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Li L, Liu Y, Wang K, Mo J, Weng Z, Jiang H, Jin C. Stem cell exosomes: new hope and future potential for relieving liver fibrosis. Clin Mol Hepatol 2025; 31:333-349. [PMID: 39510097 PMCID: PMC12016649 DOI: 10.3350/cmh.2024.0854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 10/30/2024] [Accepted: 11/05/2024] [Indexed: 11/15/2024] Open
Abstract
Liver fibrosis is a chronic liver injury resulting from factors like viral hepatitis, autoimmune hepatitis, non-alcoholic steatohepatitis, fatty liver disease, and cholestatic liver disease. Liver transplantation is currently the gold standard for treating severe liver diseases. However, it is limited by a shortage of donor organs and the necessity for lifelong immunosuppressive therapy. Mesenchymal stem cells (MSCs) can differentiate into various liver cells and enhance liver function when transplanted into patients due to their differentiation and proliferation capabilities. Therefore, it can be used as an alternative therapy for treating liver diseases, especially for liver cirrhosis, liver failure, and liver transplant complications. However, due to the potential tumorigenic effects of MSCs, researchers are exploring a new approach to treating liver fibrosis using extracellular vesicles (exosomes) secreted by stem cells. Many studies show that exosomes released by stem cells can promote liver injury repair through various pathways, contributing to the treatment of liver fibrosis. In this review, we focus on the molecular mechanisms by which stem cell exosomes affect liver fibrosis through different pathways and their potential therapeutic targets. Additionally, we discuss the advantages of exosome therapy over stem cell therapy and the possible future directions of exosome research, including the prospects for clinical applications and the challenges to be overcome.
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Affiliation(s)
- Lihua Li
- 1 Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou University, Taizhou, Zhejiang Province, P. R. China
| | - Yongjie Liu
- Department of Cell biology, School of Medicine, Taizhou University, Taizhou, Zhejiang Province, P. R. China
- Department of Pathophysiology, School of Basic Medicine, Shenyang Medical College, Shenyang, Liaoning Province, P. R. China
| | - Kunpeng Wang
- 1 Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou University, Taizhou, Zhejiang Province, P. R. China
| | - Jinggang Mo
- 1 Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou University, Taizhou, Zhejiang Province, P. R. China
| | - Zhiyong Weng
- 1 Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou University, Taizhou, Zhejiang Province, P. R. China
| | - Hao Jiang
- 1 Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou University, Taizhou, Zhejiang Province, P. R. China
| | - Chong Jin
- 1 Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou University, Taizhou, Zhejiang Province, P. R. China
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Tandon R, Srivastava N. Unravelling exosome paradigm: Therapeutic, diagnostic and theranostics application and regulatory consideration. Life Sci 2025; 366-367:123472. [PMID: 39956185 DOI: 10.1016/j.lfs.2025.123472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 01/13/2025] [Accepted: 02/13/2025] [Indexed: 02/18/2025]
Abstract
In the recent decade, extracellular vesicles (EVs) have been released from nearly all the kingdoms, modulating intercellular communication and maintaining the human body's homeostasis by regulating different cellular processes. Among EVs, exosomes are the emerging field in biopharmaceuticals. They have lipid bilayer ranging from 30 to 150 nm in size and encompass DNA, RNA, protein lipids, etc. Their sources are widespread, easy to acquire, and cost-effective in manufacturing. This review focuses on the detailed classification of exosomes existing in nature, knowledge and application of omics, therapeutic, diagnostic and theranostic application of exosomes. It covers diseases such as cancer, infectious diseases (viral, bacterial, fungal infections), neurodegenerative diseases, metabolic diseases, lifestyle diseases (diabetes, cardiovascular, gastric disorder (IBD)), autoimmune disorders and their biodistribution. This article unfolds the recent progress in the exosomes arena and covers all the regulatory considerations (FDA, EMA, and other nations) involved with it. Moreover, a detailed discussion about clinical trials and its manifestation with exosomes and challenges associated with their isolation procedures, reproducibility, and safety concerns.
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Affiliation(s)
- Reetika Tandon
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow 226002, India
| | - Nidhi Srivastava
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow 226002, India.
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Chen Y, Yang F, Wang Y, Shi Y, Liu L, Luo W, Zhou J, Yan Y. Mesenchymal stem cell-derived small extracellular vesicles reduced hepatic lipid accumulation in MASLD by suppressing mitochondrial fission. Stem Cell Res Ther 2025; 16:116. [PMID: 40045380 PMCID: PMC11884000 DOI: 10.1186/s13287-025-04228-2] [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: 11/22/2024] [Accepted: 02/11/2025] [Indexed: 03/09/2025] Open
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disease characterized by lipid accumulation in liver cells. Human umbilical cord mesenchymal stem cell-derived small extracellular vesicles (MSC-sEV) have great potential in repairing and regenerating liver diseases. However, it is still unclear whether MSC-sEV can inhibit hepatocyte lipid accumulation by regulating mitochondrial fission. METHODS We investigated the effects of MSC-sEV on mitochondrial fission and its potential mechanism in lipotoxic hepatocytes and high-fat diet (HFD)-induced MASLD mice. RESULTS We found that MSC-sEV can effectively inhibit the expression of the Dynamin-related protein 1 (DRP1), thereby reducing mitochondrial fission, mitochondrial damage, and lipid deposition in lipotoxic hepatocytes and livers of HFD-induced MASLD in mice. Further mechanistic studies revealed that RING finger protein 31 (RNF31) played a crucial role in mediating the inhibitory effect of MSC-sEV on DRP1 and mitochondrial fission. RNF31 can suppress DRP1 expression and mitochondrial fission, thereby improving mitochondrial dysfunction and reducing hepatocyte lipid deposition. These findings suggest that MSC-sEV may downregulate hepatocyte DRP1-mediated mitochondrial fission by transporting RNF31, ultimately inhibiting hepatocyte lipid accumulation. CONCLUSIONS The insights from this study provide a new perspective on the mechanism of MSC-sEV in reducing lipid accumulation and offer a potential therapeutic target by targeting DRP1 to inhibit hepatocyte steatosis and the progression of MASLD.
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Affiliation(s)
- Yifei Chen
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Changzhou, 213017, China
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, China
| | - Fuji Yang
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Changzhou, 213017, China
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, China
| | - Yanjin Wang
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Changzhou, 213017, China
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, China
| | - Yujie Shi
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Changzhou, 213017, China
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, China
| | - Likang Liu
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Changzhou, 213017, China
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, China
| | - Wei Luo
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, 213017, China
- Changzhou Key Laboratory of Exosome Foundation and Transformation Application, Wujin Hospital Affiliated with Jiangsu University (Wujin Clinical College of Xuzhou Medical University, Changzhou, 213017, China
| | - Jing Zhou
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, 213017, China
- Changzhou Key Laboratory of Exosome Foundation and Transformation Application, Wujin Hospital Affiliated with Jiangsu University (Wujin Clinical College of Xuzhou Medical University, Changzhou, 213017, China
| | - Yongmin Yan
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Changzhou, 213017, China.
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, 213017, China.
- Changzhou Key Laboratory of Exosome Foundation and Transformation Application, Wujin Hospital Affiliated with Jiangsu University (Wujin Clinical College of Xuzhou Medical University, Changzhou, 213017, China.
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Zhao B, Zhang Z, Guo X, Liu X, Lei M, Guo S, Yao Q, Zhang F, Peng T, Liu A, Jiang B, Zhu D. Mesenchymal stem cell-derived exosomes in renal ischemia-reperfusion injury: a new therapeutic strategy. Int Urol Nephrol 2025; 57:875-884. [PMID: 39520637 DOI: 10.1007/s11255-024-04258-4] [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: 08/20/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024]
Abstract
Renal ischemia-reperfusion injury (RIRI) is a serious kidney condition that causes significant damage due to lack of blood flow. This injury leads to oxidative stress and inflammation, which can cause acute tubular necrosis and kidney failure. Stem cell-derived exosomes, small vesicles released by stem cells, have shown promise in treating RIRI. Mesenchymal stem cells (MSCs) have been used to mitigate RIRI, and their exosomes have been found to play a crucial role in repairing damaged tissues. This review explores the key roles of exosomes from different sources of MSCs in RIRI, the potential of MSC-derived exosomes in treating this disease, and future research directions.
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Affiliation(s)
- Bo Zhao
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Hubei University of Science and Technology, No.88, Xianning Avenue, Xianan District, 437000, Xianning, Hubei Province, People's Republic of China
- Xianning Central Hospital, First Affiliated Hospital of Hubei University of Science and Technology , 228 Jingui Road, Xian'an District, 437000, Xianning, Hubei Province, People's Republic of China
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, 437000, Xianning, Hubei Province, People's Republic of China
| | - Zhenwang Zhang
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Hubei University of Science and Technology, No.88, Xianning Avenue, Xianan District, 437000, Xianning, Hubei Province, People's Republic of China
| | - Xiying Guo
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Hubei University of Science and Technology, No.88, Xianning Avenue, Xianan District, 437000, Xianning, Hubei Province, People's Republic of China
| | - Xiufen Liu
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Hubei University of Science and Technology, No.88, Xianning Avenue, Xianan District, 437000, Xianning, Hubei Province, People's Republic of China
| | - Min Lei
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Hubei University of Science and Technology, No.88, Xianning Avenue, Xianan District, 437000, Xianning, Hubei Province, People's Republic of China
| | - Shuang Guo
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Hubei University of Science and Technology, No.88, Xianning Avenue, Xianan District, 437000, Xianning, Hubei Province, People's Republic of China
| | - Qing Yao
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Hubei University of Science and Technology, No.88, Xianning Avenue, Xianan District, 437000, Xianning, Hubei Province, People's Republic of China
| | - Feixue Zhang
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Hubei University of Science and Technology, No.88, Xianning Avenue, Xianan District, 437000, Xianning, Hubei Province, People's Republic of China
| | - Tie Peng
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Hubei University of Science and Technology, No.88, Xianning Avenue, Xianan District, 437000, Xianning, Hubei Province, People's Republic of China
| | - Aimei Liu
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Hubei University of Science and Technology, No.88, Xianning Avenue, Xianan District, 437000, Xianning, Hubei Province, People's Republic of China.
| | - Botao Jiang
- Xianning Central Hospital, First Affiliated Hospital of Hubei University of Science and Technology , 228 Jingui Road, Xian'an District, 437000, Xianning, Hubei Province, People's Republic of China.
| | - Dan Zhu
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Hubei University of Science and Technology, No.88, Xianning Avenue, Xianan District, 437000, Xianning, Hubei Province, People's Republic of China.
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, 437000, Xianning, Hubei Province, People's Republic of China.
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Mittal A, Jakhmola VR, Baweja S. Bioengineered extracellular vesicles: The path to precision medicine in liver diseases. LIVER RESEARCH (BEIJING, CHINA) 2025; 9:17-28. [PMID: 40206438 PMCID: PMC11977285 DOI: 10.1016/j.livres.2025.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 02/07/2025] [Accepted: 02/17/2025] [Indexed: 04/11/2025]
Abstract
Extracellular vesicles (EVs) are membrane-bound entities secreted by each cell, categorized as, exosomes, microvesicles or apoptotic bodies based on their size and biogenesis. They serve as promising vectors for drug delivery due to their capacity to carry diverse molecular signatures reflective of their cell of origin. EV research has significantly advanced since their serendipitous discovery, with recent studies focusing on their roles in various diseases and their potential for targeted therapy. In liver diseases, EVs are particularly promising for precision medicine, providing diagnostic and therapeutic potential in conditions such as metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis, hepatocellular carcinoma, alcoholic liver disease, liver fibrosis, and acute liver failure. Despite challenges in isolation and characterization, engineered EVs have shown efficacy in delivering therapeutic agents with improved targeting and reduced side effects. As research progresses, EVs hold great promise to revolutionize precision medicine in liver diseases, offering targeted, efficient, and versatile therapeutic options. In this review, we summarize various techniques for loading EVs with therapeutic cargo including both passive and active methods, and the potential of bioengineered EVs loaded with various molecules, such as miRNAs, proteins, and anti-inflammatory drugs in ameliorating clinical pathologies of liver diseases.
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Affiliation(s)
| | | | - Sukriti Baweja
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
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Tian Y, Jin M, Ye N, Gao Z, Jiang Y, Yan S. Mesenchymal stem cells-derived exosomes attenuate mouse non-heart-beating liver transplantation through Mir-17-5p-regulated Kupffer cell pyroptosis. Stem Cell Res Ther 2025; 16:57. [PMID: 39920844 PMCID: PMC11806715 DOI: 10.1186/s13287-025-04169-w] [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: 07/23/2024] [Accepted: 01/23/2025] [Indexed: 02/09/2025] Open
Abstract
BACKGROUND Liver transplantation is the most effective treatment for end-stage liver disease. However, the shortage of donor livers has become a significant obstacle to the advancement of liver transplantation. Mesenchymal stem cells-derived exosomes (MSCs-Exo) have been extensively investigated in liver diseases. However, the underlying mechanisms of how they can protect organ donation after cardiac death (DCD) livers remain unclear. METHODS In this study, an arterialized mouse non-heart-beating (NHB) liver transplantation model was used to investigate the effect of MSCs-Exo on NHB liver transplantation. The survival rates, histology, pro-inflammatory cytokine and chemokine expression, and underlying mechanisms were investigated. RESULTS The infusion of MSCs-Exo reduced the injury to DCD liver graft tissue. In vitro and in vivo experiments demonstrated that MSCs-Exo could inhibit hydrogen peroxide-induced pyroptosis of Kupffer cells. We found that miR-17-5p was significantly abundant in MSCs-Exo, targeting and regulating the TXNIP expression. This action inhibited NLRP3-mediated pyroptosis of Kupffer cells through the classical Caspase1-dependent pathway, alleviating DCD liver graft injury. CONCLUSION Our study elucidated a protective role for MSCs-Exo in a NHB liver transplantation model. This mechanism provides a theoretical basis and new strategies for the clinical application of MSCs-Exo to improve liver graft quality and alleviate the organ shortage in liver transplantation.
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Affiliation(s)
- Yang Tian
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Jie-Fang Road #88, Hangzhou, Zhejiang Province, 310009, China
| | - Ming Jin
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Jie-Fang Road #88, Hangzhou, Zhejiang Province, 310009, China
| | - Nanwei Ye
- Department of Medical Research Center, Shaoxing People's Hospital, Zhejiang University School of Medicine, Shaoxing, China
| | - Zhenzhen Gao
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Jie-Fang Road #88, Hangzhou, Zhejiang Province, 310009, China
| | - Yuancong Jiang
- Department of Surgery, Shaoxing People's Hospital, Zhejiang University School of Medicine, Zhong-Xing North Road #568, Shaoxing, Zhejiang Province, 312000, China.
| | - Sheng Yan
- Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Jie-Fang Road #88, Hangzhou, Zhejiang Province, 310009, China.
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Hu C, Wang L. Advances in the treatment of liver injury based on mesenchymal stem cell-derived exosomes. Stem Cell Res Ther 2024; 15:474. [PMID: 39696473 DOI: 10.1186/s13287-024-04087-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Accepted: 11/28/2024] [Indexed: 12/20/2024] Open
Abstract
Mesenchymal stem cells (MSCs) have shown a great potential role in treating liver injury. MSCs can promote liver regeneration by differentiating into hepatocytes, and can also secrete exosomes to participate in the repair of liver injury. Increasing evidence has shown that mesenchymal stem cell-derived exosomes (MSC-EXOs) play an important role in treating liver injury. In this review, the biogenesis and function of exosomes and the characteristics of MSC-EXOs were analyzed based on recent research results. MSC-EXOs are significant in liver injuries such as liver fibrosis, liver failure, hepatocellular carcinoma, oxidative stress, and lipid steatosis, and participate in the process of liver regeneration.
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Affiliation(s)
- Changlong Hu
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, 710000, China
| | - Lin Wang
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, 710000, China.
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8
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Zhang L, Deng Y, Bai X, Wei X, Ren Y, Chen S, Deng H. Cell therapy for end-stage liver disease: Current state and clinical challenge. Chin Med J (Engl) 2024; 137:2808-2820. [PMID: 39602326 DOI: 10.1097/cm9.0000000000003332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Indexed: 11/29/2024] Open
Abstract
ABSTRACT Liver disease involves a complex interplay of pathological processes, including inflammation, hepatocyte necrosis, and fibrosis. End-stage liver disease (ESLD), such as liver failure and decompensated cirrhosis, has a high mortality rate, and liver transplantation is the only effective treatment. However, to overcome problems such as the shortage of donor livers and complications related to immunosuppression, there is an urgent need for new treatment strategies that need to be developed for patients with ESLD. For instance, hepatocytes derived from donor livers or stem cells can be engrafted and multiplied in the liver, substituting the host hepatocytes and rebuilding the liver parenchyma. Stem cell therapy, especially mesenchymal stem cell therapy, has been widely proved to restore liver function and alleviate liver injury in patients with severe liver disease, which has contributed to the clinical application of cell therapy. In this review, we discussed the types of cells used to treat ESLD and their therapeutic mechanisms. We also summarized the progress of clinical trials around the world and provided a perspective on cell therapy.
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Affiliation(s)
- Lin Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
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Xiong Z, Li X, Xie M, Guo J, Yin S, Huang D, Jin L, Wang C, Zhang F, Mao C, Chen H, Luo D, Tang H, Chen X, Lian L. Small extracellular vesicles derived from adipose mesenchymal stem cells alleviate intestinal fibrosis by inhibiting the FAK/Akt signaling pathway via MFGE8. J Gastroenterol 2024; 59:1092-1106. [PMID: 39305336 DOI: 10.1007/s00535-024-02152-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 09/13/2024] [Indexed: 11/07/2024]
Abstract
BACKGROUND Intestinal fibrosis is one of the most frequent and severe complications of Crohn's disease. Accumulating studies have reported that adipose mesenchymal stem cell-derived small extracellular vesicles (AMSC-sEVs) could alleviate renal fibrosis, hepatic fibrosis, etc., while their potential for treating intestinal fibrosis remains uncertain. Therefore, this study aims to determine the therapeutic effects of AMSC-sEVs on intestinal fibrosis and identify the mechanisms underlying these effects. METHODS AMSC-sEVs were characterized using transmission electron microscopy, nanoparticle tracking analysis, and western blot. Whether AMSC-sEVs exert antifibrotic effects was investigated in two different murine models of intestinal fibrosis. Besides, AMSC-sEVs were co-cultured with primary human fibroblasts and CCD18co during transforming growth factor (TGF)-β1 stimulation. Label-free proteomics and rescue experiments were performed to identify candidate molecules in AMSC-sEVs. Transcriptome sequencing revealed changes in mRNA levels among different groups. Lastly, proteins related to relevant signaling pathways were identified by western blotting, and their expression and activation status were assessed. RESULTS AMSC-sEVs positively expressed CD63 and Alix and presented a classical "rim of a cup" and granule shape with approximately 43-100 nm diameter. AMSCs significantly alleviated intestinal fibrosis through secreted sEVs in vitro and in vivo. The milk fat globule-EGF factor 8 (MFGE8) was stably enriched in AMSC-sEVs and was an active compound contributing to the treatment of intestinal fibrosis by AMSCs. Mechanistically, AMSC-sEV-based therapies attenuated intestinal fibrosis by inhibiting the FAK/Akt signaling pathway. CONCLUSIONS MFGE8-containing AMSC-sEVs attenuate intestinal fibrosis, partly through FAK/Akt pathway inhibition.
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Affiliation(s)
- Zhizhong Xiong
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuancun Er Heng Rd. Guangzhou, Guangzhou, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xianzhe Li
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuancun Er Heng Rd. Guangzhou, Guangzhou, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Medical Faculty Heidelberg, Heidelberg University, 69120, Heidelberg, Germany
| | - Minghao Xie
- Department of General Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Jianping Guo
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuancun Er Heng Rd. Guangzhou, Guangzhou, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Shi Yin
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuancun Er Heng Rd. Guangzhou, Guangzhou, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Dayin Huang
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuancun Er Heng Rd. Guangzhou, Guangzhou, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Longyang Jin
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuancun Er Heng Rd. Guangzhou, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Caiqin Wang
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuancun Er Heng Rd. Guangzhou, Guangzhou, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Fengxiang Zhang
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuancun Er Heng Rd. Guangzhou, Guangzhou, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Chaobin Mao
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuancun Er Heng Rd. Guangzhou, Guangzhou, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Huaxian Chen
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuancun Er Heng Rd. Guangzhou, Guangzhou, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Dandong Luo
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuancun Er Heng Rd. Guangzhou, Guangzhou, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Haijie Tang
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xijie Chen
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuancun Er Heng Rd. Guangzhou, Guangzhou, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Lei Lian
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuancun Er Heng Rd. Guangzhou, Guangzhou, China.
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
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10
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Yadav S, Maity P, Kapat K. The Opportunities and Challenges of Mesenchymal Stem Cells-Derived Exosomes in Theranostics and Regenerative Medicine. Cells 2024; 13:1956. [PMID: 39682706 PMCID: PMC11640604 DOI: 10.3390/cells13231956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 11/19/2024] [Accepted: 11/22/2024] [Indexed: 12/18/2024] Open
Abstract
Cell-secreted nanovesicles of endosomal origin, called exosomes, are vital for mediating intracellular communication. As local or distal transporters of intracellular cargo, they reflect the unique characteristics of secretory cells and establish cell-specific interactions via characteristic surface proteins and receptors. With the advent of rapid isolation, purification, and identification techniques, exosomes have become an attractive choice for disease diagnosis (exosomal content as biomarkers), cell-free therapy, and tissue regeneration. Mesenchymal stem cell (MSC)-derived exosomes (MSC-exosomes) display angiogenic, immune-modulatory, and other therapeutic effects crucial for cytoprotection, ischemic wound repair, myocardial regeneration, etc. The primary focus of this review is to highlight the widespread application of MSC-exosomes in therapeutics, theranostics, and tissue regeneration. After a brief introduction of exosome properties, biogenesis, isolation, and functions, recent studies on therapeutic and regenerative applications of MSC-exosomes are described, focusing on bone, cartilage, periodontal, cardiovascular, skin, and nerve regeneration. Finally, the review highlights the theranostic potential of exosomes followed by challenges, summary, and outlook.
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Affiliation(s)
- Sachin Yadav
- Department of Medical Devices, National Institute of Pharmaceutical Education and Research Kolkata, 168, Maniktala Main Road, Kankurgachi, Kolkata 700054, West Bengal, India;
| | - Pritiprasanna Maity
- School of Medicine, University of California Riverside, Riverside, CA 92525, USA
| | - Kausik Kapat
- Department of Medical Devices, National Institute of Pharmaceutical Education and Research Kolkata, 168, Maniktala Main Road, Kankurgachi, Kolkata 700054, West Bengal, India;
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11
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Gai C, Li T, Zhao Y, Cheng Y, Song Y, Luo Q, Liu D, Wang Z. Mesenchymal stromal cells deliver H 2S-enhanced Nrf2 via extracellular vesicles to mediate mitochondrial homeostasis for repairing hypoxia-ischemia brain damage. Free Radic Biol Med 2024; 225:528-545. [PMID: 39427747 DOI: 10.1016/j.freeradbiomed.2024.10.292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 10/15/2024] [Accepted: 10/17/2024] [Indexed: 10/22/2024]
Abstract
Mesenchymal stromal cells (MSCs) are considered a therapeutic approach for neurological diseases via extracellular vesicles (EVs). Modified EVs contain active components with enhanced therapeutic potential. In this study, we aimed to explore the role and underlying mechanism of EVs from MSCs preconditioned by NaHS (an Hydrogen sulfide donor) (H2S-EVs) in hypoxia-ischemia (HI) brain damage. Our results showed that H2S-EVs treatment via the non-invasive intranasal route in HI mice was able to reduce oxidative stress and mitochondrial dysfunction compared to EVs treatment. Mechanistic studies demonstrated that NaHS promoted nuclear factor erythroid-2 related factor 2 (Nrf2) expression in the cytoplasm by inducing Parkinson disease protein 7 (PARK7)-dependent disintegration of Nrf2/Keap-1 complex in MSCs. In particular, the free Nrf2 was loaded into the EVs as a result of its KFERQ motif being recognized by 70-kDa heat shock proteins and lysosomal-associated membrane protein 2A. Subsequently, H2S-EVs were internalized into neurons in the ipsilateral hemisphere, thus delivering abundant Nrf2 to accumulate in the mitochondria and remodeling mitochondrial function following H2S-EVs treatment in HI mice. Moreover, Nrf2 knockdown in MSCs remarkably impaired H2S-EVs-mediated therapeutic effects on HI mice. In brief, the present study for the first time demonstrated that H2S-modified MSCs significantly accumulated higher Nrf2 in EVs via upregulating PARK7 expression, revealing the mechanism through which antioxidant protein Nrf2 delivered by H2S-EVs protect against mitochondrial dysfunction in HI brain damage.
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Affiliation(s)
- Chengcheng Gai
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, PR China
| | - Tingting Li
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, PR China
| | - Yijing Zhao
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, PR China
| | - Yahong Cheng
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, PR China
| | - Yan Song
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, PR China
| | - Qian Luo
- Department of Medical Psychology and Ethics, School of Basic Medicine Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, PR China
| | - Dexiang Liu
- Department of Medical Psychology and Ethics, School of Basic Medicine Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, PR China
| | - Zhen Wang
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, PR China.
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12
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Sitbon A, Delmotte PR, Pistorio V, Halter S, Gallet J, Gautheron J, Monsel A. Mesenchymal stromal cell-derived extracellular vesicles therapy openings new translational challenges in immunomodulating acute liver inflammation. J Transl Med 2024; 22:480. [PMID: 38773651 PMCID: PMC11106935 DOI: 10.1186/s12967-024-05282-9] [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: 03/27/2024] [Accepted: 05/07/2024] [Indexed: 05/24/2024] Open
Abstract
Inflammation plays a critical role in conditions such as acute liver failure, acute-on-chronic liver failure, and ischemia-reperfusion-induced liver injury. Various pathogenic pathways contribute to liver inflammation, involving inflammatory polarization of macrophages and Küpffer cells, neutrophil infiltration, dysregulation of T cell subsets, oxidative stress, and activation of hepatic stellate cells. While mesenchymal stromal cells (MSCs) have demonstrated beneficial properties, their clinical translation is limited by their cellular nature. However, MSC-derived extracellular vesicles (MSC-EVs) have emerged as a promising cell-free therapeutic approach for immunomodulation. MSC-EVs naturally mirror their parental cell properties, overcoming the limitations associated with the use of MSCs. In vitro and in vivo preclinical studies have demonstrated that MSC-EVs replicate the beneficial effects of MSCs in liver injury. This includes the reduction of cell death and oxidative stress, improvement of hepatocyte function, induction of immunomodulatory effects, and mitigation of cytokine storm. Nevertheless, MSC-EVs face challenges regarding the necessity of defining consistent isolation methods, optimizing MSCs culture conditions, and establishing quality control measures for EV characterization and functional assessment. By establishing standardized protocols, guidelines, and affordable cost mass production, clinicians and researchers will have a solid foundation to conduct further studies, validate the therapeutic efficacy of MSC-EVs, and ultimately pave the way for their clinical implementation in acute liver injury.
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Affiliation(s)
- Alexandre Sitbon
- Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne Université, Paris, France.
- Sorbonne Université, INSERM UMRS-938, Centre de Recherche de Saint-Antoine (CRSA), 75012, Paris, France.
| | - Pierre-Romain Delmotte
- Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne Université, Paris, France
| | - Valéria Pistorio
- Sorbonne Université, INSERM UMRS-938, Centre de Recherche de Saint-Antoine (CRSA), 75012, Paris, France
| | - Sébastien Halter
- Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne Université, Paris, France
- Sorbonne Université, INSERM UMRS-959, Immunology-Immunopathology-Immunotherapy (I3), 75013, Paris, France
| | - Jérémy Gallet
- Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne Université, Paris, France
| | - Jérémie Gautheron
- Sorbonne Université, INSERM UMRS-938, Centre de Recherche de Saint-Antoine (CRSA), 75012, Paris, France
| | - Antoine Monsel
- Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne Université, Paris, France
- Sorbonne Université, INSERM UMRS-938, Centre de Recherche de Saint-Antoine (CRSA), 75012, Paris, France
- Sorbonne Université, INSERM UMRS-959, Immunology-Immunopathology-Immunotherapy (I3), 75013, Paris, France
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13
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Bhat A, Malik A, Yadav P, Ware WJ, Kakalij P, Chand S. Mesenchymal stem cell‐derived extracellular vesicles: Recent therapeutics and targeted drug delivery advances. JOURNAL OF EXTRACELLULAR BIOLOGY 2024; 3. [DOI: 10.1002/jex2.156] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 04/25/2024] [Indexed: 01/03/2025]
Abstract
AbstractThe targeted drug delivery field is rapidly advancing, focusing on developing biocompatible nanoparticles that meet rigorous criteria of non‐toxicity, biocompatibility, and efficient release of encapsulated molecules. Conventional synthetic nanoparticles (SNPs) face complications such as elevated immune responses, complex synthesis methods, and toxicity, which restrict their utility in therapeutics and drug delivery. Extracellular vesicles (EVs) have emerged as promising substitutes for SNPs, leveraging their ability to cross biological barriers, biocompatibility, reduced toxicity, and natural origin. Notably, mesenchymal stem cell‐derived EVs (MSC‐EVs) have garnered much curiosity due to their potential in therapeutics and drug delivery. Studies suggest that MSC‐EVs, the central paracrine contributors of MSCs, replicate the therapeutic effects of MSCs. This review explores the characteristics of MSC‐EVs, emphasizing their potential in therapeutics and drug delivery for various diseases, including CRISPR/Cas9 delivery for gene editing. It also delves into the obstacles and challenges of MSC‐EVs in clinical applications and provides insights into strategies to overcome the limitations of biodistribution and target delivery.
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Affiliation(s)
- Anjali Bhat
- Department of Anesthesiology University of Nebraska Medical Center Omaha Nebraska USA
| | - Anshu Malik
- Institute for Quantitative Health Science and Engineering (IQ) Michigan State University East Lansing Michigan USA
- Department of Biomedical Engineering Michigan State University East Lansing Michigan USA
| | - Poonam Yadav
- Medical Science Interdepartmental Area University of Nebraska Medical Center Omaha Omaha Nebraska USA
| | | | - Pratiksha Kakalij
- Department of Pharmaceutical Sciences University of Nebraska Medical Center Omaha Omaha Nebraska USA
| | - Subhash Chand
- Department of Anesthesiology University of Nebraska Medical Center Omaha Nebraska USA
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Jiang S, Tian S, Wang P, Liu J, Sun K, Zhou X, Han Y, Shang Y. Native and engineered extracellular vesicles: novel tools for treating liver disease. J Mater Chem B 2024; 12:3840-3856. [PMID: 38532706 DOI: 10.1039/d3tb01921g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/28/2024]
Abstract
Liver diseases are classified as acute liver damage and chronic liver disease, with recurring liver damage causing liver fibrosis and progression to cirrhosis and hepatoma. Liver transplantation is the only effective treatment for end-stage liver diseases; therefore, novel therapies are required. Extracellular vesicles (EVs) are endogenous nanocarriers involved in cell-to-cell communication that play important roles in immune regulation, tissue repair and regeneration. Native EVs can potentially be used for various liver diseases owing to their high biocompatibility, low immunogenicity and tissue permeability and engineered EVs with surface modification or cargo loading could further optimize therapeutic effects. In this review, we firstly introduced the mechanisms and effects of native EVs derived from different cells and tissues to treat liver diseases of different etiologies. Additionally, we summarized the possible methods to facilitate liver targeting and improve cargo-loading efficiency. In the treatment of liver disease, the detailed engineered methods and the latest delivery strategies were also discussed. Finally, we pointed out the limitations and challenges of EVs for future development and applications. We hope that this review could provide a useful reference for the development of EVs and promote the clinical translation.
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Affiliation(s)
- Shuangshuang Jiang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China.
| | - Siyuan Tian
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China.
| | - Punan Wang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China.
| | - Jingyi Liu
- Department of Radiation Oncology, Xijing Hospital, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Keshuai Sun
- Department of Gastroenterology, The Air Force Hospital From Eastern Theater of PLA, Nanjing, 210002, Jiangsu, China
| | - Xia Zhou
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China.
| | - Ying Han
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China.
| | - Yulong Shang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China.
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15
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Tian H, Wang X, Li X, Song W, Mi J, Zou K. Regulation of spermatogonial stem cell differentiation by Sertoli cells-derived exosomes through paracrine and autocrine signaling. J Cell Physiol 2024; 239:e31202. [PMID: 38291718 DOI: 10.1002/jcp.31202] [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: 10/07/2023] [Revised: 12/28/2023] [Accepted: 01/17/2024] [Indexed: 02/01/2024]
Abstract
In the orchestrated environment of the testicular niche, the equilibrium between self-renewal and differentiation of spermatogonial stem cells (SSCs) is meticulously maintained, ensuring a stable stem cell reserve and robust spermatogenesis. Within this milieu, extracellular vesicles, specifically exosomes, have emerged as critical conveyors of intercellular communication. Despite their recognized significance, the implications of testicular exosomes in modulating SSC fate remain incompletely characterized. Given the fundamental support and regulatory influence of Sertoli cells (SCs) on SSCs, we were compelled to explore the role of SC-derived exosomes (SC-EXOs) in the SSC-testicular niche. Our investigation hinged on the hypothesis that SC-EXOs, secreted by SCs from the testes of 5-day-old mice-a developmental juncture marking the onset of SSC differentiation-participate in the regulation of this process. We discovered that exposure to SC-EXOs resulted in an upsurge of PLZF, MVH, and STRA8 expression in SSC cultures, concomitant with a diminution of ID4 and GFRA1 levels. Intriguingly, obstructing exosomal communication in a SC-SSC coculture system with the exosome inhibitor GW4869 attenuated SSC differentiation, suggesting that SC-EXOs may modulate this process via paracrine signaling. Further scrutiny revealed the presence of miR-493-5p within SC-EXOs, which suppresses Gdnf mRNA in SCs to indirectly restrain SSC differentiation through the modulation of GDNF expression-an indication of autocrine regulation. Collectively, our findings illuminate the complex regulatory schema by which SC-EXOs affect SSC differentiation, offering novel perspectives and laying the groundwork for future preclinical and clinical investigations.
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Affiliation(s)
- Hairui Tian
- Germline Stem Cells and Microenvironment Lab, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
- Stem Cell Research and Translation Center, Nanjing Agricultural University, Nanjing, China
| | - Xingju Wang
- Germline Stem Cells and Microenvironment Lab, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
- Stem Cell Research and Translation Center, Nanjing Agricultural University, Nanjing, China
| | - Xiaoxiao Li
- Germline Stem Cells and Microenvironment Lab, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
- Stem Cell Research and Translation Center, Nanjing Agricultural University, Nanjing, China
| | - Weixiang Song
- Germline Stem Cells and Microenvironment Lab, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
- Stem Cell Research and Translation Center, Nanjing Agricultural University, Nanjing, China
| | - Jiaqi Mi
- Department of Cancer Biology, Cancer Center and Beckman Research Institute, City of Hope, Duarte, California, USA
| | - Kang Zou
- Germline Stem Cells and Microenvironment Lab, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
- Stem Cell Research and Translation Center, Nanjing Agricultural University, Nanjing, China
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16
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van Griensven M, Balmayor ER. Extracellular vesicles are key players in mesenchymal stem cells' dual potential to regenerate and modulate the immune system. Adv Drug Deliv Rev 2024; 207:115203. [PMID: 38342242 DOI: 10.1016/j.addr.2024.115203] [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: 06/01/2023] [Revised: 10/15/2023] [Accepted: 02/05/2024] [Indexed: 02/13/2024]
Abstract
MSCs are used for treatment of inflammatory conditions or for regenerative purposes. MSCs are complete cells and allogenic transplantation is in principle possible, but mostly autologous use is preferred. In recent years, it was discovered that cells secrete extracellular vesicles. These are active budded off vesicles that carry a cargo. The cargo can be miRNA, protein, lipids etc. The extracellular vesicles can be transported through the body and fuse with target cells. Thereby, they influence the phenotype and modulate the disease. The extracellular vesicles have, like the MSCs, immunomodulatory or regenerative capacities. This review will focus on those features of extracellular vesicles and discuss their dual role. Besides the immunomodulation, the regeneration will concentrate on bone, cartilage, tendon, vessels and nerves. Current clinical trials with extracellular vesicles for immunomodulation and regeneration that started in the last five years are highlighted as well. In summary, extracellular vesicles have a great potential as disease modulating entity and treatment. Their dual characteristics need to be taken into account and often are both important for having the best effect.
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Affiliation(s)
- Martijn van Griensven
- Department of Cell Biology-Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, 6229 ER Maastricht, the Netherlands; Musculoskeletal Gene Therapy Laboratory, Rehabilitation Medicine Research Center, Mayo Clinic, Rochester, MN 55905, USA.
| | - Elizabeth R Balmayor
- Musculoskeletal Gene Therapy Laboratory, Rehabilitation Medicine Research Center, Mayo Clinic, Rochester, MN 55905, USA; Experimental Orthopaedics and Trauma Surgery, Department of Orthopaedic, Trauma, and Reconstructive Surgery, RWTH Aachen University Hospital, 52074 Aachen, Germany
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17
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Turano E, Scambi I, Bonafede R, Dusi S, Angelini G, Lopez N, Marostica G, Rossi B, Furlan R, Constantin G, Mariotti R, Bonetti B. Extracellular vesicles from adipose mesenchymal stem cells target inflamed lymph nodes in experimental autoimmune encephalomyelitis. Cytotherapy 2024; 26:276-285. [PMID: 38231166 DOI: 10.1016/j.jcyt.2023.12.007] [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: 05/07/2023] [Revised: 11/29/2023] [Accepted: 12/26/2023] [Indexed: 01/18/2024]
Abstract
BACKGROUND AIMS Adipose mesenchymal stem cells (ASCs) represent a promising therapeutic approach in inflammatory neurological disorders, including multiple sclerosis (MS). Recent lines of evidence indicate that most biological activities of ASCs are mediated by the delivery of soluble factors enclosed in extracellular vesicles (EVs). Indeed, we have previously demonstrated that small EVs derived from ASCs (ASC-EVs) ameliorate experimental autoimmune encephalomyelitis (EAE), a murine model of MS. The precise mechanisms and molecular/cellular target of EVs during EAE are still unknown. METHODS To investigate the homing of ASC-EVs, we intravenously injected small EVs loaded with ultra-small superparamagnetic iron oxide nanoparticles (USPIO) at disease onset in EAE-induced C57Bl/6J mice. Histochemical analysis and transmission electron microscopy were carried out 48 h after EV treatment. Moreover, to assess the cellular target of EVs, flow cytometry on cells extracted ex vivo from EAE mouse lymph nodes was performed. RESULTS Histochemical and ultrastructural analysis showed the presence of labeled EVs in lymph nodes but not in lungs and spinal cord of EAE injected mice. Moreover, we identified the cellular target of EVs in EAE lymph nodes by flow cytometry: ASC-EVs were preferentially located in macrophages, with a consistent amount also noted in dendritic cells and CD4+ T lymphocytes. CONCLUSIONS This represents the first direct evidence of the privileged localization of ASC-EVs in draining lymph nodes of EAE after systemic injection. These data provide prominent information on the distribution, uptake and retention of ASC-EVs, which may help in the development of EV-based therapy in MS.
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Affiliation(s)
- Ermanna Turano
- Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
| | - Ilaria Scambi
- Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
| | - Roberta Bonafede
- Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
| | - Silvia Dusi
- Division of General Pathology, Department of Medicine, University of Verona, Verona, Italy
| | - Gabriele Angelini
- Division of General Pathology, Department of Medicine, University of Verona, Verona, Italy
| | - Nicola Lopez
- Division of General Pathology, Department of Medicine, University of Verona, Verona, Italy
| | - Giulia Marostica
- Clinical Neuroimmunology Unit, Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy
| | - Barbara Rossi
- Division of General Pathology, Department of Medicine, University of Verona, Verona, Italy
| | - Roberto Furlan
- Clinical Neuroimmunology Unit, Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy
| | - Gabriela Constantin
- Division of General Pathology, Department of Medicine, University of Verona, Verona, Italy
| | - Raffaella Mariotti
- Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
| | - Bruno Bonetti
- Neurology Unit, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy.
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Chaaban A, Salman Z, Karam L, Kobeissy PH, Ibrahim JN. Updates on the role of epigenetics in familial mediterranean fever (FMF). Orphanet J Rare Dis 2024; 19:90. [PMID: 38409042 PMCID: PMC10898143 DOI: 10.1186/s13023-024-03098-w] [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: 12/13/2023] [Accepted: 02/21/2024] [Indexed: 02/28/2024] Open
Abstract
Familial Mediterranean Fever (FMF) is an autosomal recessive autoinflammatory disease caused by mutations in the MEFV (MEditerranean FeVer) gene that affects people originating from the Mediterranean Sea. The high variability in severity and clinical manifestations observed not only between ethnic groups but also between and within families is mainly related to MEFV allelic heterogeneity and to some modifying genes. In addition to the genetic factors underlying FMF, the environment plays a significant role in the development and manifestation of this disease through various epigenetic mechanisms, including DNA methylation, histone modification, and noncoding RNAs. Indeed, epigenetic events have been identified as an important pathophysiological determinant of FMF and co-factors shaping the clinical picture and outcome of the disease. Therefore, it is essential to better understand the contribution of epigenetic factors to autoinflammatory diseases, namely, FMF, to improve disease prognosis and potentially develop effective targeted therapies. In this review, we highlight the latest updates on the role of epigenetics in FMF.
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Affiliation(s)
- Ahlam Chaaban
- Department of Natural Sciences, School of Arts and Sciences, Lebanese American University (LAU), Beirut, Lebanon
| | - Zeina Salman
- Department of Natural Sciences, School of Arts and Sciences, Lebanese American University (LAU), Beirut, Lebanon
| | - Louna Karam
- Department of Natural Sciences, School of Arts and Sciences, Lebanese American University (LAU), Beirut, Lebanon
| | - Philippe Hussein Kobeissy
- Department of Natural Sciences, School of Arts and Sciences, Lebanese American University (LAU), Beirut, Lebanon.
| | - José-Noel Ibrahim
- Department of Natural Sciences, School of Arts and Sciences, Lebanese American University (LAU), Beirut, Lebanon.
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19
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Li X, Ji LJ, Feng KD, Huang H, Liang MR, Cheng SJ, Meng XD. Emerging role of exosomes in ulcerative colitis: Targeting NOD-like receptor family pyrin domain containing 3 inflammasome. World J Gastroenterol 2024; 30:527-541. [PMID: 38463022 PMCID: PMC10921143 DOI: 10.3748/wjg.v30.i6.527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 11/21/2023] [Accepted: 01/09/2024] [Indexed: 02/05/2024] Open
Abstract
Ulcerative colitis (UC) is a chronic recurrent inflammatory bowel disease. Despite ongoing advances in our understanding of UC, its pathogenesis is yet unelucidated, underscoring the urgent need for novel treatment strategies for patients with UC. Exosomes are nanoscale membrane particles that mediate intercellular communication by carrying various bioactive molecules, such as proteins, RNAs, DNA, and metabolites. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a cytosolic tripartite protein complex whose activation induces the maturation and secretion of proinflammatory cytokines interleukin-1β (IL-1β) and IL-18, triggering the inflammatory response to a pathogenic agent or injury. Growing evidence suggests that exosomes are new modulators of the NLRP3 inflammasome, with vital roles in the pathological process of UC. Here, recent evidence is reviewed on the role of exosomes and NLRP3 inflammasome in UC. First, the dual role of exosomes on NLRP3 inflammasome and the effect of NLRP3 inflammasome on exosome secretion are summarized. Finally, an outlook on the directions of exosome-NLRP3 inflammasome crosstalk research in the context of UC is proposed and areas of further research on this topic are highlighted.
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Affiliation(s)
- Xin Li
- School of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, Guizhou Province, China
| | - Li-Jiang Ji
- Department of Anorectal Surgery, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu 215500, Jiangsu Province, China
| | - Kai-Di Feng
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Hua Huang
- Department of Anorectal Surgery, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu 215500, Jiangsu Province, China
| | - Mei-Rou Liang
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Shi-Jin Cheng
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Xiu-Dong Meng
- School of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, Guizhou Province, China
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Miron RJ, Estrin NE, Sculean A, Zhang Y. Understanding exosomes: Part 2-Emerging leaders in regenerative medicine. Periodontol 2000 2024; 94:257-414. [PMID: 38591622 DOI: 10.1111/prd.12561] [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: 02/04/2024] [Revised: 02/16/2024] [Accepted: 02/21/2024] [Indexed: 04/10/2024]
Abstract
Exosomes are the smallest subset of extracellular signaling vesicles secreted by most cells with the ability to communicate with other tissues and cell types over long distances. Their use in regenerative medicine has gained tremendous momentum recently due to their ability to be utilized as therapeutic options for a wide array of diseases/conditions. Over 5000 publications are currently being published yearly on this topic, and this number is only expected to dramatically increase as novel therapeutic strategies continue to be developed. Today exosomes have been applied in numerous contexts including neurodegenerative disorders (Alzheimer's disease, central nervous system, depression, multiple sclerosis, Parkinson's disease, post-traumatic stress disorders, traumatic brain injury, peripheral nerve injury), damaged organs (heart, kidney, liver, stroke, myocardial infarctions, myocardial infarctions, ovaries), degenerative processes (atherosclerosis, diabetes, hematology disorders, musculoskeletal degeneration, osteoradionecrosis, respiratory disease), infectious diseases (COVID-19, hepatitis), regenerative procedures (antiaging, bone regeneration, cartilage/joint regeneration, osteoarthritis, cutaneous wounds, dental regeneration, dermatology/skin regeneration, erectile dysfunction, hair regrowth, intervertebral disc repair, spinal cord injury, vascular regeneration), and cancer therapy (breast, colorectal, gastric cancer and osteosarcomas), immune function (allergy, autoimmune disorders, immune regulation, inflammatory diseases, lupus, rheumatoid arthritis). This scoping review is a first of its kind aimed at summarizing the extensive regenerative potential of exosomes over a broad range of diseases and disorders.
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Affiliation(s)
- Richard J Miron
- Department of Periodontology, University of Bern, Bern, Switzerland
| | - Nathan E Estrin
- Advanced PRF Education, Venice, Florida, USA
- School of Dental Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, Florida, USA
| | - Anton Sculean
- Department of Periodontology, University of Bern, Bern, Switzerland
| | - Yufeng Zhang
- Department of Oral Implantology, University of Wuhan, Wuhan, China
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21
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Zhu L, Wang Q, Guo M, Fang H, Li T, Zhu Y, Jiang H, Xiao P, Hu M. Mesenchymal Stem Cell-Derived Exosomes in Various Chronic Liver Diseases: Hype or Hope? J Inflamm Res 2024; 17:171-189. [PMID: 38223423 PMCID: PMC10788055 DOI: 10.2147/jir.s439974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 12/27/2023] [Indexed: 01/16/2024] Open
Abstract
Chronic liver conditions are associated with high mortality rates and have a large adverse effect on human well-being as well as a significant financial burden. Currently, the only effective treatment available for the effects of liver failure and cirrhosis resulting from the progression of several chronic liver diseases is liver transplantation carried out at the original location. This implies that developing novel and effective treatments is imperative. Regenerative medicine has long been associated with stem cell therapy. Mesenchymal stem cells (MSCs), a type of cell with great differentiation potential, have become the preferred source for stem cell therapy. According to recent studies, MSCs' paracrine products-rather than their capacity for differentiation-play a significant therapeutic effect. MSC exosomes, a type of extracellular vesicle (MSC-EV), came into view as the paracrine substances of MSCs. According to research, MSC exosomes can maintain tissue homeostasis, which is necessary for healthy tissue function. All tissues contain them, and they take part in a variety of biological activities that support cellular activity and tissue regeneration in order to preserve tissue homeostasis. The outcomes support the use of MSCs and the exosomes they produce as a therapeutic option for a range of diseases. This review provides a brief overview of the source of MSC-EVs and outlines their physiological roles and biochemical capabilities. The elucidation of the role of MSC-EVs in the recovery and repair of hepatic tissues, as well as their contribution to maintaining tissue homeostasis, is discussed in relation to different chronic liver diseases. This review aims to provide new insights into the unique roles that MSC-EVs play in the treatment of chronic liver diseases.
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Affiliation(s)
- Lujian Zhu
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China
| | - Qin Wang
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China
| | - Maodong Guo
- Department of Gastroenterology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China
| | - Hao Fang
- Department of Traumatology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China
| | - Ting Li
- Department of Emergency Medicine, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
| | - Yin Zhu
- Department of Infectious Diseases, Taizhou Enze Medical Center (Group), Enze Hospital, Taizhou, People’s Republic of China
| | - Huimian Jiang
- Department of Infectious Diseases, the First Affiliated Hospital of Ningbo University, Ningbo, People’s Republic of China
| | - Peiguang Xiao
- Department of Gastroenterology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China
| | - Minli Hu
- Department of Gastroenterology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China
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22
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Han H, Chen BT, Liu Y, Wang Y, Xing L, Wang H, Zhou TJ, Jiang HL. Engineered stem cell-based strategy: A new paradigm of next-generation stem cell product in regenerative medicine. J Control Release 2024; 365:981-1003. [PMID: 38123072 DOI: 10.1016/j.jconrel.2023.12.024] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 12/06/2023] [Accepted: 12/16/2023] [Indexed: 12/23/2023]
Abstract
Stem cells have garnered significant attention in regenerative medicine owing to their abilities of multi-directional differentiation and self-renewal. Despite these encouraging results, the market for stem cell products yields limited, which is largely due to the challenges faced to the safety and viability of stem cells in vivo. Besides, the fate of cells re-infusion into the body unknown is also a major obstacle to stem cell therapy. Actually, both the functional protection and the fate tracking of stem cells are essential in tissue homeostasis, repair, and regeneration. Recent studies have utilized cell engineering techniques to modify stem cells for enhancing their treatment efficiency or imparting them with novel biological capabilities, in which advances demonstrate the immense potential of engineered cell therapy. In this review, we proposed that the "engineered stem cells" are expected to represent the next generation of stem cell therapies and reviewed recent progress in this area. We also discussed potential applications of engineered stem cells and highlighted the most common challenges that must be addressed. Overall, this review has important guiding significance for the future design of new paradigms of stem cell products to improve their therapeutic efficacy.
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Affiliation(s)
- Han Han
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
| | - Bi-Te Chen
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
| | - Yang Liu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
| | - Yi Wang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
| | - Lei Xing
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China; College of Pharmacy, Yanbian University, Yanji 133002, China
| | - Hui Wang
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Tian-Jiao Zhou
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China.
| | - Hu-Lin Jiang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China; College of Pharmacy, Yanbian University, Yanji 133002, China.
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23
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Wang Y, Piao C, Liu T, Lu X, Ma Y, Zhang J, Liu G, Wang H. Effects of the exosomes of adipose-derived mesenchymal stem cells on apoptosis and pyroptosis of injured liver in miniature pigs. Biomed Pharmacother 2023; 169:115873. [PMID: 37979374 DOI: 10.1016/j.biopha.2023.115873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 11/07/2023] [Accepted: 11/07/2023] [Indexed: 11/20/2023] Open
Abstract
Hepatic ischemia-reperfusion injury (HIRI) is a complication of hepatectomy that affects the functional recovery of the remnant liver, which has been demonstrated to be associated with pyroptosis and apoptosis. Mesenchymal stem cells (MSCs) can protect against HIRI in rodents. Paracrine mechanisms of MSCs indicated that MSCs-derived exosomes (MSCs-exo) are one of the important components within the paracrine substances of MSCs. Moreover, miniature pigs are ideal experimental animals in comparative medicine compared to rodents. Accordingly, this study aimed to investigate whether hepatectomy combined with HIRI in miniature pigs would induce pyroptosis and whether adipose-derived MSCs (ADSCs) and their exosomes (ADSCs-exo) could positively mitigate apoptosis and pyroptosis. The study also compared the differences in the effects and the role of ADSCs and ADSCs-exo in pyroptosis and apoptosis. Results showed that severe ultrastructure damage occurred in liver tissues and systemic inflammatory response was induced after surgery, with TLR4/MyD88/NFκB/HMGB1 activation, NLRP3-ASC-Caspase1 complex generation, GSDMD revitalization, and IL-1β, IL-18, and LDH elevation in the serum. Furthermore, expression of Fas-Fasl-Caspase8 and CytC-APAF1-Caspase9 was increased in the liver. The ADSCs or ADSCs-exo intervention could inhibit the expression of these indicators and improve the ultrastructural pathological changes and systemic inflammatory response. There was no significant difference between the two intervention groups. In summary, ADSCs-exo could effectively inhibit pyroptosis and apoptosis similar to ADSCs and may be considered a safe and effective cell-free therapy to protect against liver injury.
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Affiliation(s)
- Yue Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Chenxi Piao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Tao Liu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Xiangyu Lu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Yajun Ma
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Jiantao Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Guodong Liu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Hongbin Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China.
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24
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Deng C, Hu J, He L, Ge L, Wu N, Xie M, Yang X, Wu C, Liu Q. Daucosterol combined with umbilical cord mesenchymal stem cell-derived exosomes can alleviate liver damage in liver failure mice by regulating the IL-6/STAT3 signaling pathway. Cancer Biol Ther 2023; 24:2184150. [PMID: 36919480 PMCID: PMC10026879 DOI: 10.1080/15384047.2023.2184150] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023] Open
Abstract
Daucosterol is a phytosterol glycoside with hepatoprotective properties. The objective of the present study was to confirm the role of daucosterol in liver failure. Exosomes were isolated from primary mouse umbilical cord mesenchymal stem cells (UCMSCs). A liver failure mouse model was generated by injecting lipopolysaccharide/D-galactosamine. Mice were treated with exosomes alone or in combination with daucosterol (5, 10, or 20 mg/kg). Liver tissue damage was examined by hematoxylin-eosin, Masson's trichrome, and TUNEL staining. The levels of genes, proteins, and inflammatory factors were determined using real-time qPCR, western blotting, and enzyme-linked immunosorbent assay, respectively. Compared with normal mice, we noted severe damage, fibrosis, and apoptosis in the liver tissues of liver failure-induced mice. UCMSC-derived exosomes effectively alleviated hepatic damage in the mouse model. Compared with exosome treatment alone, exosomes combined with daucosterol significantly and dose-dependently reduced pathological changes in model mice. Exosome treatment alone or combined with daucosterol also markedly decreased the liver index and reduced levels of alanine aminotransferase, aspartate aminotransferase, tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 in model mice. Exosome treatment alone or combined with daucosterol suppressed mRNA expression levels of IL-6 and signal transducer and activator of transcription (STAT3) and STAT3 protein expression in model mice. Our findings revealed that treatment with daucosterol combined with UCMSC-derived exosomes was superior to exosomes alone for alleviating hepatic damage in mice with liver failure by regulating the IL-6/STAT3 signaling pathway. Accordingly, daucosterol combined with UCMSC-derived exosomes may be a prospective treatment strategy for liver failure.
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Affiliation(s)
- Changqing Deng
- Department of Gastroenterology, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, P.R. China
| | - Jia Hu
- Department of Gastroenterology, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, P.R. China
| | - Ling He
- Department of Gastroenterology, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, P.R. China
| | - Laian Ge
- Department of Gastroenterology, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, P.R. China
| | - Na Wu
- Department of Gastroenterology, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, P.R. China
| | - Mingjun Xie
- Department of Gastroenterology, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, P.R. China
| | - Xiaojuan Yang
- Department of Gastroenterology, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, P.R. China
| | - Chuncheng Wu
- Department of Gastroenterology, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, P.R. China
| | - Qin Liu
- Department of Anesthesiology, Second Affiliated Hospital of Nanchang University, Nanchang, P.R. China
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25
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Zheng L, Gong H, Zhang J, Guo L, Zhai Z, Xia S, Hu Z, Chang J, Jiang Y, Huang X, Ge J, Zhang B, Yan M. Strategies to improve the therapeutic efficacy of mesenchymal stem cell-derived extracellular vesicle (MSC-EV): a promising cell-free therapy for liver disease. Front Bioeng Biotechnol 2023; 11:1322514. [PMID: 38155924 PMCID: PMC10753838 DOI: 10.3389/fbioe.2023.1322514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 11/29/2023] [Indexed: 12/30/2023] Open
Abstract
Liver disease has emerged as a significant worldwide health challenge due to its diverse causative factors and therapeutic complexities. The majority of liver diseases ultimately progress to end-stage liver disease and liver transplantation remains the only effective therapy with the limitations of donor organ shortage, lifelong immunosuppressants and expensive treatment costs. Numerous pre-clinical studies have revealed that extracellular vesicles released by mesenchymal stem cells (MSC-EV) exhibited considerable potential in treating liver diseases. Although natural MSC-EV has many potential advantages, some characteristics of MSC-EV, such as heterogeneity, uneven therapeutic effect, and rapid clearance in vivo constrain its clinical translation. In recent years, researchers have explored plenty of ways to improve the therapeutic efficacy and rotation rate of MSC-EV in the treatment of liver disease. In this review, we summarized current strategies to enhance the therapeutic potency of MSC-EV, mainly including optimization culture conditions in MSC or modifications of MSC-EV, aiming to facilitate the development and clinical application of MSC-EV in treating liver disease.
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Affiliation(s)
- Lijuan Zheng
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Hui Gong
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Jing Zhang
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China
| | - Linna Guo
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Zhuofan Zhai
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Shuang Xia
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Zhiyu Hu
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Jing Chang
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Yizhu Jiang
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Xinran Huang
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Jingyi Ge
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Bikui Zhang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Miao Yan
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
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26
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Shen L, Lu K, Chen Z, Zhu Y, Zhang C, Zhang L. Pre-treatment with galectin-1 attenuates lipopolysaccharide-induced myocarditis by regulating the Nrf2 pathway. Eur J Histochem 2023; 67:3816. [PMID: 38058290 PMCID: PMC10773196 DOI: 10.4081/ejh.2023.3816] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 11/20/2023] [Indexed: 12/08/2023] Open
Abstract
Galectin-1 (Gal-1), a member of a highly conserved family of animal lectins, plays a crucial role in controlling inflammation and neovascularization. However, the potential role of Gal-1 in preventing myocarditis remains uncertain. We aimed to explore the functions and mechanisms of Gal-1 in preventing myocarditis. In vivo, C57/BL6 mice were pre-treated with or without Gal-1 and then exposed to lipopolysaccharide (LPS) to induce myocarditis. Subsequently, cardiac function, histopathology, inflammation, oxidative stress, and apoptosis of myocardial tissues were detected. Following this, qRT-PCR and Western blotting were applied to measure iNOS, COX2, TXNIP, NLRP3 and Caspase-1 p10 expressions. In vitro, H9c2 cells pre-treated with different doses of Gal-1 were stimulated by LPS to induce myocarditis models. CCK8, flow cytometry and reactive oxygen species (ROS) assay were then employed to estimate cell viability, apoptosis and oxidative stress. Furthermore, Nrf2 and HO-1 protein expressions were evaluated by Western blotting in vivo and in vitro. The results showed that in vivo, Gal-1 pre-treatment not only moderately improved cardiac function and cardiomyocyte apoptosis, but also ameliorated myocardial inflammation and oxidative damage in mice with myocarditis. Furthermore, Gal-1 inhibited TXNIP-NLRP3 inflammasome activation. In vitro, Gal-1 pre-treatment prevented LPS-induced apoptosis, cell viability decrease and ROS generation. Notably, Gal-1 elevated HO-1, total Nrf2 and nuclear Nrf2 protein expressions both in vivo and in vitro. In conclusion, pre-treatment with Gal-1 exhibited cardioprotective effects in myocarditis via anti-inflammatory and antioxidant functions, and the mechanism may relate to the Nrf2 pathway, which offered new solid evidence for the use of Gal-1 in preventing myocarditis.
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Affiliation(s)
- Liying Shen
- Department of Cardiology, Huzhou Central Hospital, Huzhou, Zhejiang.
| | - Kongjie Lu
- Department of Cardiology, Huzhou Central Hospital, Huzhou, Zhejiang.
| | - Zhenfeng Chen
- Department of Cardiology, Huzhou Central Hospital, Huzhou, Zhejiang.
| | - Yingwei Zhu
- Department of Cardiology, Huzhou Central Hospital, Huzhou, Zhejiang.
| | - Cong Zhang
- Department of Cardiology, Huzhou Central Hospital, Huzhou, Zhejiang.
| | - Li Zhang
- Department of Cardiology, Huzhou Central Hospital, Huzhou, Zhejiang.
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Xie W, Luo T, Ma Z, Xue S, Jia X, Yang T, Song Z. Tumor Necrosis Factor Alpha Preconditioned Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles Enhance the Inhibition of Necroptosis of Acinar cells in Severe Acute Pancreatitis. Tissue Eng Part A 2023; 29:607-619. [PMID: 37565286 DOI: 10.1089/ten.tea.2023.0139] [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] [Indexed: 08/12/2023] Open
Abstract
Severe acute pancreatitis (SAP) is a common abdominal emergency with a high mortality rate and a lack of effective therapeutic options. Although mesenchymal stem cell (MSC) transplantation is a potential treatment for SAP, the mechanism remains unclear. It has been suggested that MSCs may act mainly through paracrine effects; therefore, we aimed to demonstrate the therapeutic efficacy of extracellular vesicles (EVs) derived from human umbilical cord mesenchymal stem cells (UCMSCs) for SAP. Na-taurocholate was used to induce a rat SAP model through retrograde injection into the common biliopancreatic duct. After 72 h of EVs transplantation, pancreatic pathological damage was alleviated, along with a decrease in serum amylase activity and pro-inflammatory cytokine levels. Interestingly, when UCMSCs were preconditioned with 10 ng/mL tumor necrosis factor alpha (TNF-α) for 48 h, the obtained EVs (named TNF-α-EVs) performed an enhanced efficacy. Furthermore, both animal and cellular experiments showed that TNF-α-EVs alleviated the necroptosis of acinar cells of SAP through RIPK3/MLKL axis. In conclusion, our study demonstrated that TNF-α-EVs were able to enhance the therapeutic effect on SAP by inhibiting necroptosis compared to normal EVs. This study heralds that TNF-α-EVs may be a promising therapeutic approach for SAP in the future.
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Affiliation(s)
- Wangcheng Xie
- Department of General Surgery and Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
- Department of Hepatic-Biliary-Pancreatic Surgery, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Tingyi Luo
- Department of General Surgery and Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
- Department of Hepatic-Biliary-Pancreatic Surgery, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Zhilong Ma
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shaobo Xue
- Central Laboratory, Clinical Medicine Scientific and Technical Innovation Park, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xuyang Jia
- Department of Metabolic Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Tingsong Yang
- Department of General Surgery and Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Zhenshun Song
- Department of Hepatic-Biliary-Pancreatic Surgery, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China
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28
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Didamoony MA, Soubh AA, Atwa AM, Ahmed LA. Innovative preconditioning strategies for improving the therapeutic efficacy of extracellular vesicles derived from mesenchymal stem cells in gastrointestinal diseases. Inflammopharmacology 2023; 31:2973-2993. [PMID: 37874430 PMCID: PMC10692273 DOI: 10.1007/s10787-023-01350-6] [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: 08/28/2023] [Accepted: 09/20/2023] [Indexed: 10/25/2023]
Abstract
Gastrointestinal (GI) diseases have become a global health issue and an economic burden due to their wide distribution, late prognosis, and the inefficacy of recent available medications. Therefore, it is crucial to search for new strategies for their management. In the recent decades, mesenchymal stem cells (MSCs) therapy has attracted attention as a viable option for treating a myriad of GI disorders such as hepatic fibrosis (HF), ulcerative colitis (UC), acute liver injury (ALI), and non-alcoholic fatty liver disease (NAFLD) due to their regenerative and paracrine properties. Importantly, recent studies have shown that MSC-derived extracellular vesicles (MSC-EVs) are responsible for most of the therapeutic effects of MSCs. In addition, EVs have revealed several benefits over their parent MSCs, such as being less immunogenic, having a lower risk of tumour formation, being able to cross biological barriers, and being easier to store. MSC-EVs exhibited regenerative, anti-oxidant, anti-inflammatory, anti-apoptotic, and anti-fibrotic effects in different experimental models of GI diseases. However, a key issue with their clinical application is the maintenance of their stability and efficacy following in vivo transplantation. Preconditioning of MSC-EVs or their parent cells is one of the novel methods used to improve their effectiveness and stability. Herein, we discuss the application of MSC-EVs in several GI disorders taking into account their mechanism of action. We also summarise the challenges and restrictions that need to be overcome to promote their clinical application in the treatment of various GI diseases as well as the recent developments to improve their effectiveness. A representation of the innovative preconditioning techniques that have been suggested for improving the therapeutic efficacy of MSC-EVs in GI diseases. The pathological conditions in various GI disorders (ALI, UC, HF and NAFLD) create a harsh environment for EVs and their parents, increasing the risk of apoptosis and senescence of MSCs and thereby diminishing MSC-EVs yield and restricting their large-scale applications. Preconditioning with pharmacological agents or biological mediators can improve the therapeutic efficacy of MSC-EVs through their adaption to the lethal environment to which they are subjected. This can result in establishment of a more conducive environment and activation of numerous vital trajectories that act to improve the immunomodulatory, reparative and regenerative activities of the derived EVs, as a part of MSCs paracrine system. ALI, acute liver injury; GI diseases, gastrointestinal diseases; HF, hepatic fibrosis; HSP, heat shock protein; miRNA, microRNA; mRNA, messenger RNA; MSC-EVs, mesenchymal stem cell-derived extracellular vesicles; NAFLD, non-alcoholic fatty liver disease; UC, ulcerative colitis.
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Affiliation(s)
- Manar A Didamoony
- Faculty of Pharmacy, Pharmacology and Toxicology Department, Egyptian Russian University, Cairo, 11829, Egypt.
| | - Ayman A Soubh
- Faculty of Pharmacy, Pharmacology and Toxicology Department, Ahram Canadian University, 4th Industrial Zone, Banks Complex, 6th of October City, Giza, 12451, Egypt
| | - Ahmed M Atwa
- Faculty of Pharmacy, Pharmacology and Toxicology Department, Egyptian Russian University, Cairo, 11829, Egypt
| | - Lamiaa A Ahmed
- Faculty of Pharmacy, Pharmacology and Toxicology Department, Cairo University, Cairo, 11562, Egypt.
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29
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Zhang R, Lian T, Liu J, Du F, Chen Z, Zhang R, Wang Q. Dendritic Cell-Derived Exosomes Stimulated by Treponema pallidum Induce Endothelial Cell Inflammatory Response through the TLR4/MyD88/NF-κB Signaling Pathway. ACS Infect Dis 2023; 9:2299-2305. [PMID: 37843010 DOI: 10.1021/acsinfecdis.3c00348] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2023]
Abstract
Exosomes have been implicated in vascular damage in recent research. The influence of dendritic cell-derived exosomes generated by Treponema pallidum (T. pallidum) on the inflammatory process of vascular cells was examined in this study. Human umbilical vein endothelial cells (HUVECs) were cocultured with exosomes isolated from dendritic cells induced by T. pallidum. Western blot and reverse transcription-quantitative real-time polymerase chain reaction were used to assess toll-like receptor 4 (TLR4) expression and the quantity of proinflammatory cytokines. The findings showed that the expression of TLR4 was considerably upregulated, and TLR4 knockdown dramatically reduced interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) production in exosome-treated HUVECs. Furthermore, TLR4 silencing reduced myeloid differentiation primary response protein 88 (MyD88) and nuclear factor kappa light chain enhancer of activated B cells (NF-κB) levels in exosome-treated HUVECs. Additionally, suppression of the activity of NF-κB with BAY11-7082, an NF-κB inhibitor, also reduced the exosome-treated inflammatory response. Our results suggested that dendritic cell-derived exosomes stimulated by T. pallidum induced endothelial cell inflammation, and the TLR4/MyD88/NF-κB signal axis was activated, significantly increasing IL-1β, IL-6, and TNF-α expression. This may have a significant role in the vascular inflammatory response in syphilis, which would contribute to the understanding of the pathogenesis of syphilis and the host immunological response to T. pallidum.
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Affiliation(s)
- Ruihua Zhang
- Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China
| | - Tingting Lian
- Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China
| | - Jinquan Liu
- Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China
| | - Fangzhi Du
- Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China
| | - Zuoxi Chen
- Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China
| | - RuiLi Zhang
- Department of Dermatology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China
| | - QianQiu Wang
- Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China
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30
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Dehnavi S, Sadeghi M, Tavakol Afshari J, Mohammadi M. Interactions of mesenchymal stromal/stem cells and immune cells following MSC-based therapeutic approaches in rheumatoid arthritis. Cell Immunol 2023; 393-394:104771. [PMID: 37783061 DOI: 10.1016/j.cellimm.2023.104771] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 09/21/2023] [Accepted: 09/21/2023] [Indexed: 10/04/2023]
Abstract
Rheumatoid arthritis (RA) is considered to be a degenerative and progressive autoimmune disorder. Although several medicinal regimens are used to treat RA, potential adverse events such as metabolic disorders and increased risk of infection, as well as drug resistance in some patients, make it essential to find an effective and safe therapeutic approach. Mesenchymal stromal/stem cells (MSCs) are a group of non-hematopoietic stromal cells with immunomodulatory and inhibitory potential. These cells exert their regulatory properties through direct cell-to-cell interactions and paracrine effects on various immune and non-immune cells. As conventional therapeutic approaches for RA are limited due to their side effects, and some patients became refractory to the treatment, MSCs are considered as a promising alternative treatment for RA. In this review, we introduced various experimental and clinical studies conducted to evaluate the therapeutic effects of MSCs on animal models of arthritis and RA patients. Then, possible modulatory and suppressive effects of MSCs on different innate and adaptive immune cells, including dendritic cells, neutrophils, macrophages, natural killer cells, B lymphocytes, and various subtypes of T cells, were categorized and summarized. Finally, limitations and future considerations for the efficient application of MSCs as a therapeutic approach in RA patients were presented.
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Affiliation(s)
- Sajad Dehnavi
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahvash Sadeghi
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | | | - Mojgan Mohammadi
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Chen Y, Yang L, Li X. Advances in Mesenchymal stem cells regulating macrophage polarization and treatment of sepsis-induced liver injury. Front Immunol 2023; 14:1238972. [PMID: 37954578 PMCID: PMC10634316 DOI: 10.3389/fimmu.2023.1238972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Accepted: 10/17/2023] [Indexed: 11/14/2023] Open
Abstract
Sepsis is a syndrome of dysregulated host response caused by infection, which leads to life-threatening organ dysfunction. It is a familiar reason of death in critically ill patients. Liver injury frequently occurs in septic patients, yet the development of targeted and effective treatment strategies remains a pressing challenge. Macrophages are essential parts of immunity system. M1 macrophages drive inflammation, whereas M2 macrophages possess anti-inflammatory properties and contribute to tissue repair processes. Mesenchymal stem cells (MSCs), known for their remarkable attributes including homing capabilities, immunomodulation, anti-inflammatory effects, and tissue regeneration potential, hold promise in enhancing the prognosis of sepsis-induced liver injury by harmonizing the delicate balance of M1/M2 macrophage polarization. This review discusses the mechanisms by which MSCs regulate macrophage polarization, alongside the signaling pathways involved, providing an idea for innovative directions in the treatment of sepsis-induced liver injury.
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Affiliation(s)
- Yuhao Chen
- Department of Emergency Medicine, West China Second Hospital of Sichuan University, Sichuan, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Sichuan, China
| | - Lihong Yang
- Department of Emergency Medicine, West China Second Hospital of Sichuan University, Sichuan, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Sichuan, China
| | - Xihong Li
- Department of Emergency Medicine, West China Second Hospital of Sichuan University, Sichuan, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Sichuan, China
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32
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Leszczynska A, Stoess C, Sung H, Povero D, Eguchi A, Feldstein A. Extracellular Vesicles as Therapeutic and Diagnostic Tools for Chronic Liver Diseases. Biomedicines 2023; 11:2808. [PMID: 37893181 PMCID: PMC10604241 DOI: 10.3390/biomedicines11102808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 10/12/2023] [Accepted: 10/12/2023] [Indexed: 10/29/2023] Open
Abstract
Chronic liver diseases can lead to fibrotic changes that may progress to the development of cirrhosis, which poses a significant risk for morbidity and increased mortality rates. Metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), and viral hepatitis are prevalent liver diseases that may lead to cirrhosis. The advanced stages of cirrhosis can be further complicated by cancer development or end-stage liver disease and liver failure. Hence, early detection and diagnosis of liver fibrosis is crucial for preventing the progression to cirrhosis and improving patient outcomes. Traditionally, invasive liver biopsy has been considered the gold standard for diagnosing and staging liver fibrosis. In the last decade, research has focused on non-invasive methods, known as liquid biopsies, which involve the identification of disease-specific biomarkers in human fluids, such as blood. Among these alternative approaches, extracellular vesicles (EVs) have emerged as promising diagnostic and therapeutic tools for various diseases, including chronic liver diseases. EVs are released from stressed or damaged cells and can be isolated and quantified. Moreover, EVs facilitate cell-to-cell communication by transporting various cargo, and they have shown the potential to reduce the expression of profibrogenic markers, making them appealing tools for novel anti-fibrotic treatments. This review focuses on the impact of EVs in chronic liver diseases and exploring their potential applications in innovative therapeutic and diagnostic approaches.
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Affiliation(s)
| | - Christian Stoess
- Department of Pediatrics, University of California, San Diego, CA 92037, USA; (A.L.)
- Department of Surgery, TUM School of Medicine, Technical University of Munich, 81675 Munich, Germany
| | - Hana Sung
- Department of Pediatrics, University of California, San Diego, CA 92037, USA; (A.L.)
| | - Davide Povero
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA;
| | - Akiko Eguchi
- Biobank Center, Mie University Hospital, Tsu 514-8507, Japan;
| | - Ariel Feldstein
- Department of Pediatrics, University of California, San Diego, CA 92037, USA; (A.L.)
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Sui J, Dai F, Shi J, Zhou C. Ubiquitin-specific peptidase 25 exacerbated osteoarthritis progression through facilitating TXNIP ubiquitination and NLRP3 inflammasome activation. J Orthop Surg Res 2023; 18:762. [PMID: 37814350 PMCID: PMC10561454 DOI: 10.1186/s13018-023-04083-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 08/06/2023] [Indexed: 10/11/2023] Open
Abstract
Several members of the ubiquitin-specific proteases (USPs) family have been revealed to regulate the progression of osteoarthritis (OA). The current study aimed to investigate the role and the underlying mechanism of USP25 in IL-1β-induced chondrocytes and OA rat model. It was discovered that IL-1β stimulation upregulated USP25, increased ROS level, and suppressed cell viability in rat chondrocytes. Besides, USP25 knockdown alleviated IL-1β-induced injury by decreasing ROS level, attenuating pyroptosis, and downregulating the expression of IL-18, NLRP3, GSDMD-N, active caspase-1, MMP-3, and MMP-13. Furthermore, we discovered that USP25 affected the IL-1β-induced injury in chondrocytes in a ROS-dependent manner. Moreover, USP25 was revealed to interact with TXNIP, and USP25 knockdown increased the ubiquitination of TXNIP. The pro-OA effect of USP25 abundance could be overturned by TXNIP suppression in IL-1β-induced chondrocytes. Finally, in vivo experiment results showed that USP25 inhibition alleviated cartilage destruction in OA rats. In conclusion, we demonstrated that USP25 stimulated the overproduction of ROS to activate the NLRP3 inflammasome via regulating TXNIP, resulting in increased pyroptosis and inflammation in OA.
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Affiliation(s)
- Jie Sui
- Department of Orthopedics, 904 Hospital of PLA Joint Logistic Support Force, 55 Heping North Road, Changzhou, 213003, Jiangsu Province, China
| | - Fei Dai
- Department of Orthopedics, 904 Hospital of PLA Joint Logistic Support Force, 55 Heping North Road, Changzhou, 213003, Jiangsu Province, China
| | - Jiusheng Shi
- Department of Orthopedics, 904 Hospital of PLA Joint Logistic Support Force, 55 Heping North Road, Changzhou, 213003, Jiangsu Province, China.
| | - Changcheng Zhou
- Department of Orthopedics, 904 Hospital of PLA Joint Logistic Support Force, 55 Heping North Road, Changzhou, 213003, Jiangsu Province, China.
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Lan T, Wang W, Huang DL, Zeng XX, Wang XX, Wang J, Tong YH, Mao ZJ, Wang SW. Essential oil extracted from Quzhou Aurantii Fructus prevents acute liver failure through inhibiting lipopolysaccharide-mediated inflammatory response. NATURAL PRODUCTS AND BIOPROSPECTING 2023; 13:36. [PMID: 37804362 PMCID: PMC10560171 DOI: 10.1007/s13659-023-00398-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Accepted: 09/11/2023] [Indexed: 10/09/2023]
Abstract
Quzhou Aurantii Fructus (QAF) has a long history as a folk medicine and food for the treatment of liver diseases. While our earlier study provided evidence of hepatoprotective properties contained within the flavonoids and limonins constituents in QAF, the potential preventative effects afforded by essential oil components present within QAF remains enigmatic. In this study, we prepared Quzhou Aurantii Fructus essential oil (QAFEO) and confirmed its anti-inflammatory effects on liver inflammation through experimentation on lipopolysaccharide and D-galactosamine (LPS/D-GalN) induced acute liver failure (ALF) mouse models. Using RNA-sequence (RNA-seq) analysis, we found that QAFEO prevented ALF by systematically blunting the pathways involved in response to LPS and toll-like receptor signaling pathways. QAFEO effectively suppressed the phosphorylation of tank-binding kinase 1 (TBK1), TGF-beta activated kinase 1 (TAK1), interferon regulatory factor 3 (IRF3), and the activation of mitogen activated kinase-like protein (MAPK) and nuclear factor-kappa B (NF-κB) pathways in vivo and in vitro. Importantly, QAFEO substantially reduced myeloid differentiation primary response gene 88 (MyD88)- toll-like receptor 4 (TLR4) interaction levels. Moreover, 8 compounds from QAFEO could directly bind to REAL, TAK1, MyD88, TBK1, and IRF3. Taken together, the results of our study support the notion that QAFEO exerts a hepatoprotective effect through inhibiting LPS-mediated inflammatory response.
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Affiliation(s)
- Tian Lan
- The Joint Innovation Center for Health and Medicine, Quzhou People's Hospital, The Quzhou Affiliated Hospital of Wenzhou Medical University, No. 100 Minjiang Road, Quzhou, 324000, China
| | - Wen Wang
- Preventive Treatment Center, Zhejiang Chinese Medical University Affiliated Four-provinces Marginal Hospital of Traditional Chinese Medicine, Quzhou Hospital of Traditional Chinese Medicine, Quzhou, 324000, China
| | - De-Lian Huang
- School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Xi-Xi Zeng
- The Joint Innovation Center for Health and Medicine, Quzhou People's Hospital, The Quzhou Affiliated Hospital of Wenzhou Medical University, No. 100 Minjiang Road, Quzhou, 324000, China
| | - Xiao-Xiao Wang
- Department of Drug Analysis Center, Quzhou Institute for Food and Drug Control, Quzhou, 324000, China
| | - Jian Wang
- Department of Drug Analysis Center, Quzhou Institute for Food and Drug Control, Quzhou, 324000, China
| | - Yu-Hua Tong
- The Joint Innovation Center for Health and Medicine, Quzhou People's Hospital, The Quzhou Affiliated Hospital of Wenzhou Medical University, No. 100 Minjiang Road, Quzhou, 324000, China.
- Department of Ophthalmology, Quzhou People's Hospital, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou, 324000, China.
| | - Zhu-Jun Mao
- Department of Ophthalmology, Quzhou People's Hospital, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou, 324000, China.
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou, 310053, China.
| | - Si-Wei Wang
- The Joint Innovation Center for Health and Medicine, Quzhou People's Hospital, The Quzhou Affiliated Hospital of Wenzhou Medical University, No. 100 Minjiang Road, Quzhou, 324000, China.
- Department of Ophthalmology, Quzhou People's Hospital, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou, 324000, China.
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35
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Liu C, Chen X, Liu Y, Sun L, Yu Z, Ren Y, Zeng C, Li Y. Engineering Extracellular Matrix-Bound Nanovesicles Secreted by Three-Dimensional Human Mesenchymal Stem Cells. Adv Healthc Mater 2023; 12:e2301112. [PMID: 37225144 PMCID: PMC10723826 DOI: 10.1002/adhm.202301112] [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: 04/08/2023] [Revised: 05/19/2023] [Indexed: 05/26/2023]
Abstract
Extracellular matrix (ECM) in the human tissue contains vesicles, which are defined as matrix-bound nanovesicles (MBVs). MBVs serve as one of the functional components in ECM, recapitulating part of the regulatory roles and in vivo microenvironment. In this study, extracellular vesicles from culture supernatants (SuEVs) and MBVs are isolated from the conditioned medium or ECM, respectively, of 3D human mesenchymal stem cells. Nanoparticle tracking analysis shows that MBVs are smaller than SuEVs (100-150 nm). Transmission electron microscopy captures the typical cup shape morphology for both SuEVs and MBVs. Western blot reveals that MBVs have low detection of some SuEV markers such as syntenin-1. miRNA analysis of MBVs shows that 3D microenvironment enhances the expression of miRNAs such as miR-19a and miR-21. In vitro functional analysis shows that MBVs can facilitate human pluripotent stem cell-derived forebrain organoid recovery after starvation and promote high passage fibroblast proliferation. In macrophage polarization, 2D MBVs tend to suppress the pro-inflammatory cytokine IL-12β, while 3D MBVs tend to enhance the anti-inflammatory cytokine IL-10. This study has the significance in advancing the understanding of the bio-interface of nanovesicles with human tissue and the design of cell-free therapy for treating neurological disorders such as ischemic stroke.
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Affiliation(s)
- Chang Liu
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University
| | - Xingchi Chen
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University
- High Performance Materials Institute, FAMU-FSU College of Engineering, Florida State University
| | - Yuan Liu
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University
| | - Li Sun
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University
- Department of Biomedical Sciences, College of Medicine, Florida State University
| | - Zhibin Yu
- High Performance Materials Institute, FAMU-FSU College of Engineering, Florida State University
- Department of Industrial and Manufacturing Engineering, FAMU-FSU College of Engineering, Florida State University
| | - Yi Ren
- Department of Biomedical Sciences, College of Medicine, Florida State University
| | - Changchun Zeng
- High Performance Materials Institute, FAMU-FSU College of Engineering, Florida State University
- Department of Industrial and Manufacturing Engineering, FAMU-FSU College of Engineering, Florida State University
| | - Yan Li
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University
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36
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Zhang ZX, Zhou YJ, Gu P, Zhao W, Chen HX, Wu RY, Zhou LY, Cui QZ, Sun SK, Zhang LQ, Zhang K, Xu HJ, Chai XQ, An SJ. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate Parkinson's disease and neuronal damage through inhibition of microglia. Neural Regen Res 2023; 18:2291-2300. [PMID: 37056150 PMCID: PMC10328268 DOI: 10.4103/1673-5374.368300] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 11/19/2022] [Accepted: 12/06/2022] [Indexed: 04/15/2023] Open
Abstract
Microglia-mediated inflammatory responses have been shown to play a crucial role in Parkinson's disease. In addition, exosomes derived from mesenchymal stem cells have shown anti-inflammatory effects in the treatment of a variety of diseases. However, whether they can protect neurons in Parkinson's disease by inhibiting microglia-mediated inflammatory responses is not yet known. In this study, exosomes were isolated from human umbilical cord mesenchymal stem cells and injected into a 6-hydroxydopamine-induced rat model of Parkinson's disease. We found that the exosomes injected through the tail vein and lateral ventricle were absorbed by dopaminergic neurons and microglia on the affected side of the brain, where they repaired nigral-striatal dopamine system damage and inhibited microglial activation. Furthermore, in an in vitro cell model, pretreating lipopolysaccharide-stimulated BV2 cells with exosomes reduced interleukin-1β and interleukin-18 secretion, prevented the adoption of pyroptosis-associated morphology by BV2 cells, and increased the survival rate of SH-SY5Y cells. Potential targets for treatment with human umbilical cord mesenchymal stem cells and exosomes were further identified by high-throughput microRNA sequencing and protein spectrum sequencing. Our findings suggest that human umbilical cord mesenchymal stem cells and exosomes are a potential treatment for Parkinson's disease, and that their neuroprotective effects may be mediated by inhibition of excessive microglial proliferation.
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Affiliation(s)
- Zhong-Xia Zhang
- Department of Neurology, the First Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Yong-Jie Zhou
- Research Center, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, China
| | - Ping Gu
- Department of Neurology, the First Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Wei Zhao
- Research Center, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, China
| | - Hong-Xu Chen
- Research Center, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, China
| | - Ruo-Yu Wu
- Research Center, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, China
| | - Lu-Yang Zhou
- Research Center, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, China
| | - Qing-Zhuo Cui
- Research Center, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, China
| | - Shao-Kang Sun
- Research Center, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, China
| | - Lin-Qi Zhang
- Research Center, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, China
| | - Ke Zhang
- Research Center, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, China
| | - Hong-Jun Xu
- Research Center, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, China
| | - Xi-Qing Chai
- Department of Neurology, the First Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Sheng-Jun An
- Research Center, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, China
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Wang YH, Chen EQ. Mesenchymal Stem Cell Therapy in Acute Liver Failure. Gut Liver 2023; 17:674-683. [PMID: 36843422 PMCID: PMC10502502 DOI: 10.5009/gnl220417] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 11/04/2022] [Accepted: 11/18/2022] [Indexed: 02/28/2023] Open
Abstract
Acute liver failure (ALF) is a severe liver disease syndrome with rapid deterioration and high mortality. Liver transplantation is the most effective treatment, but the lack of donor livers and the high cost of transplantation limit its broad application. In recent years, there has been no breakthrough in the treatment of ALF, and the application of stem cells in the treatment of ALF is a crucial research field. Mesenchymal stem cells (MSCs) are widely used in disease treatment research due to their abundant sources, low immunogenicity, and no ethical restrictions. Although MSCs are effective for treating ALF, the application of MSCs to ALF needs to be further studied and optimized. In this review, we discuss the potential mechanisms of MSCs therapy for ALF, summarize some methods to enhance the efficacy of MSCs, and explore optimal approaches for MSC transplantation.
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Affiliation(s)
- Yong-Hong Wang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - En-Qiang Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
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38
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Yang H, Chen J, Li J. Isolation, culture, and delivery considerations for the use of mesenchymal stem cells in potential therapies for acute liver failure. Front Immunol 2023; 14:1243220. [PMID: 37744328 PMCID: PMC10513107 DOI: 10.3389/fimmu.2023.1243220] [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: 06/20/2023] [Accepted: 08/18/2023] [Indexed: 09/26/2023] Open
Abstract
Acute liver failure (ALF) is a high-mortality syndrome for which liver transplantation is considered the only effective treatment option. A shortage of donor organs, high costs and surgical complications associated with immune rejection constrain the therapeutic effects of liver transplantation. Recently, mesenchymal stem cell (MSC) therapy was recognized as an alternative strategy for liver transplantation. Bone marrow mesenchymal stem cells (BMSCs) have been used in clinical trials of several liver diseases due to their ease of acquisition, strong proliferation ability, multipotent differentiation, homing to the lesion site, low immunogenicity and anti-inflammatory and antifibrotic effects. In this review, we comprehensively summarized the harvest and culture expansion strategies for BMSCs, the development of animal models of ALF of different aetiologies, the critical mechanisms of BMSC therapy for ALF and the challenge of clinical application.
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Affiliation(s)
| | | | - Jun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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39
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Huai Q, Zhu C, Zhang X, Dai H, Li X, Wang H. Mesenchymal stromal/stem cells and their extracellular vesicles in liver diseases: insights on their immunomodulatory roles and clinical applications. Cell Biosci 2023; 13:162. [PMID: 37670393 PMCID: PMC10478279 DOI: 10.1186/s13578-023-01122-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 08/30/2023] [Indexed: 09/07/2023] Open
Abstract
Liver disease is a leading cause of mortality and morbidity that is rising globally. Liver dysfunctions are classified into acute and chronic diseases. Various insults, including viral infections, alcohol or drug abuse, and metabolic overload, may cause chronic inflammation and fibrosis, leading to irreversible liver dysfunction. Up to now, liver transplantation could be the last resort for patients with end-stage liver disease. However, liver transplantation still faces unavoidable difficulties. Mesenchymal stromal/stem cells (MSCs) with their broad ranging anti-inflammatory and immunomodulatory properties can be effectively used for treating liver diseases but without the limitation that are associated with liver transplantation. In this review, we summarize and discuss recent advances in the characteristics of MSCs and the potential action mechanisms of MSCs-based cell therapies for liver diseases. We also draw attention to strategies to potentiate the therapeutic properties of MSCs through pre-treatments or gene modifications. Finally, we discuss progress toward clinical application of MSCs or their extracellular vesicles in liver diseases.
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Affiliation(s)
- Qian Huai
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Cheng Zhu
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Xu Zhang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Hanren Dai
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Xiaolei Li
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
| | - Hua Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, 230032, China.
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40
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Lu D, Jiao X, Jiang W, Yang L, Gong Q, Wang X, Wei M, Gong S. Mesenchymal stem cells influence monocyte/macrophage phenotype: Regulatory mode and potential clinical applications. Biomed Pharmacother 2023; 165:115042. [PMID: 37379639 DOI: 10.1016/j.biopha.2023.115042] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 06/16/2023] [Accepted: 06/20/2023] [Indexed: 06/30/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are pluripotent stem cells derived from a variety of tissues, such as umbilical cord, fat, and bone marrow. Today, MSCs are widely recognized for their prominent anti-inflammatory properties in a variety of acute and chronic inflammatory diseases. In inflammatory diseases, monocytes/macrophages are an important part of the innate immune response in the body, and the alteration of the inflammatory phenotype plays a crucial role in the secretion of pro-inflammatory/anti-inflammatory factors, the repair of injured sites, and the infiltration of inflammatory cells. In this review, starting from the effect of MSCs on the monocyte/macrophage phenotype, we have outlined in detail the process by which MSCs influence the transformation of the monocyte/macrophage inflammatory phenotype, emphasizing the central role of monocytes/macrophages in MSC-mediated anti-inflammatory and damage site repair. MSCs are phagocytosed by monocytes/macrophages in various physiological states, the paracrine effect of MSCs and mitochondrial transfer of MSCs to macrophages to promote the transformation of monocytes/macrophages into anti-inflammatory phenotypes. We also review the clinical applications of the MSCs-monocytes/macrophages system and describe novel pathways between MSCs and tissue repair, the effects of MSCs on the adaptive immune system, and the effects of energy metabolism levels on monocyte/macrophage phenotypic changes.
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Affiliation(s)
- Dejin Lu
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Xue Jiao
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Wenjian Jiang
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Li Yang
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Qian Gong
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Xiaobin Wang
- Center of Reproductive Medicine, Shengjing Hospital of China Medical University, Shenyang 110004, China.
| | - Minjie Wei
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China.
| | - Shiqiang Gong
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China.
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Cen Y, Qi J, Chen L, Xia C, Zheng M, Liu Y, Lou G. Decreased miR-17-92 cluster correlates with senescence features, disrupted oxidative homeostasis, and impaired therapeutic efficacy of mesenchymal stem cells. Am J Physiol Cell Physiol 2023; 325:C443-C455. [PMID: 37366574 DOI: 10.1152/ajpcell.00515.2022] [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: 11/14/2022] [Revised: 06/23/2023] [Accepted: 06/23/2023] [Indexed: 06/28/2023]
Abstract
Aging and replicative cellular senescence are associated with the reduced therapeutic potential of mesenchymal stem cells (MSCs) on a variety of diseases. This study aimed to determine the mechanism in MSC senescence and further explore a modification strategy to reverse senescence-associated cell dysfunction to improve the therapeutic efficacy of MSCs on acute liver failure (ALF). We found that the adipose tissue-derived MSCs from old mice (oAMSCs) exhibited senescence phenotypes and showed reduced therapeutic efficacy in lipopolysaccharide and D-galactosamine-induced ALF, as shown by the increased hepatic necrosis, liver histology activity index scores, serum liver function indicator levels, and inflammatory cytokine levels. The expression of miR-17-92 cluster members, especially miR-17 and miR-20a, was obviously decreased in oAMSCs and replicatively senescent AMSCs, and was consistent with the decreased oncogene c-Myc level during AMSC senescence and may mediate c-Myc stemness addiction. Further experiments revealed that c-Myc-regulated miR-17-92 expression contributed to increased p21 expression and redox system dysregulation during AMSC senescence. Furthermore, modification of AMSCs with the two key miRNAs in the miR-17-92 cluster mentioned above reversed the senescence features of oAMSCs and restored the therapeutic effect of senescent AMSCs on ALF. In conclusion, the cellular miR-17-92 cluster level is correlated with AMSC senescence and can be used both as an index for evaluating and as a modification target for improving the therapeutic potential of AMSCs.NEW & NOTEWORTHY We reported for the first time that c-Myc-regulated miR-17-92 contributed to increased p21 expression and redox system dysregulation during AMSC senescence and was associated with the reduced therapeutic effects of senescent AMSCs on ALF. Moreover, modifying the expression of the miR-17-92 cluster members, especially miR-17 and/or miR-20a, could reverse AMSC senescence. Thus, miR-17-92 cluster can be used both as an index for evaluating and as a modification strategy for improving the therapeutic potential of AMSCs.
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Affiliation(s)
- Yelei Cen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jinjin Qi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Liang Chen
- Thyroid Disease Diagnosis and Treatment Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Caixia Xia
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Department of Infectious Diseases, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Min Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yanning Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Guohua Lou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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Ren P, Qian F, Fu L, He W, He Q, Jin J, Zheng D. Adipose-derived stem cell exosomes regulate Nrf2/Keap1 in diabetic nephropathy by targeting FAM129B. Diabetol Metab Syndr 2023; 15:149. [PMID: 37403164 DOI: 10.1186/s13098-023-01119-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 06/19/2023] [Indexed: 07/06/2023] Open
Abstract
BACKGROUND Exosomes from adipose-derived stem cells (ADSCs-Exos) have exhibited a therapeutic role in diabetic nephropathy (DN). Further studies are needed to investigate how ADSCs-Exos regulate oxidative stress and inflammation in high glucose-induced podocyte injury. METHODS An enzyme-linked immunosorbent assay (ELISA) was used to detect cellular inflammation. Reactive oxygen species (ROS) levels were assessed using flow cytometry in podocytes with different treatments. A malondialdehyde (MDA) kit was used to evaluate the lipid peroxidation levels in podocytes and kidney tissues of mice. Western blotting and co-immunoprecipitation were performed to detect protein expression and protein-protein interactions. RESULTS ADSCs-Exos reversed oxidative stress and inflammation in podocytes and kidney tissues of DN mice induced by high glucose levels in vitro and in vivo. Interference with heme oxygenase-1 expression could reverse the improvement effect of ADSCs-Exos on oxidative stress induced by high glucose levels. Furthermore, high glucose inhibited nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression and promoted Kelch-like ECH-associated protein 1 (Keap1) protein expression in podocytes, as well as their binding ability. As a potential target for Nrf2/Keap1 pathway regulation, FAM129B expression in podocytes is regulated by high glucose and ADSCs-Exos. Moreover, FAM129B siRNA blocked the inhibitory effect of ADSCs-Exos on intracellular ROS and MDA upregulation induced by high glucose in podocytes. CONCLUSION ADSCs-Exos regulate the Nrf2/Keap1 pathway to alleviate inflammation and oxidative stress in DN by targeting FAM129B, which may provide a potential therapeutic strategy for DN.
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Affiliation(s)
- Peiyao Ren
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310003, China
| | - Fengmei Qian
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310003, China
| | - Lanjun Fu
- Department of Nephrology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, Zhejiang, 310000, China
| | - Wenfang He
- Department of Nephrology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, Zhejiang, 310000, China
| | - Qiang He
- Department of Nephrology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, Zhejiang, 310000, China.
| | - Juan Jin
- Department of Nephrology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, Zhejiang, 310000, China.
| | - Danna Zheng
- Urology & Nephrology Center, Department of Nephrology, Affiliated People's Hospital, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China.
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Sitbon A, Delmotte PR, Goumard C, Turco C, Gautheron J, Conti F, Aoudjehane L, Scatton O, Monsel A. Therapeutic potentials of mesenchymal stromal cells-derived extracellular vesicles in liver failure and marginal liver graft rehabilitation: a scoping review. Minerva Anestesiol 2023; 89:690-706. [PMID: 37079286 DOI: 10.23736/s0375-9393.23.17265-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/21/2023]
Abstract
Liver failure includes distinct subgroups of diseases: Acute liver failure (ALF) without preexisting cirrhosis, acute-on-chronic liver failure (ACLF) (severe form of cirrhosis associated with organ failures and excess mortality), and liver fibrosis (LF). Inflammation plays a key role in ALF, LF, and more specifically in ACLF for which we have currently no treatment other than liver transplantation (LT). The increasing incidence of marginal liver grafts and the shortage of liver grafts require us to consider strategies to increase the quantity and quality of available liver grafts. Mesenchymal stromal cells (MSCs) have shown beneficial pleiotropic properties with limited translational potential due to the pitfalls associated with their cellular nature. MSC-derived extracellular vesicles (MSC-EVs) are innovative cell-free therapeutics for immunomodulation and regenerative purposes. MSC-EVs encompass further advantages: pleiotropic effects, low immunogenicity, storage stability, good safety profile, and possibility of bioengineering. Currently, no human studies explored the impact of MSC-EVs on liver disease, but several preclinical studies highlighted their beneficial effects. In ALF and ACLF, data showed that MSC-EVs attenuate hepatic stellate cells activation, exert antioxidant, anti-inflammatory, anti-apoptosis, anti-ferroptosis properties, and promote regeneration of the liver, autophagy, and improve metabolism through mitochondrial function recovery. In LF, MSC-EVs demonstrated anti-fibrotic properties associated with liver tissue regeneration. Normothermic-machine perfusion (NMP) combined with MSC-EVs represents an attractive therapy to improve liver regeneration before LT. Our review suggests a growing interest in MSC-EVs in liver failure and gives an appealing insight into their development to rehabilitate marginal liver grafts through NMP.
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Affiliation(s)
- Alexandre Sitbon
- Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France -
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France -
| | - Pierre-Romain Delmotte
- Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France
| | - Claire Goumard
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France
- Department of Digestive, Hepatobiliary Surgery and Liver Transplantation, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France
| | - Célia Turco
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France
- Liver Transplantation Unit, Department of Digestive and Oncologic Surgery, University Hospital of Besançon, Besançon, France
| | - Jérémie Gautheron
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France
| | - Filomena Conti
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France
- Department of Digestive, Hepatobiliary Surgery and Liver Transplantation, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France
- IHU-Innovation of Cardiometabolism and Nutrition (ICAN), INSERM, Sorbonne University, Paris, France
| | - Lynda Aoudjehane
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France
- IHU-Innovation of Cardiometabolism and Nutrition (ICAN), INSERM, Sorbonne University, Paris, France
| | - Olivier Scatton
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France
- Department of Digestive, Hepatobiliary Surgery and Liver Transplantation, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France
| | - Antoine Monsel
- Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France
- INSERM UMRS-959 Immunology-Immunopathology-Immunotherapy (I3), Sorbonne University, Paris, France
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Parthasarathy G, Hirsova P, Kostallari E, Sidhu GS, Ibrahim SH, Malhi H. Extracellular Vesicles in Hepatobiliary Health and Disease. Compr Physiol 2023; 13:4631-4658. [PMID: 37358519 PMCID: PMC10798368 DOI: 10.1002/cphy.c210046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/27/2023]
Abstract
Extracellular vesicles (EVs) are membrane-bound nanoparticles released by cells and are an important means of intercellular communication in physiological and pathological states. We provide an overview of recent advances in the understanding of EV biogenesis, cargo selection, recipient cell effects, and key considerations in isolation and characterization techniques. Studies on the physiological role of EVs have relied on cell-based model systems due to technical limitations of studying endogenous nanoparticles in vivo . Several recent studies have elucidated the mechanistic role of EVs in liver diseases, including nonalcoholic fatty liver disease, viral hepatitis, cholestatic liver disease, alcohol-associated liver disease, acute liver injury, and liver cancers. Employing disease models and human samples, the biogenesis of lipotoxic EVs downstream of endoplasmic reticulum stress and microvesicles via intracellular activation stress signaling are discussed in detail. The diverse cargoes of EVs including proteins, lipids, and nucleic acids can be enriched in a disease-specific manner. By carrying diverse cargo, EVs can directly confer pathogenic potential, for example, recruitment and activation of monocyte-derived macrophages in NASH and tumorigenicity and chemoresistance in hepatocellular carcinoma. We discuss the pathogenic role of EVs cargoes and the signaling pathways activated by EVs in recipient cells. We review the literature that EVs can serve as biomarkers in hepatobiliary diseases. Further, we describe novel approaches to engineer EVs to deliver regulatory signals to specific cell types, and thus use them as therapeutic shuttles in liver diseases. Lastly, we identify key lacunae and future directions in this promising field of discovery and development. © 2023 American Physiological Society. Compr Physiol 13:4631-4658, 2023.
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Affiliation(s)
| | - Petra Hirsova
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Enis Kostallari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Guneet S. Sidhu
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Samar H. Ibrahim
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Harmeet Malhi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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Lu X, Guo H, Wei X, Lu D, Shu W, Song Y, Qiu N, Xu X. Current Status and Prospect of Delivery Vehicle Based on Mesenchymal Stem Cell-Derived Exosomes in Liver Diseases. Int J Nanomedicine 2023; 18:2873-2890. [PMID: 37283714 PMCID: PMC10239634 DOI: 10.2147/ijn.s404925] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Accepted: 05/10/2023] [Indexed: 06/08/2023] Open
Abstract
With the improvement of the average life expectancy and increasing incidence of obesity, the burden of liver disease is increasing. Liver disease is a serious threat to human health. Currently, liver transplantation is the only effective treatment for end-stage liver disease. However, liver transplantation still faces unavoidable difficulties. Mesenchymal stem cells (MSCs) can be used as an alternative therapy for liver disease, especially liver cirrhosis, liver failure, and liver transplantation complications. However, MSCs may have potential tumorigenic effects. Exosomes derived from MSCs (MSC-Exos), as the important intercellular communication mode of MSCs, contain various proteins, nucleic acids, and DNA. MSC-Exos can be used as a delivery system to treat liver diseases through immune regulation, apoptosis inhibition, regeneration promotion, drug delivery, and other ways. Good histocompatibility and material exchangeability make MSC-Exos a new treatment for liver diseases. This review summarizes the latest research on MSC-Exos as delivery vehicles in different liver diseases, including liver injury, liver failure, liver fibrosis, hepatocellular carcinoma (HCC), and ischemia and reperfusion injury. In addition, we discuss the advantages, disadvantages, and clinical application prospects of MSC-Exos-based delivery vectors in the treatment of liver diseases.
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Affiliation(s)
- Xinfeng Lu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310000, People’s Republic of China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
| | - Haijun Guo
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People’s Republic of China
| | - Xuyong Wei
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People’s Republic of China
| | - Di Lu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People’s Republic of China
| | - Wenzhi Shu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
- Zhejiang University School of Medicine, Hangzhou, 310058, People’s Republic of China
| | - Yisu Song
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
- Zhejiang University School of Medicine, Hangzhou, 310058, People’s Republic of China
| | - Nasha Qiu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310000, People’s Republic of China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
| | - Xiao Xu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310000, People’s Republic of China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People’s Republic of China
- Zhejiang University School of Medicine, Hangzhou, 310058, People’s Republic of China
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Zhang J, Gao J, Li X, Lin D, Li Z, Wang J, Chen J, Gao Z, Lin B. Bone marrow mesenchymal stem cell-derived small extracellular vesicles promote liver regeneration via miR-20a-5p/PTEN. Front Pharmacol 2023; 14:1168545. [PMID: 37305542 PMCID: PMC10248071 DOI: 10.3389/fphar.2023.1168545] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 05/15/2023] [Indexed: 06/13/2023] Open
Abstract
Balancing hepatocyte death and proliferation is key to non-transplantation treatments for acute liver failure (ALF), which has a high short-term mortality rate. Small extracellular vesicles (sEVs) may act as mediators in the repair of damaged liver tissue by mesenchymal stem cells (MSCs). We aimed to investigate the efficacy of human bone marrow MSC-derived sEVs (BMSC-sEVs) in treating mice with ALF and the molecular mechanisms involved in regulating hepatocyte proliferation and apoptosis. Small EVs and sEV-free BMSC concentrated medium were injected into mice with LPS/D-GalN-induced ALF to assess survival, changes in serology, liver pathology, and apoptosis and proliferation in different phases. The results were further verified in vitro in L-02 cells with hydrogen peroxide injury. BMSC-sEV-treated mice with ALF had higher 24 h survival rates and more significant reductions in liver injury than mice treated with sEV-free concentrated medium. BMSC-sEVs reduced hepatocyte apoptosis and promoted cell proliferation by upregulating miR-20a-5p, which targeted the PTEN/AKT signaling pathway. Additionally, BMSC-sEVs upregulated the mir-20a precursor in hepatocytes. The application of BMSC-sEVs showed a positive impact by preventing the development of ALF, and may serve as a promising strategy for promoting ALF liver regeneration. miR-20a-5p plays an important role in liver protection from ALF by BMSC-sEVs.
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Affiliation(s)
- Jing Zhang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Juan Gao
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xianlong Li
- Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Dengna Lin
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zhihui Li
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jialei Wang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Junfeng Chen
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zhiliang Gao
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Bingliang Lin
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong, China
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Sani F, Sani M, Moayedfard Z, Darayee M, Tayebi L, Azarpira N. Potential advantages of genetically modified mesenchymal stem cells in the treatment of acute and chronic liver diseases. Stem Cell Res Ther 2023; 14:138. [PMID: 37226279 DOI: 10.1186/s13287-023-03364-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Accepted: 05/04/2023] [Indexed: 05/26/2023] Open
Abstract
Liver damage caused by toxicity can lead to various severe conditions, such as acute liver failure (ALF), fibrogenesis, and cirrhosis. Among these, liver cirrhosis (LC) is recognized as the leading cause of liver-related deaths globally. Unfortunately, patients with progressive cirrhosis are often on a waiting list, with limited donor organs, postoperative complications, immune system side effects, and high financial costs being some of the factors restricting transplantation. Although the liver has some capacity for self-renewal due to the presence of stem cells, it is usually insufficient to prevent the progression of LC and ALF. One potential therapeutic approach to improving liver function is the transplantation of gene-engineered stem cells. Several types of mesenchymal stem cells from various sources have been suggested for stem cell therapy for liver disease. Genetic engineering is an effective strategy that enhances the regenerative potential of stem cells by releasing growth factors and cytokines. In this review, we primarily focus on the genetic engineering of stem cells to improve their ability to treat damaged liver function. We also recommend further research into accurate treatment methods that involve safe gene modification and long-term follow-up of patients to increase the effectiveness and reliability of these therapeutic strategies.
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Affiliation(s)
- Farnaz Sani
- Hematology and Cell Therapy Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mahsa Sani
- Department of Tissue Engineering and Cell Therapy, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Moayedfard
- Department of Tissue Engineering and Cell Therapy, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maryam Darayee
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Lobat Tayebi
- Marquette University School of Dentistry, Milwaukee, WI, 53233, USA
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Khalili Street, P.O. Box: 7193711351, Shiraz, Iran.
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Zhang J, Lu T, Xiao J, Du C, Chen H, Li R, Sui X, Pan Z, Xiao C, Zhao X, Yao J, Liu Y, Lei Y, Ruan Y, Zhang J, Li H, Zhang Q, Zhang Y, Cai J, Yang Y, Zheng J. MSC-derived extracellular vesicles as nanotherapeutics for promoting aged liver regeneration. J Control Release 2023; 356:402-415. [PMID: 36858264 DOI: 10.1016/j.jconrel.2023.02.032] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 02/22/2023] [Accepted: 02/23/2023] [Indexed: 03/03/2023]
Abstract
Aging is one of the critical factors to impair liver regeneration leading to a high incidence of severe complications after hepatic surgery in the elderly population without any effective treatment for clinical administration. As cell-free nanotherapeutics, mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been demonstrated the therapeutic potentials on liver diseases. However, the effects of MSC-EVs on the proliferation of aged hepatocytes are largely unclear. In this study, we found MSCs could reduce the expression of senescence-associated markers in the liver and stimulate its regeneration in aged mice after receiving a two-thirds partial hepatectomy (PHx) through their secreted MSC-EVs. Using RNA-Seq and AAV9 vector, we mechanistically found that these effects of UC-MSC-EVs partially attributed to inducing Atg4B-related mitophagy. This effect repairs the mitochondrial status and functions of aged hepatocytes to promote their proliferation. And protein mass spectrum analysis uncovered that DEAD-Box Helicase 5 (DDX5) enriches in UC-MSC-EVs, which interacts with E2F1 to facilitate its nuclear translocation for activating the expression of Atg4B. Collectively, our data show that MSC-EVs act nanotherapeutic potentials in anti-senescence and promoting regeneration of aged liver by transferring DDX5 to regulate E2F1-Atg4B signaling pathway that induce mitophagy, which highlights the clinical application valuation of MSC-EVs for preventing severe complications in aged population receiving liver surgery.
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Affiliation(s)
- Jiebin Zhang
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine. Guangzhou 510630, China; Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Tongyu Lu
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine. Guangzhou 510630, China; Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Jiaqi Xiao
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine. Guangzhou 510630, China; Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Cong Du
- Biological Treatment Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Haitian Chen
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine. Guangzhou 510630, China; Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Rong Li
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Xin Sui
- Surgical ICU, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Zihao Pan
- Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China
| | - Cuicui Xiao
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China; Department of Anesthesiology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Xuegang Zhao
- Surgical ICU, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Jia Yao
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine. Guangzhou 510630, China; Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Yasong Liu
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine. Guangzhou 510630, China; Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Yunguo Lei
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine. Guangzhou 510630, China; Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Ying Ruan
- Department of thyroid and breast surgery, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Jian Zhang
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine. Guangzhou 510630, China; Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Hua Li
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine. Guangzhou 510630, China; Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Qi Zhang
- Biological Treatment Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Yingcai Zhang
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine. Guangzhou 510630, China; Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
| | - Jianye Cai
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine. Guangzhou 510630, China; Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
| | - Yang Yang
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine. Guangzhou 510630, China; Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
| | - Jun Zheng
- Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine. Guangzhou 510630, China; Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
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Zhang Q, Piao C, Xu J, Wang Y, Liu T, Ma H, Wang H. ADSCs-exo attenuates hepatic ischemia-reperfusion injury after hepatectomy by inhibiting endoplasmic reticulum stress and inflammation. J Cell Physiol 2023; 238:659-669. [PMID: 36780378 DOI: 10.1002/jcp.30968] [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: 11/12/2022] [Revised: 01/10/2023] [Accepted: 01/23/2023] [Indexed: 02/15/2023]
Abstract
Hepatic ischemia-reperfusion (I/R) injury commonly occurs during liver surgery. Exosomes from adipose-derived stem cells (ADSCs-exo) induce a hepatoprotective effect during hepatic I/R injury. This study aimed to investigate the possible mechanism by which ADSCs-exo attenuates hepatic I/R injury in rats. Rats were randomly divided into four groups: Sham, I30R + PH, ADSCs, and ADSCs-exo groups. Liver tissues were collected immediately after 24 h of reperfusion for further analyses. The content of inflammatory factors in liver tissue was detected using enzyme-linked immunosorbent assay. The pathological changes in liver tissue were analyzed using HE staining. Transmission electron microscopy was used to visualize the ultrastructural changes of hepatocytes. Real-time quantitative polymerase chain reaction (RT-qPCR) and western blot analysis were used to detect the expression of endoplasmic reticulum stress (ERS)-related genes and proteins. Liver histomorphology and hepatocyte ultrastructure changes improved after ADSCs-exo treatment. Moreover, ADSCs-exo treatment significantly downregulated tumor necrosis factor-α, interleukin-1β (IL-1β), and IL-6 levels while upregulating IL-10 levels. Western blot analysis suggested that the protein expressions of GRP78, p-PERK, p-eIF2α, p-IRE1α, XBP1s, ATF-6, ATF-4, CHOP, p-JNK, cleaved-Caspase-3, cleaved Caspase-9, and cleaved Caspase-12 significantly decreased after ADSCs-exo treatment. RT-qPCR results demonstrated that mRNA expression of GRP78, IRE1α, XBP1, ATF-6, ATF-4, CHOP, JNK, Caspase-3, Caspase-9, and Caspase-12 markedly reduced after ADSCs-exo treatment. In conclusion, ADSCs-exo protects against hepatic I/R injury after hepatectomy by inhibiting ERS and inflammation. Therefore, ADSCs-exo can be considered as a viable option for the treatment of hepatic I/R injury.
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Affiliation(s)
- Qianzhen Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, P.R. China
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, P.R. China
| | - Chenxi Piao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, P.R. China
| | - Jiayuan Xu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, P.R. China
| | - Yue Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, P.R. China
| | - Tao Liu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, P.R. China
| | - Haiyang Ma
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, P.R. China
| | - Hongbin Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, P.R. China
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50
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Fang X, Gao F, Yao Q, Xu H, Yu J, Cao H, Li S. Pooled Analysis of Mesenchymal Stromal Cell-Derived Extracellular Vesicle Therapy for Liver Disease in Preclinical Models. J Pers Med 2023; 13:441. [PMID: 36983624 PMCID: PMC10056150 DOI: 10.3390/jpm13030441] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 02/25/2023] [Accepted: 02/26/2023] [Indexed: 03/05/2023] Open
Abstract
BACKGROUND Although increasing preclinical studies have emphasized the benefits of exosome-related therapies, the efficacy of mesenchymal stromal cell (MSC)-derived extracellular vesicles (EV) for liver injury is unclear. In this work, a pooled analysis was conducted to explore the overall effect of MSC-EV in animal models. METHODS A systematic search of the PubMed, EMBASE, Web of Science, and Cochrane Library databases was performed, from initiation to February 2022, for preclinical studies with liver disease models. The treatment outcomes were evaluated based on liver function, histological analysis, and inflammatory cytokines. RESULTS After screening, 39 studies were included. Pooled analyses demonstrated that MSC-EV therapy significantly improved liver functions (ALB, ALT, AST, ALP, and γ-GT), promoted the repair of injured liver tissue (damaged area, Ishak's score), reduced inflammatory factors (TNF-α, IL-1β, IL-6, and IFN-γ), and increased an anti-inflammatory cytokine (IL-10) compared to the placebo control group. Subgroup analyses indicated that MSC-EV had therapeutic effects on liver fibrosis (n = 16), acute liver injury (n = 11), non-alcoholic fatty liver disease (n = 3), autoimmune hepatitis (n = 4), and hepatic ischemia-reperfusion injury (n = 6). Additionally, the therapeutic effect of EV was comparable to that of MSCs. CONCLUSION MSC-EV have therapeutic potential for acute and chronic liver diseases.
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Affiliation(s)
- Xinru Fang
- Department of Infectious Disease, Zhoushan Hospital, Zhejiang University School of Medicine, Zhoushan 316021, China
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
- Department of Laboratory Medicine, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu 310003, China
| | - Feiqiong Gao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qigu Yao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Haoying Xu
- Department of Infectious Disease, Zhoushan Hospital, Zhejiang University School of Medicine, Zhoushan 316021, China
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
- Department of Laboratory Medicine, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu 310003, China
| | - Jiong Yu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Hongcui Cao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250117, China
- Key Laboratory of Diagnosis and Treatment of Aging and Physic-Chemical Injury Diseases of Zhejiang Province, 79 Qingchun Rd, Hangzhou 310003, China
| | - Shibo Li
- Department of Infectious Disease, Zhoushan Hospital, Zhejiang University School of Medicine, Zhoushan 316021, China
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