|
1
|
Elliot SJ, Anderson-Terhune D, Roos B, Rubio GA, Xia X, Pereira-Simon S, Catanuto P, Civettini G, Hagen ES, Arvanitis C, Shahzeidi S, Glassberg MK. Ratio of miRNA-29 to miRNA-199 expression coordinates mesenchymal stem cell repair of bleomycin-induced pulmonary injury. MOLECULAR THERAPY. NUCLEIC ACIDS 2025; 36:102461. [PMID: 40124162 PMCID: PMC11930095 DOI: 10.1016/j.omtn.2025.102461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 01/17/2025] [Indexed: 03/25/2025]
Abstract
Our previous work demonstrated the anti-fibrotic effects of infusion of adipose-derived mesenchymal stem cells (ASCs) to prevent or repair bleomycin (BLM)-induced lung injury. The present study investigates mechanisms driving these anti-fibrotic effects. Pulmonary fibrosis developed at day 12 in 22-month-old C57BL/6 male mice after intratracheal BLM instillation. There was a decrease in indices of pulmonary fibrosis, including collagen content, AKT activation, collagen types I and III, αV-integrin, tumor necrosis factor alpha, and transforming growth factor β mRNA after infusion of ASCs 12 days post-BLM treatment compared to BLM alone. Infusion of ASCs increased the population of alveolar types I and II epithelial cells that had been reduced after BLM treatment. miRNAscope technology and reverse-transcription polymerase chain reaction revealed that ASC-treated mice demonstrated increased miR-29a, decreased miR-199, and increased telomere length, telomerase RNA component, and telomerase reverse transcriptase compared to BLM alone. In vitro and ex vivo experiments using double-transfected mouse or human myofibroblasts (miR-29 mimic, and miR-199 inhibitor) confirmed that alterations of these miRNAs regulate downstream effectors of fibrosis. These data suggest that alteration of the ratio of anti-fibrotic to fibrotic miRNAs and increase in telomere length are critical mechanisms of ASC-mediated repair of BLM-induced pulmonary fibrosis.
Collapse
Affiliation(s)
- Sharon J. Elliot
- Stritch School of Medicine, Department of Medicine, Loyola University Chicago, Maywood, IL 60153, USA
| | - Dustin Anderson-Terhune
- Department of Pulmonary and Critical Care, University of Utah, Salt Lake City, UT 84112, USA
| | - Benjamin Roos
- Stritch School of Medicine, Department of Medicine, Loyola University Chicago, Maywood, IL 60153, USA
| | - Gustavo A. Rubio
- Associate Medical Director, Jackson Health System, 1611 NW 12 Avenue, Miami, FL 33136, USA
| | - Xiaomei Xia
- Department of Medicine, Division of Pulmonary, Critical Care, and Sleep, University of Arizona College of Medicine-Phoenix University Medical Center-Phoenix, Phoenix, AZ 85004, USA
| | - Simone Pereira-Simon
- Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33101, USA
| | - Paola Catanuto
- Department of Ophthalmology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33101, USA
| | - Gina Civettini
- Stritch School of Medicine, Department of Medicine, Loyola University Chicago, Maywood, IL 60153, USA
| | - Emily S. Hagen
- Stritch School of Medicine, Department of Medicine, Loyola University Chicago, Maywood, IL 60153, USA
| | - Constadina Arvanitis
- Director of Center for Advanced Microscopy & Nikon Imaging Center, Northwestern University, Chicago, IL 60611, USA
| | - Shahriar Shahzeidi
- Grand Health Institute, 1717 N. Bayshore Drive, Suite R244, Miami, FL 33132, USA
| | - Marilyn K. Glassberg
- Stritch School of Medicine, Department of Medicine, Loyola University Chicago, Maywood, IL 60153, USA
| |
Collapse
|
|
2
|
Zhang Y, Zhao Y, An C, Guo Y, Ma Y, Shao F, Zhang Y, Sun K, Cheng F, Ren C, Zhang L, Sun B, Zhang Y, Wang H. Material-driven immunomodulation and ECM remodeling reverse pulmonary fibrosis by local delivery of stem cell-laden microcapsules. Biomaterials 2025; 313:122757. [PMID: 39178558 DOI: 10.1016/j.biomaterials.2024.122757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 08/13/2024] [Accepted: 08/15/2024] [Indexed: 08/26/2024]
Abstract
Recent progress in stem cell therapy has demonstrated the therapeutic potential of intravenous stem cell infusions for treating the life-threatening lung disease of pulmonary fibrosis (PF). However, it is confronted with limitations, such as a lack of control over cellular function and rapid clearance by the host after implantation. In this study, we developed an innovative PF therapy through tracheal administration of microfluidic-templated stem cell-laden microcapsules, which effectively reversed the progression of inflammation and fibrotic injury. Our findings highlight that hydrogel microencapsulation can enhance the persistence of donor mesenchymal stem cells (MSCs) in the host while driving MSCs to substantially augment their therapeutic functions, including immunoregulation and matrix metalloproteinase (MMP)-mediated extracellular matrix (ECM) remodeling. We revealed that microencapsulation activates the MAPK signaling pathway in MSCs to increase MMP expression, thereby degrading overexpressed collagen accumulated in fibrotic lungs. Our research demonstrates the potential of hydrogel microcapsules to enhance the therapeutic efficacy of MSCs through cell-material interactions, presenting a promising yet straightforward strategy for designing advanced stem cell therapies for fibrotic diseases.
Collapse
Affiliation(s)
- Yujie Zhang
- MOE Key Laboratory of Bio-Intelligent Manufacturing, Dalian Key Laboratory of Artificial Organ and Regenerative Medicine, School of Bioengineering, Dalian University of Technology, Dalian, Liaoning, PR China
| | - Yuan Zhao
- MOE Key Laboratory of Bio-Intelligent Manufacturing, Dalian Key Laboratory of Artificial Organ and Regenerative Medicine, School of Bioengineering, Dalian University of Technology, Dalian, Liaoning, PR China
| | - Chuanfeng An
- MOE Key Laboratory of Bio-Intelligent Manufacturing, Dalian Key Laboratory of Artificial Organ and Regenerative Medicine, School of Bioengineering, Dalian University of Technology, Dalian, Liaoning, PR China
| | - Yiyang Guo
- State Key Laboratory of Fine Chemicals, Frontiers Science Center for Smart Materials Oriented Chemical Engineering, Dalian University of Technology, Dalian, 116024, PR China; School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, 116024, Dalian, PR China
| | - Yubin Ma
- State Key Laboratory of Fine Chemicals, Frontiers Science Center for Smart Materials Oriented Chemical Engineering, Dalian University of Technology, Dalian, 116024, PR China; School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, 116024, Dalian, PR China
| | - Fei Shao
- MOE Key Laboratory of Bio-Intelligent Manufacturing, Dalian Key Laboratory of Artificial Organ and Regenerative Medicine, School of Bioengineering, Dalian University of Technology, Dalian, Liaoning, PR China
| | - Yonggang Zhang
- MOE Key Laboratory of Bio-Intelligent Manufacturing, Dalian Key Laboratory of Artificial Organ and Regenerative Medicine, School of Bioengineering, Dalian University of Technology, Dalian, Liaoning, PR China
| | - Kai Sun
- MOE Key Laboratory of Bio-Intelligent Manufacturing, Dalian Key Laboratory of Artificial Organ and Regenerative Medicine, School of Bioengineering, Dalian University of Technology, Dalian, Liaoning, PR China
| | - Fang Cheng
- State Key Laboratory of Fine Chemicals, Frontiers Science Center for Smart Materials Oriented Chemical Engineering, Dalian University of Technology, Dalian, 116024, PR China
| | - Changle Ren
- Faculty of Medicine, Dalian University of Technology, Dalian, 116023, PR China; Department of Joint Surgery, Dalian Municipal Central Hospital, Dalian, 116044, PR China
| | - Lijun Zhang
- Third People's Hospital of Dalian, Dalian Eye Hospital, Dalian, 116024, PR China
| | - Bingbing Sun
- State Key Laboratory of Fine Chemicals, Frontiers Science Center for Smart Materials Oriented Chemical Engineering, Dalian University of Technology, Dalian, 116024, PR China; School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, 116024, Dalian, PR China
| | - Yang Zhang
- School of Dentistry, Health Science Center, Shenzhen University, Shenzhen, 518015, PR China
| | - Huanan Wang
- MOE Key Laboratory of Bio-Intelligent Manufacturing, Dalian Key Laboratory of Artificial Organ and Regenerative Medicine, School of Bioengineering, Dalian University of Technology, Dalian, Liaoning, PR China; State Key Laboratory of Fine Chemicals, Frontiers Science Center for Smart Materials Oriented Chemical Engineering, Dalian University of Technology, Dalian, 116024, PR China.
| |
Collapse
|
|
3
|
Qiu H, Zhang R, Si D, Shu Y, Liu J, Xia Y, Zhou O, Tan W, Yang K, Tian D, Luo Z, Liu E, Zou L, Fu Z, Peng D. Human Umbilical Cord-Mesenchymal Stem Cells Combined With Low Dosage Nintedanib Rather Than Using Alone Mitigates Pulmonary Fibrosis in Mice. Stem Cells Int 2025; 2025:9445735. [PMID: 39817116 PMCID: PMC11732289 DOI: 10.1155/sci/9445735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 11/15/2024] [Accepted: 12/16/2024] [Indexed: 01/18/2025] Open
Abstract
Pulmonary fibrosis (PF) is a lethal pathological change of fibrotic interstitial lung diseases (ILDs) with abundant fibroblasts proliferation after severely or continually alveolar epithelial cells (AECs) injury. Barely therapies are helpful for PF. Here we use bleomycin intratracheally injection to model PF with or without human umbilical cord-mesenchymal stem cells (hUC-MSCs) and/or nintedanib intervention. RNA-Seq followed with real-time PCR and western blot were used to find out the specific possible mechanisms of the effects of hUC-MSC and nintedanib on PF. Immunostaining, cell counting kit-8 (CCK-8), and 5-bromo-2'-deoxyuridine (BrdU) incorporation assay were used to detect the cell proliferation in vivo or in vitro separately. We found that hUC-MSCs alone had prophylactic, but not therapeutic effects on bleomycin induced mouse PF. Nevertheless, the combination therapy of hUC-MSCs and low-dose nintedanib significantly improved survival and reversed lung fibrosis in PF model mice. The factors secreted by hUC-MSCs have promotional effects on the proliferation both of fibroblasts and AECs. Nintedanib could hamper the facilitation of fibroblasts caused by hUC-MSCs without influence on AECs proliferation, which might be related with the inhibition on FGFR, PDGFR, and VEGFR activities. Our study indicated that the combination therapy of hUC-MSCs and nintedanib should be a promising strategy for PF.
Collapse
Affiliation(s)
- Huijun Qiu
- Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, China
| | - Rong Zhang
- Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, China
| | - Daozhu Si
- Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, China
| | - Yi Shu
- Centre for Clinical Molecular Medicine, Children's Hospital of Chongqing Medical University, Chongqing 400014, China
| | - Jiang Liu
- Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, China
| | - Yunqiu Xia
- Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, China
| | - Ou Zhou
- Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, China
| | - Wen Tan
- Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, China
| | - Ke Yang
- Chongqing Engineering Research Centre of Stem Cell Therapy, Chongqing 400014, China
| | - Daiyin Tian
- Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, China
| | - Zhengxiu Luo
- Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, China
| | - Enmei Liu
- Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, China
| | - Lin Zou
- Centre for Clinical Molecular Medicine, Children's Hospital of Chongqing Medical University, Chongqing 400014, China
- Chongqing Engineering Research Centre of Stem Cell Therapy, Chongqing 400014, China
| | - Zhou Fu
- Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, China
- Chongqing Engineering Research Centre of Stem Cell Therapy, Chongqing 400014, China
| | - Danyi Peng
- Department of Respiratory Medicine Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, China
| |
Collapse
|
|
4
|
Petersen AG, Korntner SH, Bousamaki J, Oró D, Arraut AM, Pors SE, Salinas CG, Andersen MW, Madsen MR, Nie Y, Butts J, Roqueta‐Rivera M, Simonsen U, Hansen HH, Feigh M. Reproducible lung protective effects of a TGFβR1/ALK5 inhibitor in a bleomycin-induced and spirometry-confirmed model of IPF in male mice. Physiol Rep 2024; 12:e70077. [PMID: 39394052 PMCID: PMC11469938 DOI: 10.14814/phy2.70077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 08/30/2024] [Accepted: 09/20/2024] [Indexed: 10/13/2024] Open
Abstract
This study comprehensively validated the bleomycin (BLEO) induced mouse model of IPF for utility in preclinical drug discovery. To this end, the model was rigorously evaluated for reproducible phenotype and TGFβ-directed treatment outcomes. Lung disease was profiled longitudinally in male C57BL6/JRJ mice receiving a single intratracheal instillation of BLEO (n = 10-12 per group). A TGFβR1/ALK5 inhibitor (ALK5i) was profiled in six independent studies in BLEO-IPF mice, randomized/stratified to treatment according to baseline body weight and non-invasive whole-body plethysmography. ALK5i (60 mg/kg/day) or vehicle (n = 10-16 per study) was administered orally for 21 days, starting 7 days after intratracheal BLEO installation. BLEO-IPF mice recapitulated functional, histological and biochemical hallmarks of IPF, including declining expiratory/inspiratory capacity and inflammatory and fibrotic lung injury accompanied by markedly elevated TGFβ levels in bronchoalveolar lavage fluid and lung tissue. Pulmonary transcriptome signatures of inflammation and fibrosis in BLEO-IPF mice were comparable to reported data in IPF patients. ALK5i promoted reproducible and robust therapeutic outcomes on lung functional, biochemical and histological endpoints in BLEO-IPF mice. The robust lung fibrotic disease phenotype, along with the consistent and reproducible lung protective effects of ALK5i treatment, makes the spirometry-confirmed BLEO-IPF mouse model highly applicable for profiling novel drug candidates for IPF.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | | | - Yaohui Nie
- Enanta PharmaceuticalsWatertownMassachusettsUSA
| | | | | | - Ulf Simonsen
- Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Faculty of HealthAarhus UniversityAarhusDenmark
| | | | | |
Collapse
|
|
5
|
Hou XY, Danzeng LM, Wu YL, Ma QH, Yu Z, Li MY, Li LS. Mesenchymal stem cells and their derived exosomes for the treatment of COVID-19. World J Stem Cells 2024; 16:353-374. [PMID: 38690515 PMCID: PMC11056634 DOI: 10.4252/wjsc.v16.i4.353] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 02/17/2024] [Accepted: 03/15/2024] [Indexed: 04/25/2024] Open
Abstract
Coronavirus disease 2019 (COVID-19) is an acute respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infection typically presents with fever and respiratory symptoms, which can progress to severe respiratory distress syndrome and multiple organ failure. In severe cases, these complications may even lead to death. One of the causes of COVID-19 deaths is the cytokine storm caused by an overactive immune response. Therefore, suppressing the overactive immune response may be an effective strategy for treating COVID-19. Mesenchymal stem cells (MSCs) and their derived exosomes (MSCs-Exo) have potent homing abilities, immunomodulatory functions, regenerative repair, and antifibrotic effects, promising an effective tool in treating COVID-19. In this paper, we review the main mechanisms and potential roles of MSCs and MSCs-Exo in treating COVID-19. We also summarize relevant recent clinical trials, including the source of cells, the dosage and the efficacy, and the clinical value and problems in this field, providing more theoretical references for the clinical use of MSCs and MSCs-Exo in the treatment of COVID-19.
Collapse
Affiliation(s)
- Xiang-Yi Hou
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, Jilin Province, China
| | - La-Mu Danzeng
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, Jilin Province, China
| | - Yi-Lin Wu
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, Jilin Province, China
| | - Qian-Hui Ma
- Department of Pharmacy, Jilin University, Changchun 130021, Jilin Province, China
| | - Zheng Yu
- The First Hospital of Jilin University, Jilin University, Changchun 130021, Jilin Province, China
| | - Mei-Ying Li
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, Jilin Province, China
| | - Li-Sha Li
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun 130021, Jilin Province, China.
| |
Collapse
|
|
6
|
Escarrer-Garau G, Martín-Medina A, Truyols-Vives J, Gómez-Bellvert C, Elowsson L, Westergren-Thorsson G, Molina-Molina M, Mercader-Barceló J, Sala-Llinàs E. In Vivo and In Vitro Pro-Fibrotic Response of Lung-Resident Mesenchymal Stem Cells from Patients with Idiopathic Pulmonary Fibrosis. Cells 2024; 13:160. [PMID: 38247851 PMCID: PMC10814068 DOI: 10.3390/cells13020160] [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: 11/28/2023] [Revised: 01/05/2024] [Accepted: 01/09/2024] [Indexed: 01/23/2024] Open
Abstract
Lung-resident mesenchymal stem cells (LR-MSC) are thought to participate in idiopathic pulmonary fibrosis (IPF) by differentiating into myofibroblasts. On the other hand, LR-MSC in IPF patients present senescence-related features. It is unclear how they respond to a profibrotic environment. Here, we investigated the profibrotic response of LR-MSC isolated from IPF and control (CON) patients. LR-MSC were inoculated in mice 48 h after bleomycin (BLM) instillation to analyze their contribution to lung damage. In vitro, LR-MSC were exposed to TGFβ. Mice inoculated with IPF LR-MSC exhibited worse maintenance of their body weight. The instillation of either IPF or CON LR-MSC sustained BLM-induced histological lung damage, bronchoalveolar lavage fluid cell count, and the expression of the myofibroblast marker, extracellular matrix (ECM) proteins, and proinflammatory cytokines in the lungs. In vitro, IPF LR-MSC displayed higher basal protein levels of aSMA and fibronectin than CON LR-MSC. However, the TGFβ response in the expression of TGFβ, aSMA, and ECM genes was attenuated in IPF LR-MSC. In conclusion, IPF LR-MSC have acquired myofibroblastic features, but their capacity to further respond to profibrotic stimuli seems to be attenuated. In an advanced stage of the disease, LR-MSC may participate in disease progression owing to their limited ability to repair epithelial damage.
Collapse
Affiliation(s)
| | - Aina Martín-Medina
- iRESPIRE Research Group, Health Research Institute of the Balearic Islands (IdISBa), 07120 Palma, Spain
| | - Joan Truyols-Vives
- MolONE Research Group, University of the Balearic Islands (UIB), 07122 Palma, Spain
| | | | - Linda Elowsson
- Lung Biology, Department of Experimental Medical Science, Lund University, 08908 Lund, Sweden
| | | | - Maria Molina-Molina
- ILD Unit, Respiratory Department, University Hospital of Bellvitge-Bellvitge Biomedical Research Institute (IDIBELL), 08908 Hospitalet de Llobregat, Barcelona, Spain
- Centre of Biomedical Research Network in Respiratory Diseases (CIBERES), 28029 Madrid, Spain
| | - Josep Mercader-Barceló
- MolONE Research Group, University of the Balearic Islands (UIB), 07122 Palma, Spain
- iRESPIRE Research Group, Health Research Institute of the Balearic Islands (IdISBa), 07120 Palma, Spain
- Centre of Biomedical Research Network in Respiratory Diseases (CIBERES), 28029 Madrid, Spain
| | - Ernest Sala-Llinàs
- iRESPIRE Research Group, Health Research Institute of the Balearic Islands (IdISBa), 07120 Palma, Spain
- Centre of Biomedical Research Network in Respiratory Diseases (CIBERES), 28029 Madrid, Spain
| |
Collapse
|
|
7
|
Liu Q, Bi Y, Song S, Zhu K, Qiao X, Wang H, Ji G. Exosomal miR-17-5p from human embryonic stem cells prevents pulmonary fibrosis by targeting thrombospondin-2. Stem Cell Res Ther 2023; 14:234. [PMID: 37667335 PMCID: PMC10478444 DOI: 10.1186/s13287-023-03449-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 08/11/2023] [Indexed: 09/06/2023] Open
Abstract
BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible lung disease characterized by pulmonary fibrosis and lung dysfunction, ultimately leading to respiratory failure. Many preclinical studies have investigated the therapeutic potential of stem cell-derived exosomes in this disease, particularly mesenchymal stem cell-derived exosomes. However, the effects of embryonic stem cell-derived exosomes in IPF remain unclear. METHODS We established a bleomycin (BLM)-induced pulmonary fibrosis mice model and administered human embryonic stem cell exosomes (hESC-exo) from the first day after BLM treatment. The effects of hESC-exo were assessed by pulmonary function tests, biochemical analysis, histochemistry, quantitative real-time polymerase chain reaction (qPCR), and western blot (WB). RNA-seq was used to screen for the potential therapeutic targets of hESC-exo in fibrotic lungs; the identified signaling axis was characterized using a luciferase assay, qPCR, and WB. RESULTS Results indicated hESC-exo administration notably alleviated inflammation, removed deposited collagen, and rescued alveolar architecture in the lungs of BLM-induced mice. In vivo and in vitro tests revealed that hESC-exo-derived miR-17-5p directly bound thrombospondin-2 (Thbs2) to regulate inflammation and fibrosis; thus, hESC-exo protected against BLM toxicity in the lungs via the miR-17-5p/Thbs2 axis. CONCLUSION These results suggest a promising new treatment for fibrosis-associated diseases.
Collapse
Affiliation(s)
- Qun Liu
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Youkun Bi
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Shaole Song
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Keqi Zhu
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xinlong Qiao
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Huiwen Wang
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Guangju Ji
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
| |
Collapse
|
|
8
|
Armstrong BBS, Pedroso JCM, Conceição Carvalho JD, Ferreira LM. Mesenchymal stem cells in lung diseases and their potential use in COVID-19 ARDS: A systematized review. Clinics (Sao Paulo) 2023; 78:100237. [PMID: 37454534 PMCID: PMC10368758 DOI: 10.1016/j.clinsp.2023.100237] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 01/23/2023] [Accepted: 04/24/2023] [Indexed: 07/18/2023] Open
Abstract
COVID-19 can converge with the pro-inflammatory immunoregulatory mechanisms of chronic lung diseases. Given the disorders inherent to lung transplantation and the inexistence of other definitive therapeutic alternatives, Adipose tissue-derived Stem Cells (ASCs) presented themselves as a therapeutic hope. The purpose of this review is to assess the basis for the potential use of ASCs in lung diseases unresponsive to conventional therapy, relating to their possible use in COVID-19 ARDS. 35 studies comprised this review, 14 being narrative reviews, 19 preclinical trials and two proofs of concept. COVID-19 can converge with the pro-inflammatory immunoregulatory mechanisms of chronic lung diseases. In view of the disorders inherent to lung transplantation and the inexistence of definitive therapeutic alternatives, Adipose tissue-derived Stem Cells (ASCs) presented themselves as a therapeutic hope. Its detailed reading indicated the absence of serious adverse effects and toxicity to the administration of ASCs and suggested possible effectiveness in reducing lung damage, in addition to promoting the recovery of leukocytes and lymphocytes with its immunomodulatory and anti-apoptotic effects. The revised clinical data suggests optimism in the applicability of ASCs in other immunoinflammatory diseases and in severe COVID-19 ARDS. However, further studies are needed to develop a consensus on the methods of collection of ASCs, the ideal dosage schedule, the most effective time and route of administration, as well as on the definition of indications for the administration of ASCs in cases of COVID-19 for conducting clinical trials in near future.
Collapse
Affiliation(s)
| | | | | | - Lydia Masako Ferreira
- Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil.
| |
Collapse
|
|
9
|
Wei S, Geng L, Yu H, Wang J, Yue Y, Zhang Q, Wu N. Isolation, Characterization, and Anti-Idiopathic Pulmonary Fibrosis Activity of a Fucoidan from Costaria costata. Molecules 2023; 28:molecules28114343. [PMID: 37298817 DOI: 10.3390/molecules28114343] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Revised: 05/12/2023] [Accepted: 05/19/2023] [Indexed: 06/12/2023] Open
Abstract
Pulmonary fibrosis is a chronic, progressive, and fatal disease of the interstitial lung. There is currently a lack of efficient therapy to reverse the prognosis of patients. In this study, a fucoidan from Costaria costata was isolated, and its anti-idiopathic fibrosis activity was investigated both in vitro and in vivo. The chemical composition analysis showed that C. costata polysaccharide (CCP) consists of galactose and fucose as the main monosaccharides with a sulfate group content of 18.54%. Further study found that CCP could resist TGF-β1-induced epithelial-mesenchymal transition (EMT) in A549 cells by inhibiting the TGF-β/Smad and PI3K/AKT/mTOR signaling pathways. Moreover, in vivo study found that CCP treatment alleviated bleomycin (BLM)-stimulated fibrosis and inflammation in mice lung tissue. In conclusion, the present study suggests that CCP could protect the lung from fibrosis by relieving the EMT process and inflammation in lung cells.
Collapse
Affiliation(s)
- Sijie Wei
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China
- University of Chinese Academy of Sciences, Beijing 101408, China
| | - Lihua Geng
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China
| | - Haoyu Yu
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China
- University of Chinese Academy of Sciences, Beijing 101408, China
| | - Jing Wang
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China
| | - Yang Yue
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China
| | - Quanbin Zhang
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China
- University of Chinese Academy of Sciences, Beijing 101408, China
| | - Ning Wu
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China
- Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China
- Nantong Zhongke Marine Science and Technology Research and Development Center, Nantong 226682, China
| |
Collapse
|
|
10
|
The Restoring Effect of Human Umbilical Cord-Derived Mesenchymal Cell-Conditioned Medium (hMSC-CM) against Carbon Tetrachloride-Induced Pulmonary Fibrosis in Male Wistar Rats. Int J Inflam 2022; 2022:7179766. [PMID: 36588784 PMCID: PMC9800074 DOI: 10.1155/2022/7179766] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 11/19/2022] [Accepted: 11/29/2022] [Indexed: 12/24/2022] Open
Abstract
Objective Pulmonary toxicity induced by CCl4, a model of idiopathic pulmonary fibrosis (IPF), leads to tissue remodeling and inflammation. Human umbilical cord mesenchymal cell-conditioned medium (hMSC-CM) is a potent anti-inflammatory, antioxidative, and antifibrotic agent. Methods Forty male Wistar rats were assigned to the control (C), olive oil control (C.O) (hMSC-CM), control (C.Ms), fibrosis (fb), and fibrosis with hMSC-CM (f.Ms) treatment groups. The groups C, C.O, and C.Ms received PBS (200 µl), olive oil (1 ml/kg), and hMSC-CM (100 μg protein/kg), respectively. The fibrosis group was administered with only CCl4 (1 ml/kg). The last group, f.Ms was treated with CCl4 (1 ml/kg) and 100 μg protein/kg IV hMSC-CM. While the treatment with olive oil and CCl4 was performed for 2 days/week from the first week for 12 weeks, the treatment with PBS and hMSC-CM was carried out 2 days/week from week 4th to week 12th. The effect of the UC-MSC culture medium treatment on the lung was evaluated by assessing lysyl oxidase (LOX), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-β1 (TGF-β1) genes, and proteins expression by real-time RCR and western blotting, respectively. Results Lysyl oxidase (LOX), tumor necrosis factor-alpha (TNF-α), transforming growth factor-b1 (TGF-β1), malondialdehyde (MDA), and oxidative stress levels were markedly higher in the fibrosis group than in the control groups (p ≤ 0.001). Additionally, glutathione (GSH) in the fibrosis group was markedly lower than those in the control groups (p ≤ 0.001). Fibrosis in the UC-MSC treatment group had milder histopathological injuries than in the fibrosis group. Conclusion hMSC-MSC as a strong anti-inflammatory, antioxidative, and antifibrotic decreases the level of oxidative stress, proinflammatory cytokines, and MDA causing a restoring effect against CCl4-induced pulmonary fibrosis.
Collapse
|
|
11
|
Fikry H, Saleh LA, Gawad SA. Therapeutic effect of adipose-derived mesenchymal stem cells (AD-MSCs) compared to pirfenidone on corticosteroid resistance in a mouse model of acute exacerbation of idiopathic pulmonary fibrosis. Histol Histopathol 2022; 37:1065-1083. [PMID: 35816024 DOI: 10.14670/hh-18-493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Acute exacerbation-idiopathic pulmonary fibrosis (AE-IPF) is a life-threatening condition. In the treatment of AE-IPF, corticosteroid medication is commonly utilized. However, there is insufficient evidence to justify its usage. Pirfenidone (PFD) has recently been discovered to be effective in the treatment of AE-IPF patients. However, regenerative therapy, such as stem cell therapy or tissue engineering, is necessary due to ineffective and limited therapies. Combining MSC transplantation with pharmacological therapy may also give additional benefits; nevertheless, its use must be proven experimentally. As a result, the goal of this study was to assess the therapeutic effects of adipose-derived mesenchymal stem cells (AD-MSCs) on corticosteroid resistance in an animal model of AE-IPF caused by bleomycin compared to PFD. MATERIALS AND METHODS Seventy C57BL/6J male mice were randomly divided into seven groups, control, BLM, methylprednisolone (MP), PFD, AD-MSCs, PFD +MP, and AD-MSCs +MP. RESULTS In terms of survival, collagen deposition, the acute lung injury score (ALI), and the Ashcroft score, AD-MSCs exceeded PFD. AD-MSCs + MP provided protection and preserved the lung's architecture in BLM-induced AE. In addition, AD-MSCs successfully decreased chemokine (CC motif) ligand-2 (CCL2) positive cells and lower pro-fibrotic and pro-inflammatory cytokines. CONCLUSIONS AD-MSCs enhanced histological structure, Ashcroft and ALI scores, lung collagen deposition, survival, and cytokines in an animal model of AE-IPF. As a result, we believe that AD-MSCs may be more therapeutically helpful for AE-IPF than presently available therapies, either alone or in conjunction with MP.
Collapse
Affiliation(s)
- Heba Fikry
- Department of Histology and Cell Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | - Lobna A Saleh
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Sara Abdel Gawad
- Department of Histology and Cell Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| |
Collapse
|
|
12
|
Promises and Challenges of Cell-Based Therapies to Promote Lung Regeneration in Idiopathic Pulmonary Fibrosis. Cells 2022; 11:cells11162595. [PMID: 36010671 PMCID: PMC9406501 DOI: 10.3390/cells11162595] [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: 07/11/2022] [Revised: 08/15/2022] [Accepted: 08/18/2022] [Indexed: 12/17/2022] Open
Abstract
The lung epithelium is constantly exposed to harmful agents present in the air that we breathe making it highly susceptible to damage. However, in instances of injury to the lung, it exhibits a remarkable capacity to regenerate injured tissue thanks to the presence of distinct stem and progenitor cell populations along the airway and alveolar epithelium. Mechanisms of repair are affected in chronic lung diseases such as idiopathic pulmonary fibrosis (IPF), a progressive life-threatening disorder characterized by the loss of alveolar structures, wherein excessive deposition of extracellular matrix components cause the distortion of tissue architecture that limits lung function and impairs tissue repair. Here, we review the most recent findings of a study of epithelial cells with progenitor behavior that contribute to tissue repair as well as the mechanisms involved in mouse and human lung regeneration. In addition, we describe therapeutic strategies to promote or induce lung regeneration and the cell-based strategies tested in clinical trials for the treatment of IPF. Finally, we discuss the challenges, concerns and limitations of applying these therapies of cell transplantation in IPF patients. Further research is still required to develop successful strategies focused on cell-based therapies to promote lung regeneration to restore lung architecture and function.
Collapse
|
|
13
|
Bao H, Cheng S, Li X, Li Y, Yu C, Huang J, Zhang Z. Functional Au nanoparticles for engineering and long-term CT imaging tracking of mesenchymal stem cells in idiopathic pulmonary fibrosis treatment. Biomaterials 2022; 288:121731. [PMID: 35970616 DOI: 10.1016/j.biomaterials.2022.121731] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 07/24/2022] [Accepted: 08/04/2022] [Indexed: 11/30/2022]
Abstract
Idiopathic pulmonary fibrosis (IPF) therapy has always been a big and long-standing challenge in clinical practice due to the lack of miraculous medicine. Mesenchymal stem cells (MSCs)-based therapy has recently emerged as a promising candidate for redefining IPF therapy. Enhancing the therapeutic efficacy of MSCs and understanding of their growth, migration and differentiation in harsh lung microenviroments are two keys to improving the stem cell-based IPF treatment. Herein, a non-viral dual-functional nanocarrier is fabricated by a one-pot approach, using protamine sulfate stabilized Au nanoparticles (AuPS), to genetically engineer MSCs for simultaneous IPF treatment and monitoring the biological behavior of the MSCs. AuPS exhibits superior cellular uptake ability, which results in efficient genetic engineering of MSCs to overexpress hepatocyte growth factor for enhanced IPF therapy. In parallel, the intracellular accumulation of AuPS improves the CT imaging contrast of MSCs, allowing visual tracking of the therapeutic engineered MSCs up to 48 days. Overall, this work has described for the first time a novel strategy for enhanced therapeutic efficacy and long-term CT imaging tracking of transplanted MSCs in IPF therapy, providing great prospect for stem cell therapy of lung disease.
Collapse
Affiliation(s)
- Hongying Bao
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China; School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei, 230026, China
| | - Shengnan Cheng
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China; School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei, 230026, China
| | - Xiaodi Li
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China; School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei, 230026, China
| | - Yuxuan Li
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China; School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei, 230026, China
| | - Chenggong Yu
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China; School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei, 230026, China
| | - Jie Huang
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China; School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei, 230026, China.
| | - Zhijun Zhang
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China; School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei, 230026, China.
| |
Collapse
|
|
14
|
Surtaieva YV, Mazurkevich AY, Bokotko RR. Effects of transplanted mesenchymal stem cells on repair of the lung tissue of rats with experimental pulmonary fibrosis. REGULATORY MECHANISMS IN BIOSYSTEMS 2022. [DOI: 10.15421/022240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Pulmonary fibrosis is one of the commonest forms of interstitial lung diseases with poorly studied methods of its treatment in both human and veterinary medicines. Therefore, this paper focused on seeking alternative methods of its diagnostics and treatment. The article provides the results of the study of bronchoalveolar lavage fluid of rats with experimental lung fibrosis and influence of transplanted allogeneic mesenchymal stem cells of the bone marrow on stimulation of regenerative processes in damaged lung tissues. The studies were conducted on female Wistar rats with pulmonary fibrosis modeled using single transthoracic injection of solution of bleomycin hydrochloride. For the purpose of treatment, we used allogeneic mesenchymal stem cells introduced by various methods and the traditional treatment. We determined that best normalization of the parameters of the studied brochoalveolar lavage occurred in animals that received mesenchymal stem cells. The most active repair processes were in the experimental group that received the mesenchymal stem cells directly to the lung tissue. The animals that received intravenous injection of mesenchymal stemm cells were observed to have lower clinical parameters of the brochoalveolar lavage, but still better than such in the group treated traditionally. The lowest parameters were in animals that received the traditional treatment; they were greater than the phisological parameters, but significantly exceeded them in animals of the control group, indicating presence of inflammatory process in the lung tissue. The conducted cytological assays of the samples of the brochoalveolar lavage revealed that experimental animals with experimental pulmonary fibrosis had development of macrophage and lymphocytic reactions under the influence of transplanted mesenchymal stemm cells. We observed no atypical cells in all the experimental groups. This allows us to draw a conclusion that using stem cells by various methods of transplantation does not stimulate the onset of negative reactons (formation of atypical cells, metastatic processes, etc). Thus, the results of the study of the influence of transplanted mesenchymal stem cells demonstrate that in the conditions of experimental pulmonary fibrosis, the activity of regenerative processes in pathologically altered lung tissue may be an effective method of treatment of animals with this kind of pathology.
Collapse
|
|
15
|
Therapeutic Effect of Astragali Radix Extract Injection Combined with Bone Marrow Mesenchymal Stem Cells in Bleomycin-Induced Pulmonary Fibrotic Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:4933255. [PMID: 35733628 PMCID: PMC9208943 DOI: 10.1155/2022/4933255] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 04/23/2022] [Accepted: 05/17/2022] [Indexed: 02/07/2023]
Abstract
Pulmonary fibrosis is a serious disease for which effective drugs are unavailable. Here, we treated rat models of bleomycin (BLM)-induced pulmonary fibrosis with Astragali Radix extract injection (AI) combined with or without bone marrow mesenchymal stem cells (BMSCs). We injected rats intratracheally with BLM and transplanted BMSCs via tail vein injection 15 days later. We also intraperitoneally injected AI daily from days 15 to 28. Changes in lung pathology and function, as well as the levels of matrix metalloproteinases, collagen, C-X-C motif chemokine ligand 12 (CXCL12), and cluster of differentiation 90 (CD90) were assessed. The results revealed that compared with the BLM group, groups treated with ARE and BMSCs (alone or combined) reduced the expression levels of TGF-β1 and collagens I and III, ameliorated pathological lung fibrotic damage, and improved lung function. The expression levels of MMP-1, MMP-3, and MMP-9 were reduced by either AI or BMSCs alone, whereas those of MMP-3, MMP-9, TIMP-1, CXCL12, and CD90 were elevated by combined AI and BMSCs compared with the BLM group. Overall, these findings demonstrated that AI and BMSCs both can reduce damage caused by PF in rats and that AI altered the expression of chemokines and surface markers in BMSCs.
Collapse
|
|
16
|
Saito Y, Imai K, Furumoto H, Kudo Y, Makino Y, Maehara S, Shimada Y, Ohtani K, Hagiwara M, Kakihana M, Ohira T, Matsubayashi J, Ikeda N. Effect of photodynamic therapy (PDT) on a rat model of bleomycin-induced interstitial pneumonia. Photodiagnosis Photodyn Ther 2022; 37:102659. [PMID: 34852311 DOI: 10.1016/j.pdpdt.2021.102659] [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: 08/26/2021] [Revised: 11/03/2021] [Accepted: 11/24/2021] [Indexed: 11/16/2022]
Abstract
BACKGROUND Even if lung cancer is detected at an early stage, surgery may be difficult in patients with severe comorbidities, like interstitial pneumonia (IP). Radiation therapy cannot be performed due to the high risk of acute IP exacerbation. Therefore, an effective alternative, such as photodynamic therapy (PDT), is required. To prove that acute exacerbation is not induced after PDT in peripheral lung cancer, we investigated the effects of PDT on IP rat models. METHODS Bleomycin (BLM) was administered intratracheally. Seven days after administration, left thoracotomy was performed. Talaporfin sodium was injected, and diode laser irradiation (664 nm, 150mW, 100J/cm2) was performed. Seven days after PDT, the whole blood and left lungs were collected. A total of 23 rats, comprising BLM + PDT (n = 4), BLM + non-PDT (n = 10), non-BLM + PDT (n = 2), non-BLM + non-PDT (n = 5), and two rats that died immediately after PDT were observed. Serum levels of Krebs von den Lungen-6, surfactant protein-D, lactate dehydrogenase, and serum C-reactive protein were measured. Fibrosis and macrophage scorings, and the collagen fibers percentage were examined by staining with hematoxylin and eosin, Elastica van Gieson, anti-α smooth muscle antibody, and anti-CD68 antibodies. RESULTS There was no remarkable difference in the values of each marker in fibrosis and macrophage scores with or without PDT. In case of death, fibrosis was mild, and PDT was not affected. CONCLUSIONS In IP rat models, PDT did not induce lung fibrosis or acute exacerbation.
Collapse
Affiliation(s)
- Yuka Saito
- Department of Surgery, Tokyo Medical University, Tokyo, Japan.
| | - Kentaro Imai
- Department of Surgery, Tokyo Medical University, Tokyo, Japan
| | | | - Yujin Kudo
- Department of Surgery, Tokyo Medical University, Tokyo, Japan
| | - Yojiro Makino
- Department of Surgery, Tokyo Medical University, Tokyo, Japan
| | - Sachio Maehara
- Department of Surgery, Tokyo Medical University, Tokyo, Japan
| | | | - Keishi Ohtani
- Department of Surgery, Tokyo Medical University, Tokyo, Japan
| | - Masaru Hagiwara
- Department of Surgery, Tokyo Medical University, Tokyo, Japan
| | | | - Tatsuo Ohira
- Department of Surgery, Tokyo Medical University, Tokyo, Japan
| | - Jun Matsubayashi
- Department of Human Pathology, Tokyo Medical University, Tokyo, Japan
| | - Norihiko Ikeda
- Department of Surgery, Tokyo Medical University, Tokyo, Japan
| |
Collapse
|
|
17
|
Kusuma GD, Li A, Zhu D, McDonald H, Inocencio IM, Chambers DC, Sinclair K, Fang H, Greening DW, Frith JE, Lim R. Effect of 2D and 3D Culture Microenvironments on Mesenchymal Stem Cell-Derived Extracellular Vesicles Potencies. Front Cell Dev Biol 2022; 10:819726. [PMID: 35237601 PMCID: PMC8882622 DOI: 10.3389/fcell.2022.819726] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 01/17/2022] [Indexed: 02/06/2023] Open
Abstract
Therapeutic benefits of mesenchymal stem cells (MSCs) are now widely believed to come from their paracrine signalling, i.e. secreted factors such as cytokines, chemokines, and extracellular vesicles (EVs). Cell-free therapy using EVs is an active and emerging field in regenerative medicine. Typical 2D cultures on tissue culture plastic is far removed from the physiological environment of MSCs. The application of 3D cell culture allows MSCs to adapt to their cellular environment which, in turn, influences their paracrine signalling activity. In this study we evaluated the impact of 3D MSCs culture on EVs secretion, cargo proteome composition, and functional assessment in immunomodulatory, anti-inflammatory and anti-fibrotic properties.MSC-EVs from 2D and 3D cultures expressed classical EV markers CD81, CD63, and CD9 with particle diameter of <100 nm. There were distinct changes in immunomodulatory potencies where 3D cultures exhibited reduced indoleamine 2,3-dioxygenase (IDO) activity and significantly reduced macrophage phagocytosis. Administration of 2D and 3D EVs following double dose bleomycin challenge in aged mice showed a marked increase of bodyweight loss in 3D group throughout days 7–28. Histopathological observations of lung tissues in 3D group showed increased collagen deposition, myofibroblast differentiation and leukocytes infiltrations. Assessment of lung mechanics showed 3D group did not improve lung function and instead exhibited increased resistance and tissue damping. Proteome profiling of MSC-EV composition revealed molecular enrichment of EV markers (compared to parental cells) and differential proteome between EVs from 2D and 3D culture condition associated with immune-based and fibrosis/extracellular matrix/membrane organization associated function.This study provides insight into distinct variation in EV protein composition dependent on the cellular microenvironment of the parental cells, which could have implications in their therapeutic effect and potency. Overall, this work suggests that EVs produced from 3D MSC cultures did not enhance typical MSC-EV properties expected from 2D cultures (immunomodulation, anti-fibrotic, anti-inflammatory). The outcome highlights critical differences between MSC-EVs obtained from different culture microenvironments, which should be considered when scaling up MSC culture for clinical manufacturing.
Collapse
Affiliation(s)
- Gina D. Kusuma
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
- *Correspondence: Gina D. Kusuma, ; Rebecca Lim,
| | - Anqi Li
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
| | - Dandan Zhu
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
| | - Hannah McDonald
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
| | - Ishmael M. Inocencio
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
| | - Daniel C. Chambers
- Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, QLD, Australia
- School of Clinical Medicine, Faculty of Health Sciences, University of Queensland, Brisbane, QLD, Australia
| | - Kenneth Sinclair
- Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, QLD, Australia
| | - Haoyun Fang
- Molecular Proteomics, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - David W. Greening
- Molecular Proteomics, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
- Baker Department of Cardiometabolic Health, The University of Melbourne, Melbourne, VIC, Australia
- Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Melbourne, VIC, Australia
- Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Jessica E. Frith
- Department of Materials Science and Engineering, Monash University, Melbourne, VIC, Australia
| | - Rebecca Lim
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
- *Correspondence: Gina D. Kusuma, ; Rebecca Lim,
| |
Collapse
|
|
18
|
Inhibition of aberrant tissue remodelling by mesenchymal stromal cells singly coated with soft gels presenting defined chemomechanical cues. Nat Biomed Eng 2022; 6:54-66. [PMID: 34083763 PMCID: PMC8908879 DOI: 10.1038/s41551-021-00740-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 04/28/2021] [Indexed: 02/06/2023]
Abstract
The precise understanding and control of microenvironmental cues could be used to optimize the efficacy of cell therapeutics. Here, we show that mesenchymal stromal cells (MSCs) singly coated with a soft conformal gel presenting defined chemomechanical cues promote matrix remodelling by secreting soluble interstitial collagenases in response to the presence of tumour necrosis factor alpha (TNF-α). In mice with fibrotic lung injury, treatment with the coated MSCs maintained normal collagen levels, fibre density and microelasticity in lung tissue, and the continuous presentation of recombinant TNF-α in the gel facilitated the reversal of aberrant tissue remodelling by the cells when inflammation subsided in the host. Gel coatings with predefined chemomechanical cues could be used to tailor cells with specific mechanisms of action for desired therapeutic outcomes.
Collapse
|
|
19
|
Wang X, Zhao S, Lai J, Guan W, Gao Y. Anti-Inflammatory, Antioxidant, and Antifibrotic Effects of Gingival-Derived MSCs on Bleomycin-Induced Pulmonary Fibrosis in Mice. Int J Mol Sci 2021; 23:ijms23010099. [PMID: 35008524 PMCID: PMC8745316 DOI: 10.3390/ijms23010099] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 12/02/2021] [Accepted: 12/09/2021] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Mesenchymal stem cell (MSC) intervention has been associated with lung protection. We attempted to determine whether mouse gingival-derived mesenchymal stem cells (GMSCs) could protect against bleomycin-induced pulmonary fibrosis. METHODS Mice were divided into three groups: control (Con), bleomycin (Bl), and bleomycin + MSCs (Bl + MSCs). Mice were treated with 5 mg/kg bleomycin via transtracheal instillation to induce pulmonary fibrosis. We assessed the following parameters: histopathological severity of injury in the lung, liver, kidney, and aortic tissues; the degree of pulmonary fibrosis; pulmonary inflammation; pulmonary oedema; profibrotic factor levels in bronchoalveolar lavage fluid (BALF) and lung tissue; oxidative stress-related indicators and apoptotic index in lung tissue; and gene expression levels of IL-1β, IL-8, TNF-α, lysophosphatidic acid (LPA), lysophosphatidic acid receptor 1 (LPA1), TGF-β, matrix metalloproteinase 9 (MMP-9), neutrophil elastase (NE), MPO, and IL-10 in lung tissue. RESULTS GMSC intervention attenuated bleomycin-induced pulmonary fibrosis, pulmonary inflammation, pulmonary oedema, and apoptosis. Bleomycin instillation notably increased expression levels of the IL-1β, IL-8, TNF-α, LPA, LPA1, TGF-β, MMP-9, NE, and MPO genes and attenuated expression levels of the IL-10 gene in lung tissue, and these effects were reversed by GMSC intervention. Bleomycin instillation notably upregulated MDA and MPO levels and downregulated GSH and SOD levels in lung tissue, and these effects were reversed by GMSC intervention. GMSC intervention prevented upregulation of neutrophil content in the lung, liver, and kidney tissues and the apoptotic index in lung tissue. CONCLUSIONS GMSC intervention exhibits anti-inflammatory and antioxidant capacities. Deleterious accumulation of neutrophils, which is reduced by GMSC intervention, is a key component of bleomycin-induced pulmonary fibrosis. GMSC intervention impairs bleomycin-induced NE, MMP-9, LPA, APL1, and TGF-β release.
Collapse
Affiliation(s)
- Xishuai Wang
- Department of Animal Genetic Resources, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (X.W.); (S.Z.); (J.L.)
- College of P.E and Sport, Beijing Normal University, Beijing 100193, China
| | - Shiyu Zhao
- Department of Animal Genetic Resources, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (X.W.); (S.Z.); (J.L.)
| | - Junhui Lai
- Department of Animal Genetic Resources, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (X.W.); (S.Z.); (J.L.)
| | - Weijun Guan
- Department of Animal Genetic Resources, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (X.W.); (S.Z.); (J.L.)
- Correspondence: (W.G.); (Y.G.)
| | - Yang Gao
- Institute of Physical Educational Training, Capital University of Physical Education and Sports, Beijing 100193, China
- Correspondence: (W.G.); (Y.G.)
| |
Collapse
|
|
20
|
Chang H, Meng HY, Bai WF, Meng QG. A metabolomic approach to elucidate the inhibitory effects of baicalin in pulmonary fibrosis. PHARMACEUTICAL BIOLOGY 2021; 59:1016-1025. [PMID: 34362286 PMCID: PMC8354164 DOI: 10.1080/13880209.2021.1950192] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/10/2023]
Abstract
CONTEXT Baicalin, a major flavonoid extracted from Scutellaria baicalensis Georgi (Lamiaceae), has been shown to exert therapeutic effects on pulmonary fibrosis (PF). OBJECTIVE To use serum metabolomics combined with biochemical and histopathological analyses to clarify anti-PF mechanisms of baicalin on metabolic pathways and the levels of potential biomarkers. MATERIALS AND METHODS Forty male Sprague-Dawley rats were randomly divided into the control, PF model, prednisolone acetate-treated (4.2 mg/kg/day) and baicalin-treated (25 and 100 mg/kg/day) groups. A rat model of PF was established using a tracheal injection of bleomycin, and the respective drugs were administered intragastrically for 4 weeks. Histomorphology of lung tissue was examined after H&E and Masson's trichrome staining. Biochemical indicators including SOD, MDA and HYP were measured. Serum-metabonomic analysis based on UPLC-Q-TOF/MS was used to clarify the changes in potential biomarkers among different groups of PF rats. RESULTS Both doses of baicalin effectively alleviated bleomycin-induced pathological changes, and increased the levels of SOD (from 69.48 to 99.50 and 112.30, respectively), reduced the levels of MDA (from 10.91 to 5.0 and 7.53, respectively) and HYP (from 0.63 to 0.41 and 0.49, respectively). Forty-eight potential biomarkers associated with PF were identified. Meanwhile, the metabolic profiles and fluctuating metabolite levels were normalized or partially reversed after baicalin treatment. Furthermore, baicalin was found to improve PF potentially by the regulation of four key biomarkers involving taurine and hypotaurine metabolism, glutathione metabolism, and glycerophospholipid metabolism. CONCLUSIONS These findings revealed the anti-fibrotic mechanisms of baicalin and it may be considered as an effective therapy for PF.
Collapse
Affiliation(s)
- Hong Chang
- Department of Pharmacy, Baotou Medical College, Baotou, China
| | - Hong-yu Meng
- Nephroendocrine Department, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Wan-fu Bai
- Department of Pharmacy, Baotou Medical College, Baotou, China
| | - Qing-gang Meng
- Department of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
- CONTACT Qing-gang Meng Department of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11, North third Ring Road East, Chaoyang District, Beijing100700, China
| |
Collapse
|
|
21
|
Ebrahimi A, Ahmadi H, Ghasrodashti ZP, Tanideh N, Shahriarirad R, Erfani A, Ranjbar K, Ashkani-Esfahani S. Therapeutic effects of stem cells in different body systems, a novel method that is yet to gain trust: A comprehensive review. Bosn J Basic Med Sci 2021; 21:672-701. [PMID: 34255619 PMCID: PMC8554700 DOI: 10.17305/bjbms.2021.5508] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 04/25/2021] [Indexed: 11/30/2022] Open
Abstract
Stem cell therapy has been used to treat several types of diseases, and it is expected that its therapeutic uses shall increase as novel lines of evidence begin to appear. Furthermore, stem cells have the potential to make new tissues and organs. Thus, some scientists propose that organ transplantation will significantly rely on stem cell technology and organogenesis in the future. Stem cells and its robust potential to differentiate into specific types of cells and regenerate tissues and body organs, have been investigated by numerous clinician scientists and researchers for their therapeutic effects. Degenerative diseases in different organs have been the main target of stem cell therapy. Neurodegenerative diseases such as Alzheimer's, musculoskeletal diseases such as osteoarthritis, congenital cardiovascular diseases, and blood cell diseases such as leukemia are among the health conditions that have benefited from stem cell therapy advancements. One of the most challenging parts of the process of incorporating stem cells into clinical practice is controlling their division and differentiation potentials. Sometimes, their potential for uncontrolled growth will make these cells tumorigenic. Another caveat in this process is the ability to control the differentiation process. While stem cells can easily differentiate into a wide variety of cells, a paracrine effect controlled activity, being in an appropriate medium will cause abnormal differentiation leading to treatment failure. In this review, we aim to provide an overview of the therapeutic effects of stem cells in diseases of various organ systems. In order to advance this new treatment to its full potential, researchers should focus on establishing methods to control the differentiation process, while policymakers should take an active role in providing adequate facilities and equipment for these projects. Large population clinical trials are a necessary tool that will help build trust in this method. Moreover, improving social awareness about the advantages and adverse effects of stem cell therapy is required to develop a rational demand in the society, and consequently, healthcare systems should consider established stem cell-based therapeutic methods in their treatment algorithms.
Collapse
Affiliation(s)
- Alireza Ebrahimi
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hanie Ahmadi
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Pourfraidon Ghasrodashti
- Molecular Pathology and Cytogenetics Laboratory, Department of Pathology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Nader Tanideh
- Stem Cells Technology Research Center, Department of Pharmacology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Shahriarirad
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
- Thoracic and Vascular Surgery Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amirhossein Erfani
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Keivan Ranjbar
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Soheil Ashkani-Esfahani
- Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| |
Collapse
|
|
22
|
Takao S, Nakashima T, Masuda T, Namba M, Sakamoto S, Yamaguchi K, Horimasu Y, Miyamoto S, Iwamoto H, Fujitaka K, Hamada H, Takahashi S, Nakashima A, Hattori N. Human bone marrow-derived mesenchymal stromal cells cultured in serum-free media demonstrate enhanced antifibrotic abilities via prolonged survival and robust regulatory T cell induction in murine bleomycin-induced pulmonary fibrosis. Stem Cell Res Ther 2021; 12:506. [PMID: 34530920 PMCID: PMC8444523 DOI: 10.1186/s13287-021-02574-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 08/27/2021] [Indexed: 12/29/2022] Open
Abstract
Background Mesenchymal stromal cells (MSCs) are a potential therapeutic tool for pulmonary fibrosis. However, ex vivo MSC expansion using serum poses risks of harmful immune responses or unknown pathogen infections in the recipients. Therefore, MSCs cultured in serum-free media (SF-MSCs) are ideal for clinical settings; however, their efficacy in pulmonary fibrosis is unknown. Here, we investigated the effects of SF-MSCs on bleomycin-induced pulmonary inflammation and fibrosis compared to those of MSCs cultured in serum-containing media (S-MSCs). Methods SF-MSCs and S-MSCs were characterized in vitro using RNA sequence analysis. The in vivo kinetics and efficacy of SF-MSC therapy were investigated using a murine model of bleomycin-induced pulmonary fibrosis. For normally distributed data, Student’s t test and one-way repeated measures analysis of variance followed by post hoc Tukey’s test were used for comparison between two groups and multiple groups, respectively. For non-normally distributed data, Kruskal–Wallis and Mann–Whitney U tests were used for comparison between groups, using e Bonferroni’s correction for multiple comparisons. All tests were two-sided, and P < 0.05 was considered statistically significant. Results Serum-free media promoted human bone marrow-derived MSC expansion and improved lung engraftment of intravenously administered MSCs in recipient mice. SF-MSCs inhibited the reduction in serum transforming growth factor-β1 and the increase of interleukin-6 in both the serum and the bronchoalveolar lavage fluid during bleomycin-induced pulmonary fibrosis. SF-MSC administration increased the numbers of regulatory T cells (Tregs) in the blood and lungs more strongly than in S-MSC administration. Furthermore, SF-MSCs demonstrated enhanced antifibrotic effects on bleomycin-induced pulmonary fibrosis, which were diminished by antibody-mediated Treg depletion. Conclusions SF-MSCs significantly suppressed BLM-induced pulmonary inflammation and fibrosis through enhanced induction of Tregs into the lungs and corrected the dysregulated cytokine balance. Therefore, SF-MSCs could be a useful tool for preventing pulmonary fibrosis progression without the demerits of serum use. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02574-5.
Collapse
Affiliation(s)
- Shun Takao
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Taku Nakashima
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
| | - Takeshi Masuda
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Masashi Namba
- Department of Clinical Oncology, Hiroshima University Hospital, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Shinjiro Sakamoto
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Kakuhiro Yamaguchi
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Yasushi Horimasu
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Shintaro Miyamoto
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Hiroshi Iwamoto
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Kazunori Fujitaka
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Hironobu Hamada
- Department of Physical Analysis and Therapeutic Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Shinya Takahashi
- Department of Cardiovascular Surgery, Graduate School of Medicine, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Ayumu Nakashima
- Department of Stem Cell Biology and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan
| | - Noboru Hattori
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| |
Collapse
|
|
23
|
Wang M, Zhou T, Zhang Z, Liu H, Zheng Z, Xie H. Current therapeutic strategies for respiratory diseases using mesenchymal stem cells. MedComm (Beijing) 2021; 2:351-380. [PMID: 34766151 PMCID: PMC8554668 DOI: 10.1002/mco2.74] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 03/15/2021] [Accepted: 03/18/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stromal/stem cells (MSCs) have a great potential to proliferate, undergo multi-directional differentiation, and exert immunoregulatory effects. There is already much enthusiasm for their therapeutic potentials for respiratory inflammatory diseases. Although the mechanism of MSCs-based therapy has been well explored, only a few articles have summarized the key advances in this field. We hereby provide a review over the latest progresses made on the MSCs-based therapies for four types of inflammatory respiratory diseases, including idiopathic pulmonary fibrosis, acute respiratory distress syndrome, chronic obstructive pulmonary disease, and asthma, and the uncovery of their underlying mechanisms from the perspective of biological characteristics and functions. Furthermore, we have also discussed the advantages and disadvantages of the MSCs-based therapies and prospects for their optimization.
Collapse
Affiliation(s)
- Ming‐yao Wang
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Ting‐yue Zhou
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Zhi‐dong Zhang
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Hao‐yang Liu
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Zhi‐yao Zheng
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| | - Hui‐qi Xie
- Laboratory of Stem Cell and Tissue EngineeringOrthopedic Research InstituteMed‐X Center for MaterialsState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina
| |
Collapse
|
|
24
|
Zhao Y, Yan Z, Liu Y, Zhang Y, Shi J, Li J, Ji F. Effectivity of mesenchymal stem cells for bleomycin-induced pulmonary fibrosis: a systematic review and implication for clinical application. Stem Cell Res Ther 2021; 12:470. [PMID: 34420515 PMCID: PMC8380478 DOI: 10.1186/s13287-021-02551-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 08/09/2021] [Indexed: 12/24/2022] Open
Abstract
Pulmonary fibrosis (PF) is a chronic, progressive, fibrotic interstitial disease of the lung with poor prognosis and without effective treatment currently. Data from previous coronavirus infections, such as the Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome, as well as current clinical evidence from the Coronavirus disease 2019 (COVID-19), support that SARS-CoV-2 infection may lead to PF, seriously impacting patient prognosis and quality of life. Therefore, effective prevention and treatment of PF will improve patient prognosis and reduce the overall social and economic burdens. Stem cells, especially mesenchymal stem cells (MSCs) have many great advantages, including migration to damaged lung tissue and secretion of various paracrine factors, thereby regulating the permeability of endothelial and epithelial cells, reducing inflammatory response, promoting tissue repair and inhibiting bacterial growth. Clinical trials of MSCs for the treatment of acute lung injury, PF and severe and critically ill COVID-19 are ongoing. The purpose of this study is to systematically review preclinical studies, explored the effectiveness of MSCs in the treatment of bleomycin (BLM)-induced pulmonary fibrosis and analyze the potential mechanism, combined with clinical trials of current MSCs for idiopathic pulmonary fibrosis (IPF) and COVID-19, so as to provide support for clinical research and transformation of MSCs. Searching PubMed and Embase (- 2021.4) identified a total of 36 preclinical studies of MSCs as treatment of BLM-induced acute lung injury and PF in rodent models. Most of the studies showed the MSCs treatment to reduce BLM-induced lung tissue inflammatory response, inflammatory cell infiltration, inflammatory cytokine expression, extracellular matrix production and collagen deposition, and to improve Ashcroft score. The results of present studies indicate that MSCs may serve as a potential therapeutic modality for the treatment of PF, including viral-induced PF and IPF.
Collapse
Affiliation(s)
- Yunyu Zhao
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xi Wu Road, Xi'an, 710004, Shaanxi, China
| | - Zhipeng Yan
- Department of Liver Diseases, The Hospital Affiliated to Shaanxi University of Chinese Medicine, Xianyang, 712046, China
| | - Ying Liu
- The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China
| | - Yue Zhang
- The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China
| | - Jie Shi
- Department of Respiratory, The Hospital Affiliated to Shaanxi University of Chinese Medicine, Xianyang, China
| | - Jingtao Li
- Department of Liver Diseases, The Hospital Affiliated to Shaanxi University of Chinese Medicine, Xianyang, 712046, China.
| | - Fanpu Ji
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xi Wu Road, Xi'an, 710004, Shaanxi, China. .,National and Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. .,Key Laboratory of Environment and Genes Related To Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, China.
| |
Collapse
|
|
25
|
Kadota T, Fujita Y, Araya J, Watanabe N, Fujimoto S, Kawamoto H, Minagawa S, Hara H, Ohtsuka T, Yamamoto Y, Kuwano K, Ochiya T. Human bronchial epithelial cell-derived extracellular vesicle therapy for pulmonary fibrosis via inhibition of TGF-β-WNT crosstalk. J Extracell Vesicles 2021; 10:e12124. [PMID: 34377373 PMCID: PMC8329991 DOI: 10.1002/jev2.12124] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Revised: 06/16/2021] [Accepted: 07/04/2021] [Indexed: 01/02/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is characterized by devastating and progressive lung parenchymal fibrosis, resulting in poor patient prognosis. An aberrant recapitulation of developmental lung gene expression, including genes for transforming growth factor (TGF)-β and WNT, has been widely implicated in the pathogenic IPF wound healing process that results from repetitive alveolar epithelial injury. Extracellular vesicles (EVs) have been shown to carry bioactive molecules and to be involved in various physiological and pathological processes. Here, we demonstrate that, by attenuating WNT signalling, human bronchial epithelial cell-derived EVs (HBEC EVs) inhibit TGF-β mediated induction of both myofibroblast differentiation and lung epithelial cellular senescence. This effect of HBEC EVs is more pronounced than that observed with mesenchymal stem cell-derived EVs. Mechanistically, the HBEC EV microRNA (miRNA) cargo is primarily responsible for attenuating both myofibroblast differentiation and cellular senescence. This attenuation occurs via inhibition of canonical and non-canonical WNT signalling pathways. Among enriched miRNA species present in HBEC EVs, miR-16, miR-26a, miR-26b, miR-141, miR-148a, and miR-200a are mechanistically involved in reducing WNT5A and WNT10B expression in LFs, and in reducing WNT3A, WNT5A, and WNT10B expression in HBECs. Mouse models utilizing intratracheal administration of EVs demonstrate efficient attenuation of bleomycin-induced lung fibrosis development accompanied by reduced expression of both β-catenin and markers of cellular senescence. These findings indicate that EVs derived from normal resident lung HBECs may possess anti-fibrotic properties. They further suggest that, via miRNA-mediated inhibition of TGF-β-WNT crosstalk, HBEC EVs administration can be a promising anti-fibrotic modality of treatment for IPF.
Collapse
Affiliation(s)
- Tsukasa Kadota
- Division of Respiratory DiseasesDepartment of Internal MedicineThe Jikei University School of MedicineTokyoJapan
| | - Yu Fujita
- Division of Respiratory DiseasesDepartment of Internal MedicineThe Jikei University School of MedicineTokyoJapan
- Department of Translational Research for ExosomesThe Jikei University School of MedicineTokyoJapan
| | - Jun Araya
- Division of Respiratory DiseasesDepartment of Internal MedicineThe Jikei University School of MedicineTokyoJapan
| | - Naoaki Watanabe
- Division of Respiratory DiseasesDepartment of Internal MedicineThe Jikei University School of MedicineTokyoJapan
- Division of Cellular SignalingNational Cancer Center Research InstituteTokyoJapan
| | - Shota Fujimoto
- Division of Respiratory DiseasesDepartment of Internal MedicineThe Jikei University School of MedicineTokyoJapan
| | - Hironori Kawamoto
- Division of Respiratory DiseasesDepartment of Internal MedicineThe Jikei University School of MedicineTokyoJapan
| | - Shunsuke Minagawa
- Division of Respiratory DiseasesDepartment of Internal MedicineThe Jikei University School of MedicineTokyoJapan
| | - Hiromichi Hara
- Division of Respiratory DiseasesDepartment of Internal MedicineThe Jikei University School of MedicineTokyoJapan
| | - Takashi Ohtsuka
- Division of Thoracic SurgeryDepartment of SurgeryThe Jikei University School of MedicineTokyoJapan
| | - Yusuke Yamamoto
- Division of Cellular SignalingNational Cancer Center Research InstituteTokyoJapan
| | - Kazuyoshi Kuwano
- Division of Respiratory DiseasesDepartment of Internal MedicineThe Jikei University School of MedicineTokyoJapan
| | - Takahiro Ochiya
- Department of Molecular and Cellular MedicineInstitute of Medical ScienceTokyo Medical UniversityTokyoJapan
| |
Collapse
|
|
26
|
Yu C, Chen Z, Li X, Bao H, Wang Y, Zhang B, Huang J, Zhang Z. pH-Triggered Aggregation of Gold Nanoparticles for Enhanced Labeling and Long-Term CT Imaging Tracking of Stem Cells in Pulmonary Fibrosis Treatment. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2021; 17:e2101861. [PMID: 34235846 DOI: 10.1002/smll.202101861] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/11/2021] [Indexed: 06/13/2023]
Abstract
Gold nanoparticles (AuNPs) pose a great challenge in the development of nanotracers that can self-adaptively alter their properties in response to certain cellular environments for long-term stem cell tracking. Herein, pH-sensitive Au nanotracers (CPP-PSD@Au) are fabricated by sequential coupling of AuNPs with sulfonamide-based polymer (PSD) and cell-penetrating peptide (CPP), which can be efficiently internalized by mesenchymal stem cells (MSCs) and undergo pH-induced self-assembly in endosomes, facilitating long-term computed tomography (CT) imaging tracking MSCs in a murine model of idiopathic pulmonary fibrosis (IPF). Using the CPP-PSD@Au, the transplanted MSCs for the first time can be monitored with CT imaging for up to 35 days after transplantation into the lung of IPF mice, clearly elucidating the migration process of MSCs in vivo. Moreover, we preliminarily explored the mechanism of the CPP-PSD@Au labeled MSCs in the alleviation of IPF, including recovery of alveolar integrity, decrease of collagen deposition, as well as down-regulation of relevant cytokine level. This work facilitates our understanding of the behavior and effect of MSCs in the therapy of IPF, thereby providing an important insight into the stem cell-based treatment of lung diseases.
Collapse
Affiliation(s)
- Chenggong Yu
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-bionics, Chinese Academy of Sciences, Suzhou, 215123, China
- School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei, 230026, China
| | - Zhongjin Chen
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-bionics, Chinese Academy of Sciences, Suzhou, 215123, China
| | - Xiaodi Li
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-bionics, Chinese Academy of Sciences, Suzhou, 215123, China
- School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei, 230026, China
| | - Hongying Bao
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-bionics, Chinese Academy of Sciences, Suzhou, 215123, China
- School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei, 230026, China
| | - Yujie Wang
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-bionics, Chinese Academy of Sciences, Suzhou, 215123, China
| | - Bo Zhang
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-bionics, Chinese Academy of Sciences, Suzhou, 215123, China
| | - Jie Huang
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-bionics, Chinese Academy of Sciences, Suzhou, 215123, China
- School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei, 230026, China
| | - Zhijun Zhang
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-bionics, Chinese Academy of Sciences, Suzhou, 215123, China
- School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei, 230026, China
| |
Collapse
|
|
27
|
Liu Y, Ding Y, Hou Y, Yu T, Nie H, Cui Y. The miR-130a-3p/TGF-βRII Axis Participates in Inhibiting the Differentiation of Fibroblasts Induced by TGF-β1. Front Pharmacol 2021; 12:732540. [PMID: 34393805 PMCID: PMC8355625 DOI: 10.3389/fphar.2021.732540] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 07/19/2021] [Indexed: 12/17/2022] Open
Abstract
Pulmonary fibrosis (PF) is a chronic progressive interstitial lung disease that has a poor prognosis. Abnormal activation of transforming growth factor-β1 (TGF-β1) plays a crucial role in fibroblast differentiation. Mesenchymal stem cells (MSCs) are currently being considered for the treatment of PF, but the regulatory mechanisms are poorly understood. We co-cultured bone marrow-derived MSCs and mouse lung fibroblasts (MLg) in the presence of TGF-β1, and studied the protein/mRNA expression of fibrosis markers and related signaling pathways. The effects of miR-130a-3p and TGF-β receptor II (TGF-βRII) on the differentiation of MLg induced by TGF-β1 were studied using immunofluorescence assay, Western blot, and quantitative real-time PCR techniques, respectively. Our results showed that MSCs reversed the overexpression of fibrosis markers and TGF-β1/Smad signaling pathway proteins and mRNAs after TGF-β1 treatment and increased the level of miR-130a-3p. TGF-βRII was identified as a target of miR-130a-3p and was evaluated by dual-luciferase reporter assay. The miR-130a-3p/TGF-βRII axis could suppress the differentiation of lung fibroblasts via the TGF-β1/Smad signaling pathway, thereby reducing the process of PF.
Collapse
Affiliation(s)
- Yanhong Liu
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Yan Ding
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Yapeng Hou
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Tong Yu
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Hongguang Nie
- Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang, China
| | - Yong Cui
- Departments of Anesthesiology, The First Hospital of China Medical University, Shenyang, China
| |
Collapse
|
|
28
|
The Role of MSC in Wound Healing, Scarring and Regeneration. Cells 2021; 10:cells10071729. [PMID: 34359898 PMCID: PMC8305394 DOI: 10.3390/cells10071729] [Citation(s) in RCA: 198] [Impact Index Per Article: 49.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 07/02/2021] [Accepted: 07/03/2021] [Indexed: 02/06/2023] Open
Abstract
Tissue repair and regeneration after damage is not completely understood, and current therapies to support this process are limited. The wound healing process is associated with cell migration and proliferation, extracellular matrix remodeling, angiogenesis and re-epithelialization. In normal conditions, a wound will lead to healing, resulting in reparation of the tissue. Several risk factors, chronic inflammation, and some diseases lead to a deficient wound closure, producing a scar that can finish with a pathological fibrosis. Mesenchymal stem/stromal cells (MSCs) are widely used for their regenerative capacity and their possible therapeutically potential. Derived products of MSCs, such as exosomes or extravesicles, have shown a therapeutic potential similar to MSCs, and these cell-free products may be interesting in clinics. MSCs or their derivative products have shown paracrine beneficial effects, regulating inflammation, modifying the fibroblast activation and production of collagen and promoting neovascularization and re-epithelialization. This review describes the effects of MSCs and their derived products in each step of the wound repair process. As well, it reviews the pre-clinical and clinical use of MSCs to benefit in skin wound healing in diabetic associated wounds and in pathophysiological fibrosis.
Collapse
|
|
29
|
Wang LM, Jung S, Serban M, Chatterjee A, Lee S, Jeyaseelan K, El Naqa I, Seuntjens J, Ybarra N. Comparison of quantitative and qualitative scoring approaches for radiation-induced pulmonary fibrosis as applied to a preliminary investigation into the efficacy of mesenchymal stem cell delivery methods in a rat model. BJR Open 2021; 2:20210006. [PMID: 34381940 PMCID: PMC8320116 DOI: 10.1259/bjro.20210006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 02/25/2021] [Indexed: 11/05/2022] Open
Abstract
Objectives Compare a quantitative, algorithm-driven, and qualitative, pathologist-driven, scoring of radiation-induced pulmonary fibrosis (RIPF). And using these scoring models to derive preliminary comparisons on the effects of different mesenchymal stem cell (MSC) administration modalities in reducing RIPF. Methods 25 rats were randomized into 5 groups: non-irradiated control (CG), irradiated control (CR), intraperitoneally administered granulocyte-macrophage colony stimulating factor or GM-CSF (Drug), intravascularly administered MSC (IV), and intratracheally administered MSC (IT). All groups, except CG, received an 18 Gy conformal dose to the right lung. Drug, IV and IT groups were treated immediately after irradiation. After 24 weeks of observation, rats were euthanized, their lungs excised, fixed and stained with Masson's Trichrome. Samples were anonymized and RIPF was scored qualitatively by a certified pathologist and quantitatively using ImageScope. An analysis of association was conducted, and two binary classifiers trained to validate the integrity of both qualitative and quantitative scoring. Differences between the treatment groups, as assessed by the pathologist score, were then tested by variance component analysis and mixed models for differences in RIPF outcomes. Results There is agreement between qualitative and quantitative scoring for RIPF grades from 4 to 7. Both classifiers performed similarly on the testing set (AUC = 0.923) indicating accordance between the qualitative and quantitative scoring. For comparisons between MSC infusion modalities, the Drug group had better outcomes (mean pathologist scoring of 3.96), correlating with significantly better RIPF outcomes than IV [lower by 0.97, p = 0.047, 95% CI = (0.013, 1.918)] and resulting in an improvement over CR [lower by 0.93, p = 0.037, 95% CI = (0.062, 1.800]. Conclusion Quantitative image analysis may help in the assessment of therapeutic interventions for RIPF and can serve as a scoring surrogate in differentiating between severe and mild cases of RIPF. Preliminary data demonstrate that the use of GM-CSF was best correlated with lower RIPF severity. Advances in knowledge Quantitative image analysis can be a viable supplemental system of quality control and triaging in situations where pathologist work hours or resources are limited. The use of different MSC administration methods can result in different degrees of MSC efficacy and study outcomes.
Collapse
Affiliation(s)
- Li Ming Wang
- Research Institute of the McGill University Healthcare Centre, Montréal, Canada
| | - Sungmi Jung
- Department of Pathology, McGill University Healthcare Centre, Montréal, Canada
| | - Monica Serban
- Medical Physics Unit, Cedars Cancer Centre, McGill University Healthcare Centre, Montréal, Canada
| | - Avishek Chatterjee
- Medical Physics Unit, Cedars Cancer Centre, McGill University Healthcare Centre, Montréal, Canada
| | - Sangkyu Lee
- Memorial Sloan Kettering Cancer Centre, New York, NY, USA
| | - Krishinima Jeyaseelan
- Medical Physics Unit, Cedars Cancer Centre, McGill University Healthcare Centre, Montréal, Canada
| | - Issam El Naqa
- Radiation Oncology, University of Michigan - Ann Arbor, Ann Arbor, MI, USA
| | - Jan Seuntjens
- Medical Physics Unit, Cedars Cancer Centre, Montréal University Healthcare Centre, Montreal, Canada
| | - Norma Ybarra
- Research Institute of the McGill University Healthcare Centre & Medical Physics Unit, CedarsCancer Centre, McGill University Healthcare Centre, Montreal, Canada
| |
Collapse
|
|
30
|
Efimenko AY, Kalinina NI, Rubina KA, Semina EV, Sysoeva VY, Akopyan ZA, Tkachuk VA. Secretome of Multipotent Mesenchymal Stromal Cells as a Promising Treatment and for Rehabilitation of Patients with the Novel Coronaviral Infection. HERALD OF THE RUSSIAN ACADEMY OF SCIENCES 2021; 91:170-175. [PMID: 34131372 PMCID: PMC8192105 DOI: 10.1134/s101933162102012x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Revised: 12/28/2020] [Accepted: 01/30/2021] [Indexed: 06/12/2023]
Abstract
As a rule, coronavirus infections are mild in healthy adults and do not require special approaches to treatment. However, highly pathogenic strains, particularly the recently isolated SARS-CoV2, which causes COVID-19 infection, in about 15% of cases lead to severe complications, including acute respiratory distress syndrome, which causes high patient mortality. In addition, a common complication of COVID-19 is the development of pulmonary fibrosis. Why is the novel coronavirus so pathogenic? What new treatments can be proposed to speed up the recovery and subsequent rehabilitation of the organism? In 2020, over 34 000 scientific articles were published on the structure, distribution, pathogenesis, and possible approaches to the treatment of infection caused by the novel SARS-CoV2 coronavirus. However, there are still no definitive answers to these questions, while the number of the diseased is increasing daily. One of the comprehensive approaches to the treatment of the consequences of the infection is the use of multipotent human mesenchymal stromal cells and products of their secretion (secretome). Acting at several stages of the development of the infection, the components of the secretome can suppress the interaction of the virus with endothelial cells, regulate inflammation, and stimulate lung tissue regeneration, preventing the development of fibrosis. The results of basic and clinical research on this topic are summarized, including our own experimental data, indicating that cell therapy approaches can be successfully applied to treat patients with COVID-19.
Collapse
Affiliation(s)
- A. Yu. Efimenko
- Moscow State University, Moscow, Russia
- Institute for Regenerative Medicine, Medical Research and Educational Center, Moscow State University, Moscow, Russia
| | | | | | - E. V. Semina
- Moscow State University, Moscow, Russia
- National Medical Research Center of Cardiology, Ministry of Health of Russia, Moscow, Russia
| | | | - Zh. A. Akopyan
- Moscow State University, Moscow, Russia
- Institute for Regenerative Medicine, Medical Research and Educational Center, Moscow State University, Moscow, Russia
| | - V. A. Tkachuk
- Moscow State University, Moscow, Russia
- Institute for Regenerative Medicine, Medical Research and Educational Center, Moscow State University, Moscow, Russia
| |
Collapse
|
|
31
|
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.
Collapse
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
| |
Collapse
|
|
32
|
Dzobo K. Recent Trends in Multipotent Human Mesenchymal Stem/Stromal Cells: Learning from History and Advancing Clinical Applications. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2021; 25:342-357. [PMID: 34115524 DOI: 10.1089/omi.2021.0049] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Early cell biology reports demonstrated the presence of cells with stem-like properties in bone marrow, with both hematopoietic and mesenchymal lineages. Over the years, various investigations have purified and characterized mesenchymal stromal/stem cells (MSCs) from different human tissues as cells with multilineage differentiation potential under the appropriate conditions. Due to their appealing characteristics and versatile potentials, MSCs are leveraged in many applications in medicine such as oncology, bioprinting, and as recent as therapeutics discovery and innovation for COVID-19. To date, studies indicate that MSCs have varied differentiation capabilities into different cell types, and demonstrate immunomodulating and anti-inflammatory properties. Different microenvironments or niche for MSCs and their resulting heterogeneity may influence attendant cellular behavior and differentiation capacity. The potential clinical applications of MSCs and exosomes derived from these cells have led to an avalanche of research reports on their properties and hundreds of clinical trials being undertaken. There is ample reason to think, as discussed in this expert review that the future looks bright and promising for MSC research, with many clinical trials under way to ascertain their clinical utility. This review provides a synthesis of the latest advances and trends in MSC research to allow for broad and critically informed use of MSCs. Early observations of the presence of these cells in the bone marrow and their remarkable differentiation capabilities and immunomodulation are also presented.
Collapse
Affiliation(s)
- Kevin Dzobo
- International Center for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa.,Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| |
Collapse
|
|
33
|
Liao Z, Wang W, Deng W, Zhang Y, Song A, Deng S, Zhao H, Zhang S, Li Z. Human Umbilical Cord Mesenchymal Stem Cells-Secreted TSG-6 Is Anti-Inflammatory and Promote Tissue Repair After Spinal Cord Injury. ASN Neuro 2021. [PMCID: PMC8135204 DOI: 10.1177/17590914211010628] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Spinal cord injury (SCI) causes patients paralysis and hard to recover. The therapeutic effects of current clinical drugs are accompanied by side effects. In recent years, stem cell therapy has attracted the attention of researchers. Human umbilical cord mesenchymal stem cells (hucMSCs) have been widely used in various diseases due to their excellent paracrine function. TNF-stimulated gene 6 (TSG-6), a secretion factor of stem cells, may play an important role in hucMSCs in the treatment of SCI. So we conducted an experiment to explore its effect. We first observed that the expression of TSG-6 increased in SCI rats after injected with hucMSCs. Then, we used siRNA to knowdown the expression of TSG-6. We treated SCI rats with TSG-6-knockdown hucMSCs. Without TSG-6 expression, hucMSCs treatment made the tissue recovery worse and the number of Nissl bodies less. Meanwhile, neutrophils infiltrated more in the damaged parts. Our research also proved that TSG-6 may help demyelination recovering and alleviate astrocytes gathering in the injury sites. Our study revealed that hucMSCs secreted TSG-6 may decrease the degeneration of myelin sheath, reduce inflammation, decrease neuron loss and promote tissue repair. These results provided a new therapeutic factor for the treatment of SCI.
Collapse
Affiliation(s)
- Ziling Liao
- Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, China
| | - Wei Wang
- Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, China
| | - Weiyue Deng
- Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, China
| | - Yuying Zhang
- Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, China
| | - Aishi Song
- Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, China
| | - Sihao Deng
- Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, China
- NHC Key Laboratory of Birth Defect for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, China
| | - Huifang Zhao
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | | | - Zhiyuan Li
- Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, China
- NHC Key Laboratory of Birth Defect for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, China
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- Changsha Stomatological Hospital, Changsha, China
- GZMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, China
| |
Collapse
|
|
34
|
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: 9] [Impact Index Per Article: 2.3] [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.
Collapse
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.
| |
Collapse
|
|
35
|
Elowsson Rendin L, Löfdahl A, Kadefors M, Söderlund Z, Tykesson E, Rolandsson Enes S, Wigén J, Westergren-Thorsson G. Harnessing the ECM Microenvironment to Ameliorate Mesenchymal Stromal Cell-Based Therapy in Chronic Lung Diseases. Front Pharmacol 2021; 12:645558. [PMID: 34040521 PMCID: PMC8142268 DOI: 10.3389/fphar.2021.645558] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 03/17/2021] [Indexed: 12/21/2022] Open
Abstract
It is known that the cell environment such as biomechanical properties and extracellular matrix (ECM) composition dictate cell behaviour including migration, proliferation, and differentiation. Important constituents of the microenvironment, including ECM molecules such as proteoglycans and glycosaminoglycans (GAGs), determine events in both embryogenesis and repair of the adult lung. Mesenchymal stromal/stem cells (MSC) have been shown to have immunomodulatory properties and may be potent actors regulating tissue remodelling and regenerative cell responses upon lung injury. Using MSC in cell-based therapy holds promise for treatment of chronic lung diseases such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). However, so far clinical trials with MSCs in COPD have not had a significant impact on disease amelioration nor on IPF, where low cell survival rate and pulmonary retention time are major hurdles to overcome. Research shows that the microenvironment has a profound impact on transplanted MSCs. In our studies on acellular lung tissue slices (lung scaffolds) from IPF patients versus healthy individuals, we see a profound effect on cellular activity, where healthy cells cultured in diseased lung scaffolds adapt and produce proteins further promoting a diseased environment, whereas cells on healthy scaffolds sustain a healthy proteomic profile. Therefore, modulating the environmental context for cell-based therapy may be a potent way to improve treatment using MSCs. In this review, we will describe the importance of the microenvironment for cell-based therapy in chronic lung diseases, how MSC-ECM interactions can affect therapeutic output and describe current progress in the field of cell-based therapy.
Collapse
Affiliation(s)
- Linda Elowsson Rendin
- Lung Biology Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Monguió-Tortajada M, Bayes-Genis A, Rosell A, Roura S. Are mesenchymal stem cells and derived extracellular vesicles valuable to halt the COVID-19 inflammatory cascade? Current evidence and future perspectives. Thorax 2021; 76:196-200. [PMID: 33323479 PMCID: PMC7815888 DOI: 10.1136/thoraxjnl-2020-215717] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Accepted: 08/28/2020] [Indexed: 12/15/2022]
Affiliation(s)
- Marta Monguió-Tortajada
- ICREC Research Program, Health Science Research Institute Germans Trias i Pujol (IGTP), Badalona, Catalunya, Spain
- CIBERCV, Instituto de Salud Carlos III, Madrid, Spain
| | - Antoni Bayes-Genis
- ICREC Research Program, Health Science Research Institute Germans Trias i Pujol (IGTP), Badalona, Catalunya, Spain
- CIBERCV, Instituto de Salud Carlos III, Madrid, Spain
- Department of Medicine, Autonomous University of Barcelona (UAB), Barcelona, Catalunya, Spain
- Cardiology Service, Germans Trias i Pujol University Hospital, Badalona, Catalunya, Spain
| | - Antoni Rosell
- Department of Medicine, Autonomous University of Barcelona (UAB), Barcelona, Catalunya, Spain
- Servei de Pneumologia, Germans Trias i Pujol University Hospital, Badalona, Catalunya, Spain
- CIBERES, Instituto de Salud Carlos III, Madrid, Spain
| | - Santiago Roura
- ICREC Research Program, Health Science Research Institute Germans Trias i Pujol (IGTP), Badalona, Catalunya, Spain
- CIBERCV, Instituto de Salud Carlos III, Madrid, Spain
| |
Collapse
|
|
37
|
Zakaria DM, Zahran NM, Arafa SAA, Mehanna RA, Abdel-Moneim RA. Histological and Physiological Studies of the Effect of Bone Marrow-Derived Mesenchymal Stem Cells on Bleomycin Induced Lung Fibrosis in Adult Albino Rats. Tissue Eng Regen Med 2021; 18:127-141. [PMID: 33090319 PMCID: PMC7579902 DOI: 10.1007/s13770-020-00294-0] [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: 07/09/2020] [Revised: 08/04/2020] [Accepted: 08/15/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Lung fibrosis is considered as an end stage for many lung diseases including lung inflammatory disease, autoimmune diseases and malignancy. There are limited therapeutic options with bad prognostic outcome. The aim of this study was to explore the effect of mesenchymal stem cells (MSCs) derived from bone marrow on Bleomycin (BLM) induced lung fibrosis in albino rats. METHODS 30 adult female albino rats were distributed randomly into 4 groups; negative control group, Bleomycin induced lung fibrosis group, lung fibrosis treated with bone marrow-MSCs (BM-MSCs) and lung fibrosis treated with cell free media. Lung fibrosis was induced with a single dose of intratracheal instillation of BLM. BM-MSCs or cell free media were injected intravenously 28 days after induction and rats were sacrificed after another 28 days for assessment. Minute respiratory volume (MRV), forced vital capacity (FVC) and forced expiratory volume 1 (FEV1) were recorded using spirometer (Power lab data acquisition system). Histological assessment was performed by light microscopic examination of H&E, and Masson's trichrome stained sections and was further supported by morphometric studies. In addition, electron microscopic examination to assess ultra-structural changes was done. Confocal Laser microscopy and PCR were used as tools to ensure MSCs homing in the lung. RESULTS Induction of lung fibrosis was confirmed by histological examination, which revealed disorganized lung architecture, thickened inter-alveolar septa due excessive collagen deposition together with inflammatory cellular infiltration. Moreover, pneumocytes depicted variable degenerative changes. Reduction in MRV, FVC and FEV1 were recorded. BM-MSCs treatment showed marked structural improvement with minimal cellular infiltration and collagen deposition and hence restored lung architecture, together with lung functions. CONCLUSION MSCs are promising potential therapy for lung fibrosis that could restore the normal structure and function of BLM induced lung fibrosis.
Collapse
Affiliation(s)
- Dina Mohamed Zakaria
- Department of Histology and Cell Biology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Noha Mahmoud Zahran
- Department of Histology and Cell Biology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Samia Abdel Aziz Arafa
- Department of Histology and Cell Biology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Radwa Ali Mehanna
- Department of Physiology, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
- Center of Excellence for Research in Regenerative Medicine and Applications (CERRMA), Faculty of Medicine, Alexandria University, Azareeta, Khartoom Square, Alexandria, 21526, Egypt.
| | - Rehab Ahmed Abdel-Moneim
- Department of Histology and Cell Biology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| |
Collapse
|
|
38
|
Yang Y, Zhu S, Li Y, Lu Q, Zhang Q, Su L, Zhang Q, Zhao Y, Luo Y, Liu Y. Human umbilical cord mesenchymal stem cells ameliorate skin fibrosis development in a mouse model of bleomycin-induced systemic sclerosis. Exp Ther Med 2020; 20:257. [PMID: 33199983 PMCID: PMC7664606 DOI: 10.3892/etm.2020.9387] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 09/22/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cell (MSC) infusion has become a novel therapeutic strategy for complex autoimmune diseases; however, few detailed studies have been performed to investigate the benefit and mechanism of MSC treatment on systemic sclerosis (SSc). The present study aimed to evaluate the therapeutic effect of human umbilical cord derived-MSCs (UC-MSCs) on bleomycin-induced SSc in mice and explore the potential underlying mechanism. The murine SSc model was established by daily subcutaneous injection of bleomycin for 4 weeks, followed with two UC-MSC infusions every 7 days. Skin fibrosis was assessed by H&E and Masson staining. Flow cytometry was used to determine IL-17A, IFN-γ, tumor necrosis factor-β, IL-10 and IL-12 levels in serum samples and T cell subsets in murine spleen. Additionally, gene expression levels of cytokines and fibrosis markers in skin samples were measured by reverse transcription-quantitative PCR. Immunofluorescence staining was performed to track UC-MSC localization and lymphocyte cell infiltration in vivo. UC-MSC treatment exerted an anti-fibrotic role in bleomycin-induced SSc mice, as confirmed by histological improvement, decreased collagen synthesis, and reduced collagen-1α1, collagen-1α2, fibronectin-1 and α-smooth muscle actin gene expression levels. The results indicated that UC-MSC treatment only had a limited systematic effect on cytokine production in serum samples and T cell activation in the spleen. By contrast, T helper (Th)17 cell infiltration and activation in skin were efficiently inhibited after UC-MSC infusion, as evidenced by the decreased IL-17A and retinoic acid-related orphan receptor γt gene expression as well as IL-17A production. UC-MSC administration significantly ameliorated bleomycin-induced skin fibrosis and collagen formation primarily by eliminating local inflammation and Th17 cell activation in the skin; however, the systemic inhibitory effect of UM-MSCs on cytokines was less profound.
Collapse
Affiliation(s)
- Yuan Yang
- Department of Rheumatology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.,Department of Rheumatology and Immunology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan 610500, P.R. China
| | - Shuai Zhu
- Department of Rheumatology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yanhong Li
- Department of Rheumatology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Qian Lu
- Department of Biomedical Engineering, College of Engineering and Applied Sciences, Nanjing University, Nanjing, Jiangsu 210023, P.R. China
| | - Qiuyi Zhang
- Department of Rheumatology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Linchong Su
- Department of Rheumatology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Qiuping Zhang
- Department of Rheumatology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yi Zhao
- Department of Rheumatology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yubin Luo
- Department of Rheumatology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yi Liu
- Department of Rheumatology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| |
Collapse
|
|
39
|
Pawitan JA, Bui TA, Mubarok W, Antarianto RD, Nurhayati RW, Dilogo IH, Oceandy D. Enhancement of the Therapeutic Capacity of Mesenchymal Stem Cells by Genetic Modification: A Systematic Review. Front Cell Dev Biol 2020; 8:587776. [PMID: 33195245 PMCID: PMC7661472 DOI: 10.3389/fcell.2020.587776] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 10/01/2020] [Indexed: 12/13/2022] Open
Abstract
Background The therapeutic capacity of mesenchymal stem cells (also known as mesenchymal stromal cells/MSCs) depends on their ability to respond to the need of the damaged tissue by secreting beneficial paracrine factors. MSCs can be genetically engineered to express certain beneficial factors. The aim of this systematic review is to compile and analyze published scientific literatures that report the use of engineered MSCs for the treatment of various diseases/conditions, to discuss the mechanisms of action, and to assess the efficacy of engineered MSC treatment. Methods We retrieved all published studies in PubMed/MEDLINE and Cochrane Library on July 27, 2019, without time restriction using the following keywords: “engineered MSC” and “therapy” or “manipulated MSC” and “therapy.” In addition, relevant articles that were found during full text search were added. We identified 85 articles that were reviewed in this paper. Results Of the 85 articles reviewed, 51 studies reported the use of engineered MSCs to treat tumor/cancer/malignancy/metastasis, whereas the other 34 studies tested engineered MSCs in treating non-tumor conditions. Most of the studies reported the use of MSCs in animal models, with only one study reporting a trial in human subjects. Thirty nine studies showed that the expression of beneficial paracrine factors would significantly enhance the therapeutic effects of the MSCs, whereas thirty three studies showed moderate effects, and one study in humans reported no effect. The mechanisms of action for MSC-based cancer treatment include the expression of “suicide genes,” induction of tumor cell apoptosis, and delivery of cytokines to induce an immune response against cancer cells. In the context of the treatment of non-cancerous diseases, the mechanism described in the reviewed papers included the expression of angiogenic, osteogenic, and growth factors. Conclusion The therapeutic capacity of MSCs can be enhanced by inducing the expression of certain paracrine factors by genetic modification. Genetically engineered MSCs have been used successfully in various animal models of diseases. However, the results should be interpreted cautiously because animal models might not perfectly represent real human diseases. Therefore, further studies are needed to explore the translational potential of genetically engineered MSCs.
Collapse
Affiliation(s)
- Jeanne Adiwinata Pawitan
- Department of Histology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.,Stem Cell Medical Technology Integrated Service Unit, Dr. Cipto Mangunkusumo General Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.,Stem Cell and Tissue Engineering Research Center, Indonesia Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Thuy Anh Bui
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, United Kingdom
| | - Wildan Mubarok
- Division of Chemical Engineering, Department of Materials Engineering Science, Graduate School of Engineering Science, Osaka University, Toyonaka, Japan
| | - Radiana Dhewayani Antarianto
- Department of Histology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.,Stem Cell and Tissue Engineering Research Center, Indonesia Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Retno Wahyu Nurhayati
- Stem Cell and Tissue Engineering Research Center, Indonesia Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.,Department of Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Ismail Hadisoebroto Dilogo
- Stem Cell Medical Technology Integrated Service Unit, Dr. Cipto Mangunkusumo General Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.,Stem Cell and Tissue Engineering Research Center, Indonesia Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.,Department of Orthopaedic and Traumatology, Dr. Cipto Mangunkusumo General Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Delvac Oceandy
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, United Kingdom.,Department of Biomedical Science, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| |
Collapse
|
|
40
|
The Therapy of Pulmonary Fibrosis in Paracoccidioidomycosis: What Are the New Experimental Approaches? J Fungi (Basel) 2020; 6:jof6040217. [PMID: 33050568 PMCID: PMC7712212 DOI: 10.3390/jof6040217] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 10/06/2020] [Accepted: 10/09/2020] [Indexed: 02/06/2023] Open
Abstract
Pulmonary fibrosis (PF) is considered the most important sequela developed in patients suffering from the chronic form of paracoccidioidomycosis (PCM), which leads to the loss of respiratory function in 50% of cases; this residual pulmonary abnormality is present even after antifungal treatment. To date, there is no effective treatment for PF. However, the use of antifungal drugs in combination with other antibiotics or immunomodulatory compounds, as well as biological therapies that include a monoclonal antibody specific to neutrophils, or prophylactic vaccination employing a recombinant antigen of Paracoccidioides brasiliensis that successfully attenuated PF, has been reported. Additionally, mesenchymal stem cell transplantation in combination with antifungal therapy slightly reduced the inflammatory response and profibrotic molecules induced by P. brasiliensis infection. In this review, I report experimental findings from several studies aiming to identify promising therapeutic strategies for treating PF developed in PCM.
Collapse
|
|
41
|
Byrnes D, Masterson CH, Artigas A, Laffey JG. Mesenchymal Stem/Stromal Cells Therapy for Sepsis and Acute Respiratory Distress Syndrome. Semin Respir Crit Care Med 2020; 42:20-39. [PMID: 32767301 DOI: 10.1055/s-0040-1713422] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Sepsis and acute respiratory distress syndrome (ARDS) constitute devastating conditions with high morbidity and mortality. Sepsis results from abnormal host immune response, with evidence for both pro- and anti-inflammatory activation present from the earliest phases. The "proinflammatory" response predominates initially causing host injury, with later-phase sepsis characterized by immune cell hypofunction and opportunistic superinfection. ARDS is characterized by inflammation and disruption of the alveolar-capillary membrane leading to injury and lung dysfunction. Sepsis is the most common cause of ARDS. Approximately 20% of deaths worldwide in 2017 were due to sepsis, while ARDS occurs in over 10% of all intensive care unit patients and results in a mortality of 30 to 45%. Given the fact that sepsis and ARDS share some-but not all-underlying pathophysiologic injury mechanisms, the lack of specific therapies, and their frequent coexistence in the critically ill, it makes sense to consider therapies for both conditions together. In this article, we will focus on the therapeutic potential of mesenchymal stem/stromal cells (MSCs). MSCs are available from several tissues, including bone marrow, umbilical cord, and adipose tissue. Allogeneic administration is feasible, an important advantage for acute conditions like sepsis or ARDS. They possess diverse mechanisms of action of relevance to sepsis and ARDS, including direct and indirect antibacterial actions, potent effects on the innate and adaptive response, and pro-reparative effects. MSCs can be preactivated thereby potentiating their effects, while the use of their extracellular vesicles can avoid whole cell administration. While early-phase clinical trials suggest safety, considerable challenges exist in moving forward to phase III efficacy studies, and to implementation as a therapy should they prove effective.
Collapse
Affiliation(s)
- Declan Byrnes
- Department of Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland.,Regenerative Medicine Institute (REMEDI), CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Galway, Ireland
| | - Claire H Masterson
- Department of Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland.,Regenerative Medicine Institute (REMEDI), CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Galway, Ireland
| | - Antonio Artigas
- Critical Care Center, Corporació Sanitaria Parc Tauli, CIBER Enfermedades Respiratorias, Autonomous University of Barcelona, Sabadell, Spain
| | - John G Laffey
- Department of Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland.,Regenerative Medicine Institute (REMEDI), CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Galway, Ireland.,Department of Anaesthesia, SAOLTA University Health Group, Galway University Hospitals, Galway, Ireland
| |
Collapse
|
|
42
|
Alveolar Type II Cells or Mesenchymal Stem Cells: Comparison of Two Different Cell Therapies for the Treatment of Acute Lung Injury in Rats. Cells 2020; 9:cells9081816. [PMID: 32751857 PMCID: PMC7464506 DOI: 10.3390/cells9081816] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/28/2020] [Accepted: 07/29/2020] [Indexed: 12/13/2022] Open
Abstract
The use of cell therapies has recently increased for the treatment of pulmonary diseases. Mesenchymal stem/stromal cells (MSCs) and alveolar type II cells (ATII) are the main cell-based therapies used for the treatment of acute respiratory distress syndrome (ARDS). Many pre-clinical studies have shown that both therapies generate positive outcomes; however, the differences in the efficiency of MSCs or ATII for reducing lung damage remains to be studied. We compared the potential of both cell therapies, administering them using the same route and dose and equal time points in a sustained acute lung injury (ALI) model. We found that the MSCs and ATII cells have similar therapeutic effects when we tested them in a hydrochloric acid and lipopolysaccharide (HCl-LPS) two-hit ALI model. Both therapies were able to reduce proinflammatory cytokines, decrease neutrophil infiltration, reduce permeability, and moderate hemorrhage and interstitial edema. Although MSCs and ATII cells have been described as targeting different cellular and molecular mechanisms, our data indicates that both cell therapies are successful for the treatment of ALI, with similar beneficial results. Understanding direct cell crosstalk and the factors released from each cell will open the door to more accurate drugs being able to target specific pathways and offer new curative options for ARDS.
Collapse
|
|
43
|
The Therapeutic Potential of Mesenchymal Stromal Cells in the Treatment of Chemotherapy-Induced Tissue Damage. Stem Cell Rev Rep 2020; 15:356-373. [PMID: 30937640 DOI: 10.1007/s12015-019-09886-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Chemotherapy constitutes one of the key treatment modalities for solid and hematological malignancies. Albeit being an effective treatment, chemotherapy application is often limited by its damage to healthy tissues, and curative treatment options for chemotherapy-related side effects are largely missing. As mesenchymal stromal cells (MSCs) are known to exhibit regenerative capacity mainly by supporting a beneficial microenvironment for tissue repair, MSC-based therapies may attenuate chemotherapy-induced tissue injuries. An increasing number of animal studies shows favorable effects of MSC-based treatments; however, clinical trials for MSC therapies in the context of chemotherapy-related side effects are rare. In this concise review, we summarize the current knowledge of the effects of MSCs on chemotherapy-induced tissue toxicities. Both preclinical and early clinical trials investigating MSC-based treatments for chemotherapy-related side reactions are presented, and mechanistic explanations about the regenerative effects of MSCs in the context of chemotherapy-induced tissue damage are discussed. Furthermore, challenges of MSC-based treatments are outlined that need closer investigations before these multipotent cells can be safely applied to cancer patients. As any pro-tumorigenicity of MSCs needs to be ruled out prior to clinical utilization of these cells for cancer patients, the pro- and anti-tumorigenic activities of MSCs are discussed in detail.
Collapse
|
|
44
|
Eiro N, Cabrera JR, Fraile M, Costa L, Vizoso FJ. The Coronavirus Pandemic (SARS-CoV-2): New Problems Demand New Solutions, the Alternative of Mesenchymal (Stem) Stromal Cells. Front Cell Dev Biol 2020; 8:645. [PMID: 32766251 PMCID: PMC7378818 DOI: 10.3389/fcell.2020.00645] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 06/26/2020] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal (stem) stromal cells (MSC) can be a therapeutic alternative for COVID-19 considering their anti-inflammatory, regenerative, angiogenic, and even antimicrobial capacity. Preliminary data point to therapeutic interest of MSC for patients with COVID-19, and their effect seems based on the MSC's ability to curb the cytokine storm caused by COVID-19. In fact, promising clinical studies using MSC to treat COVID-19, are currently underway. For this reason, now is the time to firmly consider new approaches to MSC research that addresses key issues, like selecting the most optimal type of MSC for each indication, assuming the heterogeneity of the donor-dependent MSC and the biological niche where MSC are located.
Collapse
Affiliation(s)
- Noemi Eiro
- Research Unit, Fundación Hospital de Jove, Gijón, Spain
- Foundation for Research With Uterine Stem Cells - FICEMU, Gijón, Spain
| | - Jorge Ruben Cabrera
- Research Unit, Fundación Hospital de Jove, Gijón, Spain
- Foundation for Research With Uterine Stem Cells - FICEMU, Gijón, Spain
| | - Maria Fraile
- Research Unit, Fundación Hospital de Jove, Gijón, Spain
- Foundation for Research With Uterine Stem Cells - FICEMU, Gijón, Spain
| | - Luis Costa
- Research Unit, Fundación Hospital de Jove, Gijón, Spain
- Foundation for Research With Uterine Stem Cells - FICEMU, Gijón, Spain
| | - Francisco J. Vizoso
- Research Unit, Fundación Hospital de Jove, Gijón, Spain
- Foundation for Research With Uterine Stem Cells - FICEMU, Gijón, Spain
| |
Collapse
|
|
45
|
Ji HL, Liu C, Zhao RZ. Stem cell therapy for COVID-19 and other respiratory diseases: Global trends of clinical trials. World J Stem Cells 2020; 12:471-480. [PMID: 32742564 PMCID: PMC7360994 DOI: 10.4252/wjsc.v12.i6.471] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 05/17/2020] [Accepted: 05/22/2020] [Indexed: 02/06/2023] Open
Abstract
Respiratory diseases, including coronavirus disease 2019 and chronic obstructive pulmonary disease (COPD), are leading causes of global fatality. There are no effective and curative treatments, but supportive care only. Cell therapy is a promising therapeutic strategy for refractory and unmanageable pulmonary illnesses, as proved by accumulating preclinical studies. Stem cells consist of totipotent, pluripotent, multipotent, and unipotent cells with the potential to differentiate into cell types requested for repair. Mesenchymal stromal cells, endothelial progenitor cells, peripheral blood stem cells, and lung progenitor cells have been applied to clinical trials. To date, the safety and feasibility of stem cell and extracellular vesicles administration have been confirmed by numerous phase I/II trials in patients with COPD, acute respiratory distress syndrome, bronchial dysplasia, idiopathic pulmonary fibrosis, pulmonary artery hypertension, and silicosis. Five routes and a series of doses have been tested for tolerance and advantages of different regimes. In this review, we systematically summarize the global trends for the cell therapy of common airway and lung diseases registered for clinical trials. The future directions for both new clinical trials and preclinical studies are discussed.
Collapse
Affiliation(s)
- Hong-Long Ji
- Department of Cellular and Molecular Biology, University of Texas Health Science Centre at Tyler, Tyler, TX 75708, United States
- Texas Lung Injury Institute, University of Texas Health Science Centre at Tyler, Tyler, TX 75708, United States
| | - Cong Liu
- School of Medicine, Southern University of Science and Technology, Shenzhen 518000, Guangdong Province, China
| | - Run-Zhen Zhao
- Department of Cellular and Molecular Biology, University of Texas Health Science Centre at Tyler, Tyler, TX 75708, United States
| |
Collapse
|
|
46
|
Perkins SE, Hankenson FC. Nonexperimental Xenobiotics: Unintended Consequences of Intentionally Administered Substances in Terrestrial Animal Models. ILAR J 2020; 60:216-227. [PMID: 32574354 DOI: 10.1093/ilar/ilaa003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 12/17/2019] [Accepted: 01/10/2020] [Indexed: 11/13/2022] Open
Abstract
Review of the use of nonexperimental xenobiotics in terrestrial animal models and the potential unintended consequences of these compounds, including drug-related side effects and adverse reactions.
Collapse
Affiliation(s)
- Scott E Perkins
- Tufts Comparative Medicine Services, Tufts University, Boston, Massachusetts; and Department of Environmental and Population Health, Cummings School of Veterinary Medicine, Tufts University, North Grafton, Massachusetts
| | - F Claire Hankenson
- Campus Animal Resources, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan
| |
Collapse
|
|
47
|
Huang J, Huang JH, Bao H, Ning X, Yu C, Chen Z, Chao J, Zhang Z. CT/MR Dual-Modality Imaging Tracking of Mesenchymal Stem Cells Labeled with a Au/GdNC@SiO 2 Nanotracer in Pulmonary Fibrosis. ACS APPLIED BIO MATERIALS 2020; 3:2489-2498. [PMID: 35025299 DOI: 10.1021/acsabm.0c00195] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Mesenchymal stem cells (MSCs) have shown potential as an innovative treatment for pulmonary fibrosis (PF), due to their capability to ameliorate the inflammation and moderate the deterioration of PF. The fate of the stem cells transplanted into the lung, including survival, migration, homing, and functions, however, has not been fully understood yet. In this paper, we report the development of a computed tomography/magnetic resonance (CT/MR) dual-modal nanotracer, gold/gadolinium nanoclusters overcoated with a silica shell (Au/GdNC@SiO2), for noninvasive labeling and tracking of the transplanted human MSCs (hMSCs) in a PF model. The Au/GdNC@SiO2 nanotracer exhibits good colloidal and chemical stability, high biocompatibility, enhanced longitudinal MR relaxivity, and superior X-ray attenuation property. The hMSCs can be effectively labeled with Au/GdNC@SiO2, resulting in a significantly increased cellular CT/MR imaging contrast, without any obvious adverse effect on the function, including proliferation and differentiation of the labeled stem cells. Moreover, by using the Au/GdNC@SiO2 nanotracer, the hMSCs transplanted in the lung can be tracked for 7 d via in vivo CT/MR dual-modality imaging. This work may provide an insight into the role the transplanted hMSCs play in PF therapy, thus promoting the stem cell-based regenerative medicine.
Collapse
Affiliation(s)
- Jie Huang
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123 Jiangsu, China
| | - Jie Holly Huang
- Department of Physiology, School of Medicine, Southeast University, Nanjing 210009 Jiangsu, China
| | - Hongying Bao
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123 Jiangsu, China
| | - Xinyu Ning
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123 Jiangsu, China
| | - Chenggong Yu
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123 Jiangsu, China
| | - Zhongjin Chen
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123 Jiangsu, China
| | - Jie Chao
- Department of Physiology, School of Medicine, Southeast University, Nanjing 210009 Jiangsu, China
| | - Zhijun Zhang
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123 Jiangsu, China
| |
Collapse
|
|
48
|
Behnke J, Kremer S, Shahzad T, Chao CM, Böttcher-Friebertshäuser E, Morty RE, Bellusci S, Ehrhardt H. MSC Based Therapies-New Perspectives for the Injured Lung. J Clin Med 2020; 9:jcm9030682. [PMID: 32138309 PMCID: PMC7141210 DOI: 10.3390/jcm9030682] [Citation(s) in RCA: 116] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 02/25/2020] [Accepted: 02/28/2020] [Indexed: 12/11/2022] Open
Abstract
Chronic lung diseases pose a tremendous global burden. At least one in four people suffer from severe pulmonary sequelae over the course of a lifetime. Despite substantial improvements in therapeutic interventions, persistent alleviation of clinical symptoms cannot be offered to most patients affected to date. Despite broad discrepancies in origins and pathomechanisms, the important disease entities all have in common the pulmonary inflammatory response which is central to lung injury and structural abnormalities. Mesenchymal stem cells (MSC) attract particular attention due to their broadly acting anti-inflammatory and regenerative properties. Plenty of preclinical studies provided congruent and convincing evidence that MSC have the therapeutic potential to alleviate lung injuries across ages. These include the disease entities bronchopulmonary dysplasia, asthma and the different forms of acute lung injury and chronic pulmonary diseases in adulthood. While clinical trials are so far restricted to pioneering trials on safety and feasibility, preclinical results point out possibilities to boost the therapeutic efficacy of MSC application and to take advantage of the MSC secretome. The presented review summarizes the most recent advances and highlights joint mechanisms of MSC action across disease entities which provide the basis to timely tackle this global disease burden.
Collapse
Affiliation(s)
- Judith Behnke
- Department of General Pediatrics and Neonatology, Justus-Liebig-University, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Feulgenstrasse 12, 35392 Gießen, Germany; (J.B.); (S.K.); (T.S.); (C.-M.C.)
| | - Sarah Kremer
- Department of General Pediatrics and Neonatology, Justus-Liebig-University, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Feulgenstrasse 12, 35392 Gießen, Germany; (J.B.); (S.K.); (T.S.); (C.-M.C.)
| | - Tayyab Shahzad
- Department of General Pediatrics and Neonatology, Justus-Liebig-University, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Feulgenstrasse 12, 35392 Gießen, Germany; (J.B.); (S.K.); (T.S.); (C.-M.C.)
| | - Cho-Ming Chao
- Department of General Pediatrics and Neonatology, Justus-Liebig-University, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Feulgenstrasse 12, 35392 Gießen, Germany; (J.B.); (S.K.); (T.S.); (C.-M.C.)
- Department of Internal Medicine II, Universities of Giessen and Marburg Lung Center (UGMLC), Cardiopulmonary Institute (CPI), German Center for Lung Research (DZL), Aulweg 130, 35392 Giessen, Germany;
| | | | - Rory E. Morty
- Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, German Center for Lung Research (DZL), Ludwigstrasse 43, 61231 Bad Nauheim, Germany;
| | - Saverio Bellusci
- Department of Internal Medicine II, Universities of Giessen and Marburg Lung Center (UGMLC), Cardiopulmonary Institute (CPI), German Center for Lung Research (DZL), Aulweg 130, 35392 Giessen, Germany;
| | - Harald Ehrhardt
- Department of General Pediatrics and Neonatology, Justus-Liebig-University, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Feulgenstrasse 12, 35392 Gießen, Germany; (J.B.); (S.K.); (T.S.); (C.-M.C.)
- Correspondence: ; Tel.: +49-985-43400; Fax: +49-985-43419
| |
Collapse
|
|
49
|
Mahmoudi T, Abdolmohammadi K, Bashiri H, Mohammadi M, Rezaie MJ, Fathi F, Fakhari S, Rezaee MA, Jalili A, Rahmani MR, Tayebi L. Hydrogen Peroxide Preconditioning Promotes Protective Effects of Umbilical Cord Vein Mesenchymal Stem Cells in Experimental Pulmonary Fibrosis. Adv Pharm Bull 2020; 10:72-80. [PMID: 32002364 PMCID: PMC6983995 DOI: 10.15171/apb.2020.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 06/27/2019] [Accepted: 07/02/2019] [Indexed: 12/15/2022] Open
Abstract
Purpose: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disorder with few available treatments. Mesenchymal stem cell therapy (MSCT), an innovative approach, has high therapeutic potential when used to treat IPF. According to recent data, preconditioning of MSCs can improve their therapeutic effects. Our research focuses on investigating the anti-inflammatory and antifibrotic effects of H2 O2 -preconditioned MSCs (p-MSCs) on mice with bleomycin-induced pulmonary fibrosis (PF). Methods: Eight-week-old male C57BL/6 mice were induced with PF by intratracheal (IT) instillation of bleomycin (4 U/kg). Human umbilical cord vein-derived MSCs (hUCV-MSCs) were isolated and exposed to a sub-lethal concentration (15 μM for 24 h) of H2 O2 in vitro. One week following the injection of bleomycin, 2×105 MSCs or p-MSCs were injected (IT) into the experimental PF. The survival rate and weight of mice were recorded, and 14 days after MSCs injection, all mice were sacrificed. Lung tissue was removed from these mice to examine the myeloperoxidase (MPO) activity, histopathological changes (hematoxylin-eosin and Masson's trichrome) and expression of transforming growth factor beta 1 (TGF-β1) and alpha-smooth muscle actin (α-SMA) through immunohistochemistry (IHC) staining. Results: Compared to the PF+MSC group, p-MSCs transplantation results in significantly decreased connective tissue (P<0.05) and collagen deposition. Additionally, it is determined that lung tissue in the PF+pMSC group has increased alveolar space (P<0.05) and diminished expression of TGF-β1 and α-SMA. Conclusion: The results demonstrate that MSCT using p-MSCs decreases inflammatory and fibrotic factors in bleomycin-induced PF, while also able to increase the therapeutic potency of MSCT in IPF.
Collapse
Affiliation(s)
- Tayebeh Mahmoudi
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Kamal Abdolmohammadi
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamed Bashiri
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
- Department of Medical Laboratory Sciences, Faculty of Paramedical, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Mehdi Mohammadi
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Jafar Rezaie
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Fardin Fathi
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Shohreh Fakhari
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Mohammad Ali Rezaee
- Department of Medical Laboratory Sciences, Faculty of Paramedical, Kurdistan University of Medical Sciences, Sanandaj, Iran
- Zoonoses Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Ali Jalili
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
- Cancer and Immunology Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Mohammad Reza Rahmani
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
- Zoonoses Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Lobat Tayebi
- Marquette University School of Dentistry, Milwaukee, WI, 53233, USA
| |
Collapse
|
|
50
|
Duan FF, Barron G, Meliton A, Mutlu GM, Dulin NO, Schuger L. P311 Promotes Lung Fibrosis via Stimulation of Transforming Growth Factor-β1, -β2, and -β3 Translation. Am J Respir Cell Mol Biol 2019; 60:221-231. [PMID: 30230348 DOI: 10.1165/rcmb.2018-0028oc] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Interstitial lung fibrosis, a frequently idiopathic and fatal disease, has been linked to the increased expression of profibrotic transforming growth factor (TGF)-βs. P311 is an RNA-binding protein that stimulates TGF-β1, -β2, and -β3 translation in several cell types through its interaction with the eukaryotic translation initiation factor 3b. We report that P311 is switched on in the lungs of patients with idiopathic pulmonary fibrosis (IPF) and in the mouse model of bleomycin (BLM)-induced pulmonary fibrosis. To assess the in vivo role of P311 in lung fibrosis, BLM was instilled into the lungs of P311-knockout mice, in which fibrotic changes were significantly decreased in tandem with a reduction in TGF-β1, -β2, and -β3 concentration/activity compared with BLM-treated wild-type mice. Complementing these findings, forced P311 expression increased TGF-β concentration/activity in mouse and human lung fibroblasts, thereby leading to an activated phenotype with increased collagen production, as seen in IPF. Consistent with a specific effect of P311 on TGF-β translation, TGF-β1-, -β2-, and -β3-neutralizing antibodies downregulated P311-induced collagen production by lung fibroblasts. Furthermore, treatment of BLM-exposed P311 knockouts with recombinant TGF-β1, -β2, and -β3 induced pulmonary fibrosis to a degree similar to that found in BLM-treated wild-type mice. These studies demonstrate the essential function of P311 in TGF-β-mediated lung fibrosis. Targeting P311 could prove efficacious in ameliorating the severity of IPF while circumventing the development of autoimmune complications and toxicities associated with the use of global TGF-β inhibitors.
Collapse
Affiliation(s)
| | | | - Angelo Meliton
- 2 Section of Pulmonary and Critical Care Medicine, Department of Medicine, The University of Chicago Medical School, Chicago, Illinois
| | - Gokhan M Mutlu
- 2 Section of Pulmonary and Critical Care Medicine, Department of Medicine, The University of Chicago Medical School, Chicago, Illinois
| | - Nickolai O Dulin
- 2 Section of Pulmonary and Critical Care Medicine, Department of Medicine, The University of Chicago Medical School, Chicago, Illinois
| | | |
Collapse
|