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Alimogullari E, Kartal B, Demir H, Elci MP. Protective effects of adipose-derived stem cells against testicular injury induced after ischemia-reperfusion by regulating autophagy. Histochem Cell Biol 2024; 163:18. [PMID: 39709318 DOI: 10.1007/s00418-024-02347-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/29/2024] [Indexed: 12/23/2024]
Abstract
The damaged organ may experience severe pathological alterations as a result of tissue ischemia-reperfusion (I/R). The study of stem cell-based repair therapies is actively being conducted, and the outcomes and therapeutic potential of these cells are both promising. Autophagy checks protein homeostasis by breaking down huge damaged proteins or organelles. The study's objective was to assess how ADSCs impact the autophagic process after testicular ischemia/reperfusion. In our investigation, 30 male rats were divided into five groups: control, ADSC, ischemia, I/R, and I/R + ADSC (n = 6). Hematoxylin-eosin (HE) was used to stain the testes, and histological changes were assessed. The immunoexpression of androgen receptor (AR), Beclin1, protein light chain 3B (LC3B), and p62 were examined. The seminiferous epithelium in the testis from the ischemia and I/R groups revealed significant degeneration with disorganized morphology, damaged spermatogenic cells, and interstitial space congestion, according to HE stain results. Johnsen's score were significantly better in I/R + ADSC group than in ischemia and I/R groups. We demonstrated that in rat testes from the I/R groups, immunostaining of Beclin 1 (p = 0.042) and LC3B (p = 0.011) were raised, and p62 (p = 0.047) and AR (p = 0.049) were decreased. Ischemia and I/R promoted testicular autophagy, therefore we can conclude that ADSCs prevent excessive autophagy. Additionally, these results show that the use of ADSCs cures testicular injury and dysfunction associated with I/R injury in rats even a little.
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Affiliation(s)
- Ebru Alimogullari
- Medical Faculty, Department of Histology and Embryology, Ankara Yıldırım Beyazıt University, Ankara, Turkey.
| | - Bahar Kartal
- Medical Faculty, Department of Histology and Embryology, Ankara Yıldırım Beyazıt University, Ankara, Turkey
| | - Hazal Demir
- Medical Faculty, Department of Histology and Embryology, Ankara Yıldırım Beyazıt University, Ankara, Turkey
| | - Mualla Pınar Elci
- Stem Cell Laboratory, University of Health Sciences Gulhane Health Sciences Institute, Ankara, Turkey
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Li H, Chen C, Huang W, Shi L, Zhang Q, Zhou L, Huang H, Zhou S. Long-term expanded hepatic progenitor cells ameliorate D-GalN/LPS-induced acute liver failure through repolarizing M1 macrophage to M2-Like phenotype via activation of the IL-10/JAK2/STAT3 signaling pathway. Int Immunopharmacol 2024; 142:113127. [PMID: 39276457 DOI: 10.1016/j.intimp.2024.113127] [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: 05/02/2024] [Revised: 08/25/2024] [Accepted: 09/06/2024] [Indexed: 09/17/2024]
Abstract
Acute liver failure (ALF) is a devastating liver disease characterized by the rapid deterioration of hepatocytes, which causes a series of clinical complications, including hepatic dysfunction, coagulopathy, encephalopathy, and multiorgan failure. Cell-based therapy is a promising alternative as it can bridge patients until their livers regenerate, releasing immunomodulatory molecules to suppress inflammation. This study reports an iPSCs-derived long-term expanded hepatic progenitor cell (LTHepPCs), which can differentiate into hepatocyte-like cells (HLCs) in vivo. When introduced into drug-induced ALF models, LTHepPCs mitigate liver damage by modulating the local immune microenvironment. This is achieved by shifting macrophages/Kupffer cells towards an anti-inflammatory state, resulting in a decrease in the expression of inflammatory cytokines such as TNF-a, IL-1β, and IL-8, and an increase in the expression of anti-inflammatory cytokines such as IL-10 and ARG-1. In vitro co-culturing of THP-1 or mBMDMs with LTHepPCs suggested that LTHepPCs could activate the anti-inflammatory state of macrophages/Kupffer cells via the IL-10/JAK2/STAT3 signaling pathway. Therefore, LTHepPC transplantation is a promising therapy for ALF patients.
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Affiliation(s)
- Hongsheng Li
- Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Chen Chen
- Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Weijian Huang
- Celliver Biotechnology Inc., Shanghai, PR China; Department of Anesthesiology and Critical Care Medicine, School of Medicine, Renji Hospital, Shanghai Jiaotong University, Shanghai, PR China
| | - Lei Shi
- Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Qin Zhang
- Celliver Biotechnology Inc., Shanghai, PR China
| | - Li Zhou
- Celliver Biotechnology Inc., Shanghai, PR China
| | - Hai Huang
- Department of Urinary Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin Road No.2, Shanghai, PR China.
| | - Shen'ao Zhou
- Celliver Biotechnology Inc., Shanghai, PR China; State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, CAS. Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, PR China.
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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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Abd-Allah SH, Khamis T, Samy W, Alsemeh AE, Abdullah DM, Hussein S. Mesenchymal Stem Cells and Their Derived Exosomes Mitigated Hepatic Cirrhosis in Rats by Altering the Expression of miR-23b and miR-221. IRANIAN JOURNAL OF MEDICAL SCIENCES 2024; 49:724-740. [PMID: 39678523 PMCID: PMC11645418 DOI: 10.30476/ijms.2023.99524.3159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 10/18/2023] [Accepted: 11/19/2023] [Indexed: 12/17/2024]
Abstract
Background The therapeutic effect of mesenchymal stem cells (MSCs) in liver cirrhosis is limited by their entrapment in the pulmonary vessels. Thus, the use of MSC-derived exosomes has become a promising strategy. The current work aimed to compare the role of human umbilical cord blood-MSCs (hUCB-MSCs) and their derived exosomes in the alleviation of liver cirrhosis focusing on the role of miR-23b and miR-221 and their direct effectors in inflammatory and autophagic pathways. Methods Rats were divided into six groups normal controls (negative control), liver cirrhosis group (positive control), liver cirrhotic rats that received conditioned media, liver cirrhotic rats that received hUCB-MSCs, cirrhotic rats that received exosomes, and cirrhotic rats that received both hUCB-MSCs and exosomes. The messenger RNA expression of transforming growth factor-β (TGF-β), Matrix metalloproteinase 9 (MMP 9), fibronectin, collagen type-1 (col1), alpha-smooth muscle actin (α-SMA), Suppressor of Mothers Against Decapentaplegic (SMAD) 2 and 7, Beclin, P62, and light chain 3 (LC3) were evaluated by quantitative real-time polymerase chain reaction. Immunohistochemical staining for Beclin, P62, and LC3 was performed. Results The treatment of cirrhotic rats with hUCB-MSCs, exosomes, or the combination of them significantly downregulated miRNA-221, fibronectin, collagen I, α-SMA, Smad2 (P<0.001, for each), and P62 (P=0.032, P<0.001, P<0.001, respectively). Additionally, the treatment of cirrhotic rats with hUCB-MSCs, exosomes, or the combination of them significantly upregulated mTOR, Beclin, LC3, and Smad7 (P<0.001, for each) and miRNA-23 (P=0.021, P<0.001, P<0.001, respectively). Conclusion hUCB-MSCs and their derived exosomes ameliorated liver cirrhosis by anti-inflammatory and anti-fibrotic effects besides modulation of autophagy. The exosomes had a better improvement effect either alone or combined with hUCB-MSCs, as proved by improvement in liver function tests, and molecular, histopathological, and immunohistochemical profiles.
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Affiliation(s)
- Somia H. Abd-Allah
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Zagazig University, Zagazig, Egypt
| | - Tarek Khamis
- Department of Pharmacology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
| | - Walaa Samy
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Zagazig University, Zagazig, Egypt
| | | | - Doaa M. Abdullah
- Department of Clinical Pharmacology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Samia Hussein
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Zagazig University, Zagazig, Egypt
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Jin YX, Hu HQ, Zhang JC, Xin XY, Zhu YT, Ye Y, Li D. Mechanism of mesenchymal stem cells in liver regeneration: Insights and future directions. World J Stem Cells 2024; 16:842-845. [PMID: 39351263 PMCID: PMC11438733 DOI: 10.4252/wjsc.v16.i9.842] [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: 07/13/2024] [Revised: 08/08/2024] [Accepted: 08/26/2024] [Indexed: 09/24/2024] Open
Abstract
Mesenchymal stem cells (MSCs) are a prevalent source for stem cell therapy and play a crucial role in modulating both innate and adaptive immune responses. Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of triglycerides in liver cells and involves immune system activation, leading to histological changes, tissue damage, and clinical symptoms. A recent publication by Jiang et al, highlighted the potential of MSCs to mitigate in NAFLD progression by targeting various molecular pathways, including glycolipid metabolism, inflammation, oxidative stress, endoplasmic reticulum stress, and fibrosis. In this editorial, we comment on their research and discuss the efficacy of MSC therapy in treating NAFLD.
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Affiliation(s)
- Yu-Xin Jin
- Department of Traditional Chinese Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Hang-Qi Hu
- Department of Traditional Chinese Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Jia-Cheng Zhang
- Department of Traditional Chinese Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Xi-Yan Xin
- Department of Traditional Chinese Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Yu-Tian Zhu
- Department of Traditional Chinese Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Yang Ye
- Department of Traditional Chinese Medicine, Peking University Third Hospital, Beijing 100191, China.
| | - Dong Li
- Department of Traditional Chinese Medicine, Peking University Third Hospital, Beijing 100191, China
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Salem BAA, ElKaliny HH, El-Hafez AAAA, Sarhan NI. Comparative Histological Study of Therapeutic Effect of Mesenchymal Stem Cells versus Mesenchymal Stem Cells Co-Cultured with Liver Tissue on Carbon Tetrachloride-Induced Hepatotoxicity in Adult Male Albino Rats. J Microsc Ultrastruct 2023; 11:225-236. [PMID: 38213650 PMCID: PMC10779448 DOI: 10.4103/jmau.jmau_62_21] [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: 06/18/2021] [Revised: 08/02/2021] [Accepted: 08/02/2021] [Indexed: 11/04/2022] Open
Abstract
Context Liver diseases are major causes of morbidity and mortality. Mesenchymal stem cells (MSCs) have immunomodulatory, anti-inflammatory, and antifibrotic effects, so they can be used in the treatment of liver diseases. MSCs co-cultured with diseased liver tissue improve the homing capacity, survival rate, and paracrine effects of the MSCs, as well as the ability to enhance liver function. Aims This work aimed to study the therapeutic effect of MSCs versus MSCs co-cultured with liver tissue on carbon tetrachloride (CCl4)-induced hepatotoxicity in adult male albino rats. Settings and Design Twenty adult male albino rats were divided into four equal groups; Group I (control group), Group II received CCl4 intraperitoneally (i.p.), Group III received CCl4 i.p. and then injected with MSCs intravenously (i.v.), and Group IV received CCl4 i.p. and then injected with co-cultured MSCs i.v. Materials and Methods Finally, liver specimens were processed for light microscopy (LM) and electron microscopy (EM). Statistical analysis was carried out to assess histological scoring, area percentage of collagen fibers, number of glial fibrillary acidic protein-positive cells, and biochemical analysis of alanine aminotransferase and aspartate aminotransferase. Statistical Analysis Used Statistical analysis of (histological scoring, area % of collagen fibers, and biochemical analysis) was done by using one-way analysis of variance (ANOVA) test using graphpad software (SanDiego, CA, USA). The means ± standard deviations were used for statistical analysis. Results LM of Group II revealed loss of hepatic architecture and diffuse fibrosis with dilated congested blood vessels, bile ductular proliferation, and cellular infiltrations. Vacuolated cytoplasm with or without pyknotic nuclei was observed in addition to micro- and macro-steatosis. EM demonstrated disfigured hepatocytes with abnormal organelles surrounding atypical nucleus. Group III showed restoration of the normal liver architecture with greater extent in Group IV. Statistical analysis confirmed the microscopic findings. Conclusions Co-cultured MSCs with diseased liver tissue augmented the therapeutic effects of MSCs in treating hepatotoxicity induced by CCl4 in adult male albino rats.
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Affiliation(s)
- Bothina Abo-Alazm Salem
- Department of Histology and Cell Biology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Heba Hassan ElKaliny
- Department of Histology and Cell Biology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | | | - Naglaa Ibrahim Sarhan
- Department of Histology and Cell Biology, Faculty of Medicine, Tanta University, Tanta, Egypt
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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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Wang YH, Wang ML, Tao YC, Wu DB, Chen EQ, Tang H. The high level of IL-1β in the serum of ACLF patients induces increased IL-8 expression in hUC-MSCs and reduces the efficacy of hUC-MSCs in liver failure. Stem Cell Res Ther 2023; 14:231. [PMID: 37649110 PMCID: PMC10468895 DOI: 10.1186/s13287-023-03455-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Accepted: 08/17/2023] [Indexed: 09/01/2023] Open
Abstract
BACKGROUND Stem cells play a therapeutic role mainly through immunoregulation. However, the immunomodulatory function of stem cells may be affected by inflammation-related factors in patients' serum. Therefore, this study aims to investigate the possible mechanism by which acute-on-chronic liver failure (ACLF) patient serum influences the efficacy of hUC-MSCs. METHODS The serum of surviving and dead ACLF patients was collected to culture hUC-MSCs in vitro, and the hUC-MSCs cultured in the serum of ACLF patients were used to treat acute liver failure (ALF) rats. The therapeutic effect on the rats was evaluated by a survival curve, the transaminase level and liver histopathology. The expression of cytokines in hUC-MSCs was detected by Q-PCR and ELISA. RESULTS Serum pretreatment reduced the therapeutic effect of hUC-MSCs on ALF, especially pretreatment in the serum from dead ACLF patients. After hUC-MSCs were cultured in the serum of surviving or dead ACLF patients, the most differentially expressed factor was IL-8. Interfering with the expression of IL-8 in hUC-MSCs can improve the therapeutic effect of hUC-MSCs on ALF. The high level of IL-1β in the serum of dead ACLF patients causes the increased expression of IL-8 in hUC-MSCs through the activation of the NF-κB signaling pathway. Meanwhile, we found that the neutralizing IL-1β in serum from dead ACLF patients can improve the therapeutic effect of hUC-MSCs on ALF. CONCLUSION The high level of IL-1β in ACLF serum can promote the expression of IL-8 in hUC-MSCs through the NF-κB signaling pathway, thus reducing the effect of hUC-MSCs on ALF.
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Affiliation(s)
- Yong-Hong Wang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Meng-Lan Wang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Ya-Chao Tao
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Dong-Bo Wu
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - En-Qiang Chen
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China.
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China.
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.
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Pavlovic D, Miloradovic D, Stojanovic MD, Harrell CR, Polosa R, Rust S, Volti GL, Caruso M, Jakovljevic V, Djonov V, Volarevic V. Cigarette smoke attenuates mesenchymal stem cell-based suppression of immune cell-driven acute liver failure. Toxicol Lett 2023; 385:12-20. [PMID: 37572970 DOI: 10.1016/j.toxlet.2023.08.006] [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] [Received: 04/13/2023] [Revised: 07/22/2023] [Accepted: 08/09/2023] [Indexed: 08/14/2023]
Abstract
Detrimental effects of smoking on mesenchymal stem cell (MSC)-dependent immunosuppression and hepatoprotection are unknown. Herewith, by using α-galactosylceramide (α-GalCer)-induced liver injury, a well-established murine model of fulminant hepatitis, we examined molecular mechanisms which were responsible for negative effects of cigarette smoke on MSC-dependent immunomodulation. MSC which were grown in cigarette smoke-exposed medium (MSCWS-CM) obtained pro-inflammatory phenotype, were not able to optimally produce hepatoprotective and immunosuppressive cytokines (TGF-β, HGF, IL-10, NO, KYN), and secreted significantly higher amounts of inflammatory cytokines (IFN-γ, TNF-α, IL-17, IL-6) than MSC that were cultured in standard medium never exposed to cigarette smoke (MSCCM). In contrast to MSCCM, which efficiently attenuated α-GalCer-induced hepatitis, MSCWS-CM were not able to prevent hepatocyte injury and liver inflammation. MSCWS-CM had reduced capacity for the suppression of liver-infiltrated inflammatory macrophages, dendritic cells (DCs) and lymphocytes. Although significantly lower number of IL-12-producing macrophages and DCs, TNF-α, IFN-γ or IL-17-producing CD4 + and CD8 +T lymphocytes, NK and NKT cells were noticed in the livers of α-GalCer+MSCCM-treated mice compared to α-GalCer+saline-treated animals, this phenomenon was not observed in α-GalCer-injured mice that received MSCWS-CM. MSCWS-CM could not induce expansion of anti-inflammatory IL-10-producing FoxP3 +CD4 + and CD8 + T regulatory cells and were not able to create immunosuppressive microenvironment in the liver as MSCCM. Similarly as it was observed in mice, MSCWS-CM were not able to optimally inhibit production of inflammatory and hepatototoxic cytokines in activated human Th1/Th17 and NKT1/NKT17 cells, confirming the hypothesis that cigarette smoke significantly attenuates therapeutic potential of MSC in cell-based immunotherapy of inflammatory liver diseases.
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Affiliation(s)
- Dragica Pavlovic
- Department of Genetics, Center for harm reduction of biological and chemical hazards, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia
| | - Dragana Miloradovic
- Department of Genetics, Center for harm reduction of biological and chemical hazards, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia
| | - Milica Dimitrijevic Stojanovic
- Department of Pathology, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia
| | - Carl Randall Harrell
- Regenerative Processing Plant, LLC, 34176 US Highway 19 N Palm Harbor, Palm Harbor, FL 34684, USA
| | - Riccardo Polosa
- Center of Excellence for the Acceleration of Harm Reduction (CoEHAR), University of Catania, Via S. Sofia, 89, 95123 Catania, Italy; Department of Clinical and Experimental Medicine, University of Catania, Via S. Sofia, 89, 95123 Catania, Italy
| | - Sonja Rust
- ECLAT Srl, University of Catania, Via S. Sofia, 89, 95123 Catania, Italy
| | - Giovanni Li Volti
- Center of Excellence for the Acceleration of Harm Reduction (CoEHAR), University of Catania, Via S. Sofia, 89, 95123 Catania, Italy; Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia, 89, 95123 Catania, Italy
| | - Massimo Caruso
- Center of Excellence for the Acceleration of Harm Reduction (CoEHAR), University of Catania, Via S. Sofia, 89, 95123 Catania, Italy; Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia, 89, 95123 Catania, Italy
| | - Vladimir Jakovljevic
- Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia
| | - Valentin Djonov
- Institute of Anatomy, University of Bern, Baltzerstrasse 2, 3012 Bern, Switzerland
| | - Vladislav Volarevic
- Department of Genetics, Center for harm reduction of biological and chemical hazards, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia; Departments of Genetics and Department of Microbiology and Immunology, Center for harm reduction of biological and chemical hazards, Faculty of Medical Sciences University of Kragujevac, Serbia.
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Jiang C, Chen H, Kang Y, He X, Huang J, Lu T, Sui X, Chen H, Xiao J, Zhang J, Zhang H, Zheng J, Yang Y, Yao J, Cai J, Zhang Y. Administration of AG490 decreases the senescence of umbilical cord-mesenchymal stem cells and promotes the cytotherapeutic effect in liver fibrosis. Cell Death Discov 2023; 9:273. [PMID: 37507381 PMCID: PMC10382487 DOI: 10.1038/s41420-023-01546-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 06/20/2023] [Accepted: 07/04/2023] [Indexed: 07/30/2023] Open
Abstract
The therapeutic potential of umbilical cord-mesenchymal stem cell (UC-MSC) transplantation in liver fibrosis has been highlighted. However, the fate of transplanted MSCs in the fibrotic microenvironment remains unclear. In this study, we aim to uncover the fate of transplanted MSCs and develop targeting strategies that could enhance the therapeutic efficacy of MSC therapy in liver fibrosis. We used human UC-MSCs as the study object. For in vitro experiments, we stimulated UC-MSCs with several fibrotic-related factors (Liver fibrotic Factors, LF), including TGFβ, TNFα and IFNγ for downstream investigations. We co-cultured LF-treated UC-MSCs with hepatic stellate cell line LX-2 to assess the anti-fibrotic effect. We showed that upon LF stimulation, UC-MSCs exhibited reduced anti-fibrotic activity and underwent rapid senescence. Pathway analysis showed that JAK/STAT3 signaling was highly activated upon LF stimulation, which significantly elevated senescence-associated secretory phenotype (SASP) and senescence in UC-MSCs and could be reversed by a specific JAK inhibitor AG490. Moreover, using both carbon tetrachloride (CCl4) and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induce fibrosis models, we demonstrated that AG490 pretreatment promoted UC-MSCs survival within the fibrotic liver microenvironment and exhibited enhance therapeutic efficacy. Overall, we showed that targeting MSC senescence in vivo through AG490 pretreatment could enhance the anti-fibrotic activities of UC-MSCs.
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Affiliation(s)
- Chenhao Jiang
- Department of Hepatic Surgery and Liver Transplantation Centre, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Key Laboratory of Liver Disease Research, Guangdong Engineering Laboratory for Transplantation, Guangzhou, China
| | - Huaxin Chen
- Biotherapy Centre, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yinqian Kang
- Department of Anesthesiology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xinyi He
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Jianyang Huang
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Tongyu Lu
- Department of Hepatic Surgery and Liver Transplantation Centre, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Key Laboratory of Liver Disease Research, Guangdong Engineering Laboratory for Transplantation, Guangzhou, China
| | - Xin Sui
- Surgical ICU, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Haitian Chen
- Department of Hepatic Surgery and Liver Transplantation Centre, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Key Laboratory of Liver Disease Research, Guangdong Engineering Laboratory for Transplantation, Guangzhou, China
| | - Jiaqi Xiao
- Department of Hepatic Surgery and Liver Transplantation Centre, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Key Laboratory of Liver Disease Research, Guangdong Engineering Laboratory for Transplantation, Guangzhou, China
| | - Jiebin Zhang
- Department of Hepatic Surgery and Liver Transplantation Centre, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Key Laboratory of Liver Disease Research, Guangdong Engineering Laboratory for Transplantation, Guangzhou, China
| | - Hanwen Zhang
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, 30309, USA
| | - Jun Zheng
- Department of Hepatic Surgery and Liver Transplantation Centre, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Key Laboratory of Liver Disease Research, Guangdong Engineering Laboratory for Transplantation, Guangzhou, China
| | - Yang Yang
- Department of Hepatic Surgery and Liver Transplantation Centre, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Key Laboratory of Liver Disease Research, Guangdong Engineering Laboratory for Transplantation, Guangzhou, China
| | - Jia Yao
- Department of Hepatic Surgery and Liver Transplantation Centre, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
- Guangdong Key Laboratory of Liver Disease Research, Guangdong Engineering Laboratory for Transplantation, Guangzhou, China.
| | - Jianye Cai
- Department of Hepatic Surgery and Liver Transplantation Centre, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
- Guangdong Key Laboratory of Liver Disease Research, Guangdong Engineering Laboratory for Transplantation, Guangzhou, China.
| | - Yingcai Zhang
- Department of Hepatic Surgery and Liver Transplantation Centre, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
- Guangdong Key Laboratory of Liver Disease Research, Guangdong Engineering Laboratory for Transplantation, Guangzhou, China.
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11
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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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12
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Shang LC, Wang M, Liu Y, Zhu X, Wang S. MSCs Ameliorate Hepatic IR Injury by Modulating Phenotypic Transformation of Kupffer Cells Through Drp-1 Dependent Mitochondrial Dynamics. Stem Cell Rev Rep 2023:10.1007/s12015-023-10566-6. [PMID: 37243829 DOI: 10.1007/s12015-023-10566-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/18/2023] [Indexed: 05/29/2023]
Abstract
BACKGROUND Hepatic ischemia and reperfusion (IR) injury, characterized by reactive oxygen species (ROS) production and immune disorders, leads to exogenous antigen-independent local inflammation and hepatocellular death. Mesenchymal stem cells (MSCs) have been shown to be immunomodulatory, antioxidative and contribute to liver regeneration in fulminant hepatic failure. We aimed to investigate the underlying mechanisms by which MSCs protect against liver IR injury in a mouse model. METHODS MSCs suspension was injected 30 min prior to hepatic warm IR. Primary kupffer cells (KCs) were isolated. Hepatic injury, inflammatory responses, innate immunity, KCs phenotypic polarization and mitochondrial dynamics were evaluated with or without KCs Drp-1 overexpression RESULTS: MSCs markedly ameliorated liver injury and attenuated inflammatory responses and innate immunity after liver IR injury. MSCs significantly restrained M1 phenotypic polarization but boosted M2 polarization of KCs extracted from ischemic liver, as demonstrated by lowered transcript levels of iNOS and IL-1β but raised transcript levels of Mrc-1 and Arg-1 combined with p-STAT6 up-regulation and p-STAT1 down-regulation. Moreover, MSCs inhibited KCs mitochondrial fission, as evidenced by decreased Drp1 and Dnm2 levels. We overexpressed Drp-1 in KCs which promote mitochondrial fission during IR injury. the regulation of MSCs towards KCs M1/M2 polarization was abrogated by Drp-1 overexpression after IR injury. Ultimately, in vivo Drp-1 overexpression in KCs hampered the therapeutic effects of MSCs against hepatic IR injury CONCLUSIONS: We revealed that MSCs facilitated M1-M2 phenotypic polarization through inhibiting Drp-1 dependent mitochondrial fission and further attenuated liver IR injury. These results add a new insight into regulating mechanisms of mitochondrial dynamics during hepatic IR injury and may offer novel opportunities for developing therapeutic targets to combat hepatic IR injury.
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Affiliation(s)
- Long-Cheng Shang
- Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu Province, China
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Man Wang
- Department of Hematology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yang Liu
- Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu Province, China
| | - Xinhua Zhu
- Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu Province, China.
| | - Shuai Wang
- Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu Province, China.
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China.
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13
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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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14
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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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15
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Wu HW, Chen HD, Chen YH, Mao XL, Feng YY, Li SW, Zhou XB. The Effects of Programmed Cell Death of Mesenchymal Stem Cells on the Development of Liver Fibrosis. Stem Cells Int 2023; 2023:4586398. [PMID: 37214784 PMCID: PMC10195177 DOI: 10.1155/2023/4586398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 02/06/2023] [Accepted: 04/02/2023] [Indexed: 05/24/2023] Open
Abstract
Mesenchymal stem cells have shown noticeable potential for unlimited self-renewal. They can differentiate into specific somatic cells, integrate into target tissues via cell-cell contact, paracrine effects, exosomes, and other processes and then regulate the target cells and tissues. Studies have demonstrated that transplantation of MSCs could decrease the expression and concentration of collagen in the liver, thereby reducing liver fibrosis. A growing body of evidence indicates that apoptotic MSCs could inhibit harmful immune responses and reduce inflammatory responses more effectively than viable MSCs. Accumulating evidence suggests that mitochondrial transfer from MSCs is a novel strategy for the regeneration of various damaged cells via the rescue of their respiratory activities. This study is aimed at reviewing the functions of MSCs and the related roles of the programmed cell death of MSCs, including autophagy, apoptosis, pyroptosis, and ferroptosis, as well as the regulatory pathogenic mechanisms of MSCs in liver fibrosis. Research has demonstrated that the miR-200B-3p gene is differentially expressed gene between LF and normal liver samples, and that the miR-200B-3p gene expression is positively correlated with the degree of liver fibrosis, suggesting that MSCs could inhibit liver fibrosis through pyroptosis. It was confirmed that circulating monocytes could deliver MSC-derived immunomodulatory molecules to different sites by phagocytosis of apoptotic MSCs, thereby achieving systemic immunosuppression. Accordingly, it was suggested that characterization of the programmed cell death-mediated immunomodulatory signaling pathways in MSCs should be a focus of research.
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Affiliation(s)
- Hong-wei Wu
- Department of Infectious Diseases, Taizhou Enze Medical Center (Group) Enze Hospital, Taizhou, Zhejiang, China
| | - He-dan Chen
- Department of Infectious Diseases, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Ya-hong Chen
- Health Management Center, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Xin-li Mao
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Yu-yi Feng
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Shao-wei Li
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Xian-bin Zhou
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
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16
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Hu G, Cui Z, Chen X, Sun F, Li T, Li C, Zhang L, Guo X, Zhao H, Xia Y, Yan W, Yi W, Fan M, Yang R, Wang S, Tao L, Zhang F. Suppressing Mesenchymal Stromal Cell Ferroptosis Via Targeting a Metabolism-Epigenetics Axis Corrects their Poor Retention and Insufficient Healing Benefits in the Injured Liver Milieu. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2206439. [PMID: 36808838 PMCID: PMC10161111 DOI: 10.1002/advs.202206439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 01/28/2023] [Indexed: 05/06/2023]
Abstract
Mesenchymal stromal cell (MSC) implantation is a promising option for liver repair, but their poor retention in the injured liver milieu critically blunts therapeutic effects. The aim is to clarify the mechanisms underlying massive MSC loss post-implantation and establish corresponding improvement strategies. MSC loss primarily occurs within the initial hours after implantation into the injured liver milieu or under reactive oxygen species (ROS) stress. Surprisingly, ferroptosis is identified as the culprit for rapid depletion. In ferroptosis- or ROS-provoking MSCs, branched-chain amino acid transaminase-1 (BCAT1) is dramatically decreased, and its downregulation renders MSC susceptible to ferroptosis via suppressing the transcription of glutathione peroxidase-4 (GPX4), a vital ferroptosis defensing enzyme. BCAT1 downregulation impedes GPX4 transcription via a rapid-responsive metabolism-epigenetics coordinating mechanism, involving α-ketoglutarate accumulation, histone 3 lysine 9 trimethylation loss, and early growth response protein-1 upregulation. Approaches to suppress ferroptosis (e.g., incorporating ferroptosis inhibitors in injection solvent and overexpressing BCAT1) significantly improve MSC retention and liver-protective effects post-implantation. This study provides the first evidence indicating that excessive MSC ferroptosis is the nonnegligible culprit for their rapid depletion and insufficient therapeutic efficacy after implantation into the injured liver milieu. Strategies suppressing MSC ferroptosis are conducive to optimizing MSC-based therapy.
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Affiliation(s)
- Guangyu Hu
- Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Zhe Cui
- Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Xiyao Chen
- Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, P. R. China
- Department of Geriatrics, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Fangfang Sun
- Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Tongzheng Li
- Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Congye Li
- Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Ling Zhang
- Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Xiong Guo
- Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Hang Zhao
- Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Yunlong Xia
- Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Wenjun Yan
- Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Wei Yi
- Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Miaomiao Fan
- Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Rongjin Yang
- Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Shan Wang
- Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Ling Tao
- Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, P. R. China
| | - Fuyang Zhang
- Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, P. R. China
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17
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Ma J, Xu Y, Zhang M, Li Y. Geraniol ameliorates acute liver failure induced by lipopolysaccharide/D-galactosamine via regulating macrophage polarization and NLRP3 inflammasome activation by PPAR-γ methylation Geraniol alleviates acute liver failure. Biochem Pharmacol 2023; 210:115467. [PMID: 36849063 DOI: 10.1016/j.bcp.2023.115467] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 02/18/2023] [Accepted: 02/21/2023] [Indexed: 03/01/2023]
Abstract
Geraniol (Ger), a natural acyclic monoterpene alcohol, has been reported to exert protective effects through anti-inflammation in Acute liver failure (ALF). However, its specific roles and precise mechanisms underlying anti-inflammatory effects in ALF have not yet fully explored. We aimed to investigated the hepatoprotective effects and mechanisms of Ger against ALF induced by lipopolysaccharide (LPS)/D-galactosamine (GaIN). In this study, the liver tissue and serum of LPS/D-GaIN-induced mice were collected. The degree of liver tissue injury was evaluated by HE and TUNEL staining. Serum levels of liver injury markers (ALT and AST) and inflammatory factors were measured by ELISA assays. PCR and western blotting were conducted to determine the expression of inflammatory cytokines, NLRP3 inflammasome-related proteins, PPAR-γ pathway-related proteins, DNA Methyltransferases and M1/M2 polarization cytokines. Immunofluorescence staining was used to assess the localization and expression of macrophage markers (F4/80 and CD86), NLRP3 and PPAR-γ. In vitro experiments were performed in macrophages stimulated with LPS with or without IFN-γ. Purification of macrophages and cell apoptosis was analyzed using flow cytometry. We found that Ger effectively alleviated ALF in mice, specified by the attenuation of liver tissue pathological damage, inhibition of ALT, AST and inflammatory factor levels, and inactivation of NLRP3 inflammasome. Meanwhile, downregulation M1 macrophage polarization may involve in the protective effects of Ger. In vitro, Ger reduced the activation of NLRP3 inflammasome and apoptosis through regulating PPAR-γ methylation by inhibiting M1 macrophage polarization. In conclusion, Ger protects against ALF through suppressing NLRP3 inflammasome-mediated inflammation and LPS-induced macrophage M1 polarization via modulating PPAR-γ methylation.
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Affiliation(s)
- Jing Ma
- Infectious Disease Department, The Second XIANGYA Hospital of Central South University, Changsha, Hunan, China
| | - Yun Xu
- Infectious Disease Department, The Second XIANGYA Hospital of Central South University, Changsha, Hunan, China
| | - Min Zhang
- Infectious Disease Department, The Second XIANGYA Hospital of Central South University, Changsha, Hunan, China
| | - Yi Li
- Infectious Disease Department, The Second XIANGYA Hospital of Central South University, Changsha, Hunan, China.
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18
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Wang J, Tian J, Wang L, Yang ZW, Xu P. Mesenchymal stem cells regulate M1 polarization of peritoneal macrophages through the CARD9-NF-κB signaling pathway in severe acute pancreatitis. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2023; 30:338-350. [PMID: 35738898 DOI: 10.1002/jhbp.1205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 05/19/2022] [Accepted: 06/01/2022] [Indexed: 11/07/2022]
Abstract
BACKGROUND Macrophages release large numbers of proinflammatory cytokines that trigger inflammatory cascade reactions, which promote the rapid development of severe acute pancreatitis (SAP) from local to systemic inflammation. The ability of mesenchymal stem cells (MSCs) to suppress inflammation is related to inhibition of M1 polarization of macrophages. Our previous studies revealed that caspase recruitment domain protein 9 (CARD9) was involved in SAP inflammation and activation of the CARD9-NF-κB signaling pathway plays an important proinflammatory role in SAP. At present, there is no effective treatment to control the inflammatory response in SAP. Therefore, the aim of the present study was to determine whether MSCs regulate the polarization of macrophages through the CARD9-NF-κB signaling pathway in SAP. METHODS Short hairpin RNA interference technology and coculture in vitro were used to assess the activation status of the CARD9-NF-κB signal pathway in macrophages. Furthermore, flow cytometry was used to determine the polarization state of macrophages. RESULTS The results showed MSCs inhibited CARD9 expression in vivo and in vitro (P < .05), alleviated inflammation induced by proinflammatory cytokines, and inhibited the phosphorylation of NF-κB in macrophages both in vivo and in vitro. Meanwhile, MSCs downregulated the CARD9-NF-κB signal pathway and inhibited M1 polarization of macrophages. CONCLUSION In conclusion, MSCs regulate M1 polarization of peritoneal macrophages through the CARD9-NF-κB signaling pathway in SAP and transplantation of MSCs presents an effective treatment option for SAP.
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Affiliation(s)
- Jing Wang
- Songjiang Hospital Affiliated to Shanghai Jiaotong University School of Medicine (Preparatory Stage), Shanghai, China
- Shanghai Songjiang Clinical Medical College of Nanjing Medical University, Nanjing, China
| | - Jun Tian
- Songjiang Hospital Affiliated to Shanghai Jiaotong University School of Medicine (Preparatory Stage), Shanghai, China
- Shanghai Songjiang Clinical Medical College of Nanjing Medical University, Nanjing, China
| | - Lin Wang
- Jinshan Hospital of Fudan University, Shanghai, China
| | - Zhi-Wen Yang
- Songjiang Hospital Affiliated to Shanghai Jiaotong University School of Medicine (Preparatory Stage), Shanghai, China
- Shanghai Songjiang Clinical Medical College of Nanjing Medical University, Nanjing, China
| | - Ping Xu
- Songjiang Hospital Affiliated to Shanghai Jiaotong University School of Medicine (Preparatory Stage), Shanghai, China
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Xu Y, Wang J, Ren H, Dai H, Zhou Y, Ren X, Wang Y, Feng S, Deng X, Wu J, Fu T, Nie T, He H, Wei T, Zhu B, Hui L, Li B, Wang J, Wang H, Chen L, Shi X, Cheng X. Human endoderm stem cells reverse inflammation-related acute liver failure through cystatin SN-mediated inhibition of interferon signaling. Cell Res 2023; 33:147-164. [PMID: 36670290 PMCID: PMC9892047 DOI: 10.1038/s41422-022-00760-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 11/25/2022] [Indexed: 01/22/2023] Open
Abstract
Acute liver failure (ALF) is a life-threatening disease that occurs secondary to drug toxicity, infection or a devastating immune response. Orthotopic liver transplantation is an effective treatment but limited by the shortage of donor organs, the requirement for life-long immune suppression and surgical challenges. Stem cell transplantation is a promising alternative therapy for fulminant liver failure owing to the immunomodulatory abilities of stem cells. Here, we report that when transplanted into the liver, human endoderm stem cells (hEnSCs) that are germ layer-specific and nontumorigenic cells derived from pluripotent stem cells are able to effectively ameliorate hepatic injury in multiple rodent and swine drug-induced ALF models. We demonstrate that hEnSCs tune the local immune microenvironment by skewing macrophages/Kupffer cells towards an anti-inflammatory state and by reducing the infiltrating monocytes/macrophages and inflammatory T helper cells. Single-cell transcriptomic analyses of infiltrating and resident monocytes/macrophages isolated from animal livers revealed dramatic changes, including changes in gene expression that correlated with the change of activation states, and dynamic population heterogeneity among these cells after hEnSC transplantation. We further demonstrate that hEnSCs modulate the activation state of macrophages/Kupffer cells via cystatin SN (CST1)-mediated inhibition of interferon signaling and therefore highlight CST1 as a candidate therapeutic agent for diseases that involve over-activation of interferons. We propose that hEnSC transplantation represents a novel and powerful cell therapeutic treatment for ALF.
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Affiliation(s)
- Yilin Xu
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Jinglin Wang
- Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
- Hepatobiliary Institute Nanjing University, Nanjing, Jiangsu, China
| | - Haozhen Ren
- Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
- Hepatobiliary Institute Nanjing University, Nanjing, Jiangsu, China
| | - Hao Dai
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
- Institute of Brain-Intelligence Technology, Zhangjiang Laboratory, Shanghai, China
| | - Ying Zhou
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Xiongzhao Ren
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Yang Wang
- Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Sisi Feng
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Xiaogang Deng
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Jiaying Wu
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Tianlong Fu
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Tengfei Nie
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Haifeng He
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Tongkun Wei
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Bing Zhu
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Lijian Hui
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Bin Li
- Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jing Wang
- Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hongyan Wang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
| | - Luonan Chen
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
- Key Laboratory of Systems Biology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou, Zhejiang, China.
| | - Xiaolei Shi
- Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.
- Hepatobiliary Institute Nanjing University, Nanjing, Jiangsu, China.
| | - Xin Cheng
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
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20
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Ma JF, Gao JP, Shao ZW. Acute liver failure: A systematic review and network meta-analysis of optimal type of stem cells in animal models. World J Stem Cells 2023; 15:1-15. [PMID: 36713788 PMCID: PMC9850664 DOI: 10.4252/wjsc.v15.i1.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 11/23/2022] [Accepted: 12/23/2022] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND The therapeutic effects of various stem cells in acute liver failure (ALF) have been demonstrated in preclinical studies. However, the specific type of stem cells with the highest therapeutic potential has not been determined.
AIM To validate the efficacy of stem cells in ALF model and to identify the most promising stem cells.
METHODS A search was conducted on the PubMed, Web of Science, Embase, Scopus, and Cochrane databases from inception to May 3, 2022, and updated on November 16, 2022 to identify relevant studies. Two independent reviewers performed the literature search, identification, screening, quality assessment, and data extraction.
RESULTS A total of 89 animal studies were included in the analysis. The results of traditional meta-analysis showed that stem cell therapy could significantly reduce the serum levels of alanine aminotransferase [weighted mean difference (WMD) = -181.05 (-191.71, -170.39)], aspartate aminotransferase [WMD = -309.04 (-328.45, -289.63)], tumor necrosis factor-alpha [WMD = -8.75 (-9.93, -7.56)], and interleukin-6 [WMD = -10.43 (-12.11, -8.76)] in animal models of ALF. Further subgroup analysis and network meta-analysis showed that although mesenchymal stem cells are the current research hotspot, the effect of liver stem cells (LSCs) on improving liver function is significantly better than that of the other five types of stem cells. In addition, the ranking results showed that the possibility of LSCs improving liver function ranked first. This fully proves the great therapeutic potential of LSCs, which needs to be paid more attention in the future.
CONCLUSION LSCs may have a higher therapeutic potential. Further high-quality animal experiments are needed to explore the most effective stem cells for ALF.
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Affiliation(s)
- Jun-Feng Ma
- Department of Surgical Oncology, Gansu Provincial Hospital, Lanzhou 730030, Gansu Province, China
| | - Jian-Ping Gao
- Department of Surgical Oncology, Gansu Provincial Hospital, Lanzhou 730030, Gansu Province, China
| | - Zi-Wei Shao
- Department of Surgical Oncology, Gansu Provincial Hospital, Lanzhou 730030, Gansu Province, China
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21
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Therapeutic Efficiency of Nasal Mucosa-Derived Ectodermal Mesenchymal Stem Cells in Rats with Acute Hepatic Failure. Stem Cells Int 2023; 2023:6890299. [PMID: 36655034 PMCID: PMC9842420 DOI: 10.1155/2023/6890299] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 10/06/2022] [Accepted: 12/28/2022] [Indexed: 01/11/2023] Open
Abstract
Background Liver transplantation is limited by the insufficiency of liver organ donors when treating end-stage liver disease or acute liver failure (ALF). Ectodermal mesenchymal stem cells (EMSCs) derived from nasal mucosa have emerged as an alternative cell-based therapy. However, the role of EMSCs in acute liver failure remains unclear. Methods EMSCs were obtained from the nasal mucosa tissue of rats. First, EMSCs were seeded on the gelatin-chitosan scaffolds, and the biocompatibility was evaluated. Next, the protective effects of EMSCs were investigated in carbon tetrachloride- (CCl4-) induced ALF rats. Finally, we applied an indirect coculture system to analyze the paracrine effects of EMSCs on damaged hepatocytes. A three-step nontransgenic technique was performed to transform EMSCs into hepatocyte-like cells (HLCs) in vitro. Results EMSCs exhibited a similar phenotype to other mesenchymal stem cells along with self-renewal and multilineage differentiation capabilities. EMSC-seeded gelatin-chitosan scaffolds can increase survival rates and ameliorate liver function and pathology of ALF rat models. Moreover, transplanted EMSCs can secrete paracrine factors to promote hepatocyte regeneration, targeted migration, and transdifferentiate into HLCs in response to the liver's microenvironment, which will then repair or replace the damaged hepatocytes. Similar to mature hepatocytes, HLCs generated from EMSCs possess functions of expressing specific hepatic markers, storing glycogen, and producing urea. Conclusions These results confirmed the feasibility of EMSCs in acute hepatic failure treatment. To our knowledge, this is the first time that EMSCs are used in the therapy of liver diseases. EMSCs are expected to be a novel and promising cell source in liver tissue engineering.
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22
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Anwar I, Ashfaq UA. Impact of Nanotechnology on Differentiation and Augmentation of Stem Cells for Liver Therapy. Crit Rev Ther Drug Carrier Syst 2023; 40:89-116. [PMID: 37585310 DOI: 10.1615/critrevtherdrugcarriersyst.2023042400] [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: 08/18/2023]
Abstract
The liver is one of the crucial organs of the body that performs hundreds of chemical reactions needed by the body to survive. It is also the largest gland of the body. The liver has multiple functions, including the synthesis of chemicals, metabolism of nutrients, and removal of toxins. It also acts as a storage unit. The liver has a unique ability to regenerate itself, but it can lead to permanent damage if the injury is beyond recovery. The only possible treatment of severe liver damage is liver transplant which is a costly procedure and has several other drawbacks. Therefore, attention has been shifted towards the use of stem cells that have shown the ability to differentiate into hepatocytes. Among the numerous kinds of stem cells (SCs), the mesenchymal stem cells (MSCs) are the most famous. Various studies suggest that an MSC transplant can repair liver function, improve the signs and symptoms, and increase the chances of survival. This review discusses the impact of combining stem cell therapy with nanotechnology. By integrating stem cell science and nanotechnology, the information about stem cell differentiation and regulation will increase, resulting in a better comprehension of stem cell-based treatment strategies. The augmentation of SCs with nanoparticles has been shown to boost the effect of stem cell-based therapy. Also, the function of green nanoparticles in liver therapies is discussed.
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Affiliation(s)
- Ifrah Anwar
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Faisalabad, Pakistan
| | - Usman Ali Ashfaq
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Faisalabad, Pakistan
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23
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Abdolmohammadi K, Mahmoudi T, Alimohammadi M, Tahmasebi S, Zavvar M, Hashemi SM. Mesenchymal stem cell-based therapy as a new therapeutic approach for acute inflammation. Life Sci 2023; 312:121206. [PMID: 36403645 DOI: 10.1016/j.lfs.2022.121206] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 11/12/2022] [Accepted: 11/15/2022] [Indexed: 11/19/2022]
Abstract
Acute inflammatory diseases such as acute colitis, kidney injury, liver failure, lung injury, myocardial infarction, pancreatitis, septic shock, and spinal cord injury are significant causes of death worldwide. Despite advances in the understanding of its pathophysiology, there are many restrictions in the treatment of these diseases, and new therapeutic approaches are required. Mesenchymal stem cell-based therapy due to immunomodulatory and regenerative properties is a promising candidate for acute inflammatory disease management. Based on preclinical results, mesenchymal stem cells and their-derived secretome improved immunological and clinical parameters. Furthermore, many clinical trials of acute kidney, liver, lung, myocardial, and spinal cord injury have yielded promising results. In this review, we try to provide a comprehensive view of mesenchymal stem cell-based therapy in acute inflammatory diseases as a new treatment approach.
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Affiliation(s)
- Kamal Abdolmohammadi
- Department of Immunology, School of Medicine, Iranshahr University of Medical Sciences, Iranshahr, Iran
| | - Tayebeh Mahmoudi
- 17 Shahrivar Hospital, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Safa Tahmasebi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahdi Zavvar
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Mahmoud Hashemi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Medical Nanothechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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24
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Off-the-shelf GMP-grade UC-MSCs as therapeutic drugs for the amelioration of CCl4-induced acute-on-chronic liver failure in NOD-SCID mice. Int Immunopharmacol 2022; 113:109408. [DOI: 10.1016/j.intimp.2022.109408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 10/16/2022] [Accepted: 10/28/2022] [Indexed: 11/10/2022]
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25
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Rashid S, Salim A, Qazi REM, Malick TS, Haneef K. Sodium Butyrate Induces Hepatic Differentiation of Mesenchymal Stem Cells in 3D Collagen Scaffolds. Appl Biochem Biotechnol 2022; 194:3721-3732. [PMID: 35499693 DOI: 10.1007/s12010-022-03941-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/20/2022] [Indexed: 11/10/2022]
Abstract
Stem cell-based therapy is considered an attractive tool to overcome the burden of liver diseases. However, efficient hepatic differentiation is still a big challenge for the research community. In this study, we explored a novel method for differentiation of bone marrow-derived mesenchymal stem cells (MSCs) into hepatic-like cells using 3D culture conditions and histone deacetylase inhibitor, sodium butyrate (NaBu). MSCs were characterized by the presence of cell surface markers via immunocytochemistry, flow cytometry, and by their potential for osteogenic, adipogenic, and chondrogenic differentiation. MSCs were treated with 1mM NaBu in 2D and 3D environments for 21 days. The hepatic differentiation was confirmed by qPCR and immunostaining. According to qPCR data, the 3D culture of NaBu-treated MSCs has shown significant upregulation of hepatic gene, CK-18 (P < 0.01), and hepatic proteins, AFP (P < 0.01) and ALB (P < 0.01). In addition, immunocytochemistry analysis showed significant increase (P < 0.05) in the acetylation of histones (H3 and H4) in NaBu-pretreated cells. It can be concluded from the study that NaBu-treated MSCs in 3D culture conditions can induce hepatic differentiation without the use of additional cytokines and growth factors. The method shown in this study represents an improved protocol for hepatic differentiation and could contribute to improvement in future cell-based therapeutics.
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Affiliation(s)
- Saman Rashid
- Dr. Zafar H. Zaidi Center for Proteomics, University of Karachi, Karachi, 75270, Pakistan
| | - Asmat Salim
- Dr. Panjwani Center for Molecular Medicine and Drug Research, ICCBS, University of Karachi, Karachi, 75270, Pakistan
| | - Rida -E-Maria Qazi
- Dr. Panjwani Center for Molecular Medicine and Drug Research, ICCBS, University of Karachi, Karachi, 75270, Pakistan
| | - Tuba Shakil Malick
- Dr. Panjwani Center for Molecular Medicine and Drug Research, ICCBS, University of Karachi, Karachi, 75270, Pakistan
| | - Kanwal Haneef
- Dr. Zafar H. Zaidi Center for Proteomics, University of Karachi, Karachi, 75270, Pakistan.
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26
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Mayo MJ. Mechanisms and molecules: What are the treatment targets for primary biliary cholangitis? Hepatology 2022; 76:518-531. [PMID: 35152430 DOI: 10.1002/hep.32405] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 02/05/2022] [Accepted: 02/08/2022] [Indexed: 12/22/2022]
Abstract
Treatment of primary biliary cholangitis (PBC) with ursodeoxycholic acid (UDCA) is not always sufficient to prevent progression to hepatic decompensation and/or need for liver transplant. Adjuvant therapy with obeticholic acid may provide additional biochemical improvements in some patients, but it is not well-tolerated by patients with significant itch or advanced cirrhosis. Thus, new and creative approaches to treating patients with PBC are important to identify. This review discusses major potential therapeutic targets in PBC and provides examples of some specific agents currently in development for the treatment of PBC. Targets are broadly classified into those which strive to modify bile, inflammation, cell survival, or fibrosis. In bile, shrinking the size of the bile acid pool or modifying the quality of the bile by making it more hydrophilic or enriched in phosphatidylcholine may ameliorate cholestatic injury. Biliary epithelial cell survival may be extended by fortifying the bicarbonate umbrella or improving cell membrane integrity. Autoimmunity and cholangitis have the potential to be improved via regulation of the immune system. Targeting cytokines, immune checkpoints, and anti-mitochondrial antibodies are examples of a more focused immunosuppression approach. Stem cell therapy and lymphocyte trafficking inhibition are more novel methods of broad immune regulation. Anti-fibrotic therapies are also potentially useful for preventing progression of PBC. The nuclear hormone receptors, farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR) regulate many of these pathways: cholestasis, inflammation, and fibrosis, which is why they are being enthusiastically pursued as potential therapeutic targets in PBC.
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Affiliation(s)
- Marlyn J Mayo
- Internal Medicine, University of Texas Southwestern University, Dallas, Texas, USA
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27
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Yao L, Hu X, Dai K, Yuan M, Liu P, Zhang Q, Jiang Y. Mesenchymal stromal cells: promising treatment for liver cirrhosis. Stem Cell Res Ther 2022; 13:308. [PMID: 35841079 PMCID: PMC9284869 DOI: 10.1186/s13287-022-03001-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 05/13/2022] [Indexed: 11/11/2022] Open
Abstract
Liver fibrosis is a wound-healing process that occurs in response to severe injuries and is hallmarked by the excessive accumulation of extracellular matrix or scar tissues within the liver. Liver fibrosis can be either acute or chronic and is induced by a variety of hepatotoxic causes, including lipid deposition, drugs, viruses, and autoimmune reactions. In advanced fibrosis, liver cirrhosis develops, a condition for which there is no successful therapy other than liver transplantation. Although liver transplantation is still a viable option, numerous limitations limit its application, including a lack of donor organs, immune rejection, and postoperative complications. As a result, there is an immediate need for a different kind of therapeutic approach. Recent research has shown that the administration of mesenchymal stromal cells (MSCs) is an attractive treatment modality for repairing liver injury and enhancing liver regeneration. This is accomplished through the cell migration into liver sites, immunoregulation, hepatogenic differentiation, as well as paracrine mechanisms. MSCs can also release a huge variety of molecules into the extracellular environment. These molecules, which include extracellular vesicles, lipids, free nucleic acids, and soluble proteins, exert crucial roles in repairing damaged tissue. In this review, we summarize the characteristics of MSCs, representative clinical study data, and the potential mechanisms of MSCs-based strategies for attenuating liver cirrhosis. Additionally, we examine the processes that are involved in the MSCs-dependent modulation of the immune milieu in liver cirrhosis. As a result, our findings lend credence to the concept of developing a cell therapy treatment for liver cirrhosis that is premised on MSCs. MSCs can be used as a candidate therapeutic agent to lengthen the survival duration of patients with liver cirrhosis or possibly reverse the condition in the near future.
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Affiliation(s)
- Lichao Yao
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Xue Hu
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Kai Dai
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Mengqin Yuan
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Pingji Liu
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Qiuling Zhang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Yingan Jiang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China.
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28
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Shao B, Qin YF, Ren SH, Peng QF, Qin H, Wang ZB, Wang HD, Li GM, Zhu YL, Sun CL, Zhang JY, Li X, Wang H. Structural and Temporal Dynamics of Mesenchymal Stem Cells in Liver Diseases From 2001 to 2021: A Bibliometric Analysis. Front Immunol 2022; 13:859972. [PMID: 35663940 PMCID: PMC9160197 DOI: 10.3389/fimmu.2022.859972] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 04/20/2022] [Indexed: 12/14/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) have important research value and broad application prospects in liver diseases. This study aims to comprehensively review the cooperation and influence of countries, institutions, authors, and journals in the field of MSCs in liver diseases from the perspective of bibliometrics, evaluate the clustering evolution of knowledge structure, and discover hot trends and emerging topics. Methods The articles and reviews related to MSCs in liver diseases were retrieved from the Web of Science Core Collection using Topic Search. A bibliometric study was performed using CiteSpace and VOSviewer. Results A total of 3404 articles and reviews were included over the period 2001-2021. The number of articles regarding MSCs in liver diseases showed an increasing trend. These publications mainly come from 3251 institutions in 113 countries led by China and the USA. Li L published the most papers among the publications, while Pittenger MF had the most co-citations. Analysis of the most productive journals shows that most are specialized in medical research, experimental medicine and cell biology, and cell & tissue engineering. The macroscopical sketch and micro-representation of the whole knowledge field are realized through co-citation analysis. Liver scaffold, MSC therapy, extracellular vesicle, and others are current and developing areas of the study. The keywords "machine perfusion", "liver transplantation", and "microRNAs" also may be the focus of new trends and future research. Conclusions In this study, bibliometrics and visual methods were used to review the research of MSCs in liver diseases comprehensively. This paper will help scholars better understand the dynamic evolution of the application of MSCs in liver diseases and point out the direction for future research.
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Affiliation(s)
- Bo Shao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Ya-Fei Qin
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Shao-Hua Ren
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Qiu-Feng Peng
- Department of Respiratory and Critical Care Medicine, Tianjin Fourth Central Hospital, Tianjin, China
| | - Hong Qin
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Zhao-Bo Wang
- School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Hong-da Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Guang-Ming Li
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Yang-Lin Zhu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Cheng-Lu Sun
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Jing-Yi Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Xiang Li
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Hao Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
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29
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Abo-Aziza FAM, Zaki AKA, Adel RM, Fotouh A. Amelioration of aflatoxin acute hepatitis rat model by bone marrow mesenchymal stem cells and their hepatogenic differentiation. Vet World 2022; 15:1347-1364. [PMID: 35765490 PMCID: PMC9210847 DOI: 10.14202/vetworld.2022.1347-1364] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 04/18/2022] [Indexed: 11/16/2022] Open
Abstract
Background and Aim: Bone marrow-derived mesenchymal stem cells (BM-MSCs) transplantation and their hepatogenic differentiated cells (HDCs) can be applied for liver injury repair by tissue grafting. Regenerative potentiality in liver cirrhosis models was widely investigated; however, immunomodulation and anti-inflammation in acute hepatitis remain unexplored. This study aimed to explore the immunomodulatory and evaluate twice intravenous (IV) or intrahepatic (IH) administration of either BM-MSCs or middle-stage HDCs on aflatoxin (AF) acute hepatitis rat model. Materials and Methods: BM-MSCs viability, phenotypes, and proliferation were evaluated. Hepatogenic differentiation, albumin, and mmmmmmmm-fetoprotein gene expression were assessed. AF acute hepatitis was induced in rats using AFB1 supplementation. The transplantation of BM-MSCs or their HDCs was done either by IV or IH route. Hepatic ultrasound was performed after 3-weeks of therapy. Cytokines profile (tumor necrosis factor-α [TNF-α], interleukin [IL]-4, and IL-10) was assessed. Hepatic bio-indices, serum, and hepatic antioxidant activity were evaluated, besides examining liver histological sections. Results: Acute AFB1 showed a significant increase in TNF-α (p<0.01), liver enzyme activities (p<0.05), as well as decrease in IL-4, IL-10, and antioxidant enzyme activities (p<0.05). Cytokines profile was ameliorated in groups treated with IV and IH BM-MCs, showed a negative correlation between IL-4 and TNF-α (p<0.05), and a positive correlation between IL-10 upregulation and TNF-α (p<0.01). In IV HDCs treated group, positive correlations between IL-4 and IL-10 downregulation and TNF-α were observed. However, in IH HDCs group, a significant positive correlation between IL-4 and IL-10 upregulation and TNF-α, were recorded (p<0.05). In addition, IV BM-MSCs and IH HDCs treatments significantly increased antioxidant enzymes activity (p<0.05). IV and IH BM-MSCs significantly ameliorated liver transaminase levels, whereas IH HDCs significantly ameliorated alanine aminotransferase activity and nitric oxide concentration (p<0.05). Conclusion: The administration routes of BM-MSCs did not demonstrate any significant difference; however, the IH route of HDCs showed significant amelioration from the IV route. On the other hand, it showed noticeable anti-inflammatory and immunomodulatory improvements in aflatoxicosis rats. Therefore, it can be concluded that acute hepatitis can be treated by a noninvasive IV route without the expense of hepatogenic differentiation. Further research using clinical trials that address several problems regarding engraftment and potentiation are needed to determine the optimal manipulation strategy as well as to achieve better long term effects.
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Affiliation(s)
- Faten A. M. Abo-Aziza
- Department of Parasitology and Animal Diseases, Veterinary Research Institute, National Research Centre, Cairo, Egypt
| | - Abdel Kader A. Zaki
- Department of Physiology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt; Department of Veterinary Medicine, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah, Saudi Arabia
| | - Rana M. Adel
- Zoology Department, Faculty of Women for Arts, Science and Education, Ain Shams University, Cairo, Egypt
| | - Ahmed Fotouh
- Department of Pathology and Clinical Pathology, Faculty of Veterinary Medicine, New Valley University, El-Kharga, Egypt
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Yang Y, Dong G, Bi Y, Zhang X, Yao X, Jin G, Zhang K, Shu Z, Hong F. Human liver stem cells alleviate Con-A induced liver injury by regulating the balance of Treg/Th17 cells. Transpl Immunol 2022; 74:101632. [PMID: 35623594 DOI: 10.1016/j.trim.2022.101632] [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: 01/17/2022] [Revised: 05/12/2022] [Accepted: 05/20/2022] [Indexed: 12/01/2022]
Abstract
BACKGROUND Liver injury is a serious threat to human health that has become a worldwide problem. To date, there is still no effective treatment strategy. In the present study, we examined the protective effects of Human liver stem cells (HLSCs) against concanavalin A (Con A)-induced acute liver injury. METHODS Isolated HLSCs were characterized by microscopy, functional assays, and gene expression. HLSCs or HLSCs culture medium were transplanted in mice for 12 h and subsequently challenged with Con A via tail-vein injection. The effects were evaluated through survival rate, histology, blood tests, TUNEL assay, quantitative RT-PCR and flow cytometry. CellTracker™ CM-Dil labled HLSCs were tracked by fluorescence microscope. RESULTS Transplantation of HLSCs reduced the mortality rate, reduced the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL), narrowed the area of liver necrosis, and inhibited hepatocyte apoptosis induced by Con A. Injection of HLSCs culture medium could also alleviate Con A-induced liver injury. Of note, HLSCs-transplanted mice exhibited lower frequencies of Th17 cells and higher frequencies of Tregs in their liver and spleen following Con A injection. Moreover, transplantation of HLSCs significantly reduced the expression of IL-17A, IL-17F and ROR-γt induced by Con A, while reversed Con A-induced downregulation of Foxp3 expression and IL-10. CONCLUSIONS HLSCs protect mice from immune-mediated liver injury by regulating the balance of Treg/Th17 cells, suggesting that transplantation of HLSCs is a potential and effective therapeutic method for amelioration of liver injury.
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Affiliation(s)
- Yonghong Yang
- Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, PR China
| | - Guanjun Dong
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, PR China
| | - Yanzhen Bi
- Department of Infectious Disease, Qingdao Municipal Hospital, Qingdao, PR China
| | - Xiaobei Zhang
- Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, PR China
| | - Xiaoying Yao
- Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, PR China
| | - Guiyuan Jin
- Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, PR China
| | - Kai Zhang
- Jilin University No 3 Hospital, Jilin, PR China
| | - Zhenfeng Shu
- Shanghai Meifeng Biotechnology Co., Ltd, Shanghai, PR China
| | - Feng Hong
- Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, PR China; Institute of Liver Diseases, Affiliated Hospital of Jining Medical University, Jining, PR China.
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Shokravi S, Borisov V, Zaman BA, Niazvand F, Hazrati R, Khah MM, Thangavelu L, Marzban S, Sohrabi A, Zamani A. Mesenchymal stromal cells (MSCs) and their exosome in acute liver failure (ALF): a comprehensive review. Stem Cell Res Ther 2022; 13:192. [PMID: 35527304 PMCID: PMC9080215 DOI: 10.1186/s13287-022-02825-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 02/28/2022] [Indexed: 12/13/2022] Open
Abstract
Recently, mesenchymal stromal cells (MSCs) and their derivative exosome have become a promising approach in the context of liver diseases therapy, in particular, acute liver failure (ALF). In addition to their differentiation into hepatocytes in vivo, which is partially involved in liver regeneration, MSCs support liver regeneration as a result of their appreciated competencies, such as antiapoptotic, immunomodulatory, antifibrotic, and also antioxidant attributes. Further, MSCs-secreted molecules inspire hepatocyte proliferation in vivo, facilitating damaged tissue recovery in ALF. Given these properties, various MSCs-based approaches have evolved and resulted in encouraging outcomes in ALF animal models and also displayed safety and also modest efficacy in human studies, providing a new avenue for ALF therapy. Irrespective of MSCs-derived exosome, MSCs-based strategies in ALF include administration of native MSCs, genetically modified MSCs, pretreated MSCs, MSCs delivery using biomaterials, and also MSCs in combination with and other therapeutic molecules or modalities. Herein, we will deliver an overview regarding the therapeutic effects of the MSCs and their exosomes in ALF. As well, we will discuss recent progress in preclinical and clinical studies and current challenges in MSCs-based therapies in ALF, with a special focus on in vivo reports.
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Affiliation(s)
- Samin Shokravi
- Department of Research and Academic Affairs, Larkin Community Hospital, Miami, FL USA
| | - Vitaliy Borisov
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation
| | - Burhan Abdullah Zaman
- Basic Sciences Department, College of Pharmacy, University of Duhok, Duhok, Kurdistan Region Iraq
| | - Firoozeh Niazvand
- School of Medicine, Abadan University of Medical Sciences, Abadan, Iran
| | - Raheleh Hazrati
- Department of Medicinal Chemistry, Pharmacy Faculty, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Meysam Mohammadi Khah
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Lakshmi Thangavelu
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Science, Saveetha University, Chennai, India
| | - Sima Marzban
- Department of Research and Academic Affairs, Larkin Community Hospital, Miami, FL USA
| | - Armin Sohrabi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Zamani
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Liu M, He J, Zheng S, Zhang K, Ouyang Y, Zhang Y, Li C, Wu D. Human umbilical cord mesenchymal stem cells ameliorate acute liver failure by inhibiting apoptosis, inflammation and pyroptosis. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1615. [PMID: 34926659 PMCID: PMC8640895 DOI: 10.21037/atm-21-2885] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 09/05/2021] [Indexed: 12/18/2022]
Abstract
Background Human umbilical cord mesenchymal stem cells (UC-MSCs) are multipotent progenitor cells representing an attractive therapeutic tool for tissue damage and inflammation owing to their unique immunomodulatory properties. This study was designed to determine the protective effects and underlying mechanisms of UC-MSCs on acute liver failure (ALF). Methods ALF was induced in mice by intraperitoneal injection of D-galactosamine (D-GalN) and lipopolysaccharide (LPS). Mice were intravenously injected with 1×106 UC-MSCs one hour before or six hours after D-GalN/LPS injection. Liver function was valued by serum biochemical parameters and hematoxylin-eosin staining. Inflammatory cytokine and chemokine levels were measured by real-time PCR, and inflammatory cells infiltration was observed by immunofluorescence staining. Hepatocyte apoptosis and pyroptosis related proteins were detected by western blot. Murine macrophage Raw264.7 in the presentation of LPS was treated with the UC-MSCs condition medium (UC-MSCs-CM), and then the levels of inflammatory cytokines and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in Raw264.7 were measured. Results UC-MSCs significantly reduced the mortality, decreased serum alanine aminotransferase and aspartate aminotransferase levels, and improved the pathological damage. Moreover, UC-MSCs inhibited inflammatory cytokine and chemokine levels, especially TNF-α, interleukins-6 (IL-6), IL-1β, monocyte chemoattractant protein (MCP-1), CC-chemokines ligand 2 (CCL2), C-X-C motif ligand 2 (CXCL2), and reduced macrophage, neutrophil and T lymphocyte infiltration into the liver tissue. UC-MSCs also attenuated hepatocyte apoptosis, as evidenced by decreased TUNEL positive cells, increased Bcl-xl/Bax protein ratio and downregulated cleaved caspase 3 levels. NLRP3 inflammasome activation, IL-1β maturation and cleaved caspase1 were suppressed by UC-MSC administration. Furthermore, the UC-MSCs-CM reduced the levels of inflammatory cytokines and the activation of NLRP3 inflammasome in Raw264.7. Conclusions Our results demonstrated that UC-MSCs exerted therapeutic effects on ALF by inhibiting apoptosis, inflammation, and pyroptosis.
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Affiliation(s)
- Mengting Liu
- Department of Biochemistry and Molecular Biology, Wuhan University School of Basic Medical Sciences, Wuhan, China.,R&D Center, Wuhan Hamilton Biotechnology Co., Ltd, Wuhan, China
| | - Jing He
- Department of Biochemistry and Molecular Biology, Wuhan University School of Basic Medical Sciences, Wuhan, China
| | - Shuo Zheng
- R&D Center, Wuhan Hamilton Biotechnology Co., Ltd, Wuhan, China
| | - Ke Zhang
- Department of Biochemistry and Molecular Biology, Wuhan University School of Basic Medical Sciences, Wuhan, China
| | - Yu Ouyang
- Department of Biochemistry and Molecular Biology, Wuhan University School of Basic Medical Sciences, Wuhan, China
| | - Yaqi Zhang
- Department of Biochemistry and Molecular Biology, Wuhan University School of Basic Medical Sciences, Wuhan, China
| | - Changyong Li
- Department of Physiology, Wuhan University School of Basic Medical Sciences, Wuhan, China
| | - Dongcheng Wu
- Department of Biochemistry and Molecular Biology, Wuhan University School of Basic Medical Sciences, Wuhan, China.,R&D Center, Wuhan Hamilton Biotechnology Co., Ltd, Wuhan, China.,R&D Center, Guangzhou Hamilton Biotechnology Co., Ltd, Guangzhou, China
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Mesenchymal Stem Cells Versus Covid-19. Can They Win the Battle? SERBIAN JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2021. [DOI: 10.2478/sjecr-2021-0024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Mesenchymal stem cells (MSCs) are multipotent stem cells with numerous features potentially useful in various pathologies. It has been shown that MSCs have regenerative potential due to modulation of immune system response, inflammation diminishing, trans differentiation into various types of cells, proangiogenetic and anti fibrotic influence. Besides all of these traits, MSCs posses anti viral capacity and have been further employed in clinical trails since last year. Here, we revised immunomodulatory, biological and antiviral traits of MSCs, but also pathogenesis of Covid-19 and it’s impact on immune system. Conspicuously, there is a growing number of studies examining effect of MSCs in patients suffering from Covid-19 pneumonia and ARDS. Since MSCs are in theory capable of healing lung injury and inflammation, here we discuss hypothesis, pros and cons of MSCs treatment in Covid-19 patients. Finally, we debate if MSCs based therapy can be promising tool for Covid-19 lung pathologies.
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Foroutan T, Kassaee MZ, Salari M, Ahmady F, Molavi F, Moayer F. Magnetic Fe 3 O 4 @graphene oxide improves the therapeutic effects of embryonic stem cells on acute liver damage. Cell Prolif 2021; 54:e13126. [PMID: 34569673 PMCID: PMC8560617 DOI: 10.1111/cpr.13126] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 08/12/2021] [Accepted: 09/09/2021] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE Acute liver failure is usually associated with inflammation and oxidation of hepatocytes and has high mortality and resource costs. Mesenchymal stem cell (MSCs) has occasionally been reported to have no beneficial effect due to poor transplantation and the survival of implanted cells. Recent studies showed that embryonic stem cell (ESC)-derived MSCs are an alternative for regenerative medicine. On the other hand, graphene-based nanostructures have proven useful in biomedicine. In this study, we investigated whether magnetic graphene oxide (MGO) improved the effects of ESC-MSC conditioned medium (CM) on protecting hepatocytes and stimulating the regeneration of damaged liver cells. MATERIALS AND METHODS To provide a rat model of acute liver failure, male rats were injected intraperitoneally with carbon tetrachloride (CCl4 ). The rats were randomly divided into six groups, namely control, sham, CCl4 , ESC-MSC-CM, MGO and ESC-MSC-CM + MGO. In the experimental groups, the rats received, depending on the group, 2 ml/kg body weight CCl4 and either ESC-MSC-CM with 5 × 106 MSCs or 300 μg/kg body weight MGO or both. Symptoms of acute liver failure appeared 4 days after the injection. All groups were compared and analysed both histologically and biochemically 4 days after the injection. Finally, the results of ESC-MSC-CM and MSC-CM were compared. RESULTS The results indicated that the use of MGO enhanced the effect of ESC-MSC-CM on reducing necrosis, inflammation, aspartate transaminase, alanine aminotransferase and alkaline phosphatase in the CCl4 -induced liver failure of the rat model. Also, the expression of vascular endothelial growth factor and matrix metalloproteinase-9 (MMP-9) was significantly upregulated after treatment with MGO. Also, the results showed that the ESC-MSC-CM has more efficient effective compared to MSC-CM. CONCLUSION Magnetic graphene oxide improved the hepatoprotective effects of ESC-MSC-CM on acute liver damage, probably by suppressing necrosis, apoptosis and inflammation of hepatocytes.
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Affiliation(s)
- Tahereh Foroutan
- Department of Animal BiologyFaculty of Biological SciencesKharazmi UniversityTehranIran
| | | | - Mahdi Salari
- Department of Environmental Health EngineeringSchool of Public HealthHamadan University of Medical SciencesHamadanIran
| | - Fatemeh Ahmady
- Department of Animal BiologyFaculty of Biological SciencesKharazmi UniversityTehranIran
| | - Fatemeh Molavi
- Department of Animal BiologyFaculty of Biological SciencesKharazmi UniversityTehranIran
| | - Fariborz Moayer
- Faculty of Veterinary MedicineIslamic Azad UniversityKarajIran
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Kawakatsu-Hatada Y, Murata S, Mori A, Kimura K, Taniguchi H. Serous Membrane Detachment with Ultrasonic Homogenizer Improves Engraftment of Fetal Liver to Liver Surface in a Rat Model of Cirrhosis. Int J Mol Sci 2021; 22:11589. [PMID: 34769019 PMCID: PMC8584093 DOI: 10.3390/ijms222111589] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/23/2021] [Accepted: 10/24/2021] [Indexed: 11/16/2022] Open
Abstract
Liver transplantation is the most effective treatment for end-stage cirrhosis. However, due to serious donor shortages, new treatments to replace liver transplantation are sorely needed. Recent studies have focused on novel therapeutic methods using hepatocytes and induced pluripotent stem cells, we try hard to develop methods for transplanting these cells to the liver surface. In the present study, we evaluated several methods for their efficiency in the detachment of serous membrane covering the liver surface for transplantation to the liver surface. The liver surface of dipeptidyl peptidase IV (DPPIV)-deficient rats in a cirrhosis model was detached by various methods, and then fetal livers from DPPIV-positive rats were transplanted. We found that the engraftment rate and area as well as the liver function were improved in rats undergoing transplantation following serous membrane detachment with an ultrasonic homogenizer, which mimics the Cavitron Ultrasonic Surgical Aspirator® (CUSA), compared with no detachment. Furthermore, the bleeding amount was lower with the ultrasonic homogenizer method than with the needle and electric scalpel methods. These findings provide evidence that transplantation to the liver surface with serous membrane detachment using CUSA might contribute to the development of new treatments for cirrhosis using cells or tissues.
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Affiliation(s)
- Yumi Kawakatsu-Hatada
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (Y.K.-H.); (A.M.); (K.K.); (H.T.)
| | - Soichiro Murata
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (Y.K.-H.); (A.M.); (K.K.); (H.T.)
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
| | - Akihiro Mori
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (Y.K.-H.); (A.M.); (K.K.); (H.T.)
| | - Kodai Kimura
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (Y.K.-H.); (A.M.); (K.K.); (H.T.)
| | - Hideki Taniguchi
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; (Y.K.-H.); (A.M.); (K.K.); (H.T.)
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
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Foroutan T, Kabiri F, Motamedi E. Silica Magnetic Graphene Oxide Improves the Effects of Stem Cell-Conditioned Medium on Acute Liver Failure. ACS OMEGA 2021; 6:21194-21206. [PMID: 34471725 PMCID: PMC8387984 DOI: 10.1021/acsomega.0c05395] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 07/28/2021] [Indexed: 05/05/2023]
Abstract
OBJECTIVE Acute liver failure (ALF) is usually associated with inflammation and oxidation of hepatocytes and has high mortality and resource costs. Although mesenchymal stem cell-conditioned medium (MSC-CM) has therapeutic effects similar to MSC transplant in treating liver failure, it may not increase survival. On the other hand, graphene-based nanostructures have been proven useful in biomedicine. In this study, we investigated whether silica magnetic graphene oxide (SMGO) improved the effects of MSC-CM in protecting hepatocytes and stimulating the regeneration of damaged liver cells. MATERIALS AND METHODS To provide a rat model of ALF, male rats were injected intraperitoneally with carbon tetrachloride (CCl4). The rats were randomly divided into six groups, namely control, sham, CCl4, MSC-CM, SMGO, and MSC-CM + SMGO. In the experimental groups, the rats received, depending on the group, 2 mL/kg body weight CCl4 and either MSC-CM with 5 × 106 MSCs or 300 μg/kg body weight SMGO or both. Symptoms of ALF appeared 4 days after the injection. All groups were compared and analyzed both histologically and biochemically 4 days after the injection. RESULTS The results indicated that the use of SMGO enhanced the effect of MSC-CM in reducing necrosis, inflammation, aspartate transaminase, alanine aminotransferase, and alkaline phosphatase in the CCl4-induced liver failure of the rat model. Also, the expression of vascular endothelial growth factor and matrix metalloproteinase-9 (MMP-9) was significantly upregulated after treatment with SMGO. CONCLUSION SMGO improved the hepatoprotective effects of MSC-CM on acute liver damage, probably by suppressing necrosis, apoptosis, and inflammation of hepatocytes.
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Affiliation(s)
- Tahereh Foroutan
- Department
of Animal Biology, Faculty of Biological Sciences, Kharazmi University, Tehran 15614, Iran
| | - Fahimeh Kabiri
- Department
of Animal Biology, Faculty of Biological Sciences, Kharazmi University, Tehran 15614, Iran
| | - Elaheh Motamedi
- Department
of Nanotechnology, Agricultural Biotechnology
Research Institute of Iran (ABRII), Agricultural Research, Education
and Extension Organization (AREEO), Karaj 3173655111, Iran
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Lai J, Jiang S, Shuai L, Zhang Y, Xia R, Chen Q, Bai L. Comparison of the biological and functional characteristics of mesenchymal stem cells from intrahepatic and identical bone marrow. Stem Cell Res 2021; 55:102477. [PMID: 34343826 DOI: 10.1016/j.scr.2021.102477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 07/11/2021] [Accepted: 07/21/2021] [Indexed: 02/07/2023] Open
Abstract
In our privious work, our reseach group characterized a population of hepatic-sourced mesenchymal stem cells (MSCs) called MLpvNG2+ cells. In the present study, we compared the biological and functional characteristics of naïve MLpvNG2 cells with identical bone marrow-derived MSCs (niBM-MSCs) using in vitro (conditioned media) and in vivo (a well-set diethylnitrosamine (DEN)-induced liver fibrotic/cirrhotic murine model) procedures. The intrahepatic-sourced mesodermal MLpvNG2+ cells exhibited some biological characteristics (e.g., a set of surface markers) similar to those of extrahepatic niBM-MSCs. In responsed to signals of pathological conditions, such as singals of fibrotic/cirrhotic liver, MLpvNG2+ cells showed higher survival and favored differentiation into ALB(+) and G6Pc(+) hepatocytes, whereas niBM-MSCs predominantly differentiated into CK/KRT19(+) cholangiocytes. We identified C/EBPα/β expression as a biological characteristic differentiating these two populations of MSCs, wherein MLpvNG2+ cells are likely regulated by C/EBPβ transcriptional signaling, whereas niBM-MSCs are likely controlled by C/EBPα transcriptional signaling. Notably, although C/EBPα and C/EBPβ transcriptional signaling regulate hepatocyte and cholangiocyte fate, respectively, the expression of these proteins in MLpvNG2+ cells is, to our knowledge, reported for the first time in the present study. We used anti-C/EBP neutralizing antibodies (Abs) both in vitro and in vivo to determine the functional characteristics of these proteins. We conclude that the biological characteristics of these two populations of MSCs depend on their differential C/EBPα/β expression patterns.
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Affiliation(s)
- Jiejuan Lai
- Hepatobiliary Institute, Southwest Hospital, the Army Medical University, No 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China
| | - Shifang Jiang
- Hepatobiliary Institute, Southwest Hospital, the Army Medical University, No 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China
| | - Ling Shuai
- Hepatobiliary Institute, Southwest Hospital, the Army Medical University, No 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China
| | - Yujun Zhang
- Hepatobiliary Institute, Southwest Hospital, the Army Medical University, No 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China
| | - Renpei Xia
- Hepatobiliary Institute, Southwest Hospital, the Army Medical University, No 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China
| | - Quanyu Chen
- Hepatobiliary Institute, Southwest Hospital, the Army Medical University, No 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China; Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Laboratory of Molecular Developmental Biology, School of Life Sciences, Southwest University, Beibei, Chongqing 400715, China
| | - Lianhua Bai
- Hepatobiliary Institute, Southwest Hospital, the Army Medical University, No 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China.
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Yin S, Cao Y. Hydrogels for Large-Scale Expansion of Stem Cells. Acta Biomater 2021; 128:1-20. [PMID: 33746032 DOI: 10.1016/j.actbio.2021.03.026] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/25/2021] [Accepted: 03/10/2021] [Indexed: 12/18/2022]
Abstract
Stem cells demonstrate considerable promise for various preclinical and clinical applications, including drug screening, disease treatments, and regenerative medicine. Producing high-quality and large amounts of stem cells is in demand for these applications. Despite challenges, as hydrogel-based cell culture technology has developed, tremendous progress has been made in stem cell expansion and directed differentiation. Hydrogels are soft materials with abundant water. Many hydrogel properties, including biodegradability, mechanical strength, and porosity, have been shown to play essential roles in regulating stem cell proliferation and differentiation. The biochemical and physical properties of hydrogels can be specifically tailored to mimic the native microenvironment that various stem cells reside in vivo. A few hydrogel-based systems have been developed for successful stem cell cultures and expansion in vitro. In this review, we summarize various types of hydrogels that have been designed to effectively enhance the proliferation of hematopoietic stem cells (HSCs), mesenchymal stem/stromal cells (MSCs), and pluripotent stem cells (PSCs), respectively. According to each stem cell type's preference, we also discuss strategies for fabricating hydrogels with biochemical and mechanical cues and other characteristics representing microenvironments of stem cells in vivo. STATEMENT OF SIGNIFICANCE: In this review article we summarize current progress on the construction of hydrogel systems for the culture and expansion of various stem cells, including hematopoietic stem cells (HSCs), mesenchymal stem/stromal cells (MSCs), and pluripotent stem cells (PSCs). The Significance includes: (1) Provide detailed discussion on the stem cell niches that should be considered for stem cell in vitro expansion. (2) Summarize various strategies to construct hydrogels that can largely recapture the microenvironment of native stem cells. (3) Suggest a few future directions that can be implemented to improve current in vitro stem cell expansion systems.
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Affiliation(s)
- Sheng Yin
- National Laboratory of Solid State Microstructure, Department of Physics, Nanjing University, Nanjing, 210093, China; Chemistry and Biomedicine innovation center, Nanjing University, Nanjing, 210093, China; Institute for Brain Sciences, Nanjing University, Nanjing, 210093, China; Shenzhen Research Institute of Nanjing University, Shenzhen, China, 518057
| | - Yi Cao
- National Laboratory of Solid State Microstructure, Department of Physics, Nanjing University, Nanjing, 210093, China; Chemistry and Biomedicine innovation center, Nanjing University, Nanjing, 210093, China; Institute for Brain Sciences, Nanjing University, Nanjing, 210093, China; Shenzhen Research Institute of Nanjing University, Shenzhen, China, 518057.
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LIU L, YANG F. Application of Modified Mesenchymal Stem Cells Transplantation in the Treatment of Liver Injury. Physiol Res 2021. [DOI: 10.33549/physiolres.934623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Acute and chronic hepatitis, cirrhosis, and other liver diseases pose a serious threat to human health; however, liver transplantation is the only reliable treatment for the terminal stage of liver diseases. Previous researchers have shown that mesenchymal stem cells (MSCs) are characterized by differentiation and paracrine effects, as well as anti-oxidative stress and immune regulation functions. When MSCs are transplanted into animals, they migrate to the injured liver tissue along with the circulation, to protect the liver and alleviate the injury through the paracrine, immune regulation and other characteristics, making mesenchymal stem cell transplantation a promising alternative therapy for liver diseases. Although the efficacy of MSCs transplantation has been confirmed in various animal models of liver injury, many researchers have also proposed various pretreatment methods to improve the efficacy of mesenchymal stem cell transplantation, but there is still lack a set of scientific methods system aimed at improving the efficacy of transplantation therapy in scientific research and clinical practice. In this review, we summarize the possible mechanisms of MSCs therapy and compare the existing methods of MSCs modification corresponding to the treatment mechanism, hoping to provide as a reference to help future researchers explore a safe and simple transplantation strategy.
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Affiliation(s)
- L LIU
- School of Basic Medicine, Yangtze University Health Science Center, Jingzhou, China
| | - F YANG
- School of Basic Medicine, Yangtze University Health Science Center, Jingzhou, China
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Tan HL, Guan XH, Hu M, Wu J, Li RZ, Wang LF, Huang HD, Yu ZP, Wang XY, Xiao YF, Deng KY, Xin HB. Human amniotic mesenchymal stem cells-conditioned medium protects mice from high-fat diet-induced obesity. Stem Cell Res Ther 2021; 12:364. [PMID: 34174964 PMCID: PMC8235646 DOI: 10.1186/s13287-021-02437-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 06/07/2021] [Indexed: 12/24/2022] Open
Abstract
Background Obesity is a metabolic disorder syndrome characterized by excessive fat accumulation that is related to many diseases. Human amniotic mesenchymal stem cells (hAMSCs) have a great potential for cell-based therapy due to their characteristics such as pluripotency, low immunogenicity, no tumorigenicity, potent paracrine effects, and no ethical concern. Recently, we observed that both hAMSCs and their conditioned medium (hAMSCs-CM) efficiently repaired skin injury, inhibited hepatocellular carcinoma, and alleviated high-fat diet (HFD)-induced diabetes. However, the effects and the underlying mechanisms of hAMSCs-CM on high-fat diet (HFD)-induced obesity were not explored. Methods The characteristics of hAMSCs were confirmed by flow cytometry, RT-PCR, and immunofluorescence. Obese mice were induced by administrating HFD for 15 weeks and simultaneously, the mice were intraperitoneally injected with hAMSCs-CM weekly to evaluate the effects of hAMSCs-CM on HFD-induced obesity. GTT and ITT assays were used to assess the effects of hAMSCs-CM on HFD-induced glucose tolerance and insulin resistance. The lipid accumulation and adipocytes hypertrophy in mouse adipose tissues were determined by histological staining, in which the alterations of blood lipid, liver, and kidney function were also examined. The role of hAMSCs-CM in energy homeostasis was monitored by examining the oxygen consumption (VO2), carbon dioxide production (VCO2), and food and water intake in mice. Furthermore, the expressions of the genes related to glucose metabolism, fatty acid β oxidation, thermogenesis, adipogenesis, and inflammation were determined by western blot analysis, RT-PCR, and immunofluorescence staining. The roles of hAMSCs-CM in adipogenesis and M1/M2 macrophage polarization were investigated with 3T3-L1 preadipocytes or RAW264.7 cells in vitro. Results hAMSCs-CM significantly restrained HFD-induced obesity in mice by inhibiting adipogenesis and lipogenesis, promoting energy expenditure, and reducing inflammation. The underlying mechanisms of the anti-obesity of hAMSCs-CM might be involved in inhibiting PPARγ and C/EBPα-mediated lipid synthesis and adipogenesis, promoting GLUT4-mediated glucose metabolism, elevating UCP1/PPARα/PGC1α-regulated energy expenditure, and enhancing STAT3-ARG1-mediated M2-type macrophage polarization. Conclusion Our studies demonstrated that hAMSCs significantly alleviated HFD-induced obesity through their paracrine effects. Obviously, our results open up an attractive therapeutic modality for the prevention and treatment of obesity and other metabolic disorders clinically. Graphic Abstract The cytokines, exosomes, or micro-vesicles secreted from hAMSCs significantly inhibited HFD-induced obesity in mice by inhibiting lipid production and adipogenesis, promoting energy consumption, and reducing inflammation.
![]() Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02437-z.
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Affiliation(s)
- Hui-Lan Tan
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, No. 1299 Xuefu Road, Honggutan District, Nanchang, 330031, China.,School of Pharmacy, Nanchang University, Nanchang, China
| | - Xiao-Hui Guan
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, No. 1299 Xuefu Road, Honggutan District, Nanchang, 330031, China
| | - Min Hu
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, No. 1299 Xuefu Road, Honggutan District, Nanchang, 330031, China
| | - Jie Wu
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, No. 1299 Xuefu Road, Honggutan District, Nanchang, 330031, China.,School of Life and Science, Nanchang University, Nanchang, China
| | - Rong-Zhen Li
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, No. 1299 Xuefu Road, Honggutan District, Nanchang, 330031, China.,School of Life and Science, Nanchang University, Nanchang, China
| | - Ling-Fang Wang
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, No. 1299 Xuefu Road, Honggutan District, Nanchang, 330031, China
| | - Hou-Da Huang
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, No. 1299 Xuefu Road, Honggutan District, Nanchang, 330031, China
| | - Zhen-Ping Yu
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, No. 1299 Xuefu Road, Honggutan District, Nanchang, 330031, China.,School of Life and Science, Nanchang University, Nanchang, China
| | - Xiao-Yu Wang
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, No. 1299 Xuefu Road, Honggutan District, Nanchang, 330031, China.,School of Life and Science, Nanchang University, Nanchang, China
| | - Yun-Fei Xiao
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, No. 1299 Xuefu Road, Honggutan District, Nanchang, 330031, China
| | - Ke-Yu Deng
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, No. 1299 Xuefu Road, Honggutan District, Nanchang, 330031, China. .,School of Pharmacy, Nanchang University, Nanchang, China. .,School of Life and Science, Nanchang University, Nanchang, China.
| | - Hong-Bo Xin
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, No. 1299 Xuefu Road, Honggutan District, Nanchang, 330031, China. .,School of Pharmacy, Nanchang University, Nanchang, China. .,School of Life and Science, Nanchang University, Nanchang, China.
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Varkouhi AK, Monteiro APT, Tsoporis JN, Mei SHJ, Stewart DJ, Dos Santos CC. Genetically Modified Mesenchymal Stromal/Stem Cells: Application in Critical Illness. Stem Cell Rev Rep 2021; 16:812-827. [PMID: 32671645 PMCID: PMC7363458 DOI: 10.1007/s12015-020-10000-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Critical illnesses including sepsis, acute respiratory distress syndromes, ischemic cardiovascular disorders and acute organ injuries are associated with high mortality, morbidity as well as significant health care system expenses. While these diverse conditions require different specific therapeutic approaches, mesenchymal stem/stromal cell (MSCs) are multipotent cells capable of self-renewal, tri-lineage differentiation with a broad range regenerative and immunomodulatory activities, making them attractive for the treatment of critical illness. The therapeutic effects of MSCs have been extensively investigated in several pre-clinical models of critical illness as well as in phase I and II clinical cell therapy trials with mixed results. Whilst these studies have demonstrated the therapeutic potential for MSC therapy in critical illness, optimization for clinical use is an ongoing challenge. MSCs can be readily genetically modified by application of different techniques and tools leading to overexpress or inhibit genes related to their immunomodulatory or regenerative functions. Here we will review recent approaches designed to enhance the therapeutic potential of MSCs with an emphasis on the technology used to generate genetically modified cells, target genes, target diseases and the implication of genetically modified MSCs in cell therapy for critical illness.
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Affiliation(s)
- Amir K Varkouhi
- Department of Chemistry and Environmental Science, New Jersey Institute of Technology (NJIT), Newark, NJ, 07102, USA
| | - Ana Paula Teixeira Monteiro
- Keenan and Li Ka Shing Knowledge Institute, University Health Toronto - St. Michael's Hospital, Toronto, Ontario, Canada.,Institute of Medical Sciences and Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - James N Tsoporis
- Keenan and Li Ka Shing Knowledge Institute, University Health Toronto - St. Michael's Hospital, Toronto, Ontario, Canada
| | - Shirley H J Mei
- Ottawa Hospital Research Institute and the University of Ottawa, Ottawa, ON, Canada
| | - Duncan J Stewart
- Ottawa Hospital Research Institute and the University of Ottawa, Ottawa, ON, Canada
| | - Claudia C Dos Santos
- Keenan and Li Ka Shing Knowledge Institute, University Health Toronto - St. Michael's Hospital, Toronto, Ontario, Canada. .,Interdepartmental Division of Critical Care, St. Michael's Hospital/University of Toronto, 30 Bond Street, Room 4-008, Toronto, ON, M5B 1WB, Canada.
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Luan Y, Kong X, Feng Y. Mesenchymal stem cells therapy for acute liver failure: Recent advances and future perspectives. LIVER RESEARCH 2021; 5:53-61. [PMID: 39959343 PMCID: PMC11791815 DOI: 10.1016/j.livres.2021.03.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 02/16/2021] [Accepted: 03/24/2021] [Indexed: 12/21/2022]
Abstract
Acute liver failure (ALF) is a life-threatening disease characterized by the rapid development of hepatocyte death and a systemic inflammatory response, which leads to high mortality. Despite the prevention of ALF complications, therapeutic effectiveness remains limited because of the rapid disease progression. Thus, there is a need to explore various therapeutic approaches. Currently, the only effective treatment is liver transplantation; However, the lack of donors, surgical complications, immunosuppression, and high medical costs limit its clinical application. Recently, mesenchymal stem cells (MSCs) have been found to exert hepatoprotective effects in ALF through suppression of inflammation, immunoregulation, promotion of mitosis, anti-apoptosis effects, and alleviation of the metabolic and oxidative stress imbalance. In this review, we summarize the advantages and disadvantages of MSCs from different sources and their molecular mechanisms in ALF treatment, along with future perspectives that may provide guidance to improve the current status of MSCs therapy for ALF.
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Affiliation(s)
- Yuling Luan
- Department of General Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaoni Kong
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yu Feng
- Department of General Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Yang Y, Zhao Y, Zhang L, Zhang F, Li L. The Application of Mesenchymal Stem Cells in the Treatment of Liver Diseases: Mechanism, Efficacy, and Safety Issues. Front Med (Lausanne) 2021; 8:655268. [PMID: 34136500 PMCID: PMC8200416 DOI: 10.3389/fmed.2021.655268] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 04/15/2021] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cell (MSC) transplantation is a novel treatment for liver diseases due to the roles of MSCs in regeneration, fibrosis inhibition and immune regulation. However, the mechanisms are still not completely understood. Despite the significant efficacy of MSC therapy in animal models and preliminary clinical trials, issues remain. The efficacy and safety of MSC-based therapy in the treatment of liver diseases remains a challenging issue that requires more investigation. This article reviews recent studies on the mechanisms of MSCs in liver diseases and the associated challenges and suggests potential future applications.
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Affiliation(s)
- Ya Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research 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
| | - Yalei Zhao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research 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
| | - Lingjian Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research 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
| | - Fen Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research 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
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research 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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Aithal AP, Bairy LK, Seetharam RN. Safety and therapeutic potential of human bone marrow-derived mesenchymal stromal cells in regenerative medicine. Stem Cell Investig 2021; 8:10. [PMID: 34124233 DOI: 10.21037/sci-2020-036] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 03/24/2021] [Indexed: 12/20/2022]
Abstract
Regenerative medicine is considered as an alternative approach to healthcare. Owing to their pluripotent abilities and their relative lack of ethical and legal issues, adult stem cells are considered as optimal candidates for use in the treatment of various diseases. Bone marrow-derived mesenchymal stem cells are among the most promising candidates for clinical applications as they have expressed a higher degree of plasticity in vitro. Many investigators have begun to examine how bone marrow stem cells might be used to rebuild damaged tissues. The systemic administration of cells for therapeutic applications requires efficient migration and homing of cells to the target site. Cell adhesion molecules and their ligands, chemokines, extracellular matrix components and specialized bone marrow niches all participate in the proper regulation of this process. MSCs suppress the pathophysiological process that is mediated by chronic inflammation and contributes to a modification of the microenvironment and tissue regeneration. Due to the intricacy of the mesenchymal stem cell, there is ever-increasing amount of data emerging about their migration and regenerative mechanisms. Many factors influence MSC mobilization and their homing to injured tissues. This review summarizes the current clinical and pre-clinical data available in literature regarding the use of MSC in tissue repair and their prospective therapeutic role in various diseases and the underlying repair mechanisms will be discussed.
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Affiliation(s)
- Ashwini P Aithal
- Department of Anatomy, Melaka Manipal Medical College (Manipal Campus), Manipal Academy of Higher Education, Manipal, India
| | - Laxminarayana K Bairy
- Department of Pharmacology, RAK College of Medical Sciences, RAK Medical and Health Sciences University, Ras Al Khaimah, UAE
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Denu RA, Hematti P. Optimization of oxidative stress for mesenchymal stromal/stem cell engraftment, function and longevity. Free Radic Biol Med 2021; 167:193-200. [PMID: 33677063 DOI: 10.1016/j.freeradbiomed.2021.02.042] [Citation(s) in RCA: 12] [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: 12/01/2020] [Revised: 02/24/2021] [Accepted: 02/26/2021] [Indexed: 12/18/2022]
Abstract
Mesenchymal stromal/stem cells (MSCs) are multipotent cells that possess great potential as a cellular therapeutic based on their ability to differentiate to different lineages and to modulate immune responses. However, their potential is limited by their low tissue abundance, and thus the need for robust ex vivo expansion prior to their application. This creates its own issues, namely replicative senescence, which could lead to reduced MSC functionality and negatively impact their engraftment. Ex vivo expansion and MSC aging are associated with greater oxidative stress. Therefore, there is great need to identify strategies to reduce oxidative stress in MSCs. This review summarizes the achievements made to date in addressing oxidative stress in MSCs and speculates about interesting avenues of future investigation to solve this critical problem.
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Affiliation(s)
- Ryan A Denu
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
| | - Peiman Hematti
- Departments of Medicine, Pediatrics, Surgery and Biomedical Engineering, Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
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Extracellular Vesicles as Biomarkers and Therapeutic Tools: From Pre-Clinical to Clinical Applications. BIOLOGY 2021; 10:biology10050359. [PMID: 33922446 PMCID: PMC8145169 DOI: 10.3390/biology10050359] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/19/2021] [Accepted: 04/20/2021] [Indexed: 12/15/2022]
Abstract
Simple Summary Extracellular vesicles (EVs) are membrane-bound vesicles released by all cell types, differing in biogenesis, physical characteristics, and contents. Due to their central role in intercellular communication and their variable cargo, EVs are involved in several biological processes. The possibility of isolating them from different biofluids makes EVs valuable biomarkers to be analyzed for the diagnosis or prognosis of several conditions. Moreover, these natural nanoparticles have been investigated as therapeutic tools in many pathological conditions. In this context, EVs have shown innate immunosuppressive and anti-inflammatory properties when isolated from stem/progenitor cells and have also been considered vehicles to be edited for drug delivery. The aim of the review is to report some of the pre-clinical and clinical studies distinguishing those in which EVs have been examined as biomarkers from those in which they have been used as therapeutics. Abstract Extracellular vesicles (EVs) are ubiquitous masters of intercellular communication, being detectable in tissues, circulation, and body fluids. Their complex cargo reflects the (patho)physiologic status of the cells from which they originate. Due to these properties, the potential of EVs, and in particular exosomes, to serve as biomarkers or therapeutics has grown exponentially over the past decade. On one side, numerous studies have demonstrated that EV-associated nucleic acids and proteins are implicated in cancer progression, as well as neurodegenerative, infectious, and autoimmune disorders. On the other, the therapeutic use of EVs secreted by various cell types, and in particular stem/progenitor cells, present significant advantages in comparison to the corresponding parental cells, such as the less complex production and storage conditions. In this review, we examine some of the major pre-clinical studies dealing with EVs and exosomes, that led to the development of numerous completed clinical trials.
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Mesenchymal Stromal Cell Therapy in Novel Porcine Model of Diffuse Liver Damage Induced by Repeated Biliary Obstruction. Int J Mol Sci 2021; 22:ijms22094304. [PMID: 33919123 PMCID: PMC8122325 DOI: 10.3390/ijms22094304] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/18/2021] [Accepted: 04/19/2021] [Indexed: 12/11/2022] Open
Abstract
In liver surgery, biliary obstruction can lead to secondary biliary cirrhosis, a life-threatening disease with liver transplantation as the only curative treatment option. Mesenchymal stromal cells (MSC) have been shown to improve liver function in both acute and chronic liver disease models. This study evaluated the effect of allogenic MSC transplantation in a large animal model of repeated biliary obstruction followed by partial hepatectomy. MSC transplantation supported the growth of regenerated liver tissue after 14 days (MSC group, n = 10: from 1087 ± 108 (0 h) to 1243 ± 92 mL (14 days); control group, n = 11: from 1080 ± 95 (0 h) to 1100 ± 105 mL (14 days), p = 0.016), with a lower volume fraction of hepatocytes in regenerated liver tissue compared to resected liver tissue (59.5 ± 10.2% vs. 70.2 ± 5.6%, p < 0.05). Volume fraction of connective tissue, blood vessels and bile vessels in regenerated liver tissue, serum levels of liver enzymes (AST, ALT, ALP and GGT) and liver metabolites (albumin, bilirubin, urea and creatinine), as well as plasma levels of IL-6, IL-8, TNF-α and TGF-β, were not affected by MSC transplantation. In our novel, large animal (pig) model of repeated biliary obstruction followed by partial hepatectomy, MSC transplantation promoted growth of liver tissue without any effect on liver function. This study underscores the importance of translating results between small and large animal models as well as the careful translation of results from animal model into human medicine.
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Kim J, Lee C, Shin Y, Wang S, Han J, Kim M, Kim JM, Shin SC, Lee BJ, Kim TJ, Jung Y. sEVs from tonsil-derived mesenchymal stromal cells alleviate activation of hepatic stellate cells and liver fibrosis through miR-486-5p. Mol Ther 2021; 29:1471-1486. [PMID: 33348053 PMCID: PMC8058446 DOI: 10.1016/j.ymthe.2020.12.025] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 09/24/2020] [Accepted: 12/15/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) are considered as a promising therapeutic tool for liver fibrosis, a main feature of chronic liver disease. Because small extracellular vesicles (sEVs) harboring a variety of proteins and RNAs are known to have similar functions with their derived cells, MSC-derived sEVs carry out the regenerative capacities of MSCs. Human tonsil-derived MSCs (T-MSCs) are reported as a novel source of MSCs, but their effects on liver fibrosis remain unclear. In the present study, we investigated the effects of T-MSC-derived sEVs on liver fibrosis. The expression of profibrotic genes decreased in human primary hepatic stellate cells (pHSCs) co-cultured with T-MSCs. Treatment of T-MSC-sEVs inactivated human and mouse pHSCs. Administration of T-MSC-sEVs ameliorated hepatic injuries and fibrosis in chronically damaged liver induced by carbon tetrachloride (CCl4). miR-486-5p highly enriched in T-MSC-sEVs targeting the hedgehog receptor, smoothened (Smo), was upregulated, whereas Smo and Gli2, the hedgehog target gene, were downregulated in pHSCs and liver tissues treated with T-MSC-sEVs or miR-486-5p mimic, indicating that sEV-miR-486 inactivates HSCs by suppressing hedgehog signaling. Our results showed that T-MSCs attenuate HSC activation and liver fibrosis by delivering sEVs, and miR-486 in the sEVs inactivates hedgehog signaling, suggesting that T-MSCs and their sEVs are novel anti-fibrotic therapeutics for treating chronic liver disease.
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Affiliation(s)
- Jieun Kim
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
| | - Chanbin Lee
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
| | - Yongbo Shin
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
| | - Sihyung Wang
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
| | - Jinsol Han
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
| | - Minju Kim
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
| | - Ji Min Kim
- Pusan National University Medical Research Institute, Pusan National University School of Medicine, Pusan 49241, Republic of Korea
| | - Sung-Chan Shin
- Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Pusan National University and Medical Research Institute, Pusan National University Hospital, Pusan 49241, Republic of Korea
| | - Byung-Joo Lee
- Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Pusan National University and Medical Research Institute, Pusan National University Hospital, Pusan 49241, Republic of Korea
| | - Tae-Jin Kim
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea; Department of Biological Sciences, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
| | - Youngmi Jung
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea; Department of Biological Sciences, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea.
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Rashid S, Qazi REM, Malick TS, Salim A, Khan I, Ilyas A, Haneef K. Effect of valproic acid on the hepatic differentiation of mesenchymal stem cells in 2D and 3D microenvironments. Mol Cell Biochem 2021; 476:909-919. [PMID: 33111212 DOI: 10.1007/s11010-020-03955-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 10/15/2020] [Indexed: 02/06/2023]
Abstract
Mesenchymal stem cells (MSCs) have multi-lineage differentiation potential which make them an excellent source for cell-based therapies. Histone modification is one of the major epigenetic regulations that play central role in stem cell differentiation. Keeping in view their ability to maintain gene expression essential for successful differentiation, it was interesting to examine the effects of valproic acid (VPA), a histone deacetylase inhibitor, in the hepatic differentiation of MSCs within the 3D scaffold. MSCs were treated with the optimized concentration of VPA in the 3D collagen scaffold. Analyses of hepatic differentiation potential of treated MSCs were performed by qPCR, immunostaining and periodic acid Schiff assay. Our results demonstrate that MSCs differentiate into hepatic-like cells when treated with 5 mM VPA for 24 h. The VPA-treated MSCs have shown significant upregulation in the expression of hepatic genes, CK-18 (P < 0.05), TAT (P < 0.01), and AFP (P < 0.001), and hepatic proteins, AFP (P < 0.05) and ALB (P < 0.01). In addition, acetylation of histones (H3 and H4) was significantly increased (P < 0.001) in VPA-pretreated cells. Further analysis showed that VPA treatment significantly enhanced (P < 0.01) glycogen storage, an important functional aspect of hepatic cells. The present study revealed the effectiveness of VPA in hepatic differentiation within the 3D collagen scaffold. These hepatic-like cells may have an extended clinical applicability in future for successful liver regeneration.
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Affiliation(s)
- Saman Rashid
- Dr. Zafar H. Zaidi Center for Proteomics, University of Karachi, Karachi, 75270, Pakistan
| | - Rida-E-Maria Qazi
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Tuba Shakil Malick
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Asmat Salim
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Irfan Khan
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Amber Ilyas
- Dr. Zafar H. Zaidi Center for Proteomics, University of Karachi, Karachi, 75270, Pakistan
| | - Kanwal Haneef
- Dr. Zafar H. Zaidi Center for Proteomics, University of Karachi, Karachi, 75270, Pakistan.
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Siregar S, Sasongko Noegroho B, Adriansjah R, Mustafa A, Wijayanti Z. Intratesticular Human Adipose-Derived Stem Cell (hADSC) Transplantation Decreased Oxidative Stress in Testicular Torsion Model of Wistar Rat. Res Rep Urol 2021; 13:1-8. [PMID: 33442548 PMCID: PMC7797314 DOI: 10.2147/rru.s283861] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 11/16/2020] [Indexed: 12/22/2022] Open
Abstract
Introduction Testicular torsion is a sudden rotation of the testis towards its axis, which causes the twisting of the spermatic cord. Post-detorsion reperfusion will cause inflammation and trigger oxidative stress, which generates reactive oxygen species (ROS). Malondialdehyde (MDA) is an organic compound formed from ROS frequently used as an oxidative stress biomarker during ischemia and ischemia-reperfusion injury. In some organs, stem cell administration on the damaged organ is essential in preventing cellular damage and death. This study aimed to learn about the effect of hADSC administration on an ischemia-reperfusion injury. Material and Methods A total of 22 Wistar rats divided into 5 groups, two groups each consist of 5 male Wistar rats with testicular torsion model without hADSC therapy (group I), while 2 other groups consist of 5 rats with testicular torsion model were given 1.0×106 cells intratesticular hADSC injection 30 minutes after testicular detorsion (group II). Both groups were euthanized at 1 and 4 weeks of observation. The last group consists of 2 rats without any treatment or model (negative control group). Following euthanasia, testicular tissue was harvested for MDA expression measurement using ELISA and histopathological examination. Statistical analysis using an one way ANOVA was done with SPSS version 21.0. Results The result of MDA examination using the ELISA method has shown a concentration difference between group I (control) and group II (hADSC treatment). Testicular MDA concentration in the treatment group was significantly lower on the 1st and 4th week of observation (p2=0.000, p4=0.016). Post hoc analysis showed no statistically different between therapy and healthy group (p=0.972). On histopathological examination, Johnsen score in the treatment group was significantly higher on the 4th week of observation (p=0.044). Post hoc analysis showed no statistically different between therapy and healthy group (p=0.195). Conclusion Intratesticular hADSC administration can inhibit ROS formation due to ischemia-reperfusion injury in testicular tissue after testicular detorsion in Wistar rats.
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Affiliation(s)
- Safendra Siregar
- Department of Urology, Faculty of Medicine Universitas Padjadjaran, Hasan Sadikin General Hospital, Banding, Indonesia
| | - Bambang Sasongko Noegroho
- Department of Urology, Faculty of Medicine Universitas Padjadjaran, Hasan Sadikin General Hospital, Banding, Indonesia
| | - Ricky Adriansjah
- Department of Urology, Faculty of Medicine Universitas Padjadjaran, Hasan Sadikin General Hospital, Banding, Indonesia
| | - Akhmad Mustafa
- Department of Urology, Faculty of Medicine Universitas Padjadjaran, Hasan Sadikin General Hospital, Banding, Indonesia
| | - Zola Wijayanti
- Department of Urology, Faculty of Medicine Universitas Padjadjaran, Hasan Sadikin General Hospital, Banding, Indonesia
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