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Li F, Liu Y, Zhang M, Wang S, Hu X, Liu X, Hou R, Cai K. Leukemia inhibitory factor promotes growth and maintains stemness in giant panda MSCs. In Vitro Cell Dev Biol Anim 2025; 61:257-263. [PMID: 40045150 DOI: 10.1007/s11626-025-01022-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 01/31/2025] [Indexed: 04/09/2025]
Affiliation(s)
- Feiping Li
- Chengdu Research Base of Giant Panda Breeding, People's Republic of China, Chengdu, 610081, Sichuan, China
- Sichuan Key Laboratory of Conservation Biology On Endangered Wildlife, Sichuan, People's Republic of China, Chengdu, 610081, Sichuan, China
| | - Yuliang Liu
- Chengdu Research Base of Giant Panda Breeding, People's Republic of China, Chengdu, 610081, Sichuan, China
- Sichuan Key Laboratory of Conservation Biology On Endangered Wildlife, Sichuan, People's Republic of China, Chengdu, 610081, Sichuan, China
| | - Mengshi Zhang
- Chengdu Research Base of Giant Panda Breeding, People's Republic of China, Chengdu, 610081, Sichuan, China
- Sichuan Key Laboratory of Conservation Biology On Endangered Wildlife, Sichuan, People's Republic of China, Chengdu, 610081, Sichuan, China
| | - Shenfei Wang
- Chengdu Research Base of Giant Panda Breeding, People's Republic of China, Chengdu, 610081, Sichuan, China
- Sichuan Key Laboratory of Conservation Biology On Endangered Wildlife, Sichuan, People's Republic of China, Chengdu, 610081, Sichuan, China
| | - Xianbiao Hu
- Chengdu Research Base of Giant Panda Breeding, People's Republic of China, Chengdu, 610081, Sichuan, China
- Sichuan Key Laboratory of Conservation Biology On Endangered Wildlife, Sichuan, People's Republic of China, Chengdu, 610081, Sichuan, China
| | - Xiangyu Liu
- Chengdu Research Base of Giant Panda Breeding, People's Republic of China, Chengdu, 610081, Sichuan, China
- Sichuan Key Laboratory of Conservation Biology On Endangered Wildlife, Sichuan, People's Republic of China, Chengdu, 610081, Sichuan, China
| | - Rong Hou
- Chengdu Research Base of Giant Panda Breeding, People's Republic of China, Chengdu, 610081, Sichuan, China
- Sichuan Key Laboratory of Conservation Biology On Endangered Wildlife, Sichuan, People's Republic of China, Chengdu, 610081, Sichuan, China
| | - Kailai Cai
- Chengdu Research Base of Giant Panda Breeding, People's Republic of China, Chengdu, 610081, Sichuan, China.
- Sichuan Key Laboratory of Conservation Biology On Endangered Wildlife, Sichuan, People's Republic of China, Chengdu, 610081, Sichuan, China.
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Wan R, Liu Y, Yan J, Lin J. Cell therapy: A beacon of hope in the battle against pulmonary fibrosis. FASEB J 2025; 39:e70356. [PMID: 39873972 DOI: 10.1096/fj.202402790r] [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: 11/10/2024] [Revised: 12/28/2024] [Accepted: 01/15/2025] [Indexed: 01/30/2025]
Abstract
Pulmonary fibrosis (PF) is a chronic and progressive interstitial lung disease characterized by abnormal activation of myofibroblasts and pathological remodeling of the extracellular matrix, with a poor prognosis and limited treatment options. Lung transplantation is currently the only approach that can extend the life expectancy of patients; however, its applicability is severely restricted due to donor shortages and patient-specific limitations. Therefore, the search for novel therapeutic strategies is imperative. In recent years, stem cells have shown great promise in the field of regenerative medicine due to their self-renewal capacity and multidirectional differentiation potential, and a growing body of literature supports the efficacy of stem cell therapy in PF treatment. This paper systematically summarizes the research progress of various stem cell types in the treatment of PF. Furthermore, it discusses the primary methods and clinical outcomes of stem cell therapy in PF, based on both preclinical and clinical data. Finally, the current challenges and key factors to consider in stem cell therapy for PF are objectively analyzed, and future directions for improving this therapy are proposed, providing new insights and references for the clinical treatment of PF patients.
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Affiliation(s)
- Ruyan Wan
- Stem Cell and Biotherapy Technology Research Center, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, China
| | - Yanli Liu
- Stem Cell and Biotherapy Technology Research Center, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, China
| | - Jingwen Yan
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
| | - Juntang Lin
- Stem Cell and Biotherapy Technology Research Center, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, China
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Biomedical Engineering, Xinxiang Medical University, Xinxiang, China
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Wu H, Zhong Y, Li Y, Zhou X, Zhao T, Wan D, Zhu Y, Zhang Z, Li X, Gan X. Wnt3a Enhances Mesenchymal Stem Cell Engraftment and Differentiation in a Chronic Obstructive Pulmonary Disease Rat Model. Int J Chron Obstruct Pulmon Dis 2025; 20:69-81. [PMID: 39802038 PMCID: PMC11725259 DOI: 10.2147/copd.s486262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 12/28/2024] [Indexed: 01/16/2025] Open
Abstract
Background Bone marrow mesenchymal stem cell (BMSC) therapy is a novel approach for treating COPD. However, the difficulty in engraftment and easy clearance of BMSCs in vivo has hindered their clinical application. Hence, exploring effective methods to improve the engraftment and differentiation rates of BMSCs in vivo is urgent. Methods We constructed BMSCs overexpressing Wnt3a by lentivirus infection and transplanted them into a COPD rat model. The damage level of COPD rat lung tissue was assessed by pathology analysis and inflammatory cytokines analysis. The engraftment of BMSC was detected by immunofluorescence staining. Statistical analysis was performed using GraphPad Prism 7. Results We found that Wnt3a significantly enhanced the engraftment rate of BMSCs in the lungs of rats and further increased their differentiation rate into type II alveolar epithelial cells. We also assessed the expression of inflammatory factors in the lung tissues of COPD rats and discovered that Wnt3a reduced the levels of the inflammatory factors IL-6 and IL-1β while increasing the level of the anti-inflammatory factor IL-10. Our study demonstrates that Wnt3a can improve the engraftment and differentiation rates of BMSCs in the host and further alleviate COPD symptoms by regulating the secretion of inflammatory factors. Conclusion Constructing BMSCs overexpressing Wnt3a could serve as a new strategy for stem cell therapy in COPD.
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Affiliation(s)
- Huala Wu
- Department of Respiratory and Critical Care Medicine, Jiangxi Provincial Key Laboratory of Respiratory Diseases, Jiangxi Institute of Respiratory Diseases, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China
| | - Yulan Zhong
- Department of Respiratory and Critical Care Medicine, Chest Hospital of Jiangxi Province, Nanchang, Jiangxi, 330006, People’s Republic of China
| | - Yangjingsi Li
- Department of Respiratory and Critical Care Medicine, Jiangxi Provincial People’s Hospital, Nanchang, Jiangxi, 330006, People’s Republic of China
| | - Xiangxiang Zhou
- Department of Respiratory and Critical Care Medicine, Chest Hospital of Jiangxi Province, Nanchang, Jiangxi, 330006, People’s Republic of China
| | - Tiantian Zhao
- Department of Respiratory and Critical Care Medicine, Jiangxi Provincial Key Laboratory of Respiratory Diseases, Jiangxi Institute of Respiratory Diseases, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China
| | - Daomou Wan
- Department of Respiratory and Critical Care Medicine, Jiangxi Provincial Key Laboratory of Respiratory Diseases, Jiangxi Institute of Respiratory Diseases, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China
| | - Yuanzhe Zhu
- Department of Respiratory and Critical Care Medicine, Jiangxi Provincial Key Laboratory of Respiratory Diseases, Jiangxi Institute of Respiratory Diseases, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China
| | - Zhiyan Zhang
- Department of Respiratory and Critical Care Medicine, Jiangxi Provincial Key Laboratory of Respiratory Diseases, Jiangxi Institute of Respiratory Diseases, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China
| | - Xiaolei Li
- Department of Respiratory and Critical Care Medicine, Jiangxi Provincial Key Laboratory of Respiratory Diseases, Jiangxi Institute of Respiratory Diseases, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China
- China-Japan Friendship Jiangxi Hospital, National Regional Center for Respiratory Medicine, Nanchang, Jiangxi, 330200, People’s Republic of China
| | - Xin Gan
- Department of Respiratory and Critical Care Medicine, Jiangxi Provincial Key Laboratory of Respiratory Diseases, Jiangxi Institute of Respiratory Diseases, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China
- China-Japan Friendship Jiangxi Hospital, National Regional Center for Respiratory Medicine, Nanchang, Jiangxi, 330200, People’s Republic of China
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Radicetti-Silva J, Oliveira M, Baldavira CM, Braga CL, Santos RT, Felix NS, Silva AL, Capelozzi VL, Cruz FF, Rocco PRM, Silva PL. Distinct effects of intravenous bone marrow-derived mesenchymal stem cell therapy on ischemic and non-ischemic lungs after ischemia-reperfusion injury. Cytotherapy 2024; 26:1505-1513. [PMID: 39115513 DOI: 10.1016/j.jcyt.2024.07.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 07/15/2024] [Accepted: 07/17/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND The preclinical efficacy of mesenchymal stem cell (MSC) therapy after intravenous infusion has been promising, but clinical studies have yielded only modest results. Although most preclinical studies have focused solely on the ischemic lung, it is crucial to evaluate both lungs after ischemia-reperfusion injury, considering the various mechanisms involved. This study aimed to bridge this gap by assessing the acute effects of bone marrow MSC(BM) infusion before ischemic insult and evaluating both ischemic and non-ischemic lungs after reperfusion. METHODS Eighteen male Wistar rats (403 ± 23 g) were anesthetized and mechanically ventilated using a protective strategy. After baseline data collection, the animals were randomized to 3 groups (n = 6/group): (1) SHAM; (2) ischemia-reperfusion (IR), and (3) intravenous MSC(BM) infusion followed by IR. Ischemia was induced by complete clamping of the left hilum, followed by 1 h of reperfusion after clamp removal. At the end of the experiment, the right and left lungs (non-ischemic and ischemic, respectively) were collected for immunohistochemistry and molecular biology analysis. RESULTS MSC(BM)s reduced endothelial cell damage and apoptosis markers and improved markers associated with endothelial cell integrity in both lungs. In addition, gene expression of catalase and nuclear factor erythroid 2-related factor 2 increased after MSC(BM) therapy. In the ischemic lung, MSC(BM) therapy mitigated endothelial cell damage and apoptosis and increased gene expression associated with endothelial cell integrity. Conversely, in the non-ischemic lung, apoptosis gene expression increased in the IR group but not after MSC(BM) therapy. CONCLUSION This study demonstrates distinct effects of MSC(BM) therapy on ischemic and non-ischemic lungs after ischemia-reperfusion injury. The findings underscore the importance of evaluating both lung types in ischemia-reperfusion studies, offering insights into the therapeutic potential of MSC(BM) therapy in the context of lung injury.
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Affiliation(s)
- Julia Radicetti-Silva
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Milena Oliveira
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Cassia Lisboa Braga
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Renata Trabach Santos
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Nathane Santanna Felix
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Adriana Lopes Silva
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Vera Luiza Capelozzi
- Department of Pathology, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
| | - Fernanda Ferreira Cruz
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Patricia Rieken Macedo Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Pedro Leme Silva
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
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Ma Z, Qiu L, Sun J, Wu Z, Liang S, Zhao Y, Yang J, Yue S, Hu M, Li Y. A novel pulmonary fibrosis NOD/SCID murine model with natural aging. BMC Pulm Med 2024; 24:457. [PMID: 39285370 PMCID: PMC11406766 DOI: 10.1186/s12890-024-03268-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 09/04/2024] [Indexed: 09/19/2024] Open
Abstract
BACKGROUND Idiopathic pulmonary fibrosis (IPF) is an age-related disease severely affecting life quality with its prevalence rising as the population ages, yet there is still no effective treatment available. Cell therapy has emerged as a promising option for IPF, however, the absence of mature and stable animal models for IPF immunodeficiency hampers preclinical evaluations of human cell therapies, primarily due to rapid immune clearance of administered cells. This study aims to establish a reliable pulmonary fibrosis (PF) model in immunodeficient mice that supports autologous cell therapy and to investigate underlying mechanism. METHODS We utilized thirty 5-week-old male NOD/SCID mice, categorizing them into three age groups: 12weeks, 32 weeks and 43 weeks, with 6 mice euthanized randomly from each cohort for lung tissue analysis. We assessed fibrosis using HE staining, Masson's trichrome staining, α-SMA immunohistochemistry and hydroxyproline content measurement. Further, β-galactosidase staining and gene expression analysis of MMP9, TGF-β1, TNF-α, IL-1β, IL-6, IL-8, SOD1, SOD2, NRF2, SIRT1, and SIRT3 were performed. ELISA was employed to quantify protein levels of TNF-α, TGF-β1, and IL-8. RESULTS When comparing lung tissues from 32-week-old and 43-week-old mice to those from 12-week-old mice, we noted a marked increase in inflammatory infiltration, fibrosis severity, and hydroxyproline content, alongside elevated expression levels of α-SMA and MMP9. Notably, the degree of fibrosis intensified with age. Additionally, β-galactosidase staining became more pronounced in older mice. Quantitative PCR analyses revealed age-related, increases in the expression of senescence markers (GLB1, P16, P21), and proinflammatory genes (TGF-β1, TNF-α, IL-1β, IL-6, and IL-8). Conversely, the expression of anti-oxidative stress-related genes (SOD1, SOD2, NRF2, SIRT1, and SIRT3) declined, showing statistically significant differences (*P < 0.05, **P < 0.01, ***P < 0.001). ELISA results corroborated these findings, indicating a progressive rise in the protein levels of TGF-β1, TNF-α, and IL-8 as the mice aged. CONCLUSIONS The findings suggest that NOD/SCID mice aged 32 weeks and 43 weeks effectively model pulmonary fibrosis in an elderly context, with the disease pathogenesis likely driven by age-associated inflammation and oxidative stress.
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Affiliation(s)
- Zhaoxia Ma
- Yunnan Key Laboratory for Basic Research on Bone and Joint Diseases, Kunming University, Kunming, Yunnan, 650214, China
| | - Lihua Qiu
- Yunnan Key Laboratory for Basic Research on Bone and Joint Diseases, Kunming University, Kunming, Yunnan, 650214, China
| | - Jianxiu Sun
- Yunnan Jici Institute for Regenerative Medicine Co., Ltd, Kunming, Yunnan, 650101, China
| | - Zhen Wu
- Shenzhen Zhendejici Pharmaceutical Research and Development Co., Ltd, Shenzhen, 518048, Guangdong, China
| | - Shu Liang
- Yunnan Key Laboratory for Basic Research on Bone and Joint Diseases, Kunming University, Kunming, Yunnan, 650214, China
| | - Yunhui Zhao
- Yunnan Jici Institute for Regenerative Medicine Co., Ltd, Kunming, Yunnan, 650101, China
| | - Jinmei Yang
- Yunnan Jici Institute for Regenerative Medicine Co., Ltd, Kunming, Yunnan, 650101, China
| | - Shijun Yue
- Yunnan Key Laboratory for Basic Research on Bone and Joint Diseases, Kunming University, Kunming, Yunnan, 650214, China
| | - Min Hu
- Yunnan Key Laboratory for Basic Research on Bone and Joint Diseases, Kunming University, Kunming, Yunnan, 650214, China.
| | - Yanjiao Li
- Yunnan Key Laboratory for Basic Research on Bone and Joint Diseases, Kunming University, Kunming, Yunnan, 650214, China.
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Mohammed SM, Al-Saedi HFS, Mohammed AQ, Amir AA, Radi UK, Sattar R, Ahmad I, Ramadan MF, Alshahrani MY, Balasim HM, Alawadi A. Mechanisms of Bleomycin-induced Lung Fibrosis: A Review of Therapeutic Targets and Approaches. Cell Biochem Biophys 2024; 82:1845-1870. [PMID: 38955925 DOI: 10.1007/s12013-024-01384-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2024] [Indexed: 07/04/2024]
Abstract
Pulmonary toxicity is a serious side effect of some specific anticancer drugs. Bleomycin is a well-known anticancer drug that triggers severe reactions in the lungs. It is an approved drug that may be prescribed for the treatment of testicular cancers, Hodgkin's and non-Hodgkin's lymphomas, ovarian cancer, head and neck cancers, and cervical cancer. A large number of experimental studies and clinical findings show that bleomycin can concentrate in lung tissue, leading to massive oxidative stress, alveolar epithelial cell death, the proliferation of fibroblasts, and finally the infiltration of immune cells. Chronic release of pro-inflammatory and pro-fibrotic molecules by immune cells and fibroblasts leads to pneumonitis and fibrosis. Both fibrosis and pneumonitis are serious concerns for patients who receive bleomycin and may lead to death. Therefore, the management of lung toxicity following cancer therapy with bleomycin is a critical issue. This review explains the cellular and molecular mechanisms of pulmonary injury following treatment with bleomycin. Furthermore, we review therapeutic targets and possible promising strategies for ameliorating bleomycin-induced lung injury.
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Affiliation(s)
- Shaimaa M Mohammed
- Department of Pharmacy, Al- Mustaqbal University College, 51001, Hilla, Babylon, Iraq
| | | | | | - Ahmed Ali Amir
- Department of Medical Laboratories Technology, Al-Nisour University College, Baghdad, Iraq
| | - Usama Kadem Radi
- College of Pharmacy, National University of Science and Technology, Nasiriyah, Dhi Qar, Iraq
| | - Ruaa Sattar
- Al-Hadi University College, Baghdad, 10011, Iraq
| | - Irfan Ahmad
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | | | - Mohammad Y Alshahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia.
| | - Halah Majeed Balasim
- Department of Medical Laboratory Technologies, Al Rafidain University College, Bagdad, Iraq
| | - Ahmed Alawadi
- College of technical engineering, the Islamic University, Najaf, Iraq
- College of technical engineering, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- College of technical engineering, the Islamic University of Babylon, Hilla, Iraq
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Le NT, Dunleavy MW, Kumar RD, Zhou W, Bhatia SS, El-Hashash AH. Cellular therapies for idiopathic pulmonary fibrosis: current progress and future prospects. AMERICAN JOURNAL OF STEM CELLS 2024; 13:191-211. [PMID: 39308764 PMCID: PMC11411253 DOI: 10.62347/daks5508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Accepted: 07/17/2024] [Indexed: 09/25/2024]
Abstract
Idiopathic pulmonary fibrosis (IPF) is an interstitial, fibrotic lung disease characterized by progressive damage. Lung tissues with IPF are replaced by fibrotic tissues with increased collagen deposition, modified extracellular matrix, all which overall damages the alveoli. These changes eventually impede the gas exchange function of the alveoli, and eventually leads to fatal respiratory failure of the lung. Investigations have been conducted to further understand IPF's pathogenesis, and significant progress in understanding its development has been made. Additionally, two therapeutic treatments, Nintedanib and Pirfenidone, have been approved and are currently used in medical applications. Moreover, cell-based treatments have recently come to the forefront of developing disease therapeutics and are the focus of many current studies. Furthermore, a sizable body of research encompassing basic, pre-clinical, and even clinical trials have all been amassed in recent years and hold a great potential for more widespread applications in patient care. Herein, this article reviews the progress in understanding the pathogenesis and pathophysiology of IPF. Additionally, different cell types used in IPF therapy were reviewed, including alveolar epithelial cells (AECs), circulating endothelial progenitors (EPCs), mixed lung epithelial cells, different types of stem cells, and endogenous lung tissue-specific stem cells. Finally, we discussed the contemporary trials that employ or explore cell-based therapy for IPF.
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Affiliation(s)
- Nicholas T Le
- Biology Department, Texas A&M University College Station, TX, USA
| | | | - Rebecca D Kumar
- Biology Department, Texas A&M University College Station, TX, USA
| | - William Zhou
- The University of Texas at Austin Austin, TX, USA
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Wang X, He W, Huang H, Han J, Wang R, Li H, Long Y, Wang G, Han X. Recent Advances in Hydrogel Technology in Delivering Mesenchymal Stem Cell for Osteoarthritis Therapy. Biomolecules 2024; 14:858. [PMID: 39062572 PMCID: PMC11274544 DOI: 10.3390/biom14070858] [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: 05/28/2024] [Revised: 07/06/2024] [Accepted: 07/13/2024] [Indexed: 07/28/2024] Open
Abstract
Osteoarthritis (OA), a chronic joint disease affecting over 500 million individuals globally, is characterized by the destruction of articular cartilage and joint inflammation. Conventional treatments are insufficient for repairing damaged joint tissue, necessitating novel therapeutic approaches. Mesenchymal stem cells (MSCs), with their potential for differentiation and self-renewal, hold great promise as a treatment for OA. However, challenges such as MSC viability and apoptosis in the ischemic joint environment hinder their therapeutic effectiveness. Hydrogels with biocompatibility and degradability offer a three-dimensional scaffold that support cell viability and differentiation, making them ideal for MSC delivery in OA treatment. This review discusses the pathological features of OA, the properties of MSCs, the challenges associated with MSC therapy, and methods for hydrogel preparation and functionalization. Furthermore, it highlights the advantages of hydrogel-based MSC delivery systems while providing insights into future research directions and the clinical potential of this approach.
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Affiliation(s)
- Xiangjiang Wang
- The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan 511518, China; (X.W.); (W.H.); (J.H.); (R.W.); (H.L.); (Y.L.)
| | - Wentao He
- The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan 511518, China; (X.W.); (W.H.); (J.H.); (R.W.); (H.L.); (Y.L.)
| | - Hao Huang
- Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, Collage of Physics and Optoelectronics Engineering, Shenzhen University, Shenzhen 518060, China;
| | - Jiali Han
- The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan 511518, China; (X.W.); (W.H.); (J.H.); (R.W.); (H.L.); (Y.L.)
| | - Ruren Wang
- The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan 511518, China; (X.W.); (W.H.); (J.H.); (R.W.); (H.L.); (Y.L.)
| | - Hongyi Li
- The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan 511518, China; (X.W.); (W.H.); (J.H.); (R.W.); (H.L.); (Y.L.)
| | - Ying Long
- The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan 511518, China; (X.W.); (W.H.); (J.H.); (R.W.); (H.L.); (Y.L.)
| | - Guiqing Wang
- The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan 511518, China; (X.W.); (W.H.); (J.H.); (R.W.); (H.L.); (Y.L.)
| | - Xianjing Han
- The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan 511518, China; (X.W.); (W.H.); (J.H.); (R.W.); (H.L.); (Y.L.)
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Mahida RY, Yuan Z, Kolluri KK, Scott A, Parekh D, Hardy RS, Matthay MA, Perkins GD, Janes SM, Thickett DR. 11β hydroxysteroid dehydrogenase type 1 transgenic mesenchymal stem cells attenuate inflammation in models of sepsis. Front Bioeng Biotechnol 2024; 12:1422761. [PMID: 39036559 PMCID: PMC11257926 DOI: 10.3389/fbioe.2024.1422761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 06/12/2024] [Indexed: 07/23/2024] Open
Abstract
Background Human bone marrow mesenchymal stem cell (MSC) administration reduces inflammation in pre-clinical models of sepsis and sepsis-related lung injury, however clinical efficacy in patients has not yet been demonstrated. We previously showed that Alveolar Macrophage (AM) 11β-hydroxysteroid dehydrogenase type-1 (HSD-1) autocrine signalling is impaired in critically ill sepsis patients, which promotes inflammatory injury. Administration of transgenic MSCs (tMSCs) which overexpress HSD-1 may enhance the anti-inflammatory effects of local glucocorticoids and be more effective at reducing inflammation in sepsis than cellular therapy alone. Methods MSCs were transfected using a recombinant lentiviral vector containing the HSD-1 and GPF transgenes under the control of a tetracycline promoter. Thin layer chromatography assessed HSD-1 reductase activity in tMSCs. Mesenchymal stem cell phenotype was assessed by flow cytometry and bi-lineage differentiation. HSD-1 tMSCs were co-cultured with LPS-stimulated monocyte-derived macrophages (MDMs) from healthy volunteers prior to assessment of pro-inflammatory cytokine release. HSD-1 tMSCs were administered intravenously to mice undergoing caecal ligation and puncture (CLP). Results MSCs were transfected with an efficiency of 91.1%, and maintained an MSC phenotype. Functional HSD-1 activity was demonstrated in tMSCs, with predominant reductase cortisol activation (peak 8.23 pM/hour/100,000 cells). HSD-1 tMSC co-culture with LPS-stimulated MDMs suppressed TNFα and IL-6 release. Administration of transgene activated HSD-1 tMSCs in a murine model of CLP attenuated neutrophilic inflammation more effectively than transgene inactive tMSCs (medians 0.403 v 1.36 × 106/ml, p = 0.033). Conclusion The synergistic impact of HSD-1 transgene expression and MSC therapy attenuated neutrophilic inflammation in a mouse model of peritoneal sepsis more effectively than MSC therapy alone. Future studies investigating the anti-inflammatory capacity of HSD-1 tMSCs in models of sepsis-related direct lung injury and inflammatory diseases are required.
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Affiliation(s)
- Rahul Y. Mahida
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Zhengqiang Yuan
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, China
| | - Krishna K. Kolluri
- Lungs for Living Research Centre, UCL Respiratory, University College London, London, United Kingdom
| | - Aaron Scott
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Dhruv Parekh
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Rowan S. Hardy
- Institute of Clinical Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Michael A. Matthay
- Cardiovascular Research Institute, Department of Medicine and Department of Anaesthesia, University of California San Francisco, San Francisco, CA, United States
| | - Gavin D. Perkins
- Warwick Medical School, University of Warwick, Warwick, United Kingdom
| | - Sam M. Janes
- Lungs for Living Research Centre, UCL Respiratory, University College London, London, United Kingdom
| | - David R. Thickett
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
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10
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Taherian M, Bayati P, Mojtabavi N. Stem cell-based therapy for fibrotic diseases: mechanisms and pathways. Stem Cell Res Ther 2024; 15:170. [PMID: 38886859 PMCID: PMC11184790 DOI: 10.1186/s13287-024-03782-5] [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: 01/29/2024] [Accepted: 06/04/2024] [Indexed: 06/20/2024] Open
Abstract
Fibrosis is a pathological process, that could result in permanent scarring and impairment of the physiological function of the affected organ; this condition which is categorized under the term organ failure could affect various organs in different situations. The involvement of the major organs, such as the lungs, liver, kidney, heart, and skin, is associated with a high rate of morbidity and mortality across the world. Fibrotic disorders encompass a broad range of complications and could be traced to various illnesses and impairments; these could range from simple skin scars with beauty issues to severe rheumatologic or inflammatory disorders such as systemic sclerosis as well as idiopathic pulmonary fibrosis. Besides, the overactivation of immune responses during any inflammatory condition causing tissue damage could contribute to the pathogenic fibrotic events accompanying the healing response; for instance, the inflammation resulting from tissue engraftment could cause the formation of fibrotic scars in the grafted tissue, even in cases where the immune system deals with hard to clear infections, fibrotic scars could follow and cause severe adverse effects. A good example of such a complication is post-Covid19 lung fibrosis which could impair the life of the affected individuals with extensive lung involvement. However, effective therapies that halt or slow down the progression of fibrosis are missing in the current clinical settings. Considering the immunomodulatory and regenerative potential of distinct stem cell types, their application as an anti-fibrotic agent, capable of attenuating tissue fibrosis has been investigated by many researchers. Although the majority of the studies addressing the anti-fibrotic effects of stem cells indicated their potent capabilities, the underlying mechanisms, and pathways by which these cells could impact fibrotic processes remain poorly understood. Here, we first, review the properties of various stem cell types utilized so far as anti-fibrotic treatments and discuss the challenges and limitations associated with their applications in clinical settings; then, we will summarize the general and organ-specific mechanisms and pathways contributing to tissue fibrosis; finally, we will describe the mechanisms and pathways considered to be employed by distinct stem cell types for exerting anti-fibrotic events.
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Affiliation(s)
- Marjan Taherian
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Paria Bayati
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Nazanin Mojtabavi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.
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11
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Liang J, Dai W, Xue S, Wu F, Cui E, Pan R. Recent progress in mesenchymal stem cell-based therapy for acute lung injury. Cell Tissue Bank 2024; 25:677-684. [PMID: 38466563 DOI: 10.1007/s10561-024-10129-0] [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: 06/07/2022] [Accepted: 01/24/2024] [Indexed: 03/13/2024]
Abstract
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening diseases in critically ill patients. Although pathophysiology of ALI/ARDS has been investigated in many studies, effective therapeutic strategies are still limited. Mesenchymal stem cell (MSC)-based therapy is emerging as a promising therapeutic intervention for patients with ALI. During the last two decades, researchers have focused on the efficacy and mechanism of MSC application in ALI animal models. MSC derived from variant resources exhibited therapeutic effects in preclinical studies of ALI with different mechanisms. Based on this, clinical studies on MSC treatment in ALI/ARDS has been tried recently, especially in COVID-19 caused lung injury. Emerging clinical trials of MSCs in treating COVID-19-related conditions have been registered in past two years. The advantages and potential of MSCs in the defense against COVID-19-related ALI or ARDS have been confirmed. This review provides a brief overview of recent research progress in MSC-based therapies in preclinical study and clinical trials in ALI treatment, as well as the underlying mechanisms.
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Affiliation(s)
- Jinfeng Liang
- Zhejiang Center for Drug and Cosmetic Evaluation, Hangzhou, China
| | - Weiyou Dai
- School of Medicine, Zhejiang University, Hangzhou, China
| | - Shihang Xue
- Xiangshan First People's Hospital Medical and Health Group, Ningbo, China
| | - Feifei Wu
- Key Laboratory of Cell-Based Drug and Applied Technology Development in Zhejiang Province, Hangzhou, China
- Institute for Cell-Based Drug Development of Zhejiang Province, S-Evans Biosciences, No.181 Wuchang Road, Hangzhou, 311122, Zhejiang, People's Republic of China
| | - Enhai Cui
- Huzhou Central Hospital, Zhejiang University Huzhou Hospital, Huzhou, 313000, People's Republic of China.
| | - Ruolang Pan
- Key Laboratory of Cell-Based Drug and Applied Technology Development in Zhejiang Province, Hangzhou, China.
- Institute for Cell-Based Drug Development of Zhejiang Province, S-Evans Biosciences, No.181 Wuchang Road, Hangzhou, 311122, Zhejiang, People's Republic of China.
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12
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Nakamura Y, Niho S, Shimizu Y. Cell-Based Therapy for Fibrosing Interstitial Lung Diseases, Current Status, and Potential Applications of iPSC-Derived Cells. Cells 2024; 13:893. [PMID: 38891026 PMCID: PMC11172081 DOI: 10.3390/cells13110893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 05/09/2024] [Accepted: 05/17/2024] [Indexed: 06/20/2024] Open
Abstract
Fibrosing interstitial lung diseases (FILDs), e.g., due to idiopathic pulmonary fibrosis (IPF), are chronic progressive diseases with a poor prognosis. The management of these diseases is challenging and focuses mainly on the suppression of progression with anti-fibrotic drugs. Therefore, novel FILD treatments are needed. In recent years, cell-based therapy with various stem cells has been investigated for FILD, and the use of mesenchymal stem cells (MSCs) has been widely reported and clinical studies are also ongoing. Induced pluripotent stem cells (iPSCs) have also been reported to have an anti-fibrotic effect in FILD; however, these have not been as well studied as MSCs in terms of the mechanisms and side effects. While MSCs show a potent anti-fibrotic effect, the possibility of quality differences between donors and a stable supply in the case of donor shortage or reduced proliferative capacity after cell passaging needs to be considered. The application of iPSC-derived cells has the potential to overcome these problems and may lead to consistent quality of the cell product and stable product supply. This review provides an overview of iPSCs and FILD, followed by the current status of cell-based therapy for FILD, and then discusses the possibilities and perspectives of FILD therapy with iPSC-derived cells.
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Affiliation(s)
- Yusuke Nakamura
- Department of Pulmonary Medicine and Clinical Immunology, Dokkyo Medical University School of Medicine, Mibu 321-0293, Japan; (Y.N.); (S.N.)
- Center of Regenerative Medicine, Dokkyo Medical University Hospital, Mibu 321-0293, Japan
| | - Seiji Niho
- Department of Pulmonary Medicine and Clinical Immunology, Dokkyo Medical University School of Medicine, Mibu 321-0293, Japan; (Y.N.); (S.N.)
| | - Yasuo Shimizu
- Department of Pulmonary Medicine and Clinical Immunology, Dokkyo Medical University School of Medicine, Mibu 321-0293, Japan; (Y.N.); (S.N.)
- Center of Regenerative Medicine, Dokkyo Medical University Hospital, Mibu 321-0293, Japan
- Respiratory Endoscopy Center, Dokkyo Medical University Hospital, Mibu 321-0293, Japan
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13
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Li K, Shen C, Wen N, Han Y, Guo L. EPO regulates the differentiation and homing of bone marrow mesenchymal stem cells through Notch1/Jagged pathway to treat pulmonary hypertension. Heliyon 2024; 10:e25234. [PMID: 38375306 PMCID: PMC10875385 DOI: 10.1016/j.heliyon.2024.e25234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Revised: 01/23/2024] [Accepted: 01/23/2024] [Indexed: 02/21/2024] Open
Abstract
Purpose To investigate whether erythropoietin (EPO) can treat pulmonary arterial hypertension (PAH) in rats by regulating the differentiation and homing of bone marrow mesenchymal stem cells (BMSCs) through Notch1/Jagged signaling pathway. Materials & methods BMSCs were isolated from the bone marrow of 6-week-old male SD rats by whole bone marrow method and identified. BMSCs were treated with 500 IU/mL EPO, and the proliferation, migration, invasion and differentiation ability, and the expression of MMP-2 and MMP-9 protein of BMSCs were detected in vitro. After the establishment of the pulmonary hypertension model in rats, BMSCs were intervened with different concentrations of EPO and injected into the rats through intravenous injection. The levels of TNF-α, IL-1β and IL-6 in lung tissue, the expression of SRY CXCR4, CCR2, Notch1 and Jagged protein in lung tissue, and the levels of TGF-α, vascular endothelial factor (VEGF), IGF-1 and HGF in serum were detected. Immunofluorescence (IF) staining was used to detect the co-localization of CD34. Results EPO promoted the proliferation, migration, and invasion of BMSCs by inhibiting Notch1/Jagged pathway in vitro, and induced BMSCs to differentiate into vascular smooth muscle cells and vascular endothelial cells. EPO inhibited Notch1/Jagged pathway in PAH rats, induced BMSCs homing and differentiation, increased the levels of TGF-α, VEGF, IGF-1 and HGF, and decreased the levels of TNF-α, IL-1β and IL-6. Discussion & conclusion EPO can inhibit the Notch1/Jagged pathway and promote the proliferation, migration, invasion, homing and differentiation of BMSCs to treat pulmonary hypertension in rats in vitro and in vivo.
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Affiliation(s)
- Kang Li
- Department of Gastroenterology, People's Hospital of Tibet Autonomous Region, Lhasa, Tibet 850000, China
| | - Chongyang Shen
- School of basic medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 230041, Sichuan, China
| | - Nianchi Wen
- Department of Health Management & Physical Examination, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, Sichuan, China
| | - Yicen Han
- Department of Pulmonary and Critical Care Medicine, Chengdu Second People's Hospital, Chengdu 610021, Sichuan, China
| | - Lu Guo
- Department of Pulmonary and Critical Care Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan, China
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14
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Wang T, Zhang Z, Deng Z, Zeng W, Gao Y, Hei Z, Yuan D. Mesenchymal stem cells alleviate sepsis-induced acute lung injury by blocking neutrophil extracellular traps formation and inhibiting ferroptosis in rats. PeerJ 2024; 12:e16748. [PMID: 38304189 PMCID: PMC10832623 DOI: 10.7717/peerj.16748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 12/12/2023] [Indexed: 02/03/2024] Open
Abstract
Acute lung injury (ALI) is one of the most serious complications of sepsis, characterized by high morbidity and mortality rates. Ferroptosis has recently been reported to play an essential role in sepsis-induced ALI. Excessive neutrophil extracellular traps (NETs) formation induces exacerbated inflammation and is crucial to the development of ALI. In this study, we explored the effects of ferroptosis and NETs and observed the therapeutic function of mesenchymal stem cells (MSCs) on sepsis-induced ALI. First, we produced a cecal ligation and puncture (CLP) model of sepsis in rats. Ferrostain-1 and DNase-1 were used to inhibit ferroptosis and NETs formation separately, to confirm their effects on sepsis-induced ALI. Next, U0126 was applied to suppress the MEK/ERK signaling pathway, which is considered to be vital to NETs formation. Finally, the therapeutic effect of MSCs was observed on CLP models. The results demonstrated that both ferrostain-1 and DNase-1 application could improve sepsis-induced ALI. DNase-1 inhibited ferroptosis significantly in lung tissues, showing that ferroptosis could be regulated by NETs formation. With the inhibition of the MEK/ERK signaling pathway by U0126, NETs formation and ferroptosis in lung tissues were both reduced, and sepsis-induced ALI was improved. MSCs also had a similar protective effect against sepsis-induced ALI, not only inhibiting MEK/ERK signaling pathway-mediated NETs formation, but also alleviating ferroptosis in lung tissues. We concluded that MSCs could protect against sepsis-induced ALI by suppressing NETs formation and ferroptosis in lung tissues. In this study, we found that NETs formation and ferroptosis were both potential therapeutic targets for the treatment of sepsis-induced ALI, and provided new evidence supporting the clinical application of MSCs in sepsis-induced ALI treatment.
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Affiliation(s)
- TieNan Wang
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-Sen University, GuangZhou, GuangDong Province, China
| | - Zheng Zhang
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-Sen University, GuangZhou, GuangDong Province, China
| | - Zhizhao Deng
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-Sen University, GuangZhou, GuangDong Province, China
| | - Weiqi Zeng
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-Sen University, GuangZhou, GuangDong Province, China
| | - Yingxin Gao
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-Sen University, GuangZhou, GuangDong Province, China
| | - Ziqing Hei
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-Sen University, GuangZhou, GuangDong Province, China
| | - Dongdong Yuan
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-Sen University, GuangZhou, GuangDong Province, China
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15
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Li XH, Huang P, Cheng HP, Zhou Y, Feng DD, Yue SJ, Han Y, Luo ZQ. NMDAR activation attenuates the protective effect of BM-MSCs on bleomycin-induced ALI via the COX-2/PGE 2 pathway. Heliyon 2024; 10:e23723. [PMID: 38205313 PMCID: PMC10776937 DOI: 10.1016/j.heliyon.2023.e23723] [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: 02/01/2023] [Revised: 12/10/2023] [Accepted: 12/12/2023] [Indexed: 01/12/2024] Open
Abstract
N-methyl-d-aspartate (NMDA) receptor (NMDAR) activation mediates glutamate (Glu) toxicity and involves bleomycin (BLM)-induced acute lung injury (ALI). We have reported that bone marrow-derived mesenchymal stem cells (BM-MSCs) are NMDAR-regulated target cells, and NMDAR activation inhibits the protective effect of BM-MSCs on BLM-induced pulmonary fibrosis, but its effect on ALI remains unknown. Here, we found that Glu release was significantly elevated in plasma of mice at d 7 after intratracheally injected with BLM. BM-MSCs were pretreated with NMDA (the selective agonist of NMDAR) and transplanted into the recipient mice after the BLM challenge. BM-MSCs administration significantly alleviated the pathological changes, inflammatory response, myeloperoxidase activity, and malondialdehyde content in the damaged lungs, but NMDA-pretreated BM-MSCs did not ameliorate BLM-induced lung injury in vivo. Moreover, NMDA down-regulated prostaglandin E2 (PGE2) secretion and cyclooxygenase (COX)-2 expression instead of COX-1 expression in BM-MSCs in vitro. We also found that NMDAR1 expression was increased and COX-2 expression was decreased, but COX-1 expression was not changed in primary BM-MSCs of BLM-induced ALI mice. Further, the cultured supernatants of lipopolysaccharide (LPS)-pretreated RAW264.7 macrophages were collected to detect inflammatory factors after co-culture with NMDA-pretreated BM-MSCs. The co-culture experiments showed that NMDA precondition inhibited the anti-inflammatory effect of BM-MSCs on LPS-induced macrophage inflammation, and PGE2 could partially alleviate this inhibition. Our findings suggest that NMDAR activation attenuated the protective effect of BM-MSCs on BLM-induced ALI in vivo. NMDAR activation inhibited COX-2 expression and PGE2 secretion in BM-MSCs and weakened the anti-inflammatory effect of BM-MSCs on LPS-induced macrophage inflammation in vitro. In conclusion, NMDAR activation attenuates the protective effect of BM-MSCs on BLM-induced ALI via the COX-2/PGE2 pathway. Keywords: Acute Lung Injury, BM-MSCs, NMDA receptor, COX-1/2, PGE2.
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Affiliation(s)
- Xiao-Hong Li
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, 410078, China
| | - Pu Huang
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, 410078, China
- Health Management Center, Changsha Central Hospital Affiliated to Nanhua University, Changsha, 410018, China
| | - Hai-Peng Cheng
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, 410078, China
| | - Yan Zhou
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, 410078, China
| | - Dan-Dan Feng
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, 410078, China
| | - Shao-Jie Yue
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yang Han
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, 410078, China
| | - Zi-Qiang Luo
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, 410078, China
- Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, 410078, China
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16
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Wu M, Mi J, Qu GX, Zhang S, Jian Y, Gao C, Cai Q, Liu J, Jiang J, Huang H. Role of Hedgehog Signaling Pathways in Multipotent Mesenchymal Stem Cells Differentiation. Cell Transplant 2024; 33:9636897241244943. [PMID: 38695366 PMCID: PMC11067683 DOI: 10.1177/09636897241244943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 03/09/2024] [Accepted: 03/14/2024] [Indexed: 05/05/2024] Open
Abstract
Multipotent mesenchymal stem cells (MSCs) have high self-renewal and multi-lineage differentiation potentials and low immunogenicity, so they have attracted much attention in the field of regenerative medicine and have a promising clinical application. MSCs originate from the mesoderm and can differentiate not only into osteoblasts, cartilage, adipocytes, and muscle cells but also into ectodermal and endodermal cell lineages across embryonic layers. To design cell therapy for replacement of damaged tissues, it is essential to understand the signaling pathways, which have a major impact on MSC differentiation, as this will help to integrate the signaling inputs to initiate a specific lineage. Hedgehog (Hh) signaling plays a vital role in the development of various tissues and organs in the embryo. As a morphogen, Hh not only regulates the survival and proliferation of tissue progenitor and stem populations but also is a critical moderator of MSC differentiation, involving tri-lineage and across embryonic layer differentiation of MSCs. This review summarizes the role of Hh signaling pathway in the differentiation of MSCs to mesodermal, endodermal, and ectodermal cells.
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Affiliation(s)
- Mengyu Wu
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
- College of Bioengineering, Chongqing University, Chongqing, China
| | - Junwei Mi
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Guo-xin Qu
- Department of Orthopedic Surgery, The First Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Shu Zhang
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Yi Jian
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
- College of Bioengineering, Chongqing University, Chongqing, China
| | - Chu Gao
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Qingli Cai
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Jing Liu
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
| | - Jianxin Jiang
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
- College of Bioengineering, Chongqing University, Chongqing, China
| | - Hong Huang
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China
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17
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Batchinsky AI, Roberts TR, Antebi B, Necsoiu C, Choi JH, Herzig M, Cap AP, McDaniel JS, Rathbone CR, Chung KK, Cancio LC. Intravenous Autologous Bone Marrow-derived Mesenchymal Stromal Cells Delay Acute Respiratory Distress Syndrome in Swine. Am J Respir Crit Care Med 2023; 208:1283-1292. [PMID: 37797214 DOI: 10.1164/rccm.202305-0865oc] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 10/05/2023] [Indexed: 10/07/2023] Open
Abstract
Rationale: Early post injury mitigation strategies in ARDS are in short supply. Treatments with allogeneic stromal cells are administered after ARDS develops, require specialized expertise and equipment, and to date have shown limited benefit. Objectives: Assess the efficacy of immediate post injury intravenous administration of autologous or allogeneic bone marrow-derived mesenchymal stromal cells (MSCs) for the treatment of acute respiratory distress syndrome (ARDS) due to smoke inhalation and burns. Methods: Yorkshire swine (n = 32, 44.3 ± 0.5 kg) underwent intravenous anesthesia, placement of lines, severe smoke inhalation, and 40% total body surface area flame burns, followed by 72 hours of around-the-clock ICU care. Mechanical ventilation, fluids, pressors, bronchoscopic cast removal, daily lung computed tomography scans, and arterial blood assays were performed. After injury and 24 and 48 hours later, animals were randomized to receive autologous concentrated bone marrow aspirate (n = 10; 3 × 106 white blood cells and a mean of 56.6 × 106 platelets per dose), allogeneic MSCs (n = 10; 6.1 × 106 MSCs per dose) harvested from healthy donor swine, or no treatment in injured control animals (n = 12). Measurements and Main Results: The intravenous administration of MSCs after injury and at 24 and 48 hours delayed the onset of ARDS in swine treated with autologous MSCs (48 ± 10 h) versus control animals (14 ± 2 h) (P = 0.004), reduced ARDS severity at 24 (P < 0.001) and 48 (P = 0.003) hours, and demonstrated visibly diminished consolidation on computed tomography (not significant). Mortality at 72 hours was 1 in 10 (10%) in the autologous group, 5 in 10 (50%) in the allogeneic group, and 6 in 12 (50%) in injured control animals (not significant). Both autologous and allogeneic MSCs suppressed systemic concentrations of TNF-α (tumor necrosis factor-α). Conclusions: The intravenous administration of three doses of freshly processed autologous bone marrow-derived MSCs delays ARDS development and reduces its severity in swine. Bedside retrieval and administration of autologous MSCs in swine is feasible and may be a viable injury mitigation strategy for ARDS.
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Affiliation(s)
- Andriy I Batchinsky
- Autonomous Reanimation and Evacuation Research Program, The Geneva Foundation, San Antonio, Texas
| | - Teryn R Roberts
- Autonomous Reanimation and Evacuation Research Program, The Geneva Foundation, San Antonio, Texas
| | - Ben Antebi
- Maryland Stem Cell Research Fund, Columbia, Maryland
| | - Corina Necsoiu
- U.S. Army Institute of Surgical Research, Joint Base San Antonio Fort Sam Houston, Fort Sam Houston, Texas
| | - Jae H Choi
- 59th Medical Wing, Joint Base San Antonio Lackland Air Force Base, San Antonio, Texas
| | - Maryanne Herzig
- U.S. Army Institute of Surgical Research, Joint Base San Antonio Fort Sam Houston, Fort Sam Houston, Texas
| | - Andrew P Cap
- U.S. Army Institute of Surgical Research, Joint Base San Antonio Fort Sam Houston, Fort Sam Houston, Texas
| | - Jennifer S McDaniel
- 59th Medical Wing, Joint Base San Antonio Lackland Air Force Base, San Antonio, Texas
| | | | | | - Leopoldo C Cancio
- U.S. Army Institute of Surgical Research, Joint Base San Antonio Fort Sam Houston, Fort Sam Houston, Texas
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18
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Wang Y, Nardo L, Spencer BA, Abdelhafez YG, Li EJ, Omidvari N, Chaudhari AJ, Badawi RD, Jones T, Cherry SR, Wang G. Total-Body Multiparametric PET Quantification of 18F-FDG Delivery and Metabolism in the Study of Coronavirus Disease 2019 Recovery. J Nucl Med 2023; 64:1821-1830. [PMID: 37591539 PMCID: PMC10626370 DOI: 10.2967/jnumed.123.265723] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 07/05/2023] [Indexed: 08/19/2023] Open
Abstract
Conventional whole-body static 18F-FDG PET imaging provides a semiquantitative evaluation of overall glucose metabolism without insight into the specific transport and metabolic steps. Here we demonstrate the ability of total-body multiparametric 18F-FDG PET to quantitatively evaluate glucose metabolism using macroparametric quantification and assess specific glucose delivery and phosphorylation processes using microparametric quantification for studying recovery from coronavirus disease 2019 (COVID-19). Methods: The study included 13 healthy subjects and 12 recovering COVID-19 subjects within 8 wk of confirmed diagnosis. Each subject had a 1-h dynamic 18F-FDG scan on the uEXPLORER total-body PET/CT system. Semiquantitative SUV and the SUV ratio relative to blood (SUVR) were calculated for different organs to measure glucose utilization. Tracer kinetic modeling was performed to quantify the microparametric blood-to-tissue 18F-FDG delivery rate [Formula: see text] and the phosphorylation rate k 3, as well as the macroparametric 18F-FDG net influx rate ([Formula: see text]). Statistical tests were performed to examine differences between healthy subjects and recovering COVID-19 subjects. The effect of COVID-19 vaccination was also investigated. Results: We detected no significant difference in lung SUV but significantly higher lung SUVR and [Formula: see text] in COVID-19 recovery, indicating improved sensitivity of kinetic quantification for detecting the difference in glucose metabolism. A significant difference was also observed in the lungs with the phosphorylation rate k 3 but not with [Formula: see text], which suggests that glucose phosphorylation, rather than glucose delivery, drives the observed difference of glucose metabolism. Meanwhile, there was no or little difference in bone marrow 18F-FDG metabolism measured with SUV, SUVR, and [Formula: see text] but a significantly higher bone marrow [Formula: see text] in the COVID-19 group, suggesting a difference in glucose delivery. Vaccinated COVID-19 subjects had a lower lung [Formula: see text] and a higher spleen [Formula: see text] than unvaccinated COVID-19 subjects. Conclusion: Higher lung glucose metabolism and bone marrow glucose delivery were observed with total-body multiparametric 18F-FDG PET in recovering COVID-19 subjects than in healthy subjects, implying continued inflammation during recovery. Vaccination demonstrated potential protection effects. Total-body multiparametric PET of 18F-FDG can provide a more sensitive tool and more insights than conventional whole-body static 18F-FDG imaging to evaluate metabolic changes in systemic diseases such as COVID-19.
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Affiliation(s)
- Yiran Wang
- Department of Radiology, Davis Medical Center, University of California, Sacramento, California;
- Department of Biomedical Engineering, University of California, Davis, Davis, California; and
| | - Lorenzo Nardo
- Department of Radiology, Davis Medical Center, University of California, Sacramento, California
| | - Benjamin A Spencer
- Department of Radiology, Davis Medical Center, University of California, Sacramento, California
- Department of Biomedical Engineering, University of California, Davis, Davis, California; and
| | - Yasser G Abdelhafez
- Department of Radiology, Davis Medical Center, University of California, Sacramento, California
- Nuclear Medicine Unit, South Egypt Cancer Institute, Assiut University, Assiut, Egypt
| | - Elizabeth J Li
- Department of Biomedical Engineering, University of California, Davis, Davis, California; and
| | - Negar Omidvari
- Department of Biomedical Engineering, University of California, Davis, Davis, California; and
| | - Abhijit J Chaudhari
- Department of Radiology, Davis Medical Center, University of California, Sacramento, California
| | - Ramsey D Badawi
- Department of Radiology, Davis Medical Center, University of California, Sacramento, California
- Department of Biomedical Engineering, University of California, Davis, Davis, California; and
| | - Terry Jones
- Department of Radiology, Davis Medical Center, University of California, Sacramento, California
| | - Simon R Cherry
- Department of Radiology, Davis Medical Center, University of California, Sacramento, California
- Department of Biomedical Engineering, University of California, Davis, Davis, California; and
| | - Guobao Wang
- Department of Radiology, Davis Medical Center, University of California, Sacramento, California
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19
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Jiménez MF, Gómez-Hernández MT, Villarón EM, López-Parra M, Sánchez-Guijo F. Autologous mesenchymal stromal cells embedded with Tissucol Duo ® for prevention of air leak after anatomical lung resection: results of a prospective phase I/II clinical trial with long-term follow-up. Stem Cell Res Ther 2023; 14:313. [PMID: 37904229 PMCID: PMC10617222 DOI: 10.1186/s13287-023-03545-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 10/25/2023] [Indexed: 11/01/2023] Open
Abstract
BACKGROUND Prolonged air leak (PAL) is the most frequent complication after pulmonary resection. Several measures have been described to prevent the occurrence of PAL in high-risk patients, however, the potential role of mesenchymal stem cells (MSCs) applied in the parenchymal suture line to prevent postoperative air leak in this setting has not been fully addressed. OBJECTIVE To analyse the feasibility, safety and potential clinical efficacy of the implantation of autologous MSCs embedded in Tissucol Duo® as a prophylactic alternative to prevent postoperative prolonged air leak after pulmonary resection in high-risk patients. STUDY DESIGN Phase I/II single-arm prospective clinical trial. METHODS Six patients with high risk of PAL undergoing elective pulmonary resection were included. Autologous bone marrow-derived MSCs were expanded at our Good Manufacturing Practice (GMP) Facility and implanted (embedded in a Tissucol Duo® carrier) in the parenchymal suture line during pulmonary resection surgery. Patients were monitored in the early postoperative period and evaluated for possible complications or adverse reactions. In addition, all patients were followed-up to 5 years for clinical outcomes. RESULTS The median age of patients included was 66 years (range: 55-70 years), and male/female ratio was 5/1. Autologous MSCs were expanded in five cases, in one case MSCs expansion was insufficient. There were no adverse effects related to cell implantation. Regarding efficacy, median air leak duration was 0 days (range: 0-2 days). The incidence of PAL was nil. Radiologically, only one patient presented pneumothorax in the chest X-ray at discharge. No adverse effects related to the procedure were recorded during the follow-up. CONCLUSIONS The use of autologous MSCs for prevention of PAL in patients with high risk of PAL is feasible, safe and potentially effective. TRIAL REGISTRATION NO EudraCT: 2013-000535-27. CLINICALTRIALS gov idenfier: NCT02045745.
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Affiliation(s)
- Marcelo F Jiménez
- Service of Thoracic Surgery, Salamanca University Hospital, 37007, Salamanca, Spain
- Salamanca Institute of Biomedical Research (IBSAL), Salamanca, Spain
- University of Salamanca, Salamanca, Spain
| | - María Teresa Gómez-Hernández
- Service of Thoracic Surgery, Salamanca University Hospital, 37007, Salamanca, Spain.
- Salamanca Institute of Biomedical Research (IBSAL), Salamanca, Spain.
- University of Salamanca, Salamanca, Spain.
| | - Eva M Villarón
- Cell Therapy Area & Hematology Department, Salamanca University Hospital, Salamanca, Spain
- Network Centre for Regenerative Medicine and Cellular Therapy of Castilla y León, Salamanca, Spain
| | - Miriam López-Parra
- Cell Therapy Area & Hematology Department, Salamanca University Hospital, Salamanca, Spain
- Salamanca Institute of Biomedical Research (IBSAL), Salamanca, Spain
- Network Centre for Regenerative Medicine and Cellular Therapy of Castilla y León, Salamanca, Spain
| | - Fermín Sánchez-Guijo
- Cell Therapy Area & Hematology Department, Salamanca University Hospital, Salamanca, Spain
- Salamanca Institute of Biomedical Research (IBSAL), Salamanca, Spain
- University of Salamanca, Salamanca, Spain
- Network Centre for Regenerative Medicine and Cellular Therapy of Castilla y León, Salamanca, Spain
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20
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Zhuang X, Jiang Y, Yang X, Fu L, Luo L, Dong Z, Zhao J, Hei F. Advances of mesenchymal stem cells and their derived extracellular vesicles as a promising therapy for acute respiratory distress syndrome: from bench to clinic. Front Immunol 2023; 14:1244930. [PMID: 37711624 PMCID: PMC10497773 DOI: 10.3389/fimmu.2023.1244930] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 08/14/2023] [Indexed: 09/16/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS) is an acute inflammatory lung injury characterized by diffuse alveolar damage. The period prevalence of ARDS was 10.4% of ICU admissions in 50 countries. Although great progress has been made in supportive care, the hospital mortality rate of severe ARDS is still up to 46.1%. Moreover, up to now, there is no effective pharmacotherapy for ARDS and most clinical trials focusing on consistently effective drugs have met disappointing results. Mesenchymal stem cells (MSCs) and their derived extracellular vesicles (EVs) have spawned intense interest of a wide range of researchers and clinicians due to their robust anti-inflammatory, anti-apoptotic and tissue regeneration properties. A growing body of evidence from preclinical studies confirmed the promising therapeutic potential of MSCs and their EVs in the treatment of ARDS. Based on the inspiring experimental results, clinical trials have been designed to evaluate safety and efficacy of MSCs and their EVs in ARDS patients. Moreover, trials exploring their optimal time window and regimen of drug administration are ongoing. Therefore, this review aims to present an overview of the characteristics of mesenchymal stem cells and their derived EVs, therapeutic mechanisms for ARDS and research progress that has been made over the past 5 years.
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Affiliation(s)
| | | | | | | | | | | | | | - Feilong Hei
- Department of Cardiopulmonary Bypass, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
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21
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Ichikado K, Kotani T, Kondoh Y, Imanaka H, Johkoh T, Fujimoto K, Nunomiya S, Kawayama T, Sawada M, Jenkins E, Tasaka S, Hashimoto S. Clinical efficacy and safety of multipotent adult progenitor cells (invimestrocel) for acute respiratory distress syndrome (ARDS) caused by pneumonia: a randomized, open-label, standard therapy-controlled, phase 2 multicenter study (ONE-BRIDGE). Stem Cell Res Ther 2023; 14:217. [PMID: 37608287 PMCID: PMC10464414 DOI: 10.1186/s13287-023-03451-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 08/11/2023] [Indexed: 08/24/2023] Open
Abstract
BACKGROUND Acute respiratory distress syndrome (ARDS) is a life-threatening inflammatory lung injury with high mortality; no approved medication exists. Efficacy and safety of bone marrow-derived, allogeneic, multipotent adult progenitor cells (invimestrocel) plus standard treatment in patients with ARDS caused by pneumonia was evaluated. METHODS A randomized, open-label, standard therapy-controlled, phase 2 study (January 2019-September 2021) conducted in 29 centers in Japan. Patients with ARDS caused by pneumonia, with extensive early fibroproliferation on high-resolution computed tomography and low risk of systemic organ failure identified by an Acute Physiology and Chronic Health Evaluation (APACHE II) score were included. Patients were randomized 2:1 to receive a single intravenous infusion of 9.0 × 108 cells of invimestrocel (administered at a rate of up to 10 mL/min over 30-60 min by free flow) plus standard treatment (N = 20) or standard treatment (N = 10) consistent with the clinical practice guidelines of the Japanese Respiratory Society for the management of ARDS. Primary endpoint was ventilator-free days (VFDs) through day 28 after study treatment. Analysis of covariance was performed with treatment group, age, partial pressure arterial oxygen/fraction of inspired oxygen ratio, and APACHE II score as covariates. RESULTS Median (interquartile range) number of VFDs was numerically higher in the invimestrocel group versus standard group (20.0 [0.0-24.0] vs 11.0 [0.0-14.0]) but was not statistically significantly different (least square [LS] means [95% confidence interval (CI)]: invimestrocel group, 11.6 [6.9-16.3]; standard group, 6.2 [- 0.4 to 12.8]; LS mean difference [95% CI], 5.4 [- 1.9 to 12.8]; p = 0.1397). Ventilator weaning rate at day 28 was 65% (13/20) versus 30% (3/10), and mortality rate was 21% (4/19) versus 29% (2/7) at day 28 and 26% (5/19 patients) versus 43% (3/7 patients) at day 180, for the invimestrocel and standard groups, respectively. No allergic or serious adverse reactions were associated with invimestrocel. CONCLUSIONS In Japanese patients with ARDS caused by pneumonia, invimestrocel plus standard treatment resulted in no significant difference in the number of VFDs but may result in improved survival compared with standard treatment. Invimestrocel was well tolerated. TRIAL REGISTRATION ClinicalTrials.gov, Identifier: NCT03807804; January 8, 2019; https://clinicaltrials.gov/ct2/show/NCT03807804 .
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Affiliation(s)
- Kazuya Ichikado
- Division of Respiratory Medicine, Social Welfare Organization Saiseikai Imperial Gift Foundation, Inc., Saiseikai Kumamoto Hospital, 5-3-1 Chikami, Minami-ku, Kumamoto City, 8614101, Japan.
| | - Toru Kotani
- Department of Intensive Care Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Yasuhiro Kondoh
- Department of Respiratory Medicine and Allergy, Tosei General Hospital, Seto, Aichi, Japan
| | - Hideaki Imanaka
- Department of Emergency Medicine, Takarazuka City Hospital, Takarazuka, Hyogo, Japan
| | - Takeshi Johkoh
- Department of Radiology, Kansai Rosai Hospital, Amagasaki, Hyogo, Japan
| | - Kiminori Fujimoto
- Department of Radiology, Kurume University School of Medicine, Fukuoka, Japan
| | - Shin Nunomiya
- Division of Intensive Care, Department of Anesthesiology and Intensive Care Medicine, Jichi Medical University School of Medicine, Tochigi, Japan
- Department of Intensive Care, Yokosuka General Hospital Uwamachi, Kanagawa, Japan
| | - Tomotaka Kawayama
- Division of Respirology, Neurology, and Rheumatology, Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan
| | | | - Eric Jenkins
- Athersys, Inc., Cleveland, OH, USA
- Kiniksa Pharmaceuticals, Lexington, MA, USA
| | - Sadatomo Tasaka
- Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine, Aomori, Japan
| | - Satoru Hashimoto
- Department of Anesthesiology and Intensive Care Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
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22
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Lee DH, Yun DW, Kim YH, Im GB, Hyun J, Park HS, Bhang SH, Choi SH. Various Three-Dimensional Culture Methods and Cell Types for Exosome Production. Tissue Eng Regen Med 2023; 20:621-635. [PMID: 37269439 PMCID: PMC10313642 DOI: 10.1007/s13770-023-00551-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 04/06/2023] [Accepted: 05/02/2023] [Indexed: 06/05/2023] Open
Abstract
Cell-based therapies have been used as promising treatments for several untreatable diseases. However, cell-based therapies have side effects such as tumorigenesis and immune responses. To overcome these side effects, therapeutic effects of exosomes have been researched as replacements for cell-based therapies. In addition, exosomes reduced the risk that can be induced by cell-based therapies. Exosomes contain biomolecules such as proteins, lipids, and nucleic acids that play an essential role in cell-cell and cell-matrix interactions during biological processes. Since the introduction of exosomes, those have been proven perpetually as one of the most effective and therapeutic methods for incurable diseases. Much research has been conducted to enhance the properties of exosomes, including immune regulation, tissue repair, and regeneration. However, yield rate of exosomes is the critical obstacle that should be overcome for practical cell-free therapy. Three-dimensional (3D) culture methods are introduced as a breakthrough to get higher production yields of exosomes. For example, hanging drop and microwell were well known 3D culture methods and easy to use without invasiveness. However, these methods have limitation in mass production of exosomes. Therefore, a scaffold, spinner flask, and fiber bioreactor were introduced for mass production of exosomes isolated from various cell types. Furthermore, exosomes treatments derived from 3D cultured cells showed enhanced cell proliferation, angiogenesis, and immunosuppressive properties. This review provides therapeutic applications of exosomes using 3D culture methods.
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Affiliation(s)
- Dong-Hyun Lee
- School of Chemical Engineering, Sungkyunkwan University (SKKU), 2066 Seobu-Ro, Jangan-Gu, Suwon, Gyeonggi-Do, 16419, Republic of Korea
| | - Dae Won Yun
- School of Chemical Engineering, Sungkyunkwan University (SKKU), 2066 Seobu-Ro, Jangan-Gu, Suwon, Gyeonggi-Do, 16419, Republic of Korea
| | - Yeong Hwan Kim
- School of Chemical Engineering, Sungkyunkwan University (SKKU), 2066 Seobu-Ro, Jangan-Gu, Suwon, Gyeonggi-Do, 16419, Republic of Korea
| | - Gwang-Bum Im
- School of Chemical Engineering, Sungkyunkwan University (SKKU), 2066 Seobu-Ro, Jangan-Gu, Suwon, Gyeonggi-Do, 16419, Republic of Korea
| | - Jiyu Hyun
- School of Chemical Engineering, Sungkyunkwan University (SKKU), 2066 Seobu-Ro, Jangan-Gu, Suwon, Gyeonggi-Do, 16419, Republic of Korea
| | - Hyun Su Park
- School of Chemical Engineering, Sungkyunkwan University (SKKU), 2066 Seobu-Ro, Jangan-Gu, Suwon, Gyeonggi-Do, 16419, Republic of Korea
| | - Suk Ho Bhang
- School of Chemical Engineering, Sungkyunkwan University (SKKU), 2066 Seobu-Ro, Jangan-Gu, Suwon, Gyeonggi-Do, 16419, Republic of Korea.
| | - Sang Hyoun Choi
- Department of Radiation Oncology, Korea Institute of Radiological and Medical Science, Seoul, Republic of Korea.
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23
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Zhang X, Xue M, Liu A, Qiu H, Guo F. Activation of Wnt/β‑Catenin‑p130/E2F4 promotes the differentiation of bone marrow‑derived mesenchymal stem cells into type II alveolar epithelial cells through cell cycle arrest. Exp Ther Med 2023; 26:330. [PMID: 37346406 PMCID: PMC10280314 DOI: 10.3892/etm.2023.12029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 04/18/2023] [Indexed: 06/23/2023] Open
Abstract
The results of our previous study demonstrated that activation of the Wnt/β-catenin pathway increased the differentiation of mesenchymal stem cells (MSCs) into type II alveolar epithelial (AT II) cells; however, the specific mechanisms remain unclear. The present study aimed to evaluate the role of Wnt/β-catenin-p130/E2F transcription factor 4 (E2F4) in regulating the differentiation of mouse MSCs (mMSCs) into AT II cells, and to determine the specific mechanisms. mMSCs with p130 or E2F4 overexpression were constructed using lentiviral vectors. Differentiation of mMSCs into AT II cells was promoted using a modified coculture system with murine lung epithelial-12 cells incubated in small airway growth medium for 7-14 days. The differentiation efficiency was detected using immunofluorescence, western blot analysis and transmission electron microscopy. To detect the association between the canonical Wnt pathway and p130/E2F4, 4 mmol/l lithium chloride (LiCl) or 200 ng/ml Dickkopf-related protein 1 (DKK-1) was also added to the coculture system. Following differentiation, the cell cycle of mMSCs was evaluated using flow cytometry. The results of the present study demonstrated that surfactant protein C (SP-C) protein expression was higher in the p130 overexpression (MSC-p130) and E2F4 overexpression (MSC-E2F4) groups compared with the normal control mMSCs group following differentiation into AT II cells. Similar results for SP-C protein expression and lamellar body-like structures were also observed using immunofluorescence analysis and electron microscopy. Following the addition of LiCl into the coculture system for activation of the Wnt/β-catenin signaling pathway, phosphorylated (p)-p130/p130 was slightly decreased at 7 days and E2F4 was increased both at 7 and 14 days in mMSCs. Furthermore, the p-p130/p130 ratio was significantly increased at 14 days and E2F4 was decreased both at 7 and 14 days following DKK-1-mediated inhibition of the Wnt pathway. The results of the present study demonstrated that the numbers of cells in G1 and S phases were increased following activation of the Wnt pathway and decreased following Wnt pathway inhibition. However, the number of cells in G1 phase was increased following the differentiation of mMSCs overexpressing p130 or E2F4. Therefore, the results of the present study revealed that the canonical Wnt signaling pathway may affect the differentiation of MSCs into AT II cells via regulation of downstream p130/E2F4. The specific mechanisms may be associated with G1 phase extension in the cell cycle of MSCs.
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Affiliation(s)
- Xiwen Zhang
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Ming Xue
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Airan Liu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Haibo Qiu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Fengmei Guo
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
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24
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Phinney DG, Hwa Lee R, Boregowda SV. Revisiting the Mesenchymal "Stem vs. Stromal" Cell Dichotomy and Its Implications for Development of Improved Potency Metrics. Stem Cells 2023; 41:444-452. [PMID: 36891977 PMCID: PMC10183967 DOI: 10.1093/stmcls/sxad019] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 02/21/2023] [Indexed: 03/10/2023]
Abstract
Mesenchymal stem/stromal cell (MSC)-based therapies have been evaluated in over 1500 human clinical trials for a diverse array of disease indication, but outcomes remain unpredictable due to knowledge gaps in the quality attributes that confer therapeutic potency onto cells and their mode of action in vivo. Based on accumulated evidence from pre-clinical models, MSCs exert therapeutic effects by repressing inflammatory and immune-mediated response via paracrine action following reprogramming by the host injury microenvironment, and by polarization of tissue resident macrophages following phagocytosis to an alternatively activated (M2) state. An important tenet of this existing paradigm is that well-established stem/progenitor functions of MSCs are independent of paracrine function and dispensable for their anti-inflammatory and immune suppressive functions. Herein, we review evidence that stem/progenitor and paracrine functions of MSCs are mechanistically linked and organized hierarchically and describe how this link may be exploited to develop metrics that predict MSC potency across a spectrum of activities and regenerative medicine applications.
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Affiliation(s)
- Donald G Phinney
- Department of Molecular Medicine, Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL, USA
| | - Ryang Hwa Lee
- Department of Cell Biology and Genetics, Texas A&M University School of Medicine, College Station, TX, USA
| | - Siddaraju V Boregowda
- Department of Molecular Medicine, Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL, USA
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25
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Yudhawati R, Shimizu K. PGE2 Produced by Exogenous MSCs Promotes Immunoregulation in ARDS Induced by Highly Pathogenic Influenza A through Activation of the Wnt-β-Catenin Signaling Pathway. Int J Mol Sci 2023; 24:ijms24087299. [PMID: 37108459 PMCID: PMC10138595 DOI: 10.3390/ijms24087299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 04/12/2023] [Accepted: 04/13/2023] [Indexed: 04/29/2023] Open
Abstract
Acute respiratory distress syndrome is an acute respiratory failure caused by cytokine storms; highly pathogenic influenza A virus infection can induce cytokine storms. The innate immune response is vital in this cytokine storm, acting by activating the transcription factor NF-κB. Tissue injury releases a danger-associated molecular pattern that provides positive feedback for NF-κB activation. Exogenous mesenchymal stem cells can also modulate immune responses by producing potent immunosuppressive substances, such as prostaglandin E2. Prostaglandin E2 is a critical mediator that regulates various physiological and pathological processes through autocrine or paracrine mechanisms. Activation of prostaglandin E2 results in the accumulation of unphosphorylated β-catenin in the cytoplasm, which subsequently reaches the nucleus to inhibit the transcription factor NF-κB. The inhibition of NF-κB by β-catenin is a mechanism that reduces inflammation.
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Affiliation(s)
- Resti Yudhawati
- Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas Airlangga-Dr. Soetomo General Academic Hospital, Surabaya 60286, Indonesia
- Indonesia-Japan Collaborative Research Center for Emerging and Re-Emerging Infectious Diseases, Institute of Tropical Disease, Airlangga University, Surabaya 60286, Indonesia
| | - Kazufumi Shimizu
- Indonesia-Japan Collaborative Research Center for Emerging and Re-Emerging Infectious Diseases, Institute of Tropical Disease, Airlangga University, Surabaya 60286, Indonesia
- Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
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26
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Wang Y, Nardo L, Spencer BA, Abdelhafez YG, Li EJ, Omidvari N, Chaudhari AJ, Badawi RD, Jones T, Cherry SR, Wang G. Total-Body Multiparametric PET Quantification of 18 F-FDG Delivery and Metabolism in the Study of COVID-19 Recovery. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.03.26.23287673. [PMID: 37034643 PMCID: PMC10081414 DOI: 10.1101/2023.03.26.23287673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/23/2023]
Abstract
Conventional whole-body 18 F-FDG PET imaging provides a semi-quantitative evaluation of overall glucose metabolism without gaining insight into the specific transport and metabolic steps. Here we demonstrate the ability of total-body multiparametric 18 F-FDG PET to quantitatively evaluate glucose metabolism using macroparametric quantification and assess specific glucose delivery and phosphorylation processes using microparametric quantification for studying recovery from coronavirus disease 2019 (COVID-19). Methods The study included thirteen healthy subjects and twelve recovering COVID-19 subjects within eight weeks of confirmed diagnosis. Each subject had a dynamic 18 F-FDG scan on the uEXPLORER total-body PET/CT system for one hour. Semiquantitative standardized uptake value (SUV) and SUV ratio relative to blood (SUVR) were calculated for regions of interest (ROIs) in different organs to measure glucose utilization. Tracer kinetic modeling was performed to quantify microparametric rate constants K 1 and k 3 that characterize 18 F-FDG blood-to-tissue delivery and intracellular phosphorylation, respectively, and a macroparameter K i that represents 18 F-FDG net influx rate. Statistical tests were performed to examine differences between the healthy controls and recovering COVID-19 subjects. Impact of COVID-19 vaccination was investigated. We further generated parametric images to confirm the ROI-based analysis. Results We detected no significant difference in lung SUV but significantly higher lung SUVR and K i in the recovering COVID-19 subjects, indicating an improved sensitivity of kinetic quantification for detecting the difference in glucose metabolism. A significant difference was also observed in the lungs with the phosphorylation rate k 3 , but not with the delivery rate K 1 , which suggests it is glucose phosphorylation, not glucose delivery, that drives the observed difference of glucose metabolism in the lungs. Meanwhile, there was no or little difference in bone marrow metabolism measured with SUV, SUVR and K i , but a significant increase in bone-marrow 18 F-FDG delivery rate K 1 in the COVID-19 group ( p < 0.05), revealing a difference of glucose delivery in this immune-related organ. The observed differences were lower or similar in vaccinated COVID-19 subjects as compared to unvaccinated ones. The organ ROI-based findings were further supported by parametric images. Conclusions Higher lung glucose metabolism and bone-marrow glucose delivery were observed with total-body multiparametric 18 F-FDG PET in recovering COVID-19 subjects as compared to healthy subjects, which suggests continued inflammation due to COVID-19 during the early stages of recovery. Total-body multiparametric PET of 18 F-FDG delivery and metabolism can provide a more sensitive tool and more insights than conventional static whole-body 18 F-FDG imaging to evaluate metabolic changes in systemic diseases such as COVID-19.
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Affiliation(s)
- Yiran Wang
- Department of Radiology, University of California Davis Medical Center
- Department of Biomedical Engineering, University of California, Davis
| | - Lorenzo Nardo
- Department of Radiology, University of California Davis Medical Center
| | - Benjamin A. Spencer
- Department of Radiology, University of California Davis Medical Center
- Department of Biomedical Engineering, University of California, Davis
| | - Yasser G. Abdelhafez
- Department of Radiology, University of California Davis Medical Center
- Nuclear Medicine Unit, South Egypt Cancer Institute, Assiut University, Egypt
| | - Elizabeth J. Li
- Department of Biomedical Engineering, University of California, Davis
| | - Negar Omidvari
- Department of Biomedical Engineering, University of California, Davis
| | | | - Ramsey D. Badawi
- Department of Radiology, University of California Davis Medical Center
- Department of Biomedical Engineering, University of California, Davis
| | - Terry Jones
- Department of Radiology, University of California Davis Medical Center
| | - Simon R. Cherry
- Department of Radiology, University of California Davis Medical Center
- Department of Biomedical Engineering, University of California, Davis
| | - Guobao Wang
- Department of Radiology, University of California Davis Medical Center
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27
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The Role of COX-2 and PGE2 in the Regulation of Immunomodulation and Other Functions of Mesenchymal Stromal Cells. Biomedicines 2023; 11:biomedicines11020445. [PMID: 36830980 PMCID: PMC9952951 DOI: 10.3390/biomedicines11020445] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 01/27/2023] [Accepted: 01/28/2023] [Indexed: 02/05/2023] Open
Abstract
The ability of MSCs to modulate the inflammatory environment is well recognized, but understanding the molecular mechanisms responsible for these properties is still far from complete. Prostaglandin E2 (PGE2), a product of the cyclooxygenase 2 (COX-2) pathway, is indicated as one of the key mediators in the immunomodulatory effect of MSCs. Due to the pleiotropic effect of this molecule, determining its role in particular intercellular interactions and aspects of cell functioning is very difficult. In this article, the authors attempt to summarize the previous observations regarding the role of PGE2 and COX-2 in the immunomodulatory properties and other vital functions of MSCs. So far, the most consistent results relate to the inhibitory effect of MSC-derived PGE2 on the early maturation of dendritic cells, suppressive effect on the proliferation of activated lymphocytes, and stimulatory effect on the differentiation of macrophages into M2 phenotype. Additionally, COX-2/PGE2 plays an important role in maintaining the basic life functions of MSCs, such as the ability to proliferate, migrate and differentiate, and it also positively affects the formation of niches that are conducive to both hematopoiesis and carcinogenesis.
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28
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Ganesan N, Chang YD, Hung SC, Lan JL, Liao JW, Fu ST, Lee CC. Mesenchymal stem cells suppressed skin and lung inflammation and fibrosis in topoisomerase I-induced systemic sclerosis associated with lung disease mouse model. Cell Tissue Res 2023; 391:323-337. [PMID: 36447073 DOI: 10.1007/s00441-022-03716-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 11/22/2022] [Indexed: 12/05/2022]
Abstract
Systemic sclerosis associated with lung interstitial lung disease (SSc-ILD) is the most common cause of death among patients with SSc. Mesenchymal stem cell (MSCs) transplantations had been treated by SSc patients that showed in the previous case report. The therapeutic mechanisms and effects of MSCs on SSc-ILD are still obscure. In this study, we investigated the therapeutic effects and mechanisms of treatment of BM-MSC derived from C57BL/6 on the topoisomerase I (TOPO I) induced SSc-ILD-like mice model. The mice were immunized with a mixture of recombinant human TOPO I in PBS solution (500 U/mL) and completed Freund's adjuvant [CFA; 1:1 (volume/volume)] twice per week for 9 weeks. On week 10, the mice were sacrificed to analyze the related pathological parameters. Lung and skin pathologies were analyzed using histochemical staining. CD4 T-helper (TH) cell differentiation in lung and skin-draining lymph nodes was detected using flow cytometry. Our results revealed that allogeneic and syngeneic MSCs exhibited similar repressive effects on TOPO I-induced IgG1 and IgG2a in the SSc group. After intravascular (IV) treatment with syngeneic or allogeneic MSCs, the dermal thickness and fibrosis dramatically condensed and significantly reduced airway hyperresponsiveness. These findings showed that both allogeneic and syngeneic MSCs have therapeutic potential for SSc-ILD.
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Affiliation(s)
- Nithya Ganesan
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, China Medical University, No. 91 Hsueh-Shih Road, Taichung, Taiwan
| | - Yu-Di Chang
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, China Medical University, No. 91 Hsueh-Shih Road, Taichung, Taiwan
| | - Shih-Chieh Hung
- New Drug Development Center, China Medical University, Taichung, Taiwan.,Institute of Translation Medicine and New Drug Development, China Medical University, Taichung, Taiwan
| | - Joung-Liang Lan
- Division of Immunology and Rheumatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Jiunn-Wang Liao
- Graduate Institute of Veterinary Pathobiology, National Chung Hsing University, Taichung, Taiwan
| | - Shih Tsung Fu
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, China Medical University, No. 91 Hsueh-Shih Road, Taichung, Taiwan
| | - Chen-Chen Lee
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, China Medical University, No. 91 Hsueh-Shih Road, Taichung, Taiwan. .,New Drug Development Center, China Medical University, Taichung, Taiwan.
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Ju H, Yun H, Kim Y, Nam YJ, Lee S, Lee J, Jeong SM, Heo J, Kwon H, Cho YS, Jeong G, Ryu CM, Shin DM. Activating transcription factor-2 supports the antioxidant capacity and ability of human mesenchymal stem cells to prevent asthmatic airway inflammation. Exp Mol Med 2023; 55:413-425. [PMID: 36765266 PMCID: PMC9981582 DOI: 10.1038/s12276-023-00943-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 11/09/2022] [Accepted: 12/04/2022] [Indexed: 02/12/2023] Open
Abstract
Glutathione (GSH), an abundant nonprotein thiol antioxidant, participates in several biological processes and determines the functionality of stem cells. A detailed understanding of the molecular network mediating GSH dynamics is still lacking. Here, we show that activating transcription factor-2 (ATF2), a cAMP-response element binding protein (CREB), plays a crucial role in maintaining the level and activity of GSH in human mesenchymal stem cells (MSCs) by crosstalking with nuclear factor erythroid-2 like-2 (NRF2), a well-known master regulator of cellular redox homeostasis. Priming with ascorbic acid 2-glucoside (AA2G), a stable vitamin C derivative, increased the expression and activity of ATF2 in MSCs derived from human embryonic stem cells and umbilical cord. Subsequently, activated ATF2 crosstalked with the CREB1-NRF2 pathway to preserve the GSH dynamics of MSCs through the induction of genes involved in GSH synthesis (GCLC and GCLM) and redox cycling (GSR and PRDX1). Accordingly, shRNA-mediated silencing of ATF2 significantly impaired the self-renewal, migratory, proangiogenic, and anti-inflammatory capacities of MSCs, and these defects were rescued by supplementation of the cells with GSH. In addition, silencing ATF2 attenuated the ability of MSCs to alleviate airway inflammatory responses in an ovalbumin-induced mouse model of allergic asthma. Consistently, activation of ATF2 by overexpression or the AA2G-based priming procedure enhanced the core functions of MSCs, improving the in vivo therapeutic efficacy of MSCs for treating asthma. Collectively, our findings suggest that ATF2 is a novel modulator of GSH dynamics that determines the core functionality and therapeutic potency of MSCs used to treat allergic asthma.
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Affiliation(s)
- Hyein Ju
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
- Department of Physiology, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - HongDuck Yun
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
- Department of Physiology, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - YongHwan Kim
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
- Department of Physiology, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - Yun Ji Nam
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
- Department of Physiology, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - Seungun Lee
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
- Department of Physiology, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - Jinwon Lee
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
- Department of Physiology, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - Seon Min Jeong
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
- Department of Physiology, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - Jinbeom Heo
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
- Department of Physiology, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - Hyungu Kwon
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
- Department of Physiology, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - You Sook Cho
- Division of Allergy and Clinical Immunology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
| | - Gowun Jeong
- AI Recommendation, T3K, SK Telecom, Seoul, 04539, South Korea
| | - Chae-Min Ryu
- Center for Cell Therapy, Asan Medical Center, Seoul, 05505, South Korea.
| | - Dong-Myung Shin
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea.
- Department of Physiology, University of Ulsan College of Medicine, Seoul, 05505, South Korea.
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Mehrabani M, Mohammadyar S, Rajizadeh MA, Bejeshk MA, Ahmadi B, Nematollahi MH, Mirtajaddini Goki M, Bahrampour Juybari K, Amirkhosravi A. Boosting therapeutic efficacy of mesenchymal stem cells in pulmonary fibrosis: The role of genetic modification and preconditioning strategies. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2023; 26:1001-1015. [PMID: 37605719 PMCID: PMC10440137 DOI: 10.22038/ijbms.2023.69023.15049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 05/14/2023] [Indexed: 08/23/2023]
Abstract
Pulmonary fibrosis (PF) is the end stage of severe lung diseases, in which the lung parenchyma is replaced by fibrous scar tissue. The result is a remarkable reduction in pulmonary compliance, which may lead to respiratory failure and even death. Idiopathic pulmonary fibrosis (IPF) is the most prevalent form of PF, with no reasonable etiology. However, some factors are believed to be behind the etiology of PF, including prolonged administration of several medications (e.g., bleomycin and amiodarone), environmental contaminant exposure (e.g., gases, asbestos, and silica), and certain systemic diseases (e.g., systemic lupus erythematosus). Despite significant developments in the diagnostic approach to PF in the last few years, efforts to find more effective treatments remain challenging. With their immunomodulatory, anti-inflammatory, and anti-fibrotic properties, stem cells may provide a promising approach for treating a broad spectrum of fibrotic conditions. However, they may lose their biological functions after long-term in vitro culture or exposure to harsh in vivo situations. To overcome these limitations, numerous modification techniques, such as genetic modification, preconditioning, and optimization of cultivation methods for stem cell therapy, have been adopted. Herein, we summarize the previous investigations that have been designed to assess the effects of stem cell preconditioning or genetic modification on the regenerative capacity of stem cells in PF.
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Affiliation(s)
- Mehrnaz Mehrabani
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Sohaib Mohammadyar
- Department of Laboratory Hematology and Blood Banking, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Amin Rajizadeh
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
- Department of Physiology and Pharmacology, Afzalipour Medical Faculty, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Abbas Bejeshk
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
- Department of Physiology and Pharmacology, Afzalipour Medical Faculty, Kerman University of Medical Sciences, Kerman, Iran
| | - Bahareh Ahmadi
- Department of Laboratory Hematology and Blood Banking, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | | | | | - Kobra Bahrampour Juybari
- Abnormal Uterine Bleeding Research Center, Semnan University of Medical Sciences, Semnan, Iran
- School of Pharmacy, Semnan University of Medical Sciences, Semnan, Iran
| | - Arian Amirkhosravi
- Pharmaceutical Sciences and Cosmetic Products Research Center, Kerman University of Medical Sciences, Kerman, Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
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Huang S, Li Y, Zeng J, Chang N, Cheng Y, Zhen X, Zhong D, Chen R, Ma G, Wang Y. Mesenchymal Stem/Stromal Cells in Asthma Therapy: Mechanisms and Strategies for Enhancement. Cell Transplant 2023; 32:9636897231180128. [PMID: 37318186 DOI: 10.1177/09636897231180128] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023] Open
Abstract
Asthma is a complex and heterogeneous disease characterized by chronic airway inflammation, airway hyperresponsiveness, and airway remodeling. Most asthmatic patients are well-established using standard treatment strategies and advanced biologicals. However, a small group of patients who do not respond to biological treatments or are not effectively controlled by available treatment strategies remain a clinical challenge. Therefore, new therapies are urgently needed for poorly controlled asthma. Mesenchymal stem/stromal cells (MSCs) have shown therapeutic potential in relieving airway inflammation and repairing impaired immune balance in preclinical trials owing to their immunomodulatory abilities. Noteworthy, MSCs exerted a therapeutic effect on steroid-resistant asthma with rare side effects in asthmatic models. Nevertheless, adverse factors such as limited obtained number, nutrient and oxygen deprivation in vitro, and cell senescence or apoptosis affected the survival rate and homing efficiency of MSCs, thus limiting the efficacy of MSCs in asthma. In this review, we elaborate on the roles and underlying mechanisms of MSCs in the treatment of asthma from the perspective of their source, immunogenicity, homing, differentiation, and immunomodulatory capacity and summarize strategies to improve their therapeutic effect.
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Affiliation(s)
- Si Huang
- Department of Pediatrics, Shunde Women and Children's Hospital of Guangdong Medical University, Foshan, China
- Institute of Respiratory Diseases, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, China
| | - Yiyang Li
- Department of Pediatrics, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jieqing Zeng
- Department of Pediatrics, Shunde Women and Children's Hospital of Guangdong Medical University, Foshan, China
- Institute of Respiratory Diseases, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, China
| | - Ning Chang
- Department of Pediatrics, Shunde Women and Children's Hospital of Guangdong Medical University, Foshan, China
- Institute of Respiratory Diseases, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, China
| | - Yisen Cheng
- Department of Pediatrics, Shunde Women and Children's Hospital of Guangdong Medical University, Foshan, China
- Institute of Respiratory Diseases, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, China
| | - Xiangfan Zhen
- Department of Pediatrics, Shunde Women and Children's Hospital of Guangdong Medical University, Foshan, China
- Institute of Respiratory Diseases, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, China
| | - Dan Zhong
- Department of Pediatrics, Shunde Women and Children's Hospital of Guangdong Medical University, Foshan, China
- Institute of Respiratory Diseases, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, China
| | - Riling Chen
- Department of Pediatrics, Shunde Women and Children's Hospital of Guangdong Medical University, Foshan, China
- Institute of Respiratory Diseases, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, China
| | - Guoda Ma
- Department of Pediatrics, Shunde Women and Children's Hospital of Guangdong Medical University, Foshan, China
- Institute of Respiratory Diseases, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, China
| | - Yajun Wang
- Department of Pediatrics, Shunde Women and Children's Hospital of Guangdong Medical University, Foshan, China
- Institute of Respiratory Diseases, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan, China
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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.
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Maurya S, Srivastava R, Arfin S, Hawthorne S, Jha NK, Agrawal K, Raj S, Rathi B, Kumar A, Raj R, Agrawal S, Paiva-Santos AC, Malik AA, Dua K, Rana R, Ojha S, Jha SK, Sharma A, Kumar D, El-Zahaby SA, Nagar A. Exploring state-of-the-art advances in targeted nanomedicines for managing acute and chronic inflammatory lung diseases. Nanomedicine (Lond) 2022; 17:2245-2264. [PMID: 36975758 DOI: 10.2217/nnm-2021-0437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 01/30/2023] [Indexed: 03/29/2023] Open
Abstract
Diagnosis and treatment of lung diseases pose serious challenges. Currently, diagnostic as well as therapeutic methods show poor efficacy toward drug-resistant bacterial infections, while chemotherapy causes toxicity and nonspecific delivery of drugs. Advanced treatment methods that cure lung-related diseases, by enabling drug bioavailability via nasal passages during mucosal formation, which interferes with drug penetration to targeted sites, are in demand. Nanotechnology confers several advantages. Currently, different nanoparticles, or their combinations, are being used to enhance targeted drug delivery. Nanomedicine, a combination of nanoparticles and therapeutic agents, that delivers drugs to targeted sites increases the bioavailability of drugs at these sites. Thus, nanotechnology is superior to conventional chemotherapeutic strategies. Here, the authors review the latest advancements in nanomedicine-based drug-delivery methods for managing acute and chronic inflammatory lung diseases.
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Affiliation(s)
- Sujata Maurya
- School of Health Sciences & Technology, UPES University, Dehradun, Uttarakhand, 248007, India
| | - Rashi Srivastava
- Chemical & Biochemical Engineering, Indian Institute of Technology, Patna, 801106, India
| | - Saniya Arfin
- School of Health Sciences & Technology, UPES University, Dehradun, Uttarakhand, 248007, India
| | - Susan Hawthorne
- SAAD Building, School of Pharmacy & Pharmaceutical Sciences, Ulster University, Coleraine, BT52 1SA, UK
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering & Technology (SET), Sharda University, Greater Noida, Uttar Pradesh, 201310, India
- School of Bioengineering and Biosciences, Lovely Professional University, Phagwara 144411, Punjab, India
| | - Kirti Agrawal
- School of Health Sciences & Technology, UPES University, Dehradun, Uttarakhand, 248007, India
| | - Sibi Raj
- School of Health Sciences & Technology, UPES University, Dehradun, Uttarakhand, 248007, India
| | - Brijesh Rathi
- Department of Chemistry, Hansraj College, Delhi University, New Delhi, 110007, Delhi, India
| | - Arun Kumar
- Mahavir Cancer Institute & Research Centre Patna, Bihar, 800002, India
| | - Riya Raj
- Department of Biochemistry, Bangalore University, Bangalore, 560056, Karnataka, India
| | - Sharad Agrawal
- Department of Life Sciences, School of Basic Science & Research, Sharda University, Greater Noida, Uttar Pradesh, 201310, India
| | - Ana Cláudia Paiva-Santos
- Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, Azinhaga Sta. Comba, 3000-548 Coimbra, Portugal
| | - Asrar Ahmad Malik
- Department of Life Sciences, School of Basic Science & Research, Sharda University, Greater Noida, Uttar Pradesh, 201310, India
| | - Kamal Dua
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW, 2007, Australia
| | - Rakesh Rana
- MSD, HILLEMAN LABS, Analytical Division, New Delhi, 110062, India
| | - Shreesh Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Saurabh Kumar Jha
- Department of Biotechnology, School of Engineering & Technology (SET), Sharda University, Greater Noida, Uttar Pradesh, 201310, India
- Department of Biotechnology Engineering & Food Technology, Chandigarh University, Mohali, 140413, India
- Department of Biotechnology, School of Applied & Life Sciences (SALS), Uttaranchal University, Dehradun 248007, India
| | - Ankur Sharma
- Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, Cathedral Street, Glasgow, G10RE, Scotland, UK
| | - Dhruv Kumar
- School of Health Sciences & Technology, UPES University, Dehradun, Uttarakhand, 248007, India
| | - Sally A El-Zahaby
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt
| | - Amka Nagar
- Department of Life Sciences, School of Basic Science & Research, Sharda University, Greater Noida, Uttar Pradesh, 201310, India
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Xiang H, Yu H, Zhou Q, Wu Y, Ren J, Zhao Z, Tao X, Dong D. Macrophages: A rising star in immunotherapy for chronic pancreatitis. Pharmacol Res 2022; 185:106508. [DOI: 10.1016/j.phrs.2022.106508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 10/10/2022] [Indexed: 11/29/2022]
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Guo Z, Zhang Y, Yan F. Potential of Mesenchymal Stem Cell-Based Therapies for Pulmonary Fibrosis. DNA Cell Biol 2022; 41:951-965. [DOI: 10.1089/dna.2022.0327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Zhihou Guo
- Stem Cell Lab, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Yaping Zhang
- Center for Molecular Diagnosis and Therapy, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Furong Yan
- Center for Molecular Diagnosis and Therapy, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
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Abstract
Pulmonary fibrosis (PF) is a chronic and relentlessly progressive interstitial lung disease in which the accumulation of fibroblasts and extracellular matrix (ECM) induces the destruction of normal alveolar structures, ultimately leading to respiratory failure. Patients with advanced PF are unable to perform physical labor and often have concomitant cough and dyspnea, which markedly impair their quality of life. However, there is a paucity of available pharmacological therapies, and to date, lung transplantation remains the only possible treatment for patients suffering from end-stage PF; moreover, the complexity of transplantation surgery and the paucity of donors greatly restrict the application of this treatment. Therefore, there is a pressing need for alternative therapeutic strategies for this complex disease. Due to their capacity for pluripotency and paracrine actions, stem cells are promising therapeutic agents for the treatment of interstitial lung disease, and an extensive body of literature supports the therapeutic efficacy of stem cells in lung fibrosis. Although stem cell transplantation may play an important role in the treatment of PF, some key issues, such as safety and therapeutic efficacy, remain to be resolved. In this review, we summarize recent preclinical and clinical studies on the stem cell-mediated regeneration of fibrotic lungs and present an analysis of concerning issues related to stem cell therapy to guide therapeutic development for this complex disease.
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Zhang Y, Yang S, Qiu Z, Huang L, Huang L, Liang Y, Liu X, Wang M, Zhou B. Pyrogallol enhances therapeutic effect of human umbilical cord mesenchymal stem cells against LPS-mediated inflammation and lung injury via activation of Nrf2/HO-1 signaling. Free Radic Biol Med 2022; 191:66-81. [PMID: 36028178 DOI: 10.1016/j.freeradbiomed.2022.08.030] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 07/31/2022] [Accepted: 08/18/2022] [Indexed: 11/25/2022]
Abstract
The main challenges in clinical applications of mesenchymal stem cells (MSCs) are attributed to their heterogeneity. It is believed that preconditioning of MSCs with active compounds may enhance the expression of potentially therapeutic molecules and thus achieve stable and effective therapeutic outcomes. In the present study, we investigated the mechanism by which pyrogallol increased the therapeutic efficacy of human umbilical cord mesenchymal stem cells (hUCMSCs) against LPS-induced acute lung injury (ALI). hUCMSCs with pyrogallol treatment increased expression of HO-1 at both mRNA and protein levels, accompanied by Kelch-Like ECH-Associated Protein 1 (Keap1) degradation, and upregulation of the Nrf2 protein levels as well as nuclear translocation of Nrf2. Moreover, the modulation of Keap1 and Nrf2 as well as HO-1 upregulation by pyrogallol was reversed by pretreatment with N-acetylcysteine (NAC) and a P38 kinase inhibitor (SB203580). Whereas, NAC pretreatment abrogated pyrogallol-mediated activation of P38 kinase, indicating that pyrogallol-derived ROS led to P38 kinase activation, thus promoting Nrf2/HO-1 signaling. Additionally, we found that the induction of p62 by the pyrogallol-mediated ROS/P38/Nrf2 axis interacted with Keap1 and resulted in autophagic degradation of Keap1, which created a positive feedback loop to further release of Nrf2. Furthermore, the increased expression of HO-1 in pyrogallol-pretreated hUCMSCs led to enhanced inhibitory effects on LPS-mediated TLR4/P-P65 signaling in BEAS-2B cells, resulting in increasing suppression of LPS-indued expression of a series of pro-inflammatory mediators. Compared to untreated hUCMSCs, Sprague-Dawley (SD) rats with pyrogallol-primed hUCMSCs transplantation showed enhanced improvements in LPS-mediated lung pathological alterations, the increased lung index (lung/body ratio), apoptosis of epithelial cells, the activation of TLR4/NF-κB signaling as well as the release of pro-inflammatory mediators. Together, these results suggested that hUCMSCs with pyrogallol pretreatment enhanced the therapeutic efficacy of hUCMSCs, which may provide a promising therapeutic strategy to maximize the therapeutic efficacy of hUCMSC-based therapy for treating LPS-associated ALI.
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Affiliation(s)
- Yuehan Zhang
- Center of Stem Cell and Regenerative Medicine, The People's Hospital of Gaozhou, Gaozhou, 525200, China
| | - Sushan Yang
- Department of Clinical Laboratory, The People's Hospital of Gaozhou, Gaozhou, 525200, China
| | - Zhenhua Qiu
- Department of Clinical Laboratory, The People's Hospital of Gaozhou, Gaozhou, 525200, China
| | - Li Huang
- Center of Stem Cell and Regenerative Medicine, The People's Hospital of Gaozhou, Gaozhou, 525200, China
| | - Linyan Huang
- Department of Hematopathology, The People's Hospital of Gaozhou, Gaozhou, 525200, China
| | - Yueyun Liang
- Center of Stem Cell and Regenerative Medicine, The People's Hospital of Gaozhou, Gaozhou, 525200, China
| | - Xuanyu Liu
- Center of Stem Cell and Regenerative Medicine, The People's Hospital of Gaozhou, Gaozhou, 525200, China
| | - Maosheng Wang
- Center of Stem Cell and Regenerative Medicine, The People's Hospital of Gaozhou, Gaozhou, 525200, China.
| | - Beixian Zhou
- Center of Stem Cell and Regenerative Medicine, The People's Hospital of Gaozhou, Gaozhou, 525200, China; Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, 510315, Guangzhou, China.
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Zhang Z, Kuang Y, Ma K, Li Y, Liu X, Shi Y, Wu X. Gclc overexpression inhibits apoptosis of bone marrow mesenchymal stem cells through the PI3K/AKT/Foxo1 pathway to alleviate inflammation in acute lung injury. Int Immunopharmacol 2022; 110:109017. [DOI: 10.1016/j.intimp.2022.109017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/28/2022] [Accepted: 06/29/2022] [Indexed: 12/15/2022]
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Liu C, Xiao K, Xie L. Advances in mesenchymal stromal cell therapy for acute lung injury/acute respiratory distress syndrome. Front Cell Dev Biol 2022; 10:951764. [PMID: 36036014 PMCID: PMC9399751 DOI: 10.3389/fcell.2022.951764] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 07/19/2022] [Indexed: 11/29/2022] Open
Abstract
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) develops rapidly and has high mortality. ALI/ARDS is mainly manifested as acute or progressive hypoxic respiratory failure. At present, there is no effective clinical intervention for the treatment of ALI/ARDS. Mesenchymal stromal cells (MSCs) show promise for ALI/ARDS treatment due to their biological characteristics, easy cultivation, low immunogenicity, and abundant sources. The therapeutic mechanisms of MSCs in diseases are related to their homing capability, multidirectional differentiation, anti-inflammatory effect, paracrine signaling, macrophage polarization, the polarization of the MSCs themselves, and MSCs-derived exosomes. In this review, we discuss the pathogenesis of ALI/ARDS along with the biological characteristics and mechanisms of MSCs in the treatment of ALI/ARDS.
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Affiliation(s)
- Chang Liu
- School of Medicine, Nankai University, Tianjin, China
- Center of Pulmonary and Critical Care Medicine, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Medical School of Chinese People’s Liberation Army (PLA), Beijing, China
| | - Kun Xiao
- Center of Pulmonary and Critical Care Medicine, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Medical School of Chinese People’s Liberation Army (PLA), Beijing, China
- *Correspondence: Kun Xiao, ; Lixin Xie,
| | - Lixin Xie
- School of Medicine, Nankai University, Tianjin, China
- Center of Pulmonary and Critical Care Medicine, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Medical School of Chinese People’s Liberation Army (PLA), Beijing, China
- *Correspondence: Kun Xiao, ; Lixin Xie,
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Wang L, Feng Y, Dou M, Wang J, Bi J, Zhang D, Hou D, Chen C, Bai C, Zhou J, Tong L, Song Y. Study of mesenchymal stem cells derived from lung-resident, bone marrow and chorion for treatment of LPS-induced acute lung injury. Respir Physiol Neurobiol 2022; 302:103914. [PMID: 35447348 DOI: 10.1016/j.resp.2022.103914] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 03/16/2022] [Accepted: 04/14/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) have been shown to improve acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). However, the optimal source of MSCs for cell-based therapy remains unknown. To determine which kind of MSCs are more effective, we compared the effects of rat lung resident MSC (LRMSC), human chorion-derived MSC (HMSC-C) and human bone marrow derived MSC (HMSC-BM) in LPS-induced ALI in mice. METHODS LPS (Pseudomonas aeruginosa) was used to induce ALI model. All three kinds of MSCs were administered via tail vein 4 h after LPS instillation. The mice were sacrificed 48 h after LPS instillation. H&E staining of lung section, wet-to-dry weight ratio of lung tissue, ratio of regulatory T cells (Tregs) and Th17 cells, and total protein concentration, leukocytes counting and cytokines in bronchoalveolar lavage fluid (BALF) were evaluated. RESULTS The data showed that compared with LRMSC and HMSC-BM, HMSC-C more significantly attenuated lung injury, upregulated the Tregs/Th17 cells ratio, and inhibited release of inflammatory cytokines (IL-1β, IL-6 and TNF-α) and recruitment of neutrophils and macrophages into alveolus. CONCLUSIONS Although all three kinds of LRMSC, HMSC-C and HMSC-BM are protective against LPS-induced lung injury, HMSC-C was more effective than LRMSC and HMSC-BM to treat LPS-induced lung injury.
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Affiliation(s)
- Linlin Wang
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yun Feng
- Department of Pulmonary Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Maosen Dou
- Department of Infectious Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Jian Wang
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Jing Bi
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Donghui Zhang
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Dongni Hou
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Cuicui Chen
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Chunxue Bai
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Jian Zhou
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
| | - Lin Tong
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
| | - Yuanlin Song
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Respiratory Research Institute, China; National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, China; Zhongshan Hospital, Qingpu Branch, Fudan University, Shanghai 201700, China; Jinshan Hospital of Fudan University, Shanghai 201508, China.
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Erasmus DB, Durand N, Alvarez FA, Narula T, Hodge DO, Zubair AC. Feasibility and Safety of Low-Dose Mesenchymal Stem Cell Infusion in Lung Transplant Recipients. Stem Cells Transl Med 2022; 11:891-899. [PMID: 35881142 PMCID: PMC9492292 DOI: 10.1093/stcltm/szac051] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 06/12/2022] [Indexed: 12/02/2022] Open
Abstract
Background We have previously shown bone marrow-derived mesenchymal stem cells (MSCs) may shift immune responses toward anti-inflammatory pathways and stabilize the course of obstructive chronic lung allograft syndrome (o-CLAD) after lung transplantation. In this study, we measured the response of lower dose infusions. Methods We infused low-dose MSCs intravenously in 13 patients who had developed moderate-to-severe o-CLAD. Three had previously received an infusion of MSCs from a different donor and were re-dosed at 1 × 106 MSC/kg, while 5 received a first dose at 1 × 106 MSC/kg and five received an even lower dose at 0.5 × 106 MSC/kg. We recorded pulmonary function tests before and after infusion, and patients were followed clinically for 12 months. Results Infusions were well tolerated, and no significant adverse events were recorded in the first 30 days. There was significant decline (mean ± SD) in forced vital capacity (FVC) (3.49 ± 1.03 vs 3.18 ± 0.94 L, P = .03) and forced expiratory volume in 1 second (FEV1) (2.28 ± 0.86 vs 1.77 ± 0.49 L, P = .04) over the year preceding infusion. FVC (3.18 ± 0.94 vs 3.46 ± 0.99 L, P = .53) and FEV1 was not significantly changed (1.77 ± 0.49 vs 1.88 ± 0.75, P = .72) when comparing values immediately prior to infusion to those obtained 1 year after infusion, indicating a possible stabilizing effect on lung function decline due to o-CLAD. Conclusion Intravenous infusions of bone marrow-derived MSCs are well tolerated in lung transplant recipients with moderate-to-severe CLAD. Low-dose MSCs appear to slow progression of CLAD in some patients.
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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.
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Lederer CW, Koniali L, Buerki-Thurnherr T, Papasavva PL, La Grutta S, Licari A, Staud F, Bonifazi D, Kleanthous M. Catching Them Early: Framework Parameters and Progress for Prenatal and Childhood Application of Advanced Therapies. Pharmaceutics 2022; 14:pharmaceutics14040793. [PMID: 35456627 PMCID: PMC9031205 DOI: 10.3390/pharmaceutics14040793] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/29/2022] [Accepted: 04/01/2022] [Indexed: 01/19/2023] Open
Abstract
Advanced therapy medicinal products (ATMPs) are medicines for human use based on genes, cells or tissue engineering. After clear successes in adults, the nascent technology now sees increasing pediatric application. For many still untreatable disorders with pre- or perinatal onset, timely intervention is simply indispensable; thus, prenatal and pediatric applications of ATMPs hold great promise for curative treatments. Moreover, for most inherited disorders, early ATMP application may substantially improve efficiency, economy and accessibility compared with application in adults. Vindicating this notion, initial data for cell-based ATMPs show better cell yields, success rates and corrections of disease parameters for younger patients, in addition to reduced overall cell and vector requirements, illustrating that early application may resolve key obstacles to the widespread application of ATMPs for inherited disorders. Here, we provide a selective review of the latest ATMP developments for prenatal, perinatal and pediatric use, with special emphasis on its comparison with ATMPs for adults. Taken together, we provide a perspective on the enormous potential and key framework parameters of clinical prenatal and pediatric ATMP application.
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Affiliation(s)
- Carsten W. Lederer
- The Molecular Genetics Thalassemia Department, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, Cyprus; (L.K.); (P.L.P.); (M.K.)
- Correspondence: ; Tel.: +357-22-392764
| | - Lola Koniali
- The Molecular Genetics Thalassemia Department, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, Cyprus; (L.K.); (P.L.P.); (M.K.)
| | - Tina Buerki-Thurnherr
- Empa, Swiss Federal Laboratories for Materials Science and Technology, 9014 St. Gallen, Switzerland;
| | - Panayiota L. Papasavva
- The Molecular Genetics Thalassemia Department, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, Cyprus; (L.K.); (P.L.P.); (M.K.)
| | - Stefania La Grutta
- Institute of Translational Pharmacology, IFT National Research Council, 90146 Palermo, Italy;
| | - Amelia Licari
- Pediatric Clinic, Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, Fondazione IRCCS Policlinico San Matteo, University of Pavia, 27100 Pavia, Italy;
| | - Frantisek Staud
- Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, 50005 Hradec Králové, Czech Republic;
| | - Donato Bonifazi
- Consorzio per Valutazioni Biologiche e Farmacologiche (CVBF) and European Paediatric Translational Research Infrastructure (EPTRI), 70122 Bari, Italy;
| | - Marina Kleanthous
- The Molecular Genetics Thalassemia Department, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, Cyprus; (L.K.); (P.L.P.); (M.K.)
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Li S, Zhu H, Zhao M, Liu W, Wang L, Zhu B, Xie W, Zhao C, Zhou Y, Ren C, Liu H, Jiang X. When stem cells meet COVID-19: recent advances, challenges and future perspectives. Stem Cell Res Ther 2022; 13:9. [PMID: 35012650 PMCID: PMC8744050 DOI: 10.1186/s13287-021-02683-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 12/11/2021] [Indexed: 02/09/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory coronavirus 2 is currently spreading throughout the world with a high rate of infection and mortality and poses a huge threat to global public health. COVID-19 primarily manifests as hypoxic respiratory failure and acute respiratory distress syndrome, which can lead to multiple organ failure. Despite advances in the supportive care approaches, there is still a lack of clinically effective therapies, and there is an urgent need to develop novel strategies to fight this disease. Currently, stem cell therapy and stem cell-derived organoid models have received extensive attention as a new treatment and research method for COVID-19. Here, we discuss how stem cells play a role in the battle against COVID-19 and present a systematic review and prospective of the study on stem cell treatment and organoid models of COVID-19, which provides a reference for the effective control of the COVID-19 pandemic worldwide.
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Affiliation(s)
- Shasha Li
- Cancer Research Institute, Department of Neurosurgery, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, School of Basic Medicine, Central South University, Changsha, 410008, China
| | - Hecheng Zhu
- Changsha Kexin Cancer Hospital, Changsha, 410205, China
| | - Ming Zhao
- Changsha Kexin Cancer Hospital, Changsha, 410205, China
| | - Weidong Liu
- Cancer Research Institute, Department of Neurosurgery, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, School of Basic Medicine, Central South University, Changsha, 410008, China
| | - Lei Wang
- Cancer Research Institute, Department of Neurosurgery, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, School of Basic Medicine, Central South University, Changsha, 410008, China
| | - Bin Zhu
- Cancer Research Institute, Department of Neurosurgery, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, School of Basic Medicine, Central South University, Changsha, 410008, China
| | - Wen Xie
- Cancer Research Institute, Department of Neurosurgery, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, School of Basic Medicine, Central South University, Changsha, 410008, China
| | - Cong Zhao
- Cancer Research Institute, Department of Neurosurgery, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, School of Basic Medicine, Central South University, Changsha, 410008, China
| | - Yao Zhou
- Cancer Research Institute, Department of Neurosurgery, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, School of Basic Medicine, Central South University, Changsha, 410008, China
| | - Caiping Ren
- Cancer Research Institute, Department of Neurosurgery, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
- The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, School of Basic Medicine, Central South University, Changsha, 410008, China.
| | - Hui Liu
- School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
| | - Xingjun Jiang
- Cancer Research Institute, Department of Neurosurgery, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, China.
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Safety and efficacy of multipotent adult progenitor cells in acute respiratory distress syndrome (MUST-ARDS): a multicentre, randomised, double-blind, placebo-controlled phase 1/2 trial. Intensive Care Med 2022; 48:36-44. [PMID: 34811567 PMCID: PMC8608557 DOI: 10.1007/s00134-021-06570-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 10/28/2021] [Indexed: 01/15/2023]
Abstract
PURPOSE Bone marrow-derived, allogeneic, multipotent adult progenitor cells demonstrated safety and efficacy in preclinical models of acute respiratory distress syndrome (ARDS). METHODS This phase 1/2 trial evaluated the safety and tolerability of intravenous multipotent adult progenitor cells in patients with moderate-to-severe ARDS in 12 UK and USA centres. Cohorts 1 and 2 were open-label, evaluating acute safety in three subjects receiving 300 or 900 million cells, respectively. Cohort 3 was a randomised, double-blind, placebo-controlled parallel trial infusing 900 million cells (n = 20) or placebo (n = 10) within 96 h of ARDS diagnosis. Primary outcomes were safety and tolerability. Secondary endpoints included clinical outcomes, quality of life (QoL) and plasma biomarkers. RESULTS No allergic or serious adverse reactions were associated with cell therapy in any cohort. At baseline, the cohort 3 cell group had less severe hypoxia. For cohort 3, 28-day mortality was 25% for cell vs. 45% for placebo recipients. Median 28-day free from intensive care unit (ICU) and ventilator-free days in the cell vs. placebo group were 12.5 (IQR 0,18.5) vs. 4.5 (IQR 0,16.8) and 18.5 (IQR 0,22) vs. 6.5 (IQR 0,18.3), respectively. A prospectively defined severe ARDS subpopulation (PaO2/FiO2 < 150 mmHg (20 kPa); n = 16) showed similar trends in mortality, ICU-free days and ventilator-free days favouring cell therapy. Cell recipients showed greater recovery of QoL through Day 365. CONCLUSIONS Multipotent adult progenitor cells were safe and well tolerated in ARDS. The clinical outcomes warrant larger trials to evaluate the therapeutic efficacy and optimal patient population.
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Liao G, Liao Y, Li D, Fu Z, Wu S, Cheng D, Ouyang Q, Tang Z, Zeng G, Liang X, Xu S, Hu J, Liu M. Human Platelet Lysate Maintains Stemness of Umbilical Cord-Derived Mesenchymal Stromal Cells and Promote Lung Repair in Rat Bronchopulmonary Dysplasia. Front Cell Dev Biol 2021; 9:722953. [PMID: 34858970 PMCID: PMC8631747 DOI: 10.3389/fcell.2021.722953] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 10/05/2021] [Indexed: 11/23/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) show potential for treating preclinical models of newborn bronchopulmonary dysplasia (BPD), but studies of their therapeutic effectiveness have had mixed results, in part due to the use of different media supplements for MSCs expansion in vitro. The current study sought to identify an optimal culture supplement of umbilical cord-derived MSCs (UC-MSCs) for BPD therapy. In this study, we found that UC-MSCs cultured with human platelet lysate (hPL-UCMSCs) were maintained a small size from Passage 1 (P1) to P10, while UC-MSCs cultured with fetal bovine serum (FBS-UCMSCs) became wide and flat. Furthermore, hPL was associated with lower levels of senescence in UC-MSCs during in vitro expansion compared with FBS, as indicated by the results of β-galactosidase staining and measures of senescence-related genes (CDKN2A, CDKN1A, and mTOR). In addition, hPL enhanced the proliferation and cell viability of the UC-MSCs and reduced their doubling time in vitro. Compared with FBS-UCMSCs, hPL-UCMSCs have a greater potential to differentiate into osteocytes and chondrocytes. Moreover, using hPL resulted in greater expression of Nestin and specific paracrine factors (VEGF, TGF-β1, FGF2, IL-8, and IL-6) in UC-MSCs compared to using FBS. Critically, we also found that hPL-UCMSCs are more effective than FBS-UCMSCs for the treatment of BPD in a rat model, with hPL leading to improvements in survival rate, lung architecture and fibrosis, and lung capillary density. Finally, qPCR of rat lung mRNA demonstrated that hPL-UCMSCs had lower expression levels of inflammatory factors (TNF-α and IL-1β) and a key chemokine (MCP-1) at postnatal day 10, and there was significant reduction of CD68+ macrophages in lung tissue after hPL-UCMSCs transplantation. Altogether, our findings suggest that hPL is an optimal culture supplement for UC-MSCs expansion in vitro, and that hPL-UCMSCs promote lung repair in rat BPD disease.
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Affiliation(s)
- Guilian Liao
- Obstetrics and Gynecology, Maternal and Child Health Hospital of Longgang District, Shenzhen, China
| | - Yan Liao
- Shenzhen Beike Biotechnology Co., Ltd., Shenzhen, China
| | - Duanduan Li
- Shenzhen Beike Biotechnology Co., Ltd., Shenzhen, China
| | - Zeqin Fu
- Shenzhen Beike Biotechnology Co., Ltd., Shenzhen, China
| | - Shiduo Wu
- Shenzhen Beike Biotechnology Co., Ltd., Shenzhen, China
| | - Danling Cheng
- Obstetrics and Gynecology, Maternal and Child Health Hospital of Longgang District, Shenzhen, China
| | - Qiuxing Ouyang
- Neurological Rehabilitation for Children, Maternal and Child Health Hospital of Luohu District, Shenzhen, China
| | - Zan Tang
- Shenzhen Beike Biotechnology Co., Ltd., Shenzhen, China
| | - Guifang Zeng
- Shenzhen Beike Biotechnology Co., Ltd., Shenzhen, China
| | - Xiao Liang
- Shenzhen Beike Biotechnology Co., Ltd., Shenzhen, China
| | - Shaokun Xu
- Shenzhen Beike Biotechnology Co., Ltd., Shenzhen, China
| | - Junyuan Hu
- Shenzhen Beike Biotechnology Co., Ltd., Shenzhen, China
| | - Muyun Liu
- National-Local Associated Engineering Laboratory for Personalized Cell Therapy, Shenzhen, China
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Pelizzo G, Silvestro S, Avanzini MA, Zuccotti G, Mazzon E, Calcaterra V. Mesenchymal Stromal Cells for the Treatment of Interstitial Lung Disease in Children: A Look from Pediatric and Pediatric Surgeon Viewpoints. Cells 2021; 10:3270. [PMID: 34943779 PMCID: PMC8699409 DOI: 10.3390/cells10123270] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/11/2021] [Accepted: 11/21/2021] [Indexed: 12/16/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) have been proposed as a potential therapy to treat congenital and acquired lung diseases. Due to their tissue-regenerative, anti-fibrotic, and immunomodulatory properties, MSCs combined with other therapy or alone could be considered as a new approach for repair and regeneration of the lung during disease progression and/or after post- surgical injury. Children interstitial lung disease (chILD) represent highly heterogeneous rare respiratory diseases, with a wild range of age of onset and disease expression. The chILD is characterized by inflammatory and fibrotic changes of the pulmonary parenchyma, leading to gas exchange impairment and chronic respiratory failure associated with high morbidity and mortality. The therapeutic strategy is mainly based on the use of corticosteroids, hydroxychloroquine, azithromycin, and supportive care; however, the efficacy is variable, and their long-term use is associated with severe toxicity. The role of MSCs as treatment has been proposed in clinical and pre-clinical studies. In this narrative review, we report on the currently available on MSCs treatment as therapeutical strategy in chILD. The progress into the therapy of respiratory disease in children is mandatory to ameliorate the prognosis and to prevent the progression in adult age. Cell therapy may be a future therapy from both a pediatric and pediatric surgeon's point of view.
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Affiliation(s)
- Gloria Pelizzo
- Pediatric Surgery Department, Children’s Hospital “Vittore Buzzi”, 20154 Milano, Italy
- Department of Biomedical and Clinical Sciences-L. Sacco, University of Milan, 20157 Milan, Italy;
| | - Serena Silvestro
- IRCCS Centro Neurolesi “Bonino-Pulejo”, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy; (S.S.); (E.M.)
| | - Maria Antonietta Avanzini
- Cell Factory, Pediatric Hematology Oncology Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy;
| | - Gianvincenzo Zuccotti
- Department of Biomedical and Clinical Sciences-L. Sacco, University of Milan, 20157 Milan, Italy;
- Department of Pediatrics, Children’s Hospital “Vittore Buzzi”, 20154 Milano, Italy;
| | - Emanuela Mazzon
- IRCCS Centro Neurolesi “Bonino-Pulejo”, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy; (S.S.); (E.M.)
| | - Valeria Calcaterra
- Department of Pediatrics, Children’s Hospital “Vittore Buzzi”, 20154 Milano, Italy;
- Pediatrics and Adolescentology Unit, Department of Internal Medicine, University of Pavia, 27100 Pavia, Italy
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Adugna DG. Current Clinical Application of Mesenchymal Stem Cells in the Treatment of Severe COVID-19 Patients: Review. STEM CELLS AND CLONING-ADVANCES AND APPLICATIONS 2021; 14:71-80. [PMID: 34785907 PMCID: PMC8590837 DOI: 10.2147/sccaa.s333800] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/28/2021] [Indexed: 01/08/2023]
Abstract
Coronavirus-2019 disease is a newly diagnosed infectious disease, which is caused by the severe acute respiratory syndrome corona virus-2. It spreads quickly and has become a major public health problem throughout the world. When the viral structural spike protein binds to the angiotensin-converting enzyme-2 receptor of the host cell membrane, the virus enters into host cells. The virus primarily affects lung epithelial cells or other target cells that express angiotensin-converting enzyme-2 receptors in COVID-19 patients. Chemokines released by the host cells stimulate the recruitment of different immune cells. A cytokine storm occurs when a high amount of pro-inflammatory cytokines are produced as a result of the accumulation of immune cells. In COVID-19 patients, cytokine storms are the leading cause of severe acute respiratory distress syndrome. Mesenchymal stem cells are multipotent and self-renewing adult stem cells, which are obtained from a variety of tissues including bone marrow, adipose tissue, Warthon's jelly tissue, and amniotic fluid. Mesenchymal stem cells primarily exert their important therapeutic effects through 2 mechanisms: immunoregulatory effects and differentiation capacity. Mesenchymal stem cells can release several cytokines via paracrine mechanism or by direct interaction with white blood cells such as natural killer cells, T-lymphocytes, B-lymphocytes, natural killer cells, and macrophages, resulting in immune system regulation. Mesenchymal stem cells may help to restore the lung microenvironment, preserve alveolar epithelial cells, prevent lung fibrosis, and treat pulmonary dysfunction that is caused by COVID-19 associated pneumonia. Mesenchymal stem cells therapy may suppress aggressive inflammatory reactions and increase endogenous restoration by improving the pulmonary microenvironment. Furthermore, clinical evidence suggests that intravenous injection of mesenchymal stem cells may radically reduce lung tissue damage in COVID-19 patients. With the advancement of research involving mesenchymal stem cells for the treatment of COVID-19, mesenchymal stem cells therapy may be the main strategy for reducing the recent pandemic.
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Affiliation(s)
- Dagnew Getnet Adugna
- Department of Human Anatomy, School of Medicine, College of Medicine and Health Science, University of Gondar, Gondar, Amhara Region, Ethiopia
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Zocchi ML, Facchin F, Pagani A, Bonino C, Sbarbati A, Conti G, Vindigni V, Bassetto F. New perspectives in regenerative medicine and surgery: the bioactive composite therapies (BACTs). EUROPEAN JOURNAL OF PLASTIC SURGERY 2021; 45:1-25. [PMID: 34728900 PMCID: PMC8554210 DOI: 10.1007/s00238-021-01874-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 08/06/2021] [Indexed: 12/26/2022]
Abstract
Regenerative medicine and surgery is a rapidly expanding branch of translational research in tissue engineering, cellular and molecular biology. To date, the methods to improve cell intake, survival, and isolation need to comply with a complex and still unclear regulatory frame, becoming everyday more restrictive and often limiting the effectiveness and outcome of the therapeutic choices. Thus, the authors developed a novel 360° regenerative strategy based on the synergic action of several new components called the bioactive composite therapies (BACTs) to improve grafted cells intake, and survival in total compliance with the legal and ethical limits of the current regulatory frame. The rationale at the origin of this new technology is based on the evidence that cells need supportive substrate to survive in vitro and this observation, applying the concept of translational medicine, is true also in vivo. Bioactive composite mixtures (BACMs) are tailor-made bioactive mixtures containing several bioactive components that support cells' survival and induce a regenerative response in vivo by stimulating the recipient site to act as an in situ real bioreactor. Many different tissues have been used in the past for the isolation of cells, molecules, and growth factors, but the adipose tissue and its stromal vascular fraction (SVF) remains the most valuable, abundant, safe, and reliable source of regenerative components and particularly of adipose-derived stems cells (ADSCs). The role of plastic surgeons as the historical experts in all the most advanced techniques for harvesting, manipulating, and grafting adipose tissue is fundamental in this constant process of expansion of regenerative procedures. In this article, we analyze the main causes of cell death and the strategies for preventing it, and we present all the technical steps for preparing the main components of BACMs and the different mixing modalities to obtain the most efficient regenerative action on different clinical and pathological conditions. The second section of this work is dedicated to the logical and sequential evolution from simple bioactive composite grafts (BACGs) that distinguished our initial approach to regenerative medicine, to BACTs where many other fundamental technical steps are analyzed and integrated for supporting and enhancing the most efficient regenerative activity. Level of Evidence: Not gradable.
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Affiliation(s)
- Michele L Zocchi
- Plastic and Reconstructive Surgery Unit, University of Padua, Padua, Italy.,Remix Institute for Regenerative Surgery, Turin, Italy
| | - Federico Facchin
- Plastic and Reconstructive Surgery Unit, University of Padua, Padua, Italy
| | - Andrea Pagani
- Department of Plastic and Hand Surgery, Technical University of Munich, Munich, Germany
| | - Claudia Bonino
- Department of Rheumatology and Immune Diseases, Humanitas Gradenigo Hospital, Turin, Italy
| | - Andrea Sbarbati
- Institute of Human Anatomy, University of Verona, Verona, Italy
| | - Giamaica Conti
- Institute of Human Anatomy, University of Verona, Verona, Italy
| | - Vincenzo Vindigni
- Plastic and Reconstructive Surgery Unit, University of Padua, Padua, Italy
| | - Franco Bassetto
- Plastic and Reconstructive Surgery Unit, University of Padua, Padua, Italy
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Wiśniewska J, Sadowska A, Wójtowicz A, Słyszewska M, Szóstek-Mioduchowska A. Perspective on Stem Cell Therapy in Organ Fibrosis: Animal Models and Human Studies. Life (Basel) 2021; 11:life11101068. [PMID: 34685439 PMCID: PMC8538998 DOI: 10.3390/life11101068] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/06/2021] [Accepted: 10/08/2021] [Indexed: 12/17/2022] Open
Abstract
Tissue fibrosis is characterized by excessive deposition of extracellular matrix (ECM) components that result from the disruption of regulatory processes responsible for ECM synthesis, deposition, and remodeling. Fibrosis develops in response to a trigger or injury and can occur in nearly all organs of the body. Thus, fibrosis leads to severe pathological conditions that disrupt organ architecture and cause loss of function. It has been estimated that severe fibrotic disorders are responsible for up to one-third of deaths worldwide. Although intensive research on the development of new strategies for fibrosis treatment has been carried out, therapeutic approaches remain limited. Since stem cells, especially mesenchymal stem cells (MSCs), show remarkable self-renewal, differentiation, and immunomodulatory capacity, they have been intensively tested in preclinical studies and clinical trials as a potential tool to slow down the progression of fibrosis and improve the quality of life of patients with fibrotic disorders. In this review, we summarize in vitro studies, preclinical studies performed on animal models of human fibrotic diseases, and recent clinical trials on the efficacy of allogeneic and autologous stem cell applications in severe types of fibrosis that develop in lungs, liver, heart, kidney, uterus, and skin. Although the results of the studies seem to be encouraging, there are many aspects of cell-based therapy, including the cell source, dose, administration route and frequency, timing of delivery, and long-term safety, that remain open areas for future investigation. We also discuss the contemporary status, challenges, and future perspectives of stem cell transplantation for therapeutic options in fibrotic diseases as well as we present recent patents for stem cell-based therapies in organ fibrosis.
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