of Micrornas in Extracellular Vesicles from Mesenchymal Stem Cells against SARS-CoV-2. Cells 2021; 10:cells10092393. [PMID: 34572043 PMCID: PMC8465096 DOI: 10.3390/cells10092393] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 08/31/2021] [Accepted: 09/09/2021] [Indexed: 12/14/2022] Open
Abstract
Extracellular vesicles (EVs) are cell-released, nanometer-scaled, membrane-bound materials and contain diverse contents including proteins, small peptides, and nucleic acids. Once released, EVs can alter the microenvironment and regulate a myriad of cellular physiology components, including cell–cell communication, proliferation, differentiation, and immune responses against viral infection. Among the cargoes in the vesicles, small non-coding micro-RNAs (miRNAs) have received attention in that they can regulate the expression of a variety of human genes as well as external viral genes via binding to the complementary mRNAs. In this study, we tested the potential of EVs as therapeutic agents for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. First, we found that the mesenchymal stem-cell-derived EVs (MSC-EVs) enabled the rescue of the cytopathic effect of SARS-CoV-2 virus and the suppression of proinflammatory responses in the infected cells by inhibiting the viral replication. We found that these anti-viral responses were mediated by 17 miRNAs matching the rarely mutated, conserved 3′-untranslated regions (UTR) of the viral genome. The top five miRNAs highly expressed in the MSC-EVs, miR-92a-3p, miR-26a-5p, miR-23a-3p, miR-103a-3p, and miR-181a-5p, were tested. They were bound to the complemented sequence which led to the recovery of the cytopathic effects. These findings suggest that the MSC-EVs are a potential candidate for multiple variants of anti-SARS-CoV-2.
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Increased In Vitro Intercellular Barrier Function of Lung Epithelial Cells Using Adipose-Derived Mesenchymal Stem/Stromal Cells. Pharmaceutics 2021; 13:pharmaceutics13081264. [PMID: 34452225 PMCID: PMC8401152 DOI: 10.3390/pharmaceutics13081264] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 08/11/2021] [Accepted: 08/13/2021] [Indexed: 11/17/2022] Open
Abstract
With the emergence of coronavirus disease-2019, researchers have gained interest in the therapeutic efficacy of mesenchymal stem/stromal cells (MSCs) in acute respiratory distress syndrome; however, the mechanisms of the therapeutic effects of MSCs are unclear. We have previously reported that adipose-derived MSCs (AD-MSCs) strengthen the barrier function of the pulmonary vessels in scaffold-based bioengineered rat lungs. In this study, we evaluated whether AD-MSCs could enhance the intercellular barrier function of lung epithelial cells in vitro using a transwell coculture system. Transepithelial electrical resistance (TEER) measurements revealed that the peak TEER value was significantly higher in the AD-MSC coculture group than in the AD-MSC non-coculture group. Similarly, the permeability coefficient was significantly decreased in the AD-MSC coculture group compared to that in the AD-MSC non-coculture group. Immunostaining of insert membranes showed that zonula occuldens-1 expression was significantly high at cell junctions in the AD-MSC coculture group. Moreover, cell junction-related gene profiling showed that the expression of some claudin genes, including claudin-4, was upregulated in the AD-MSC coculture group. Taken together, these results showed that AD-MSCs enhanced the barrier function between lung epithelial cells, suggesting that both direct adhesion and indirect paracrine effects strengthened the barrier function of lung alveolar epithelium in vitro.
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Mesenchymal Stem Cell-Based Therapy as an Alternative to the Treatment of Acute Respiratory Distress Syndrome: Current Evidence and Future Perspectives. Int J Mol Sci 2021; 22:ijms22157850. [PMID: 34360616 PMCID: PMC8346146 DOI: 10.3390/ijms22157850] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 07/17/2021] [Accepted: 07/19/2021] [Indexed: 12/25/2022] Open
Abstract
Acute respiratory distress syndrome (ARDS) represents a current challenge for medicine due to its incidence, morbidity and mortality and, also, the absence of an optimal treatment. The COVID-19 outbreak only increased the urgent demand for an affordable, safe and effective treatment for this process. Early clinical trials suggest the therapeutic usefulness of mesenchymal stem cells (MSCs) in acute lung injury (ALI) and ARDS. MSC-based therapies show antimicrobial, anti-inflammatory, regenerative, angiogenic, antifibrotic, anti-oxidative stress and anti-apoptotic actions, which can thwart the physiopathological mechanisms engaged in ARDS. In addition, MSC secretome and their derived products, especially exosomes, may reproduce the therapeutic effects of MSC in lung injury. This last strategy of treatment could avoid several safety issues potentially associated with the transplantation of living and proliferative cell populations and may be formulated in different forms. However, the following diverse limitations must be addressed: (i) selection of the optimal MSC, bearing in mind both the heterogeneity among donors and across different histological origins, (ii) massive obtention of these biological products through genetic manipulations of the most appropriate MSC, (iii) bioreactors that allow their growth in 3D, (iv) ideal culture conditions and (v) adequate functional testing of these obtaining biological products before their clinical application.
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Campo A, González-Ruiz JM, Andreu E, Alcaide AB, Ocón MM, De-Torres J, Pueyo J, Cordovilla R, Villaron E, Sanchez-Guijo F, Barrueco M, Nuñez-Córdoba J, Prósper F, Zulueta JJ. Endobronchial autologous bone marrow-mesenchymal stromal cells in idiopathic pulmonary fibrosis: a phase I trial. ERJ Open Res 2021; 7:00773-2020. [PMID: 34195252 PMCID: PMC8236617 DOI: 10.1183/23120541.00773-2020] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 03/17/2021] [Indexed: 12/12/2022] Open
Abstract
Rationale Idiopathic pulmonary fibrosis (IPF) has a dismal prognosis. Mesenchymal stromal cells (MSCs) have shown benefit in other inflammatory diseases. Objectives To evaluate the safety and feasibility of endobronchial administration of bone marrow autologous MSCs (BM-MSC) in patients with mild-to-moderate IPF. Methods A phase I multicentre clinical trial (ClinicalTrials.gov NCT01919827) with a single endobronchial administration of autologous adult BM-MSCs in patients diagnosed with mild-to-moderate IPF. In a first escalating-dose phase, three patients were included sequentially in three dose cohorts (10×106, 50×106 and 100×106 cells). In a second phase, nine patients received the highest tolerated dose. Follow-up with pulmonary function testing, 6-min walk test and St George's Respiratory Questionnaire was done at 1, 2, 3, 6 and 12 months, and with computed tomography at 3, 6 and 12 months. Results 21 bone marrow samples were obtained from 17 patients. Three patients were excluded from treatment due to chromosome aberrations detected in MSCs after culture, and one patient died before treatment. Finally, 13 patients received the BM-MSC infusion. No treatment-related severe adverse events were observed during follow-up. Compared to baseline, the mean forced vital capacity showed an initial decline of 8.1% at 3 months. The number of patients without functional progression was six (46%) at 3 months and three (23%) at 12 months. Conclusions The endobronchial infusion of BM-MSCs did not cause immediate serious adverse events in IPF patients, but a relevant proportion of patients suffered clinical and/or functional progression. Genomic instability of BM-MSCs during culture found in three patients may be troublesome for the use of autologous MSCs in IPF patients. Endobronchial autologous mesenchymal stromal cells (MSCs) did not cause direct serious adverse events in IPF patients. However, significant progression was seen in seven out of 13 patients. Genomic instability of autologous MSCs may limit use in IPF.https://bit.ly/39akv7z
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Affiliation(s)
- Arantza Campo
- Pulmonary Medicine, Clínica Universidad de Navarra, Pamplona, Spain.,Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | | | - Enrique Andreu
- Hematology - Cell Therapy Area, Clínica Universidad de Navarra, Pamplona, Spain
| | - Ana B Alcaide
- Pulmonary Medicine, Clínica Universidad de Navarra, Pamplona, Spain
| | - María M Ocón
- Pulmonary Medicine, Clínica Universidad de Navarra, Pamplona, Spain
| | - Juan De-Torres
- Pulmonary Medicine, Clínica Universidad de Navarra, Pamplona, Spain
| | - Jesús Pueyo
- Radiology Dept, Clínica Universidad de Navarra, Pamplona, Spain
| | - Rosa Cordovilla
- Pulmonary Medicine, Hospital Universitario de Salamanca, Salamanca, Spain
| | - Eva Villaron
- Hematology, Hospital Universitario de Salamanca, Salamanca, Spain
| | | | - Miguel Barrueco
- Pulmonary Medicine, Hospital Universitario de Salamanca, Salamanca, Spain
| | - Jorge Nuñez-Córdoba
- Division of Biostatistics, Research Support Service, Central Clinical Trials Unit, Clínica Universidad de Navarra, Pamplona, Spain
| | - Felipe Prósper
- Hematology - Cell Therapy Area, Clínica Universidad de Navarra, Pamplona, Spain.,These authors contributed equally
| | - Javier J Zulueta
- Pulmonary Medicine, Clínica Universidad de Navarra, Pamplona, Spain.,These authors contributed equally
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Machhi J, Shahjin F, Das S, Patel M, Abdelmoaty MM, Cohen JD, Singh PA, Baldi A, Bajwa N, Kumar R, Vora LK, Patel TA, Oleynikov MD, Soni D, Yeapuri P, Mukadam I, Chakraborty R, Saksena CG, Herskovitz J, Hasan M, Oupicky D, Das S, Donnelly RF, Hettie KS, Chang L, Gendelman HE, Kevadiya BD. A Role for Extracellular Vesicles in SARS-CoV-2 Therapeutics and Prevention. J Neuroimmune Pharmacol 2021; 16:270-288. [PMID: 33544324 PMCID: PMC7862527 DOI: 10.1007/s11481-020-09981-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 12/28/2020] [Indexed: 12/13/2022]
Abstract
Extracellular vesicles (EVs) are the common designation for ectosomes, microparticles and microvesicles serving dominant roles in intercellular communication. Both viable and dying cells release EVs to the extracellular environment for transfer of cell, immune and infectious materials. Defined morphologically as lipid bi-layered structures EVs show molecular, biochemical, distribution, and entry mechanisms similar to viruses within cells and tissues. In recent years their functional capacities have been harnessed to deliver biomolecules and drugs and immunological agents to specific cells and organs of interest or disease. Interest in EVs as putative vaccines or drug delivery vehicles are substantial. The vesicles have properties of receptors nanoassembly on their surface. EVs can interact with specific immunocytes that include antigen presenting cells (dendritic cells and other mononuclear phagocytes) to elicit immune responses or affect tissue and cellular homeostasis or disease. Due to potential advantages like biocompatibility, biodegradation and efficient immune activation, EVs have gained attraction for the development of treatment or a vaccine system against the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) infection. In this review efforts to use EVs to contain SARS CoV-2 and affect the current viral pandemic are discussed. An emphasis is made on mesenchymal stem cell derived EVs' as a vaccine candidate delivery system.
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Affiliation(s)
- Jatin Machhi
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
| | - Farah Shahjin
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
| | - Srijanee Das
- Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Milankumar Patel
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
| | - Mai Mohamed Abdelmoaty
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198, USA
- Therapeutic Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, Giza, Egypt
| | - Jacob D Cohen
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
| | - Preet Amol Singh
- Department of Pharmaceutical Sciences & Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda, PB, India
| | - Ashish Baldi
- Department of Pharmaceutical Sciences & Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda, PB, India
| | - Neha Bajwa
- Department of Pharmaceutical Sciences & Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda, PB, India
| | - Raj Kumar
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Lalit K Vora
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK
| | - Tapan A Patel
- Department of Biological Sciences, P. D. Patel Institute of Applied Sciences (PDPIAS), Charotar University of Science and Technology (CHARUSAT), Changa, Anand, Gujarat, 388421, India
| | - Maxim D Oleynikov
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
| | - Dhruvkumar Soni
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Pravin Yeapuri
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
| | - Insiya Mukadam
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Rajashree Chakraborty
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
| | - Caroline G Saksena
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
| | - Jonathan Herskovitz
- Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Mahmudul Hasan
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - David Oupicky
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Suvarthi Das
- Department of Medicine, Stanford Medical School, Stanford University, 94304, Palo Alto, CA, USA
| | - Ryan F Donnelly
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK
| | - Kenneth S Hettie
- Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Department of Otolaryngology - Head & Neck Surgery, Stanford University, 94304, Palo Alto, CA, USA
| | - Linda Chang
- Departments of Diagnostic Radiology & Nuclear Medicine, and Neurology, School of Medicine, University of Maryland, 21201, Baltimore, MD, USA
| | - Howard E Gendelman
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA.
- Department of Pharmaceutical Sciences & Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda, PB, India.
| | - Bhavesh D Kevadiya
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
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Hoang DM, Nguyen KT, Nguyen AH, Nguyen BN, Nguyen LT. Allogeneic human umbilical cord-derived mesenchymal stem/stromal cells for chronic obstructive pulmonary disease (COPD): study protocol for a matched case-control, phase I/II trial. BMJ Open 2021; 11:e045788. [PMID: 33986057 PMCID: PMC8126295 DOI: 10.1136/bmjopen-2020-045788] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION The global prevalence of chronic obstructive pulmonary disease (COPD) is increasing, and it has become a major public health burden worldwide, including in Vietnam. A large body of preclinical and clinical studies supports the safety of mesenchymal stem/stromal cells (MSCs) in the treatment of lung injury, including COPD. The aim of this trial is to investigate the safety and potential therapeutic efficacy of allogeneic administration of umbilical cord-derived MSCs (UC-MSCs) as a supplementary intervention in combination with standard COPD medication treatments in patients with moderate-to-severe COPD based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2019 and Vietnam Ministry of Health's guidelines. METHODS AND ANALYSIS This matched case-control phase I/II trial is conducted at Vinmec Times City International Hospital, Hanoi, Vietnam between June 2020 and December 2021. In this study, 40 patients will be enrolled and assigned into two age-matched, gender-matched and COPD condition-matched groups, including a UC-MSC group and a control group. Both groups will receive standard COPD medication treatment based on the GOLD 2019 guidelines and the Vietnam Ministry of Health protocol. The UC-MSC group will receive two doses of thawed UC-MSC product with an intervention interval of 3 months. The primary outcome measures will include the incidence of prespecified administration-associated adverse events and serious adverse events. The efficacy will be evaluated based on the absolute changes in the number of admissions, arterial blood gas analysis, lung function and lung fibrosis via CT scan and chest X-ray. The clinical evaluation will be conducted at baseline and 3, 6 and 12 months postintervention. ETHICS AND DISSEMINATION Ethical approval was secured from the Ethical Committee of Vinmec International Hospital (number:166/2019/QĐ-VMEC) and Vietnam Ministry of Health (number:2002/QĐ-BYT). The results will be reported to trial collaborators, publication in peer-reviewed academic journals. TRIAL REGISTRATION NUMBER NCT04433104.
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Affiliation(s)
- Duc M Hoang
- Department of Research & Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Heathcare System, Hanoi, Vietnam
| | - Kien T Nguyen
- Clinical Research Department, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Viet Nam
| | - Anh H Nguyen
- Department of Internal Medicine, Vinmec Times City International Hospital, Hanoi, Viet Nam
| | - Bach N Nguyen
- Department of Internal Medicine, Vinmec Times City International Hospital, Hanoi, Viet Nam
| | - Liem Thanh Nguyen
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, Hanoi, Viet Nam
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Sun J, Huang J, Bao G, Zheng H, Wang C, Wei J, Fu Y, Qiu J, Liao Y, Cai J. MRI detection of the malignant transformation of stem cells through reporter gene expression driven by a tumor-specific promoter. Stem Cell Res Ther 2021; 12:284. [PMID: 33980305 PMCID: PMC8117323 DOI: 10.1186/s13287-021-02359-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Accepted: 04/27/2021] [Indexed: 01/10/2023] Open
Abstract
Background Existing evidence has shown that mesenchymal stem cells (MSCs) can undergo malignant transformation, which is a serious limitation of MSC-based therapies. Therefore, it is necessary to monitor malignant transformation of MSCs via a noninvasive imaging method. Although reporter gene-based magnetic resonance imaging (MRI) has been successfully applied to longitudinally monitor MSCs, this technique cannot distinguish the cells before and after malignant transformation. Herein, we investigated the feasibility of using a tumor-specific promoter to drive reporter gene expression for MRI detection of the malignant transformation of MSCs. Methods The reporter gene ferritin heavy chain (FTH1) was modified by adding a promoter from the tumor-specific gene progression elevated gene-3 (PEG3) and transduced into MSCs to obtain MSCs-PEG3-FTH1. Cells were induced to undergo malignant transformation via indirect coculture with C6 glioma cells, and these transformed cells were named MTMSCs-PEG3-FTH1. Western blot analysis of FTH1 expression, Prussian blue staining and transmission electron microscopy (TEM) to detect intracellular iron, and MRI to detect signal changes were performed before and after malignant transformation. Then, the cells before and after malignant transformation were inoculated subcutaneously into nude mice, and MRI was performed to observe the signal changes in the xenografts. Results After induction of malignant transformation, MTMSCs demonstrated tumor-like features in morphology, proliferation, migration, and invasion. FTH1 expression was significantly increased in MTMSCs-PEG3-FTH1 compared with MSCs-PEG3-FTH1. Prussian blue staining and TEM showed a large amount of iron particles in MTMSCs-PEG3-FTH1 but a minimal amount in MSCs-PEG3-FTH1. MRI demonstrated that the T2 value was significantly decreased in MTMSCs-PEG3-FTH1 compared with MSCs-PEG3-FTH1. In vivo, mass formation was observed in the MTMSCs-PEG3-FTH1 group but not the MSCs-PEG3-FTH1 group. T2-weighted MRI showed a significant signal decrease, which was correlated with iron accumulation in the tissue mass. Conclusions We developed a novel MRI model based on FTH1 reporter gene expression driven by the tumor-specific PEG3 promoter. This approach could be applied to sensitively detect the occurrence of MSC malignant transformation.
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Affiliation(s)
- Jun Sun
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, China.,Key Laboratory of Pediatrics in Chongqing, Chongqing, 400014, China.,Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, 400014, China.,Department of Radiology, Chongqing University Central Hospital, Chongqing, 400014, China
| | - Jie Huang
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, China.,Key Laboratory of Pediatrics in Chongqing, Chongqing, 400014, China.,Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, 400014, China
| | - Guangcheng Bao
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, China.,Key Laboratory of Pediatrics in Chongqing, Chongqing, 400014, China.,Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, 400014, China
| | - Helin Zheng
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China
| | - Cui Wang
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China
| | - Jie Wei
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, China.,Key Laboratory of Pediatrics in Chongqing, Chongqing, 400014, China.,Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, 400014, China
| | - Yuanqiao Fu
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, China.,Key Laboratory of Pediatrics in Chongqing, Chongqing, 400014, China.,Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, 400014, China
| | - Jiawen Qiu
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, China.,Key Laboratory of Pediatrics in Chongqing, Chongqing, 400014, China.,Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, 400014, China
| | - Yifan Liao
- Department of Nuclear Medicine, Xinqiao Hospital affiliated with Third Military Medical University, Chongqing, 400037, China
| | - Jinhua Cai
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China. .,Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, China. .,Key Laboratory of Pediatrics in Chongqing, Chongqing, 400014, China. .,Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, 400014, China.
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Srinivasan A, Sundar IK. Recent updates on the role of extracellular vesicles in the pathogenesis of allergic asthma. EXTRACELLULAR VESICLES AND CIRCULATING NUCLEIC ACIDS 2021; 2:127-147. [PMID: 34414402 PMCID: PMC8372030 DOI: 10.20517/evcna.2021.03] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Asthma is a chronic inflammatory disease of the airway diagnosed with different endotypes and phenotypes, characterized by airway obstruction in response to allergens, bacterial/viral infections, or pollutants. Several cell types such as the airway epithelial cells, mesenchymal stem cells and different immune cells including dendritic cells (DCs), T and B cells and mast cells play an essential role during the pathobiology of asthma. Extracellular vesicles (EVs) are membranous nanovesicles produced by every cell type that facilitates intercellular communications. EVs contain heterogeneous cargos that primarily depend on the composition or cell type of origin and they can alter the physiological state of the target cells. EVs encompass a wide variety of proteins including Tetraspanins, MHC classes I and II, co-stimulatory molecules, nucleic acids such as RNA, miRNA, piRNA, circRNA, and lipids like ceramides and sphingolipids. Recent literature indicates that EVs play a pivotal role in the pathophysiology of allergic asthma and may potentially be used as a novel biomarker to determine endotypes and phenotypes in severe asthmatics. Based on the prior reports, we speculate that regulation of EVs biogenesis and release might be under the control of circadian rhythms. Thus, circadian rhythms may influence the composition of the EVs, which alter the microenvironment that results in the induction of an immune-inflammatory response to various environmental insults or allergens such as air pollutants, ozone, diesel exhaust particles, pollens, outdoor molds, environmental tobacco smoke, etc. In this mini-review, we summarize the recent updates on the novel role of EVs in the pathogenesis of asthma, and highlight the link between circadian rhythms and EVs that may be important to identify molecular mechanisms to target during the pathogenesis of chronic inflammatory lung disease such as asthma.
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Affiliation(s)
- Ashokkumar Srinivasan
- Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas Medical Center, Lawrence, KS 66160, USA
| | - Isaac Kirubakaran Sundar
- Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas Medical Center, Lawrence, KS 66160, USA
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Xia X, Yuan P, Liu Y, Wang Y, Cao W, Zheng JC. Emerging roles of extracellular vesicles in COVID-19, a double-edged sword? Immunology 2021; 163:416-430. [PMID: 33742451 PMCID: PMC8251486 DOI: 10.1111/imm.13329] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 02/17/2021] [Accepted: 03/08/2021] [Indexed: 01/08/2023] Open
Abstract
The sudden outbreak of SARS‐CoV‐2‐infected disease (COVID‐19), initiated from Wuhan, China, has rapidly grown into a global pandemic. Emerging evidence has implicated extracellular vesicles (EVs), a key intercellular communicator, in the pathogenesis and treatment of COVID‐19. In the pathogenesis of COVID‐19, cells that express ACE2 and CD9 can transfer these viral receptors to other cells via EVs, making recipient cells more susceptible for SARS‐CoV‐2 infection. Once infected, cells release EVs packaged with viral particles that further facilitate viral spreading and immune evasion, aggravating COVID‐19 and its complications. In contrast, EVs derived from stem cells, especially mesenchymal stromal/stem cells, alleviate severe inflammation (cytokine storm) and repair damaged lung cells in COVID‐19 by delivery of anti‐inflammatory molecules. These therapeutic beneficial EVs can also be engineered into drug delivery platforms or vaccines to fight against COVID‐19. Therefore, EVs from diverse sources exhibit distinct effects in regulating viral infection, immune response, and tissue damage/repair, functioning as a double‐edged sword in COVID‐19. Here, we summarize the recent progress in understanding the pathological roles of EVs in COVID‐19. A comprehensive discussion of the therapeutic effects/potentials of EVs is also provided.
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Affiliation(s)
- Xiaohuan Xia
- Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai, China.,Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai, China
| | - Ping Yuan
- Department of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yihan Liu
- Department of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yi Wang
- Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai, China.,Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai, China
| | - Weijun Cao
- Department of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jialin C Zheng
- Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai, China.,Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai, China.,Collaborative Innovation Center for Brain Science, Tongji University, Shanghai, China
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Jamalkhah M, Asaadi Y, Azangou-Khyavy M, Khanali J, Soleimani M, Kiani J, Arefian E. MSC-derived exosomes carrying a cocktail of exogenous interfering RNAs an unprecedented therapy in era of COVID-19 outbreak. J Transl Med 2021; 19:164. [PMID: 33888147 PMCID: PMC8061879 DOI: 10.1186/s12967-021-02840-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 04/16/2021] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND The onset of the SARS-CoV-2 pandemic has resulted in ever-increasing casualties worldwide, and after 15 months, standard therapeutic regimens are yet to be discovered. MAIN BODY Due to the regenerative and immunomodulatory function of MSCs, they can serve as a suitable therapeutic option in alleviating major COVID-19 complications like acute respiratory distress syndrome. However, the superior properties of their cognate exosomes as a cell-free product make them preferable in the clinic. Herein, we discuss the current clinical status of these novel therapeutic strategies in COVID-19 treatment. We then delve into the potential of interfering RNAs incorporation as COVID-19 gene therapy and introduce targets involved in SARS-CoV-2 pathogenesis. Further, we present miRNAs and siRNAs candidates with promising results in targeting the mentioned targets. CONCLUSION Finally, we present a therapeutic platform of mesenchymal stem cell-derived exosomes equipped with exogenous iRNAs, that can be employed as a novel therapeutic modality in COVID-19 management aiming to prevent further viral spread within the lung, hinder the virus life cycle and pathogenesis such as immune suppression, and ultimately, enhance the antiviral immune response.
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Affiliation(s)
- Monire Jamalkhah
- Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran
| | - Yasaman Asaadi
- Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran
| | | | - Javad Khanali
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Masoud Soleimani
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Jafar Kiani
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Ehsan Arefian
- Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran.
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Glassberg MK, Csete I, Simonet E, Elliot SJ. Stem Cell Therapy for COPD: Hope and Exploitation. Chest 2021; 160:1271-1281. [PMID: 33894254 DOI: 10.1016/j.chest.2021.04.020] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 04/05/2021] [Accepted: 04/11/2021] [Indexed: 12/21/2022] Open
Abstract
COPD is a chronic inflammatory and destructive disease characterized by progressive decline in lung function that can accelerate with aging. Preclinical studies suggest that mesenchymal stem cells (MSCs) may provide a therapeutic option for this incurable disease because of their antiinflammatory, reparative, and immunomodulatory properties. To date, clinical trials using MSCs demonstrate safety in patients with COPD. However, because of the notable absence of large, multicenter randomized trials, no efficacy or evidence exists to support the possibility that MSCs can restore lung function in patients with COPD. Unfortunately, the investigational status of cell-based interventions for lung diseases has not hindered the propagation of commercial businesses, exploitation of the public, and explosion of medical tourism to promote unproven and potentially harmful cell-based interventions for COPD in the United States and worldwide. Patients with COPD constitute the largest group of patients with lung disease flocking to these unregulated clinics. This review highlights the numerous questions and concerns that remain before the establishment of cell-based interventions as safe and efficacious treatments for patients with COPD.
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Affiliation(s)
- Marilyn K Glassberg
- Division of Pulmonary, Critical Care, and Sleep, Department of Medicine, University of Arizona College of Medicine, Phoenix, AZ.
| | | | | | - Sharon J Elliot
- Division of Pulmonary, Critical Care, and Sleep, Department of Medicine, University of Arizona College of Medicine, Phoenix, AZ; University of Miami Miller School of Medicine, Miami, FL
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Hernandez JJ, Beaty DE, Fruhwirth LL, Lopes Chaves AP, Riordan NH. Dodging COVID-19 infection: low expression and localization of ACE2 and TMPRSS2 in multiple donor-derived lines of human umbilical cord-derived mesenchymal stem cells. J Transl Med 2021; 19:149. [PMID: 33853637 PMCID: PMC8045575 DOI: 10.1186/s12967-021-02813-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 04/01/2021] [Indexed: 12/18/2022] Open
Abstract
Background Mesenchymal stem cells derived from human umbilical cord (hUC-MSCs) have immunomodulatory properties that are of interest to treat novel coronavirus disease 2019 (COVID-19). Leng et al. recently reported that hUC-MSCs derived from one donor negatively expressed Angiotensin-Converting Enzyme 2 (ACE2), a key protein for viral infection along with Transmembrane Serine Protease 2 (TMPRSS2). The purpose of this study was to quantify the expression of ACE2 and TMPRSS2 in hUC-MSCs lots derived from multiple donors using molecular-based techniques in order to demonstrate their inability to be a host to SARS-CoV-2. Methods Expression of ACE2 and TMPRSS2 was analyzed in 24 lots of hUC-MSCs derived from Wharton's jelly via quantitative polymerase chain reaction (qPCR), Western Blot, immunofluorescence and flow cytometry using 24 different donors. Results hUC-MSCs had significantly lower ACE2 (p = 0.002) and TMPRSS2 (p = 0.008) expression compared with human lung tissue homogenates in Western blot analyses. Little to no expression of ACE2 was observed in hUC-MSC by qPCR, and they were not observable with immunofluorescence in hUC-MSCs cell membranes. A negative ACE2 and TMPRSS2 population percentage of 95.3% ± 15.55 was obtained for hUC-MSCs via flow cytometry, with only 4.6% ACE2 and 29.5% TMPRSS2 observable positive populations. Conclusions We have demonstrated negative expression of ACE2 and low expression of TMPRSS2 in 24 lots of hUC-MSCs. This has crucial implications for the design of future therapeutic options for COVID-19, since hUC-MSCs would have the ability to “dodge” viral infection to exert their immunomodulatory effects. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-021-02813-6.
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Affiliation(s)
- Jonathan J Hernandez
- Aidan Research and Consulting LLC, 11496 Luna Rd, suite 1100, Farmers Branch, TX, 75234, USA. .,Medistem Inc Panama, Ciudad del Saber, Edif. 221/Clayton, Panama, Republic of Panama.
| | - Doyle E Beaty
- Aidan Research and Consulting LLC, 11496 Luna Rd, suite 1100, Farmers Branch, TX, 75234, USA
| | - Logan L Fruhwirth
- Aidan Research and Consulting LLC, 11496 Luna Rd, suite 1100, Farmers Branch, TX, 75234, USA
| | - Ana P Lopes Chaves
- Aidan Research and Consulting LLC, 11496 Luna Rd, suite 1100, Farmers Branch, TX, 75234, USA
| | - Neil H Riordan
- Aidan Research and Consulting LLC, 11496 Luna Rd, suite 1100, Farmers Branch, TX, 75234, USA.,Medistem Inc Panama, Ciudad del Saber, Edif. 221/Clayton, Panama, Republic of Panama
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Fernández-Francos S, Eiro N, Costa LA, Escudero-Cernuda S, Fernández-Sánchez ML, Vizoso FJ. Mesenchymal Stem Cells as a Cornerstone in a Galaxy of Intercellular Signals: Basis for a New Era of Medicine. Int J Mol Sci 2021; 22:ijms22073576. [PMID: 33808241 PMCID: PMC8036553 DOI: 10.3390/ijms22073576] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 03/25/2021] [Accepted: 03/26/2021] [Indexed: 02/06/2023] Open
Abstract
Around 40% of the population will suffer at some point in their life a disease involving tissue loss or an inflammatory or autoimmune process that cannot be satisfactorily controlled with current therapies. An alternative for these processes is represented by stem cells and, especially, mesenchymal stem cells (MSC). Numerous preclinical studies have shown MSC to have therapeutic effects in different clinical conditions, probably due to their mesodermal origin. Thereby, MSC appear to play a central role in the control of a galaxy of intercellular signals of anti-inflammatory, regenerative, angiogenic, anti-fibrotic, anti-oxidative stress effects of anti-apoptotic, anti-tumor, or anti-microbial type. This concept forces us to return to the origin of natural physiological processes as a starting point to understand the evolution of MSC therapy in the field of regenerative medicine. These biological effects, demonstrated in countless preclinical studies, justify their first clinical applications, and draw a horizon of new therapeutic strategies. However, several limitations of MSC as cell therapy are recognized, such as safety issues, handling difficulties for therapeutic purposes, and high economic cost. For these reasons, there is an ongoing tendency to consider the use of MSC-derived secretome products as a therapeutic tool, since they reproduce the effects of their parent cells. However, it will be necessary to resolve key aspects, such as the choice of the ideal type of MSC according to their origin for each therapeutic indication and the implementation of new standardized production strategies. Therefore, stem cell science based on an intelligently designed production of MSC and or their derivative products will be able to advance towards an innovative and more personalized medical biotechnology.
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Affiliation(s)
| | - Noemi Eiro
- Research Unit, Fundación Hospital de Jove, 33290 Gijón, Spain; (S.F.-F.); (L.A.C.)
- Correspondence: (N.E.); (F.J.V.); Tel.: +34-985320050 (ext. 84216)
| | - Luis A. Costa
- Research Unit, Fundación Hospital de Jove, 33290 Gijón, Spain; (S.F.-F.); (L.A.C.)
| | - Sara Escudero-Cernuda
- Department of Physical and Analytical Chemistry, Faculty of Chemistry, University of Oviedo, 33006 Oviedo, Spain; (S.E.-C.); (M.L.F.-S.)
| | - María Luisa Fernández-Sánchez
- Department of Physical and Analytical Chemistry, Faculty of Chemistry, University of Oviedo, 33006 Oviedo, Spain; (S.E.-C.); (M.L.F.-S.)
| | - Francisco J. Vizoso
- Research Unit, Fundación Hospital de Jove, 33290 Gijón, Spain; (S.F.-F.); (L.A.C.)
- Correspondence: (N.E.); (F.J.V.); Tel.: +34-985320050 (ext. 84216)
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Merino A, Hoogduijn MJ, Molina-Molina M, Arias-Salgado EG, Korevaar SS, Baan CC, Montes-Worboys A. Membrane particles from mesenchymal stromal cells reduce the expression of fibrotic markers on pulmonary cells. PLoS One 2021; 16:e0248415. [PMID: 33730089 PMCID: PMC7968667 DOI: 10.1371/journal.pone.0248415] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 02/26/2021] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with limited treatment options in which the telomere shortening is a strong predictive factor of poor prognosis. Mesenchymal stromal cells (MSC) administration is probed in several experimental induced lung pathologies; however, MSC might stimulate fibrotic processes. A therapy that avoids MSC side effects of transformation would be an alternative to the use of living cells. Membranes particles (MP) are nanovesicles artificially generated from the membranes of MSC containing active enzymes involved in ECM regeneration. We aimed to investigate the anti-fibrotic role of MP derived from MSC in an in vitro model of pulmonary fibrosis. METHODS Epithelial cells (A549) and lung fibroblasts, from IPF patients with different telomere length, were co-cultured with MP and TGF-β for 48h and gene expression of major pro-fibrotic markers were analyzed. RESULTS About 90% of both types of cells effectively took up MP without cytotoxic effects. MP decreased the expression of profibrotic proteins such as Col1A1, Fibronectin and PAI-1, in A549 cells. In fibroblasts culture, there was a different response in the inhibitory effect of MP on some pro-fibrotic markers when comparing fibroblast from normal telomere length patients (FN) versus short telomere length (FS), but both types showed an inhibition of Col1A1, Tenascin-c, PAI-1 and MMP-1 gene expression after MP treatment. CONCLUSIONS MP conserve some of the properties attributed to the living MSC. This study shows that MP target lung cells, via which they may have a broad anti-fibrotic effect.
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Affiliation(s)
- Ana Merino
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Martin J. Hoogduijn
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Maria Molina-Molina
- Unit of Interstitial Lung Diseases, Pulmonary Department, University Hospital of Bellvitge, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
- CIBER of Respiratory Diseases (CIBERES) Health Institute Carlos III, Madrid, Spain
| | | | - Sander S. Korevaar
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Carla C. Baan
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Ana Montes-Worboys
- Unit of Interstitial Lung Diseases, Pulmonary Department, University Hospital of Bellvitge, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
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Abreu SC, Lopes-Pacheco M, Weiss DJ, Rocco PRM. Mesenchymal Stromal Cell-Derived Extracellular Vesicles in Lung Diseases: Current Status and Perspectives. Front Cell Dev Biol 2021; 9:600711. [PMID: 33659247 PMCID: PMC7917181 DOI: 10.3389/fcell.2021.600711] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Accepted: 01/11/2021] [Indexed: 12/11/2022] Open
Abstract
Extracellular vesicles (EVs) have emerged as a potential therapy for several diseases. These plasma membrane-derived fragments are released constitutively by virtually all cell types-including mesenchymal stromal cells (MSCs)-under stimulation or following cell-to-cell interaction, which leads to activation or inhibition of distinct signaling pathways. Based on their size, intracellular origin, and secretion pathway, EVs have been grouped into three main populations: exosomes, microvesicles (or microparticles), and apoptotic bodies. Several molecules can be found inside MSC-derived EVs, including proteins, lipids, mRNA, microRNAs, DNAs, as well as organelles that can be transferred to damaged recipient cells, thus contributing to the reparative process and promoting relevant anti-inflammatory/resolutive actions. Indeed, the paracrine/endocrine actions induced by MSC-derived EVs have demonstrated therapeutic potential to mitigate or even reverse tissue damage, thus raising interest in the regenerative medicine field, particularly for lung diseases. In this review, we summarize the main features of EVs and the current understanding of the mechanisms of action of MSC-derived EVs in several lung diseases, such as chronic obstructive pulmonary disease (COPD), pulmonary infections [including coronavirus disease 2019 (COVID-19)], asthma, acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF), and cystic fibrosis (CF), among others. Finally, we list a number of limitations associated with this therapeutic strategy that must be overcome in order to translate effective EV-based therapies into clinical practice.
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Affiliation(s)
- Soraia C. Abreu
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil
| | - Miquéias Lopes-Pacheco
- Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, Lisbon, Portugal
| | - Daniel J. Weiss
- Department of Medicine, College of Medicine, University of Vermont Larner, Burlington, VT, United States
| | - Patricia R. M. Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil
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Fröhlich E. Therapeutic Potential of Mesenchymal Stem Cells and Their Products in Lung Diseases-Intravenous Administration versus Inhalation. Pharmaceutics 2021; 13:232. [PMID: 33562240 PMCID: PMC7915745 DOI: 10.3390/pharmaceutics13020232] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/29/2021] [Accepted: 02/03/2021] [Indexed: 12/13/2022] Open
Abstract
The number of publications studying the therapeutic use of stem cells has steadily increased since 2000. Compared to other applications, there has been little interest in the evaluation of mesenchymal stem cells (MSCs) and MSC-derived products (mostly extracellular vesicles) for the treatment of respiratory diseases. Due to the lack of efficient treatments for acute respiratory distress syndrome caused by infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the action of MSCs has also been studied. This review describes mode of action and use of MSCs and MSC-derived products in the treatment of lung diseases including the respective advantages and limitations of the products. Further, issues related to standardized production are addressed. Administration by inhalation of MSCs, compared to intravenous injection, could decrease cell damage by shear stress, eliminate the barrier to reach target cells in the alveoli, prevent thrombus formation in the pulmonary vasculature and retention in filter for extracorporeal membrane oxygenation. There is more feasible to deliver extracellular vesicles than MSCs with inhalers, offering the advantage of non-invasive and repeated administration by the patient. Major obstacles for comparison of results are heterogeneity of the products, differences in the treatment protocols and small study cohorts.
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Affiliation(s)
- Eleonore Fröhlich
- Center for Medical Research, Medical University of Graz, Stiftingtalstr 24, 8010 Graz, Austria; ; Tel.: +43-316-385-73011
- Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13, 8010 Graz, Austria
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Wu G, Chang F, Fang H, Zheng X, Zhuang M, Liu X, Hou W, Xu L, Chen Z, Tang C, Wu Y, Sun Y, Zhu F. Non-muscle myosin II knockdown improves survival and therapeutic effects of implanted bone marrow-derived mesenchymal stem cells in lipopolysaccharide-induced acute lung injury. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:262. [PMID: 33708889 PMCID: PMC7940885 DOI: 10.21037/atm-20-4851] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Background Bone marrow-derived mesenchymal stem cells (BMSCs) have been shown to have some beneficial effects in acute lung injury (ALI), but the therapeutic effects are limited due to apoptosis or necrosis after transplantation into injured lungs. Here, we aim to explore whether Non-muscle myosin II (NM-II) knockdown could enhance BMSCs survival and improve therapeutic effects in ALI. Methods MSCs, isolated from rat bone marrow, were transfected with the small interfering RNA (siRNA) targeted to NM-II mRNA by a lentivirus vector. Rats were equally randomized to four groups: the control group was given normal saline via tail vein; the other three groups underwent intratracheal lipopolysaccharide (LPS) instillation followed by administration with either normal saline, BMSCs transduced with lentivirus-enhanced green fluorescent protein (eGFP) empty vector, or BMSCs transduced with lentivirus-eGFP NM-II siRNA. Hematoxylin and eosin staining was used to evaluate lung histopathologic changes and Masson trichrome staining was used to assess lung fibrosis. The myeloperoxidase activity was also tested in lung tissues. The mRNA expression of inflammatory cytokines in lung tissues was determined via quantitative reverse transcription PCR. Sex-determining region of the Y chromosome gene expression was measured by fluorescence in situ hybridization (FISH) assay. The expression of self-renewal activity and apoptosis-associated proteins were measured by Western blot. Results Transplantation of NM-II siRNA-modified BMSCs could improve histopathological morphology, decrease inflammatory infiltrates, down-regulate the expression levels of inflammatory cytokines, and reduce pulmonary interstitial edema. NM-II siRNA-modified BMSCs showed antifibrotic properties and alleviated the degrees of pulmonary fibrosis induced by endotoxin. In addition, NM-II knockdown BMSCs showed slightly better therapeutic effect on lung inflammation when compared with control BMSCs. The beneficial effects of NM-II siRNA-modified BMSCs may be attributed to enhanced self-renewal activity and decreased apoptosis. Conclusions NM-II knockdown could inhibit the apoptosis of implanted BMSCs in lung tissues and improve its self-renewal activity. NM-II siRNA-modified BMSCs have a slightly enhanced ability to attenuate lung injury after LPS challenge.
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Affiliation(s)
- Guosheng Wu
- Department of Burn Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Fei Chang
- Department of Burn and Plastic Surgery, The Affiliated Zhang Jiagang Hospital of Soochow University, Suzhou, China
| | - He Fang
- Department of Burn Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Xingfeng Zheng
- Department of Burn Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Mingzhu Zhuang
- Clinical BioBank, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Xiaobin Liu
- Department of Burn Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Wenjia Hou
- Department of Burn Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Long Xu
- Department of Burn Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Zhengli Chen
- Department of Burn Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Chenqi Tang
- Department of Burn Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Yu Wu
- Department of Anesthesiology, Bethune International Peace Hospital, Shijiazhuang, China
| | - Yu Sun
- Department of Burn Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Feng Zhu
- Department of Burn Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
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The clinical and radiological course of bronchopulmonary dysplasia in twins treated with mesenchymal stem cells and followed up using lung ultrasonography. Turk Arch Pediatr 2021; 55:425-429. [PMID: 33414661 PMCID: PMC7750334 DOI: 10.14744/turkpediatriars.2019.88785] [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: 11/22/2018] [Accepted: 10/30/2019] [Indexed: 12/18/2022]
Abstract
Bronchopulmonary dysplasia is a chronic lung disease that develops in low-birth-weight infants as a result of mechanical ventilation and oxygen toxicity in the early neonatal period. In these patients, mechanical ventilation and oxygen support are needed for a long time. We already use antenatal steroid, ventilation techniques with minimal baro/volutrauma, postnatal steroid, and vitamin A to prevent the development of bronchopulmonary dysplasia. Mesenchymal stem cell treatment is another way to reduce or stop the pathophysiologic pathways in the development of bronchopulmonary dysplasia. Herein, we present mesenchymal stem cell treatment and its outcomes in twins who were born with a gestational age of 26 weeks and diagnosed as having bronchopulmonary dysplasia (the female twin was born with a birth weight of 750 g and the male twin was born with a birth weight of 930 g). These patients were followed up with clinical findings, chest radiography, and lung ultrasonography.
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Oroojalian F, Haghbin A, Baradaran B, Hemmat N, Shahbazi MA, Baghi HB, Mokhtarzadeh A, Hamblin MR. Novel insights into the treatment of SARS-CoV-2 infection: An overview of current clinical trials. Int J Biol Macromol 2020; 165:18-43. [PMID: 32991900 PMCID: PMC7521454 DOI: 10.1016/j.ijbiomac.2020.09.204] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 09/15/2020] [Accepted: 09/22/2020] [Indexed: 12/13/2022]
Abstract
The emergence of the global pandemic caused by the novel SARS-CoV-2 virus has motivated scientists to find a definitive treatment or a vaccine against it in the shortest possible time. Current efforts towards this goal remain fruitless without a full understanding of the behavior of the virus and its adaptor proteins. This review provides an overview of the biological properties, functional mechanisms, and molecular components of SARS-CoV-2, along with investigational therapeutic and preventive approaches for this virus. Since the proteolytic cleavage of the S protein is critical for virus penetration into cells, a set of drugs, such as chloroquine, hydroxychloroquine, camostat mesylate have been tested in clinical trials to suppress this event. In addition to angiotensin-converting enzyme 2, the role of CD147 in the viral entrance has also been proposed. Mepolizumab has shown to be effective in blocking the virus's cellular entrance. Antiviral drugs, such as remdesivir, ritonavir, oseltamivir, darunavir, lopinavir, zanamivir, peramivir, and oseltamivir, have also been tested as treatments for COVID-19. Regarding preventive vaccines, the whole virus, vectors, nucleic acids, and structural subunits have been suggested for vaccine development. Mesenchymal stem cells and natural killer cells could also be used against SARS-CoV-2. All the above-mentioned strategies, as well as the role of nanomedicine for the diagnosis and treatment of SARS-CoV-2 infection, have been discussed in this review.
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Affiliation(s)
- Fatemeh Oroojalian
- Department of Advanced Sciences and Technologies in Medicine, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran; Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Ali Haghbin
- Department of Pediatrics, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran; Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nima Hemmat
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad-Ali Shahbazi
- Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki FI-00014, Finland; Department of Pharmaceutical Nanotechnology, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Hossein Bannazadeh Baghi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Virology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Michael R Hamblin
- Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Dermatology, Harvard Medical School, Boston, MA 02115, USA; Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa.
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Gao Y, Raj JU. Extracellular Vesicles as Unique Signaling Messengers: Role in Lung Diseases. Compr Physiol 2020; 11:1351-1369. [PMID: 33294981 DOI: 10.1002/cphy.c200006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Extracellular vesicles (EVs) are lipid bilayer-enclosed extracellular particles carrying rich cargo such as proteins, lipids, and microRNAs with distinct characteristics of their parental cells. EVs are emerging as an important form of cellular communication with the ability to selectively deliver a kit of directional instructions to nearby or distant cells to modulate their functions and phenotypes. According to their biogenesis, EVs can be divided into two groups: those of endocytic origin are called exosomes and those derived from outward budding of the plasma membrane are called microvesicles (also known as ectosomes or microparticles). Under physiological conditions, EVs are actively involved in maintenance of pulmonary hemostasis. However, EVs can contribute to the pathogenesis of diseases such as chronic obstructive pulmonary disease, asthma, acute lung injury/acute respiratory distress syndrome, interstitial lung disease, and pulmonary arterial hypertension. EVs, especially those derived from mesenchymal/stromal stem cells, can also be beneficial and can curb the development of lung diseases. Novel technologies are continuously being developed to minimize the undesirable effects of EVs and also to engineer EVs so that they may have beneficial effects and can be used as therapeutic agents in lung diseases. © 2021 American Physiological Society. Compr Physiol 11:1351-1369, 2021.
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Affiliation(s)
- Yuansheng Gao
- Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China
| | - J Usha Raj
- Department of Pediatrics, College of Medicine at Chicago, University of Illinois, Chicago, Illinois, USA
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