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Allela OQB, Ali NAM, Sanghvi G, Roopashree R, Kashyap A, Krithiga T, Panigrahi R, Kubaev A, Kareem RA, Sameer HN, Yaseen A, Athab ZH, Adil M. The Role of Viral Infections in Acute Kidney Injury and Mesenchymal Stem Cell-Based Therapy. Stem Cell Rev Rep 2025:10.1007/s12015-025-10873-0. [PMID: 40198477 DOI: 10.1007/s12015-025-10873-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/01/2025] [Indexed: 04/10/2025]
Abstract
Viruses may cause a wide range of renal problems. Furthermore, many kidney diseases may be brought on by viral infections. Both the primary cause and a contributing factor of acute kidney injury (AKI) may be viral infections. As an example, it is recommended that patients with dengue virus (DENV) infections undergo careful monitoring of their AKI levels. Also, researchers' data so far lend credence to the several hypothesized pathophysiological mechanisms via which AKI can develop in SARS-CoV- 2 infection. Thus, it is critical to comprehend how viral infections cause AKI. Finding an effective method of treating AKI caused by viruses is also vital. Thus, a potential cell-free method for treating AKI that uses regenerative and anti-inflammatory processes is mesenchymal stem cells (MSCs) and their exosomes (MSC-EXOs). MSCs alleviate tissue damage and enhance protective effects on damaged kidneys in AKI. Furthermore, MSC-EXOs have exhibited substantial regulatory impact on a range of immune cells and exhibit robust immune regulation in the therapy of AKI. Thus, in models of AKI caused by ischemia-reperfusion damage, nephrotoxins, or sepsis, MSCs and MSC-EXOs improved renal function, decreased inflammation, and improved healing. Therefore, MSCs and MSC-EXOs may help treat AKI caused by different viruses. Consequently, we have explored several innovative and significant processes in this work that pertain to the role of viruses in AKI and the significance of viral illness in the onset of AKI. After that, we assessed the key aspects of MSCs and MSC-EXOs for AKI therapy. We have concluded by outlining the current state of and plans for future research into MSC- and EXO-based therapeutic approaches for the treatment of AKI brought on by viruses.
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Affiliation(s)
| | | | - Gaurav Sanghvi
- Department of Microbiology, Faculty of Science, Marwadi University Research Center, Marwadi University, Rajkot, 360003, Gujarat, India
| | - R Roopashree
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Aditya Kashyap
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, 140401, Punjab, India
| | - T Krithiga
- Department of Chemistry, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
| | - Rajashree Panigrahi
- Department of Microbiology, IMS and SUM Hospital, Siksha 'O' Anusandhan (Deemed to Be University), Bhubaneswar, 751003, Odisha, India
| | - Aziz Kubaev
- Department of Maxillofacial Surgery, Samarkand State Medical University, 18 Amir Temur Street, Samarkand, 140100, Uzbekistan
| | | | - Hayder Naji Sameer
- Collage of Pharmacy, National University of Science and Technology, Dhi Qar, 64001, Iraq
| | | | - Zainab H Athab
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq
| | - Mohaned Adil
- Pharmacy college, Al-Farahidi University, Baghdad, Iraq
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Wang JJ, Zheng Y, Li YL, Xiao Y, Ren YY, Tian YQ. Emerging role of mesenchymal stem cell-derived exosomes in the repair of acute kidney injury. World J Stem Cells 2025; 17:103360. [PMID: 40160687 PMCID: PMC11947899 DOI: 10.4252/wjsc.v17.i3.103360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 12/26/2024] [Accepted: 02/13/2025] [Indexed: 03/21/2025] Open
Abstract
Acute kidney injury (AKI) is a clinical syndrome characterized by a rapid deterioration in kidney function and has a significant impact on patient health and survival. Mesenchymal stem cells (MSCs) have the potential to enhance renal function by suppressing the expression of cell cycle inhibitors and reducing the expression of senescence markers and microRNAs via paracrine and endocrine mechanisms. MSC-derived exosomes can alleviate AKI symptoms by regulating DNA damage, apoptosis, and other related signaling pathways through the delivery of proteins, microRNAs, long-chain noncoding RNAs, and circular RNAs. This technique is both safe and effective. MSC-derived exosomes may have great application prospects in the treatment of AKI. Understanding the underlying mechanisms will foster the development of new and promising therapeutic strategies against AKI. This review focused on recent advancements in the role of MSCs in AKI repair as well as the mechanisms underlying the role of MSCs and their secreted exosomes. It is anticipated that novel and profound insights into the functionality of MSCs and their derived exosomes will emerge.
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Affiliation(s)
- Juan-Juan Wang
- Clinical Laboratory, The First People's Hospital of Yancheng, Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical School, Yancheng 224000, Jiangsu Province, China
| | - Yu Zheng
- Clinical Laboratory, The First People's Hospital of Yancheng, Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical School, Yancheng 224000, Jiangsu Province, China
| | - Yan-Lin Li
- Clinical Laboratory, The First People's Hospital of Yancheng, Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical School, Yancheng 224000, Jiangsu Province, China
| | - Yin Xiao
- Department of Medical Imaging, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, Xuzhou 221000, Jiangsu Province, China
| | - Yang-Yang Ren
- Clinical Laboratory, Xinyi People's Hospital, Xuzhou 221000, Jiangsu Province, China
| | - Yi-Qing Tian
- Clinical Laboratory, Xuzhou Central Hospital, Xuzhou 221000, Jiangsu Province, China.
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Habib R, Farhat R, Wahid M, Ainuddin J. Enhanced reno-protective effects of CHIR99021 modified mesenchymal stem cells against rat acute kidney injury model. BIOIMPACTS : BI 2024; 15:30600. [PMID: 40256225 PMCID: PMC12008493 DOI: 10.34172/bi.30600] [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: 07/01/2024] [Revised: 08/08/2024] [Accepted: 09/17/2024] [Indexed: 04/22/2025]
Abstract
Introduction Mesenchymal stem cells of human umbilical cord origin (hucMSCs) appear to be an attractive candidate for cell-based therapies. However, their efficacy requires improvement as poor survival and specific homing to the site of injury are the major barriers to their effective implementation in cell therapy. As Wnt signaling pathway is involved in the development and repair of organs, we adopted a preconditioning strategy of stem cells by using CHIR99021 compound (a Wnt pathway agonist) to potentiate hucMSCs beneficial effects and circumvent their therapeutic limitations. Methods We treated hucMSCs with 5 µM of CHIR99021 and evaluated the expression levels of genes involved in different biological processes through qRT-PCR. Subsequently, we examined the effectiveness of preconditioned cells (CHIR99021-hucMSCs) in a cisplatin-induced rat acute kidney injury model. Amelioration in tissue injury was evaluated by histopathology, immunohistochemistry and renal functional assessment. Results In treated groups, we observed preserved renal tissue architecture in terms of lesser epithelial cells necrosis (P ≤ 0.001) and cast formation ( ≤ 0.05). Accelerated proliferation of injured tubular cells (P ≤ 0.001) and low serum creatinine values (P ≤ 0.01) were observed in preconditioned hucMSCs group compared to untreated AKI rats. In addition, administration of preconditioned hucMSCs in kidney injury model offered better restoration of tubular cell membrane β-catenin molecules. Our findings showed that CHIR99021-modified hucMSCs may exhibit better capacity for cell migration and proliferation. Conclusion The results showed that preconditioning of stem cells with Wnt pathway activators could provide advanced benefits for organ repair, which may contribute to design a more effective therapeutic approach for renal regeneration.
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Affiliation(s)
- Rakhshinda Habib
- Dow Research Institute of Biotechnology and Biomedical Sciences, Dow University of Health Sciences (Ojha Campus), Karachi, Pakistan
| | - Rabia Farhat
- School of Postgraduate Studies, Dow University of Health Sciences (Ojha Campus), Karachi, Pakistan
| | - Mohsin Wahid
- Department of Pathology, Dow International Medical College, Dow University of Health Sciences (Ojha Campus), Karachi, Pakistan
| | - Jahanara Ainuddin
- Department of Gynecology and Obstetrics, Dow University Hospital, Karachi, Pakistan
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Clua‐Ferré L, Suau R, Vañó‐Segarra I, Ginés I, Serena C, Manyé J. Therapeutic potential of mesenchymal stem cell-derived extracellular vesicles: A focus on inflammatory bowel disease. Clin Transl Med 2024; 14:e70075. [PMID: 39488745 PMCID: PMC11531661 DOI: 10.1002/ctm2.70075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 09/13/2024] [Accepted: 10/16/2024] [Indexed: 11/04/2024] Open
Abstract
BACKGROUND Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as key regulators of intercellular communication, orchestrating essential biological processes by delivering bioactive cargoes to target cells. Available evidence suggests that MSC-EVs can mimic the functions of their parental cells, exhibiting immunomodulatory, pro-regenerative, anti-apoptotic, and antifibrotic properties. Consequently, MSC-EVs represent a cell-free therapeutic option for patients with inflammatory bowel disease (IBD), overcoming the limitations associated with cell replacement therapy, including their non-immunogenic nature, lower risk of tumourigenicity, cargo specificity and ease of manipulation and storage. MAIN TOPICS COVERED This review aims to provide a comprehensive examination of the therapeutic efficacy of MSC-EVs in IBD, with a focus on their mechanisms of action and potential impact on treatment outcomes. We examine the advantages of MSC-EVs over traditional therapies, discuss methods for their isolation and characterisation, and present mechanistic insights into their therapeutic effects through transcriptomic, proteomic and lipidomic analyses of MSC-EV cargoes. We also discuss available preclinical studies demonstrating that MSC-EVs reduce inflammation, promote tissue repair and restore intestinal homeostasis in IBD models, and compare these findings with those of clinical trials. CONCLUSIONS Finally, we highlight the potential of MSC-EVs as a novel therapy for IBD and identify challenges and opportunities associated with their translation into clinical practice. HIGHLIGHTS The source of mesenchymal stem cells (MSCs) strongly influences the composition and function of MSC-derived extracellular vesicles (EVs), affecting their therapeutic potential. Adipose-derived MSC-EVs, known for their immunoregulatory properties and ease of isolation, show promise as a treatment for inflammatory bowel disease (IBD). MicroRNAs are consistently present in MSC-EVs across cell types and are involved in pathways that are dysregulated in IBD, making them potential therapeutic agents. For example, miR-let-7a is associated with inhibition of apoptosis, miR-100 supports cell survival, miR-125b helps suppress pro-inflammatory cytokines and miR-20 promotes anti-inflammatory M2 macrophage polarisation. Preclinical studies in IBD models have shown that MSC-EVs reduce intestinal inflammation by suppressing pro-inflammatory mediators (e.g., TNF-α, IL-1β, IL-6) and increasing anti-inflammatory factors (e.g., IL-4, IL-10). They also promote mucosal healing and strengthen the integrity of the gut barrier, suggesting their potential to address IBD pathology.
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Affiliation(s)
- Laura Clua‐Ferré
- Germans Trias i Pujol Research Institute IGTPInflammatory Bowel DiseasesBadalonaSpain
| | - Roger Suau
- Germans Trias i Pujol Research Institute IGTPInflammatory Bowel DiseasesBadalonaSpain
| | - Irene Vañó‐Segarra
- Hospital Universitari Joan XXIIIInstitut d'investigació sanitària Pere VirgiliTarragonaSpain
| | - Iris Ginés
- Hospital Universitari Joan XXIIIInstitut d'investigació sanitària Pere VirgiliTarragonaSpain
| | - Carolina Serena
- Hospital Universitari Joan XXIIIInstitut d'investigació sanitària Pere VirgiliTarragonaSpain
| | - Josep Manyé
- Germans Trias i Pujol Research Institute IGTPInflammatory Bowel DiseasesBadalonaSpain
- Centro de Investigación Biomédica en RedMadridSpain
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Xie Z, Tang J, Chen Z, Wei L, Chen J, Liu Q. Human bone marrow mesenchymal stem cell-derived extracellular vesicles reduce inflammation and pyroptosis in acute kidney injury via miR-223-3p/HDAC2/SNRK. Inflamm Res 2023; 72:553-576. [PMID: 36640195 PMCID: PMC9840168 DOI: 10.1007/s00011-022-01653-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 09/23/2022] [Indexed: 01/15/2023] Open
Abstract
OBJECTIVE Bone marrow mesenchymal stem cell (BMSC)-derived extracellular vesicles (EVs) have been demonstrated as a potential therapeutic agent in acute kidney injury (AKI). However, little is known about the mechanisms of action of BMSC-derived EVs in AKI. Based on this, our research was designed to investigate the mechanism behind BMSC-derived EVs controlling inflammation and pyroptosis during AKI. METHODS Peripheral blood from AKI patients was used for detection of microRNA (miR)-223-3p, HDAC2, and SNRK expression. An AKI rat model was established, and HK-2 cell injury was induced by lipopolysaccharide (LPS) to establish a cellular model. Co-culture with BMSC-derived EVs and/or gain- and loss-of-function assays were conducted in LPS-treated HK-2 to evaluate the functions of BMSCs-EVs, miR-223-3p, HDAC2, and SNRK. AKI rats were simultaneously injected with EVs and short hairpin RNAs targeting SNRK. The interactions among miR-223-3p, HDAC2, and SNRK were evaluated by RIP, ChIP, and dual-luciferase gene reporter assays. RESULTS Patients with AKI had low miR-223-3p and SNRK expression and high HDAC2 expression in peripheral blood. Mechanistically, miR-223-3p targeted HDAC2 to accelerate SNRK transcription. In LPS-treated HK-2 cells, BMSCs-EVs overexpressing miR-223-3p increased cell viability and diminished cell apoptosis, KIM-1, LDH, IL-1β, IL-6, TNF-α, NLRP3, ASC, cleaved caspase-1, and IL-18 expression, and GSDMD cleavage, which was nullified by HDAC2 overexpression or SNRK silencing. In AKI rats, BMSCs-EV-shuttled miR-223-3p reduced CRE and BUN levels, apoptosis, inflammation, and pyroptosis, which was abrogated by SNRK silencing. CONCLUSION Conclusively, BMSC-derived EV-encapsulated miR-223-3p mitigated AKI-induced inflammation and pyroptosis by targeting HDAC2 and promoting SNRK transcription.
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Affiliation(s)
- Zhijuan Xie
- Department of Nephrology, The First Affiliated Hospital, Hengyang Medical School, University of South China, No. 69 Chuanshan Road, Hengyang, 421001, Hunan, People's Republic of China
| | - Jun Tang
- Department of Emergency, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China
| | - Zhong Chen
- Department of Nuclear Medicine, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China
| | - Lanji Wei
- Health Management Center, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China
| | - Jianying Chen
- Department of Rheumatology and Immunology, Hunan Province Mawangdui Hospital, Changsha, 410016, Hunan, People's Republic of China
| | - Qin Liu
- Department of Nephrology, The First Affiliated Hospital, Hengyang Medical School, University of South China, No. 69 Chuanshan Road, Hengyang, 421001, Hunan, People's Republic of China.
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Wei W, Li W, Yang L, Weeramantry S, Ma L, Fu P, Zhao Y. Tight junctions and acute kidney injury. J Cell Physiol 2023; 238:727-741. [PMID: 36815285 DOI: 10.1002/jcp.30976] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 01/27/2023] [Accepted: 02/04/2023] [Indexed: 02/24/2023]
Abstract
Acute kidney injury (AKI) is characterized by a rapid reduction in kidney function caused by various etiologies. Tubular epithelial cell dysregulation plays a pivotal role in the pathogenesis of AKI. Tight junction (TJ) is the major molecular structure that connects adjacent epithelial cells and is critical in maintaining barrier function and determining the permeability of epithelia. TJ proteins are dysregulated in various types of AKI, and some reno-protective drugs can reverse TJ changes caused by insult. An in-depth understanding of TJ regulation and its causality with AKI will provide more insight to the disease pathogenesis and will shed light on the potential role of TJs to serve as novel therapeutic targets in AKI.
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Affiliation(s)
- Wei Wei
- Division of Nephrology and Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Weiying Li
- Department of Internal Medicine, Florida Hospital/AdventHealth, Orlando, Florida, USA
| | - Letian Yang
- Division of Nephrology and Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Savidya Weeramantry
- Department of Internal Medicine, West China School of Medicine, Sichuan University, Chengdu, Sichuan, China
| | - Liang Ma
- Division of Nephrology and Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ping Fu
- Division of Nephrology and Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yuliang Zhao
- Division of Nephrology and Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Quaglia M, Fanelli V, Merlotti G, Costamagna A, Deregibus MC, Marengo M, Balzani E, Brazzi L, Camussi G, Cantaluppi V. Dual Role of Extracellular Vesicles in Sepsis-Associated Kidney and Lung Injury. Biomedicines 2022; 10:biomedicines10102448. [PMID: 36289710 PMCID: PMC9598620 DOI: 10.3390/biomedicines10102448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 09/25/2022] [Accepted: 09/27/2022] [Indexed: 11/16/2022] Open
Abstract
Extracellular vesicles form a complex intercellular communication network, shuttling a variety of proteins, lipids, and nucleic acids, including regulatory RNAs, such as microRNAs. Transfer of these molecules to target cells allows for the modulation of sets of genes and mediates multiple paracrine and endocrine actions. EVs exert broad pro-inflammatory, pro-oxidant, and pro-apoptotic effects in sepsis, mediating microvascular dysfunction and multiple organ damage. This deleterious role is well documented in sepsis-associated acute kidney injury and acute respiratory distress syndrome. On the other hand, protective effects of stem cell-derived extracellular vesicles have been reported in experimental models of sepsis. Stem cell-derived extracellular vesicles recapitulate beneficial cytoprotective, regenerative, and immunomodulatory properties of parental cells and have shown therapeutic effects in experimental models of sepsis with kidney and lung involvement. Extracellular vesicles are also likely to play a role in deranged kidney-lung crosstalk, a hallmark of sepsis, and may be key to a better understanding of shared mechanisms underlying multiple organ dysfunction. In this review, we analyze the state-of-the-art knowledge on the dual role of EVs in sepsis-associated kidney/lung injury and repair. PubMed library was searched from inception to July 2022, using a combination of medical subject headings (MeSH) and keywords related to EVs, sepsis, acute kidney injury (AKI), acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). Key findings are summarized into two sections on detrimental and beneficial mechanisms of actions of EVs in kidney and lung injury, respectively. The role of EVs in kidney-lung crosstalk is then outlined. Efforts to expand knowledge on EVs may pave the way to employ them as prognostic biomarkers or therapeutic targets to prevent or reduce organ damage in sepsis.
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Affiliation(s)
- Marco Quaglia
- Nephrology and Kidney Transplantation Unit, Department of Translational Medicine, University of Piemonte Orientale (UPO), 28100 Novara, Italy
| | - Vito Fanelli
- Department of Anaesthesia, Critical Care and Emergency, Città della Salute e della Scienza Hospital, University of Torino, 10126 Torino, Italy
| | - Guido Merlotti
- Nephrology and Kidney Transplantation Unit, Department of Translational Medicine, University of Piemonte Orientale (UPO), 28100 Novara, Italy
| | - Andrea Costamagna
- Department of Anaesthesia, Critical Care and Emergency, Città della Salute e della Scienza Hospital, University of Torino, 10126 Torino, Italy
| | | | - Marita Marengo
- Nephrology and Dialysis Unit, ASL CN1, 12038 Savigliano, Italy
| | - Eleonora Balzani
- Department of Anaesthesia, Critical Care and Emergency, Città della Salute e della Scienza Hospital, University of Torino, 10126 Torino, Italy
| | - Luca Brazzi
- Department of Anaesthesia, Critical Care and Emergency, Città della Salute e della Scienza Hospital, University of Torino, 10126 Torino, Italy
| | - Giovanni Camussi
- Department of Medical Sciences, University of Torino, 10126 Torino, Italy
- Correspondence: (G.C.); (V.C.)
| | - Vincenzo Cantaluppi
- Nephrology and Kidney Transplantation Unit, Department of Translational Medicine, University of Piemonte Orientale (UPO), 28100 Novara, Italy
- Correspondence: (G.C.); (V.C.)
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Yao G, Qi J, Li X, Tang X, Li W, Chen W, Xia N, Wang S, Sun L. Mesenchymal stem cell transplantation alleviated atherosclerosis in systemic lupus erythematosus through reducing MDSCs. Stem Cell Res Ther 2022; 13:328. [PMID: 35850768 PMCID: PMC9290280 DOI: 10.1186/s13287-022-03002-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 05/19/2022] [Indexed: 12/02/2022] Open
Abstract
Objective The mechanism by which mesenchymal stem cell (MSC) transplantation alleviates atherosclerosis in systemic lupus erythematosus (SLE) remains elusive. In this study, we aim to explore the efficacy and mechanism of MSC in ameliorating atherosclerosis in SLE. Methods ApoE−/− and Fas−/− mice on the B6 background were cross-bred to generate SLE mice with atherosclerosis. Myeloid-derived suppressor cells (MDSCs) were sorted and quantified. The apoE−/−Fas−/− mice were either treated with anti-Gr antibody or injected with MDSCs. The lupus-like autoimmunity and atherosclerotic lesions were evaluated. Furthermore, the apoE−/−Fas−/− mice were transplanted with MSCs and lupus-like autoimmunity and atherosclerotic lesions were assessed. Results MDSCs in peripheral blood, spleen, draining lymph nodes increased in apoE−/−Fas−/− mice compared with B6 mice. Moreover, the adoptive transfer of MDSCs aggravated both atherosclerosis and SLE pathologies, whereas depleting MDSCs ameliorated those pathologies in apoE−/−Fas−/− mice. MSC transplantation in apoE−/−Fas−/− mice decreased the percentage of MDSCs, alleviated the typical atherosclerotic lesions, including atherosclerotic lesions in aortae and liver, and reduced serum cholesterol, triglyceride and low-density lipoprotein levels. MSC transplantation also reduced SLE pathologies, including splenomegaly, glomerular lesions, anti-dsDNA antibody in serum, urine protein and serum creatinine. Moreover, MSC transplantation regulated the generation and function of MDSCs through secreting prostaglandin E 2 (PGE2). Conclusion Taken together, these results indicated that the increased MDSCs contributed to atherosclerosis in SLE. MSC transplantation ameliorated the atherosclerosis and SLE through reducing MDSCs by secreting PGE2. Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-03002-y.
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Affiliation(s)
- Genhong Yao
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Jingjing Qi
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China.,Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, China
| | - Xiaojing Li
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Xiaojun Tang
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Wenchao Li
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Weiwei Chen
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Nan Xia
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Shiying Wang
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China.
| | - Lingyun Sun
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China.
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McWilliam SJ, Turner MA, Davis JM. Nephrotoxic drugs and renal function in preterm infants: are urinary biomarkers the answer? Pediatr Res 2022; 92:22-24. [PMID: 35365759 DOI: 10.1038/s41390-022-02049-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 03/10/2022] [Accepted: 03/21/2022] [Indexed: 11/09/2022]
Affiliation(s)
- Stephen J McWilliam
- Department of Women's and Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
| | - Mark A Turner
- Department of Women's and Children's Health, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Jonathan M Davis
- Division of Newborn Medicine and the Tufts Clinical and Translational Science Institute, Tufts Medical Center, Boston, MA, USA.
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Gao Z, Chen X. Fatty Acid β-Oxidation in Kidney Diseases: Perspectives on Pathophysiological Mechanisms and Therapeutic Opportunities. Front Pharmacol 2022; 13:805281. [PMID: 35517820 PMCID: PMC9065343 DOI: 10.3389/fphar.2022.805281] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 03/31/2022] [Indexed: 11/13/2022] Open
Abstract
The kidney is a highly metabolic organ and requires a large amount of ATP to maintain its filtration-reabsorption function, and mitochondrial fatty acid β-oxidation serves as the main source of energy to meet its functional needs. Reduced and inefficient fatty acid β-oxidation is thought to be a major mechanism contributing to kidney diseases, including acute kidney injury, chronic kidney disease and diabetic nephropathy. PPARα, AMPK, sirtuins, HIF-1, and TGF-β/SMAD3 activation have all been shown to play key roles in the regulation of fatty acid β-oxidation in kidney diseases, and restoration of fatty acid β-oxidation by modulation of these molecules can ameliorate the development of such diseases. Here, we disentangle the lipid metabolism regulation properties and potential mechanisms of mesenchymal stem cells and their extracellular vesicles, and emphasize the role of mesenchymal stem cells on lipid metabolism. This review aims to highlight the important role of fatty acid β-oxidation in the progression of kidney diseases, and to explore the fatty acid β-oxidation effects and therapeutic potential of mesenchymal stem cells for kidney diseases.
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Affiliation(s)
- Zhumei Gao
- Department of Nephrology, The Second Hospital of Jilin University, Jilin, China
| | - Xiangmei Chen
- Department of Nephrology, The Second Hospital of Jilin University, Jilin, China.,Department of Nephrology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
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Sanmartin MC, Borzone FR, Giorello MB, Yannarelli G, Chasseing NA. Mesenchymal Stromal Cell-Derived Extracellular Vesicles as Biological Carriers for Drug Delivery in Cancer Therapy. Front Bioeng Biotechnol 2022; 10:882545. [PMID: 35497332 PMCID: PMC9046597 DOI: 10.3389/fbioe.2022.882545] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 03/25/2022] [Indexed: 12/11/2022] Open
Abstract
Cancer is the second leading cause of death worldwide, with 10.0 million cancer deaths in 2020. Despite advances in targeted therapies, some pharmacological drawbacks associated with anticancer chemo and immunotherapeutic agents include high toxicities, low bioavailability, and drug resistance. In recent years, extracellular vesicles emerged as a new promising platform for drug delivery, with the advantage of their inherent biocompatibility and specific targeting compared to artificial nanocarriers, such as liposomes. Particularly, mesenchymal stem/stromal cells were proposed as a source of extracellular vesicles for cancer therapy because of their intrinsic properties: high in vitro self-renewal and proliferation, regenerative and immunomodulatory capacities, and secretion of extracellular vesicles that mediate most of their paracrine functions. Moreover, extracellular vesicles are static and safer in comparison with mesenchymal stem/stromal cells, which can undergo genetic/epigenetic or phenotypic changes after their administration to patients. In this review, we summarize currently reported information regarding mesenchymal stem/stromal cell-derived extracellular vesicles, their proper isolation and purification techniques - from either naive or engineered mesenchymal stem/stromal cells - for their application in cancer therapy, as well as available downstream modification methods to improve their therapeutic properties. Additionally, we discuss the challenges associated with extracellular vesicles for cancer therapy, and we review some preclinical and clinical data available in the literature.
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Affiliation(s)
- María Cecilia Sanmartin
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
- Laboratorio de Regulación Génica y Células Madre, Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMeTTyB), Universidad Favaloro - CONICET, Buenos Aires, Argentina
| | - Francisco Raúl Borzone
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - María Belén Giorello
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Gustavo Yannarelli
- Laboratorio de Regulación Génica y Células Madre, Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMeTTyB), Universidad Favaloro - CONICET, Buenos Aires, Argentina
| | - Norma Alejandra Chasseing
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
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Liao C, Chen G, Yang Q, Liu Y, Zhou T. Potential Therapeutic Effect and Mechanisms of Mesenchymal Stem Cells-Extracellular Vesicles in Renal Fibrosis. Front Cell Dev Biol 2022; 10:824752. [PMID: 35359447 PMCID: PMC8961868 DOI: 10.3389/fcell.2022.824752] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 02/14/2022] [Indexed: 02/05/2023] Open
Abstract
Renal fibrosis (RF) is central pathological pathway for kidney diseases, with the main pathological features being the aberrant accumulation of myofibroblasts that produce accumulation of extracellular matrix in the renal interstitium and glomeruli. Acute kidney injury (AKI) and chronic kidney disease (CKD) are associated with RF. Current treatment strategies for RF are ineffective. Mesenchymal stem cells (MSCs) have been found to be able to treat organ fibrosis including RF, but they have some safety problems, such as cell rejection, carcinogenicity, and virus contamination, which limit the application of MSCs. However, current studies have found that MSCs may exert their therapeutic effect by releasing extracellular vesicles (EVs). MSC-EVs can transfer functional proteins and genetic material directly to the recipient cells. As non-cell membrane structures, MSC-EVs have the advantages of low immunogenicity, easy preservation, and artificial modification, but do not have the characteristics of self-replication and ectopic differentiation. Therefore, EVs are safer than MSCs for treatment, but might be less effective than MSCs. Recent studies have also found that MSC-EVs can improve renal function and pathological changes of RF. Thus, this review summarizes the therapeutic effect of MSC-EVs on RF and the mechanisms that have been discovered so far, so as to provide a theoretical basis for the further study of the role of MSC-EVs in treating RF diseases.
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Affiliation(s)
- Chunling Liao
- Department of Nephrology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, China
| | | | | | | | - Tianbiao Zhou
- Department of Nephrology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, China
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Franco ML, Beyerstedt S, Rangel ÉB. Klotho and Mesenchymal Stem Cells: A Review on Cell and Gene Therapy for Chronic Kidney Disease and Acute Kidney Disease. Pharmaceutics 2021; 14:11. [PMID: 35056905 PMCID: PMC8778857 DOI: 10.3390/pharmaceutics14010011] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 12/16/2021] [Accepted: 12/17/2021] [Indexed: 02/07/2023] Open
Abstract
Chronic kidney disease (CKD) and acute kidney injury (AKI) are public health problems, and their prevalence rates have increased with the aging of the population. They are associated with the presence of comorbidities, in particular diabetes mellitus and hypertension, resulting in a high financial burden for the health system. Studies have indicated Klotho as a promising therapeutic approach for these conditions. Klotho reduces inflammation, oxidative stress and fibrosis and counter-regulates the renin-angiotensin-aldosterone system. In CKD and AKI, Klotho expression is downregulated from early stages and correlates with disease progression. Therefore, the restoration of its levels, through exogenous or endogenous pathways, has renoprotective effects. An important strategy for administering Klotho is through mesenchymal stem cells (MSCs). In summary, this review comprises in vitro and in vivo studies on the therapeutic potential of Klotho for the treatment of CKD and AKI through the administration of MSCs.
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Affiliation(s)
- Marcella Liciani Franco
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, Sao Paulo 05652-900, Brazil; (M.L.F.); (S.B.)
| | - Stephany Beyerstedt
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, Sao Paulo 05652-900, Brazil; (M.L.F.); (S.B.)
| | - Érika Bevilaqua Rangel
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, Sao Paulo 05652-900, Brazil; (M.L.F.); (S.B.)
- Nephrology Division, Federal University of São Paulo, Sao Paulo 04038-901, Brazil
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Wei H, Green E, Ball L, Fan H, Lee J, Strange C, Wang H. Proteomic Analysis of Exosomes Secreted from Human Alpha-1 Antitrypsin Overexpressing Mesenchymal Stromal Cells. BIOLOGY 2021; 11:biology11010009. [PMID: 35053007 PMCID: PMC8773149 DOI: 10.3390/biology11010009] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/07/2021] [Accepted: 12/18/2021] [Indexed: 12/24/2022]
Abstract
Extracellular vesicles (EVs) mediate many therapeutic effects of stem cells during cellular therapies. Bone marrow-derived mesenchymal stromal cells (BM-MSCs) were manufactured to overexpress the human antiprotease alpha-1 antitrypsin (hAAT) and studied to compare the EV production compared to lentivirus treated control MSCs. The goal of this study was to compare protein profiles in the EVs/exosomes of control and hAAT-MSCs using unbiased, high resolution liquid chromatography and mass spectrometry to explore differences. Nanoparticle tracking analysis (NTA) showed that the particle size of the EVs from control MSCs or hAAT-MSCs ranged from 30 to 200 nm. Both MSCs and hAAT-MSCs expressed exosome-associated proteins, including CD63, CD81, and CD9. hAAT-MSCs also expressed high levels of hAAT. We next performed proteomic analysis of EVs from three healthy donor cell lines. Exosomes collected from cell supernatant were classified by GO analysis which showed proteins important to cell adhesion and extracellular matrix organization. However, there were differences between exosomes from control MSCs and hAAT-MSCs in cytokine signaling of the immune system, stem cell differentiation, and carbohydrate metabolism (p < 0.05). These results show that hAAT-MSC exosomes contain a different profile of paracrine effectors with altered immune function, impacts on MSC stemness, differentiation, and prevention of cell apoptosis and survival that could contribute to improved therapeutic functions.
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Affiliation(s)
- Hua Wei
- Departments of Surgery, Medical University of South Carolina, CRI 410, 173 Ashley Avenue, Charleston, SC 29425, USA; (H.W.); (E.G.)
| | - Erica Green
- Departments of Surgery, Medical University of South Carolina, CRI 410, 173 Ashley Avenue, Charleston, SC 29425, USA; (H.W.); (E.G.)
| | - Lauren Ball
- Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, CRI 311, 173 Ashley Avenue, Charleston, SC 29425, USA;
| | - Hongkuan Fan
- Pathology and Laboratory Medicine, Medical University of South Carolina, CRI 610, 173 Ashley Avenue, Charleston, SC 29425, USA;
| | | | - Charlie Strange
- Department of Medicine, Medical University of South Carolina, CSB 816, 96 Jonathan Lucas St., Charleston, SC 29425, USA;
| | - Hongjun Wang
- Departments of Surgery, Medical University of South Carolina, CRI 410, 173 Ashley Avenue, Charleston, SC 29425, USA; (H.W.); (E.G.)
- Center for Cellular Therapy, Medical University of South Carolina, Charleston, SC 29425, USA
- Ralph H. Johnson VA Medical Center, Charleston, SC 29425, USA
- Correspondence: ; Tel.: +843-792-1800; Fax: 843-792-3315
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