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Elzainy A, El Sadik A, Altowayan WM. Comparison between the Regenerative and Therapeutic Impacts of Bone Marrow Mesenchymal Stem Cells and Adipose Mesenchymal Stem Cells Pre-Treated with Melatonin on Liver Fibrosis. Biomolecules 2024; 14:297. [PMID: 38540717 PMCID: PMC10968153 DOI: 10.3390/biom14030297] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 02/14/2024] [Accepted: 02/28/2024] [Indexed: 01/06/2025] Open
Abstract
BACKGROUND The distinctive feature of liver fibrosis is the progressive replacement of healthy hepatic cells by the extracellular matrix protein, which is abundant in collagen I and III, with impaired matrix remodeling. The activation of myofibroblastic cells enhances the fibrogenic response of complex interactions of hepatic stellate cells, fibroblasts, and inflammatory cells to produce the excessive deposition of the extracellular protein matrix. This process is activated by multiple fibrogenic mediators and cytokines, such as TNF-α and IL-1β, accompanied with a decrease in the anti-fibrogenic factor NF-κβ. Mesenchymal stem cells (MSCs) represent a promising therapy for liver fibrosis, allowing for a more advanced regenerative influence when cultured with extrinsic or intrinsic proliferative factors, cytokines, antioxidants, growth factors, and hormones such as melatonin (MT). However, previous studies showed conflicting findings concerning the therapeutic effects of adipose (AD) and bone marrow (BM) MSCs; therefore, the present work aimed to conduct a comparative and comprehensive study investigating the impact of MT pre-treatment on the immunomodulatory, anti-inflammatory, and anti-apoptotic effects of AD- and BM-MSCs and to critically analyze whether MT-pre-treated AD-MSCs and BM-MSCs reveal equal or different therapeutic and regenerative potentials in a CCl4-injured liver experimental rat model. MATERIALS AND METHODS Six groups of experimental rats were used, with ten rats in each group: group I (control group), group II (CCl4-treated group), group III (CCl4- and BM-MSC-treated group), group IV (CCl4 and MT-pre-treated BM-MSC group), group V (CCl4- and AD-MSC-treated group), and group VI (CCl4 and MT-pre-treated AD-MSC group). Liver function tests and the gene expression of inflammatory, fibrogenic, apoptotic, and proliferative factors were analyzed. Histological and immunohistochemical changes were assessed. RESULTS The present study compared the ability of AD- and BM-MSCs, with and without MT pre-treatment, to reduce hepatic fibrosis. Both types of MSCs improved hepatocyte function by reducing the serum levels of ALT, aspartate aminotransferase (AST), alkaline phosphatase (AKP), and total bilirubin (TBIL). In addition, the changes in the hepatocellular architecture, including the hepatocytes, liver sinusoids, central veins, portal veins, biliary ducts, and hepatic arteries, showed a decrease in hepatocyte injury and cholestasis with a reduction in inflammation, apoptosis, and necrosis of the hepatic cells, together with an inhibition of liver tissue fibrosis. These results were augmented by an analysis of the expression of the pro-inflammatory cytokines TNFα and IL-1β, the anti-fibrogenic factor NF-κβ, the apoptotic factor caspase-3, and the proliferative indicators antigen Ki-67 and proliferating cell nuclear antigen (PCNA). These findings were found to be statistically significant, with the restoration of normal parameters in the rats that received AD-MSCs pre-treated with MT, denoting optimal regenerative and therapeutic effects. CONCLUSIONS AD-MSCs pre-treated with MT are the preferred choice in improving hepatic fibrosis and promoting the therapeutic and regenerative ability of liver tissue. They represent a very significant tool for future stem cell use in the tissue regeneration strategy for the treatment of liver diseases.
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Affiliation(s)
- Ahmed Elzainy
- Department of Anatomy and Histology, College of Medicine, Qassim University, Buraydah 51452, Saudi Arabia; (A.E.); (A.E.S.)
- Department of Anatomy and Embryology, College of Medicine, Cairo University, Cairo 11956, Egypt
| | - Abir El Sadik
- Department of Anatomy and Histology, College of Medicine, Qassim University, Buraydah 51452, Saudi Arabia; (A.E.); (A.E.S.)
- Department of Anatomy and Embryology, College of Medicine, Cairo University, Cairo 11956, Egypt
| | - Waleed Mohammad Altowayan
- Department of Pharmacy Practice, College of Pharmacy, Qassim University, Buraydah 51452, Saudi Arabia
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Ali Hosseinzadeh S, Sahebghadam Lotfi A, Davoodian N, Arjmand S, Rangchi M, Mashhadiabbas F. Effectiveness of human adipose tissue-derived mesenchymal stem cells expressing alpha-1 antitrypsin gene in liver fibrosis: a study in mice. GASTROENTEROLOGY AND HEPATOLOGY FROM BED TO BENCH 2024; 17:151-160. [PMID: 38994502 PMCID: PMC11234484 DOI: 10.22037/ghfbb.v17i2.2923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 03/05/2024] [Indexed: 07/13/2024]
Abstract
Aim The present study examined the protective potential of human adipose tissue-derived mesenchymal stem cells (hASCs) modified to overexpress alpha-1 antitrypsin (AAT), in a mouse model of the liver fibrosis. Background For the treatment of end-stage liver diseases, cell therapy has emerged as a promising noninvasive alternative to liver transplantation. Mesenchymal stem cells (MSCs) are being evaluated due to their dual capabilities of promoting liver regeneration and modulating the pathogenic inflammation of the immune system. Methods Liver fibrosis was induced in mice via the intraperitoneal injection of carbon tetrachloride (CCl4). MSCs were extracted from the human adipose tissue. After stemness confirmation, the cells were transduced with the lentiviruses containing the AAT gene, and then injected into the mice's tail vein. Fourteen days' post-transplantation, mice were sacrificed, and blood and tissue samples were collected for analysis. Important liver enzymes, including alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), albumin, and total bilirubin (TB), were measured. Histological studies were carried out using the hematoxylin and eosin (H&E), as well as Masson's trichrome (MT) staining. Results Compared to hASCs, treatment with AAT-hASCs resulted in greater reductions in ALT, AST, ALP, and TB, as well as normalized albumin levels. AAT-hASCs promoted enhanced liver regeneration histologically, likely attributable to anti-inflammatory and anti-proteolytic properties of AAT. Conclusion These findings indicate AAT-engineered hASCs as a promising cell-gene therapy candidate for further study in liver cirrhosis models.
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Affiliation(s)
- Sara Ali Hosseinzadeh
- Department of Clinical Biochemistry, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran
| | - Abbas Sahebghadam Lotfi
- Department of Clinical Biochemistry, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran
| | - Nahid Davoodian
- Endocrinology and Metabolism Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
- Department of Clinical Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Sareh Arjmand
- Protein Research Center, Shahid Beheshti University, Tehran, Iran
| | - Marjan Rangchi
- Department of Clinical Biochemistry, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran
| | - Fatemeh Mashhadiabbas
- Department of Oral and Maxillofacial Pathology, Dental School, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Kumar R, Kumar S, Prakash SS. Compensated liver cirrhosis: Natural course and disease-modifying strategies. World J Methodol 2023; 13:179-193. [PMID: 37771878 PMCID: PMC10523240 DOI: 10.5662/wjm.v13.i4.179] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 06/05/2023] [Accepted: 06/27/2023] [Indexed: 09/20/2023] Open
Abstract
Compensated liver cirrhosis (CLC) is defined as cirrhosis with one or more decompensating events, such as ascites, variceal haemorrhage, or hepatic encephalopathy. Patients with CLC are largely asymptomatic with preserved hepatic function. The transition from CLC to decompensated cirrhosis occurs as a result of a complex interaction between multiple predisposing and precipitating factors. The first decompensation event in CLC patients is considered a significant turning point in the progression of cirrhosis, as it signals a drastic decline in median survival rates from 10-12 years to only 1-2 years. Furthermore, early cirrhosis has the potential to regress as liver fibrosis is a dynamic condition. With the advent of effective non-invasive tools for detecting hepatic fibrosis, more and more patients with CLC are currently being recognised. This offers clinicians a unique opportunity to properly manage such patients in order to achieve cirrhosis regression or, at the very least, prevent its progression. There are numerous emerging approaches for preventing or delaying decompensation in CLC patients. A growing body of evidence indicates that treating the underlying cause can lead to cirrhosis regression, and the use of non-selective beta-blockers can prevent decompensation by lowering portal hypertension. Additionally, addressing various cofactors (such as obesity, diabetes, dyslipidaemia, and alcoholism) and precipitating factors (such as infection, viral hepatitis, and hepatotoxic drugs) that have a detrimental impact on the natural course of cirrhosis may benefit patients with CLC. However, high-quality data must be generated through well-designed and adequately powered randomised clinical trials to validate these disease-modifying techniques for CLC patients. This article discussed the natural history of CLC, risk factors for its progression, and therapeutic approaches that could alter the trajectory of CLC evolution and improve outcomes.
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Affiliation(s)
- Ramesh Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, India
| | - Sudhir Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, India
| | - Sabbu Surya Prakash
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, India
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Tawfeek GAE, Kasem HA, Elshoala SE. Curcumin Nanofiber PCL/PLGA/Collagen Enhanced the Therapeutic Efficacy of Mesenchymal Stem Cells against Liver Fibrosis in Animal Model and Prevented its Recurrence. Nanotheranostics 2023; 7:299-315. [PMID: 37064607 PMCID: PMC10093421 DOI: 10.7150/ntno.81019] [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: 11/19/2022] [Accepted: 03/04/2023] [Indexed: 04/18/2023] Open
Abstract
The aim of this study is preconditioning of hBM-MSCs using curcumin modified nanomembrane to optimize therapy of hepatic fibrosis and preventing its recurrence. Methods: The nanomembrane was prepared by electrospinning technique and characterized using conventional method (cur- nanoscaffold and cur+ nanoscaffold). Kinetic release of curcumin was also measured by spectrophotometry. MSCs were isolated from human bone marrow (hBM-MSCs) and cultured on the both nanoscaffolds. We evaluated the in-vivo effect of hBM-MSCs from both nanoscaffold cultures (cur- nanoscaffold/hMSCs and cur+ nanoscaffold/MSCs) on liver fibrosis from its effective and preventive points and we assessed the mechanisms of these effects as in vitro studies as cell proliferation, its effect on hepatogenic differentiation, its effect on paracrine release of hBM-MSCs and in-vivo studying the effect on cell migration, survival, engraftment, fate of transplanted cells, modifying the fibrogenic and inflammatory microenvironments. Results: The results of animal model showed that single injection of preconditioning of hBM-MSCs using curcumin modified nanoscaffold ameliorate the fibrosis and prevent its recurrence until 24 weeks of therapy in contrast to improvement but not ameliorative effect of hBM-MSCs/ curcumin negative nanoscaffold which recurred progressively after 12 weeks of therapy. These effects of curcumin modified nanoscaffold were results from its highly efficacy on cell proliferation, in-vitro and in-vivo hepatogenic differentiation, increasing cell migration, engraftment and survival in the inflammatory microenvironment which was markedly improved by down regulation of inflammatory mediators and upregulation of anti-oxidant factors. Conclusion: hBM-MSCs cultured on the prepared curcumin nanomembrane in this study is promising in regenerative therapy for ameliorating the hepatic fibrosis and to prevent its recurrence.
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Affiliation(s)
- Gehan Abd-Elfatah Tawfeek
- Clinical Pathology Department, Faculty of Medicine, Menoufia University, Egypt
- ✉ Corresponding author: Gehan Abd-Elfatah Tawfeek, Clinical Pathology Department, Menoufia University, Menoufia, Egypt,
| | - Hend Ahmed Kasem
- Pathology Department, Faculty of Medicine, Menoufia University, Egypt
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Transplantation of adipose-derived mesenchymal stem cells ameliorates acute hepatic injury caused by nonsteroidal anti-inflammatory drug diclofenac sodium in female rats. Biomed Pharmacother 2022; 155:113805. [PMID: 36271578 DOI: 10.1016/j.biopha.2022.113805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 09/30/2022] [Accepted: 10/02/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Although the beneficial role of adipose-derived mesenchymal stem cells (AD-MSCs) in acute liver injury has been addressed by numerous studies employing different liver injury inducers, the role of rat AD-MSCs (rAD-MSCs) in diclofenac sodium (DIC) - induced acute liver injury has not yet been clarified. OBJECTIVE This study aimed to investigate whether rat adipose- rAD-MSCs injected intraperitoneal could restore the DIC-induced hepatoxicity. METHODS Hepatotoxicity was induced by DIC in a dose-based manner, after which intraperitoneal injection of rAD-MSCs was performed. RESULTS Here, the transplanted cells migrated to the injured liver, and this was evidenced by detecting the specific SRY in the liver samples. After administering DIC, a significant decrease in body weight, survival rate, serum proteins, antioxidants, anti-apoptotic gene expression, and certain growth factors, whereas hepatic-specific markers, pro-inflammatory mediators, and oxidative, pro-apoptotic, and ER-stress markers were elevated. These adverse effects were significantly recovered after engraftment with rAD-MSCs. This was evidenced by enhanced survival and body weight, improved globulin and albumin values, increased expression of SOD, GPx, BCL-2, VEGF, and FGF-basic expression, and decreased serum ALT, AST, ALP, and total bilirubin. rAD-MSCs also reduced liver cell damage by suppressing the expression of MDA, IL-1B, IL-6, BAX, JNK, GRP78/BiP, CHOP, XBP-1, and cleaved caspase 3/7. Degenerative hepatic changes and multifocal areas of fatty change within liver cells were observed in DIC-received groups. These changes were improved with the transplantation of rAD-MSCs. CONCLUSIONS We could conclude that targeted AD-MSCs could be applied to reduce hepatic toxicity caused by NSAIDs (DIC).
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Abdelgwad M, Ewaiss M, Sabry D, Khalifa WA, Altaib ZM, Alhelf M. Comparative study on effect of mesenchymal stem cells and endothelial progenitor cells on treatment of experimental CCL4-induced liver fibrosis. Arch Physiol Biochem 2022; 128:1071-1080. [PMID: 32374186 DOI: 10.1080/13813455.2020.1752256] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND We speculated impacts of BM-MSCs and UC-EPCs on reversal of hepatic injury induced by carbon tetrachloride (CCl4). Fifty adult rats were divided into five groups: control group, CCl4A group, CCl4B group, CCl4/BM-MSCs group and CCl4/UC-EPCs group. Blood samples were driven to measure concentration of albumin and ALT. Quantitative expression of HGF, TGF-β, MMP-2, and VEGF were assessed by PCR. Histological and immunohistochemistry examination of the liver tissue were performed. RESULTS There was elevating albumin (p < .05) and reducing ALT (p < .05) concentrations in groups treated with BM-MSCs and UC-EPCs compared to untreated CCL4A&B groups. UC-EPCs treated group have significantly higher MMP-2 and VEGF (p < .01) genes expression than BM-MSCs treated group. Furthermore, UC-EPCs were more valuable than BMMSCs in increasing gene expression of HGF (p < .05) and immunohistochemistry of α-SMA and Ki-67 (p < .01). BM-MSCs have significantly lower TGF-β (p < .00) compared to UC-EPCs. CONCLUSION This study highlighted on liver regeneration role of both UC-EPCs and BM-MSCs in liver fibrosis.
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Affiliation(s)
- Marwa Abdelgwad
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Manal Ewaiss
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Beni Suef University, Beni Suef, Egypt
- Medical College, Al-Jouf University, Al-Jawf, Saudi Arabia
| | - Dina Sabry
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Warda A Khalifa
- Department of Biotechnology, Faculty of Science, Sebha University, Sabha, Libya
| | - Zeinab M Altaib
- Department of Histology and Cell Biology, Helwan Faculty of Medicine, Helwan University, Cairo, Egypt
| | - Maha Alhelf
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Giza, Egypt
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Selim NM, Melk MM, Melek FR, Saleh DO, Sobeh M, El-Hawary SS. Phytochemical profiling and anti-fibrotic activities of Plumbago indica L. and Plumbago auriculata Lam. in thioacetamide-induced liver fibrosis in rats. Sci Rep 2022; 12:9864. [PMID: 35701526 PMCID: PMC9197831 DOI: 10.1038/s41598-022-13718-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 05/26/2022] [Indexed: 11/09/2022] Open
Abstract
This study aimed at investigating the chemical composition and the hepatoprotective activities of Plumbago indica L. and P. auriculata Lam. LC-MS/MS analyses for the hydroalcoholic extracts of the aerial parts of the two Plumbago species allowed the tentative identification of thirty and twenty-five compounds from P. indica and P. auriculata, respectively. The biochemical and histopathological alterations associated with thioacetamide (TAA)-induced liver fibrosis in rats were evaluated in vivo where rats received the two extracts at three different dose levels (100, 200 and 400 mg/kg p.o, daily) for 15 consecutive days with induction of hepatotoxicity by TAA (200 mg/kg/day, i.p.) at 14th and 15th days. Results of the present study showed a significant restoration in liver function biomarkers viz. alanine transaminase (ALT), aspartate transaminase (AST), gamma glutamyl transferase and total bilirubin. The liver homogenates exhibited increased levels of antioxidant biomarkers: reduced glutathione (GSH) and catalase (CAT), accompanied with decline in malondialdehyde (MDA). Furthermore, treated groups exhibited a significant suppression in liver inflammatory cytokines: tumor necrosis factor-α (TNF-α) and interlukin-6 (IL-6), and fibrotic biomarker: alpha smooth muscle relaxant. Histopathological examination of the liver showed normality of hepatocytes. Noteworthy, P. indica extract showed better hepatoprotective activity than P. auriculata, particularly at 200 mg/kg. To sum up, all these results indicated the hepatoprotective properties of both extracts, as well as their antifibrotic effect was evidenced by reduction in hepatic collagen deposition. However, additional experiments are required to isolate their individual secondary metabolites, assess the toxicity of the extracts and explore the involved mechanism of action.
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Affiliation(s)
- Nabil Mohamed Selim
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Giza, 12613, Egypt.
| | - Mina Michael Melk
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Giza, 12613, Egypt
| | - Farouk Rasmy Melek
- Chemistry of Natural Compounds Department, National Research Centre, Giza, 12622, Egypt
| | - Dalia Osama Saleh
- Pharmacology Department, National Research Centre, Giza, 12622, Egypt
| | - Mansour Sobeh
- AgroBioSciences, Mohammed VI Polytechnic University, Lot 660-Hay MoulayRachid, 43150, Benguerir, Morocco
| | - Seham S El-Hawary
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Giza, 12613, Egypt
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The assessment of mesenchymal stem cells therapy in acute on chronic liver failure and chronic liver disease: a systematic review and meta-analysis of randomized controlled clinical trials. Stem Cell Res Ther 2022; 13:204. [PMID: 35578365 PMCID: PMC9109309 DOI: 10.1186/s13287-022-02882-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 05/04/2022] [Indexed: 11/29/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) therapy is showing potential therapeutic effects on liver function improvement in patients with chronic liver disease; however, the consensus on efficacy and safety of MSCs has not been reached. Methods We performed this systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of MSCs therapy for patients with chronic liver disease. A detailed search of the Cochrane Library, MEDLINE, Web of Science, and EMBASE databases was conducted to find studies published prior to September 15, 2021. The outcome measures were survival rate, model of end-stage liver disease (MELD) score, albumin, total bilirubin, coagulation function, and aminotransferase. Results A literature search resulted in 892 citations. Of these, 12 studies met the inclusion criteria. It was found that compared with conventional treatment, MSCs therapy was associated with improved liver function including the MELD score, albumin levels, and coagulation function. However, it had no obvious beneficial effects on survival rate and aminotransferase levels. Subgroup analyses indicated that MSCs therapy had therapeutic effects on patients with both acute on chronic liver failure (ACLF) and cirrhosis. BM-MSCs and UC-MSCs treatment had similar efficacy to improve liver function. The effectiveness varied slightly between the peripheral intravenous injection and hepatic arterial injection. Five studies reported that the only adverse event of the MSCs therapy was fever, and no serious adverse events and side effects were reported. Analysis on clinical symptoms showed that encephalopathy and gastrointestinal hemorrhage events were reduced after MSCs therapy. Conclusions In conclusion, this study suggested that MSCs therapy could be a potential therapeutic alternative for patients with chronic liver disease in clinical practice. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02882-4.
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Recent Advancements in Antifibrotic Therapies for Regression of Liver Fibrosis. Cells 2022; 11:cells11091500. [PMID: 35563807 PMCID: PMC9104939 DOI: 10.3390/cells11091500] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/21/2022] [Accepted: 04/26/2022] [Indexed: 11/18/2022] Open
Abstract
Cirrhosis is a severe form of liver fibrosis that results in the irreversible replacement of liver tissue with scar tissue in the liver. Environmental toxicity, infections, metabolic causes, or other genetic factors including autoimmune hepatitis can lead to chronic liver injury and can result in inflammation and fibrosis. This activates myofibroblasts to secrete ECM proteins, resulting in the formation of fibrous scars on the liver. Fibrosis regression is possible through the removal of pathophysiological causes as well as the elimination of activated myofibroblasts, resulting in the reabsorption of the scar tissue. To date, a wide range of antifibrotic therapies has been tried and tested, with varying degrees of success. These therapies include the use of growth factors, cytokines, miRNAs, monoclonal antibodies, stem-cell-based approaches, and other approaches that target the ECM. The positive results of preclinical and clinical studies raise the prospect of a viable alternative to liver transplantation in the near future. The present review provides a synopsis of recent antifibrotic treatment modalities for the treatment of liver cirrhosis, as well as a brief summary of clinical trials that have been conducted to date.
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Zhang Y, Liu C, Wang T, Kong F, Zhang H, Yi J, Dong X, Duan H, Tao N, Yang Y, Wang H. Therapeutic effects of mesenchymal stem cells loaded with oncolytic adenovirus carrying decorin on a breast cancer lung metastatic mouse model. Mol Ther Oncolytics 2022; 24:486-496. [PMID: 35229027 PMCID: PMC8850566 DOI: 10.1016/j.omto.2022.01.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 01/27/2022] [Indexed: 12/24/2022] Open
Abstract
Oncolytic adenoviruses (OAds) are alternative immune therapeutic strategies for tumors. However, liver uptake and antibody neutralization are two major barriers for systemic delivery during the treatment of tumor metastasis. Mesenchymal stem cells (MSCs) have emerged as potential vehicles to improve delivery. In this study, we loaded umbilical-cord-derived MSCs (UC-MSCs) with OAds expressing decorin (rAd.DCN) or without foreign genes (rAd.Null) to treat breast cancer lung metastasis. In vivo, rAd.Null, MSCs.Null, and rAd.DCN exhibited antitumor effects compared with other groups in a mouse model. Unexpectedly, MSCs.Null showed much greater antitumor responses than MSCs.DCN, including improved survival and reduced tumor burden. Compared with rAd.Null, both MSCs.Null and MSCs.DCN could improve the viral spread and distribution in metastatic tumor lesions in the lung. MSCs.DCN produced much more decorin in lungs than rAd.DCN; however, rAd.DCN reduced the downstream target genes of decorin much more strongly than MSCs.DCN, which was consistent with in vitro findings. In addition, rAd.DCN, MSCs.Null, and MSCs.DCN could reduce The cytokine levels in the lung. In conclusion, MSCs improved oncolytic adenoviral delivery and spread in tumor tissues and enhanced therapeutic effects. However, MSCs.DCN reduced OAd-evoked antitumor responses, possibly via a contact-dependent mechanism.
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Chung JS, Hwang S, Hong JE, Jo M, Rhee KJ, Kim S, Jung PY, Yoon Y, Kang SH, Ryu H, Kim MY, Bae KS, Eom YW. Skeletal muscle satellite cell-derived mesenchymal stem cells ameliorate acute alcohol-induced liver injury. Int J Med Sci 2022; 19:353-363. [PMID: 35165521 PMCID: PMC8795809 DOI: 10.7150/ijms.68971] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 01/05/2022] [Indexed: 12/03/2022] Open
Abstract
Cultured human skeletal-muscle satellite cells have properties of mesenchymal stem cells (skeletal muscle satellite cell-derived mesenchymal stem cells, SkMSCs) and play anti-inflammatory roles by secreting prostaglandin E2 and hepatocyte growth factor (HGF). To evaluate the utility of SkMSCs in treating liver diseases, we determined whether SkMSCs could ameliorate acute liver and gut inflammation induced by binge ethanol administration. Binge drinking of ethanol led to weight loss in the body and spleen, liver inflammation and steatosis, and increased serum ALT and AST levels (markers of liver injury), along with increased IL-1β, TNF-α, and iNOS expression levels in mice. However, levels of these binge-drinking-induced indicators were reduced by a single intraperitoneal treatment of SkMSCs. Furthermore, levels of bacteria-derived lipopolysaccharide decreased in the livers and sera of ethanol-exposed mice after SkMSC administration. SkMSCs decreased the extent of tissue inflammation and reduced villus and crypt lengths in the small intestine after alcohol binge drinking. SkMSCs also reduced the leakage of blood albumin, an indicator of leaky gut, in the stool of ethanol-exposed mice. Alcohol-induced damage to human colonic Caco-2/tc7 cells was also alleviated by HGF. Therefore, a single treatment with SkMSCs can attenuate alcoholic liver damage by reducing inflammatory responses in the liver and gut, suggesting that SkMSCs could be used in cell therapy to treat alcoholic liver diseases.
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Affiliation(s)
- Jae Sik Chung
- Department of Surgery, Yonsei University Wonju College of Medicine, Wonju, Gangwon-do 26426, Republic of Korea
| | - Soonjae Hwang
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Gangwon-do 26426, Republic of Korea.,Department of Biochemistry, Lee Gil Ya Cancer and Diabetes Institute, GAIHST, Gachon University College of Medicine, Incheon 21999, Republic of Korea
| | - Ju Eun Hong
- Department of Biomedical Laboratory Science, College of Health Sciences, Yonsei University MIRAE Campus, Wonju, Gangwon-do 26493, Republic of Korea
| | - Minjeong Jo
- Department of Biomedical Laboratory Science, College of Health Sciences, Yonsei University MIRAE Campus, Wonju, Gangwon-do 26493, Republic of Korea
| | - Ki-Jong Rhee
- Department of Biomedical Laboratory Science, College of Health Sciences, Yonsei University MIRAE Campus, Wonju, Gangwon-do 26493, Republic of Korea
| | - Seongyup Kim
- Department of Surgery, Yonsei University Wonju College of Medicine, Wonju, Gangwon-do 26426, Republic of Korea
| | - Pil Young Jung
- Department of Surgery, Yonsei University Wonju College of Medicine, Wonju, Gangwon-do 26426, Republic of Korea
| | - Youngdae Yoon
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Gangwon-do 26426, Republic of Korea.,Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Gangwon-do 26426, Republic of Korea
| | - Seong Hee Kang
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Gangwon-do 26426, Republic of Korea.,Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Gangwon-do 26426, Republic of Korea
| | - Hoon Ryu
- Department of Surgery, Yonsei University Wonju College of Medicine, Wonju, Gangwon-do 26426, Republic of Korea
| | - Moon Young Kim
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Gangwon-do 26426, Republic of Korea.,Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Gangwon-do 26426, Republic of Korea.,Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Gangwon-do 26426, Republic of Korea
| | - Keum Seok Bae
- Department of Surgery, Yonsei University Wonju College of Medicine, Wonju, Gangwon-do 26426, Republic of Korea
| | - Young Woo Eom
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Gangwon-do 26426, Republic of Korea.,Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Gangwon-do 26426, Republic of Korea
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12
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Wu MC, Meng QH. Current understanding of mesenchymal stem cells in liver diseases. World J Stem Cells 2021; 13:1349-1359. [PMID: 34630867 PMCID: PMC8474713 DOI: 10.4252/wjsc.v13.i9.1349] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 07/01/2021] [Accepted: 08/25/2021] [Indexed: 02/06/2023] Open
Abstract
Liver diseases caused by various factors have become a significant threat to public health worldwide. Liver transplantation has been considered as the only effective treatment for end-stage liver diseases; however, it is limited by the shortage of donor organs, postoperative complications, long-term immunosuppression, and high cost of treatment. Thus, it is not available for all patients. Recently, mesenchymal stem cells (MSCs) transplantation has been extensively explored for repairing hepatic injury in various liver diseases. MSCs are multipotent adult progenitor cells originated from the embryonic mesoderm, and can be found in mesenchymal tissues including the bone marrow, umbilical cord blood, adipose tissue, liver, lung, and others. Although the precise mechanisms of MSC transplantation remain mysterious, MSCs have been demonstrated to be able to prevent the progression of liver injury and improve liver function. MSCs can self-renew by dividing, migrating to injury sites and differentiating into multiple cell types including hepatocytes. Additionally, MSCs have immune-modulatory properties and release paracrine soluble factors. Indeed, the safety and effectiveness of MSC therapy for liver diseases have been demonstrated in animals. However, pre-clinical and clinical trials are largely required to confirm its safety and efficacy before large scale clinical application. In this review, we will explore the molecular mechanisms underlying therapeutic effects of MSCs on liver diseases. We also summarize clinical advances in MSC-based therapies.
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Affiliation(s)
- Mu-Chen Wu
- Department of Medical Oncology,You An Hospital, Capital Medical University, Beijing 100069, China
| | - Qing-Hua Meng
- Department of Medical Oncology,You An Hospital, Capital Medical University, Beijing 100069, China.
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13
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Tonon F, Farra R, Zennaro C, Pozzato G, Truong N, Parisi S, Rizzolio F, Grassi M, Scaggiante B, Zanconati F, Bonazza D, Grassi G, Dapas B. Xenograft Zebrafish Models for the Development of Novel Anti-Hepatocellular Carcinoma Molecules. Pharmaceuticals (Basel) 2021; 14:803. [PMID: 34451900 PMCID: PMC8400454 DOI: 10.3390/ph14080803] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/02/2021] [Accepted: 08/03/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common type of tumor and the second leading cause of tumor-related death worldwide. Liver cirrhosis is the most important predisposing factor for HCC. Available therapeutic approaches are not very effective, especially for advanced HCC, which is the most common form of the disease at diagnosis. New therapeutic strategies are therefore urgently needed. The use of animal models represents a relevant tool for preclinical screening of new molecules/strategies against HCC. However, several issues, including animal husbandry, limit the use of current models (rodent/pig). One animal model that has attracted the attention of the scientific community in the last 15 years is the zebrafish. This freshwater fish has several attractive features, such as short reproductive time, limited space and cost requirements for husbandry, body transparency and the fact that embryos do not show immune response to transplanted cells. To date, two different types of zebrafish models for HCC have been developed: the transgenic zebrafish and the zebrafish xenograft models. Since transgenic zebrafish models for HCC have been described elsewhere, in this review, we focus on the description of zebrafish xenograft models that have been used in the last five years to test new molecules/strategies against HCC.
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Affiliation(s)
- Federica Tonon
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Hospital, Strada di Fiume, 447, I 34149 Trieste, Italy; (F.T.); (R.F.); (C.Z.); (G.P.); (F.Z.); (D.B.)
| | - Rossella Farra
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Hospital, Strada di Fiume, 447, I 34149 Trieste, Italy; (F.T.); (R.F.); (C.Z.); (G.P.); (F.Z.); (D.B.)
| | - Cristina Zennaro
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Hospital, Strada di Fiume, 447, I 34149 Trieste, Italy; (F.T.); (R.F.); (C.Z.); (G.P.); (F.Z.); (D.B.)
| | - Gabriele Pozzato
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Hospital, Strada di Fiume, 447, I 34149 Trieste, Italy; (F.T.); (R.F.); (C.Z.); (G.P.); (F.Z.); (D.B.)
| | - Nhung Truong
- Stem Cell Research and Application Laboratory, VNUHCM, University of Science, Ho Chi Minh City 72711, Vietnam;
| | - Salvatore Parisi
- Pathology Unit, CRO Aviano, National Cancer Institute, IRCCS, I 33081 Aviano, Italy; (S.P.); (F.R.)
- Doctoral School in Molecular Biomedicine, University of Trieste, I 34127 Trieste, Italy
| | - Flavio Rizzolio
- Pathology Unit, CRO Aviano, National Cancer Institute, IRCCS, I 33081 Aviano, Italy; (S.P.); (F.R.)
- Department of Molecular Sciences and Nanosystems, Ca’ Foscari University of Venice, I 30170 Mestre, Italy
| | - Mario Grassi
- Department of Engineering and Architecture, University of Trieste, Via Valerio 6/A, I 34127 Trieste, Italy;
| | - Bruna Scaggiante
- Department of Life Sciences, Cattinara University Hospital, Trieste University, Strada di Fiume 447, I 34149 Trieste, Italy; (B.S.); (B.D.)
| | - Fabrizio Zanconati
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Hospital, Strada di Fiume, 447, I 34149 Trieste, Italy; (F.T.); (R.F.); (C.Z.); (G.P.); (F.Z.); (D.B.)
| | - Deborah Bonazza
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Hospital, Strada di Fiume, 447, I 34149 Trieste, Italy; (F.T.); (R.F.); (C.Z.); (G.P.); (F.Z.); (D.B.)
| | - Gabriele Grassi
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Hospital, Strada di Fiume, 447, I 34149 Trieste, Italy; (F.T.); (R.F.); (C.Z.); (G.P.); (F.Z.); (D.B.)
- Department of Life Sciences, Cattinara University Hospital, Trieste University, Strada di Fiume 447, I 34149 Trieste, Italy; (B.S.); (B.D.)
| | - Barbara Dapas
- Department of Life Sciences, Cattinara University Hospital, Trieste University, Strada di Fiume 447, I 34149 Trieste, Italy; (B.S.); (B.D.)
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14
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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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15
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He C, Yang Y, Zheng K, Chen Y, Liu S, Li Y, Han Q, Zhao RC, Wang L, Zhang F. Mesenchymal stem cell-based treatment in autoimmune liver diseases: underlying roles, advantages and challenges. Ther Adv Chronic Dis 2021; 12:2040622321993442. [PMID: 33633826 PMCID: PMC7887681 DOI: 10.1177/2040622321993442] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 01/18/2021] [Indexed: 12/20/2022] Open
Abstract
Autoimmune liver disease (AILD) is a series of chronic liver diseases with abnormal immune responses, including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). The treatment options for AILD remain limited, and the adverse side effects of the drugs that are typically used for treatment frequently lead to a low quality of life for AILD patients. Moreover, AILD patients may have a poor prognosis, especially those with an incomplete response to first-line treatment. Mesenchymal stem cells (MSCs) are pluripotent stem cells with low immunogenicity and can be conveniently harvested. MSC-based therapy is emerging as a promising approach for treating liver diseases based on their advantageous characteristics of immunomodulation, anti-fibrosis effects, and differentiation to hepatocytes, and accumulating evidence has revealed the positive effects of MSC therapy in AILD. In this review, we first summarize the mechanisms, safety, and efficacy of MSC treatment for AILD based on work in animal and clinical studies. We also discuss the challenges of MSC therapy in clinical applications. In summary, although promising data from preclinical studies are now available, MSC therapy is currently far for being applied in clinical practice, thus developing MSC therapy in AILD is still challenging and warrants further research.
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Affiliation(s)
- Chengmei He
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yanlei Yang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Kunyu Zheng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yiran Chen
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Suying Liu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yongzhe Li
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Qin Han
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Peking Union Medical College Hospital, Beijing, China
| | - Robert Chunhua Zhao
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Peking Union Medical College Hospital, Beijing, China
| | - Li Wang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Shuaifuyuan, Dongcheng District, Beijing 100730, China
| | - Fengchun Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Shuaifuyuan, Dongcheng District, Beijing 100730, China
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16
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Al-Dhamin Z, Liu LD, Li DD, Zhang SY, Dong SM, Nan YM. Therapeutic efficiency of bone marrow-derived mesenchymal stem cells for liver fibrosis: A systematic review of in vivo studies. World J Gastroenterol 2020; 26:7444-7469. [PMID: 33384547 PMCID: PMC7754546 DOI: 10.3748/wjg.v26.i47.7444] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 10/31/2020] [Accepted: 11/12/2020] [Indexed: 02/06/2023] Open
Abstract
Although multiple drugs are accessible for recovering liver function in patients, none are considered efficient. Liver transplantation is the mainstay therapy for end-stage liver fibrosis. However, the worldwide shortage of healthy liver donors, organ rejection, complex surgery, and high costs are prompting researchers to develop novel approaches to deal with the overwhelming liver fibrosis cases. Mesenchymal stem cell (MSC) therapy is an emerging alternative method for treating patients with liver fibrosis. However, many aspects of this therapy remain unclear, such as the efficiency compared to conventional treatment, the ideal MSC sources, and the most effective way to use it. Because bone marrow (BM) is the largest source for MSCs, this paper used a systematic review approach to study the therapeutic efficiency of MSCs against liver fibrosis and related factors. We systematically searched multiple published articles to identify studies involving liver fibrosis and BM-MSC-based therapy. Analyzing the selected studies showed that compared with conventional treatment BM-MSC therapy may be more efficient for liver fibrosis in some cases. In contrast, the cotreatment presented a more efficient way. Nevertheless, BM-MSCs are lacking as a therapy for liver fibrosis; thus, this paper also reviews factors that affect BM-MSC efficiency, such as the implementation routes and strategies employed to enhance the potential in alleviating liver fibrosis. Ultimately, our review summarizes the recent advances in the BM-MSC therapy for liver fibrosis. It is grounded in recent developments underlying the efficiency of BM-MSCs as therapy, focusing on the preclinical in vivo experiments, and comparing to other treatments or sources and the strategies used to enhance its potential while mentioning the research gaps.
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Affiliation(s)
- Zaid Al-Dhamin
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| | - Ling-Di Liu
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| | - Dong-Dong Li
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| | - Si-Yu Zhang
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| | - Shi-Ming Dong
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| | - Yue-Min Nan
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
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17
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Chiabotto G, Pasquino C, Camussi G, Bruno S. Molecular Pathways Modulated by Mesenchymal Stromal Cells and Their Extracellular Vesicles in Experimental Models of Liver Fibrosis. Front Cell Dev Biol 2020; 8:594794. [PMID: 33425900 PMCID: PMC7794013 DOI: 10.3389/fcell.2020.594794] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 11/06/2020] [Indexed: 12/18/2022] Open
Abstract
End-stage liver fibrosis is common to all chronic liver diseases. Since liver transplantation has several limitations, including lack of donors, immunological rejection, and high medical costs, therapeutic alternatives are needed. The administration of mesenchymal stromal cells (MSCs) has been proven effective in tissue regeneration after damage. However, the risk of uncontrolled side effects, such as cellular rejection and tumorigenesis, should be taken into consideration. A safer alternative to MSC transplantation is represented by the MSC secretome, which retains the same beneficial effect of the cell of origin, without showing any considerable side effect. The paracrine effect of MSCs is mainly carried out by secreted particles in the nanometer range, known as extracellular vesicles (EVs) that play a fundamental role in intercellular communication. In this review, we discuss the current literature on MSCs and MSC-EVs, focusing on their potential therapeutic action in liver fibrosis and on their molecular content (proteins and RNA), which contributes in reverting fibrosis and prompting tissue regeneration.
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Affiliation(s)
- Giulia Chiabotto
- Department of Medical Sciences, University of Turin, Turin, Italy.,Molecular Biotechnology Center, University of Turin, Turin, Italy
| | - Chiara Pasquino
- Department of Medical Sciences, University of Turin, Turin, Italy.,Molecular Biotechnology Center, University of Turin, Turin, Italy
| | - Giovanni Camussi
- Department of Medical Sciences, University of Turin, Turin, Italy.,Molecular Biotechnology Center, University of Turin, Turin, Italy
| | - Stefania Bruno
- Department of Medical Sciences, University of Turin, Turin, Italy.,Molecular Biotechnology Center, University of Turin, Turin, Italy
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18
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Ryu JS, Jeong EJ, Kim JY, Park SJ, Ju WS, Kim CH, Kim JS, Choo YK. Application of Mesenchymal Stem Cells in Inflammatory and Fibrotic Diseases. Int J Mol Sci 2020; 21:ijms21218366. [PMID: 33171878 PMCID: PMC7664655 DOI: 10.3390/ijms21218366] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 10/29/2020] [Accepted: 11/05/2020] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent stem cells that can be isolated from various tissues in the adult body. MSCs should be characterized by three criteria for regenerative medicine. MSCs must (1) adhere to plastic surfaces, (2) express specific surface antigens, and (3) differentiate into mesodermal lineages, including chondrocytes, osteoblasts, and adipocytes, in vitro. Interestingly, MSCs have immunomodulatory features and secrete trophic factors and immune receptors that regulate the microenvironment in host tissue. These specific and unique therapeutic properties make MSCs ideal as therapeutic agents in vivo. Specifically, pre-clinical and clinical investigators generated inflammatory and fibrotic diseases models, and then transplantation of MSCs into diseases models for therapeutic effects investigation. In this review, we characterize MSCs from various tissues and describe their applications for treating various inflammation and fibrotic diseases.
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Affiliation(s)
- Jae-Sung Ryu
- Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Konyang University, Daejeon 35365, Korea; (J.-S.R.); (J.-Y.K.)
- Department of Biomedical Informatics, College of Medicine, Konyang University, Daejeon 35365, Korea
| | - Eun-Jeong Jeong
- Department of Biological Science, College of Natural Sciences, Wonkwang University, Iksan 54538, Korea; (E.-J.J.); (S.J.P.); (W.S.J.)
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea;
| | - Jong-Yeup Kim
- Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Konyang University, Daejeon 35365, Korea; (J.-S.R.); (J.-Y.K.)
- Department of Biomedical Informatics, College of Medicine, Konyang University, Daejeon 35365, Korea
| | - Soon Ju Park
- Department of Biological Science, College of Natural Sciences, Wonkwang University, Iksan 54538, Korea; (E.-J.J.); (S.J.P.); (W.S.J.)
- Institute for Glycoscience, Wonkwang University, Iksan 54538, Korea
| | - Won Seok Ju
- Department of Biological Science, College of Natural Sciences, Wonkwang University, Iksan 54538, Korea; (E.-J.J.); (S.J.P.); (W.S.J.)
- Institute for Glycoscience, Wonkwang University, Iksan 54538, Korea
| | - Chang-Hyun Kim
- College of Medicine, Dongguk University, Goyang 10326, Korea;
| | - Jang-Seong Kim
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea;
- Department of Functional Genomics, University of Science and Technology (UST), Daejeon 34141, Korea
| | - Young-Kug Choo
- Department of Biological Science, College of Natural Sciences, Wonkwang University, Iksan 54538, Korea; (E.-J.J.); (S.J.P.); (W.S.J.)
- Institute for Glycoscience, Wonkwang University, Iksan 54538, Korea
- Correspondence:
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19
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El-Ashmawy NE, Al-Ashmawy GM, Fakher HE, Khedr NF. The role of WNT/β-catenin signaling pathway and glutamine metabolism in the pathogenesis of CCl 4-induced liver fibrosis: Repositioning of niclosamide and concerns about lithium. Cytokine 2020; 136:155250. [PMID: 32882667 DOI: 10.1016/j.cyto.2020.155250] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 08/09/2020] [Accepted: 08/10/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND Liver fibrosis is a serious health problem which may lead to advanced liver cirrhosis and hepatocellular carcinoma. OBJECTIVE The present study aimed to investigate the role of Wnt/β-catenin signaling pathway and glutamine aminohydrolase enzyme (l-glutaminase) in the pathogenesis of liver fibrosis and the potential benefits of niclosamide in treating liver fibrosis. METHODS Ninety male Albino rats were divided into 6 equal groups (n = 15) as follows: a normal control group (NC), CCl4-only treated group (Fib.) which received 1 mg/kg CCl4 two times weekly, niclosamide-treated group (Niclo.) which received 5 mg/kg of niclosamide one time daily, lithium chloride-treated group (LiCl) which received 100 mg/kg of LiCl one time daily, niclosamide-and-CCl4-treated group (Niclo. + Fib.) which received same doses of niclosamide and CCl4 given to other groups, and finally lithium chloride-and-CCl4-treated rat group (LiCl + Fib.) which received same doses of LiCl and CCl4 given to other groups. All treatments were administered orally for 8 weeks. Liver tissue was assessed for l-hydroxyproline, beta-catenin (β-catenin), l-glutaminase activity, as well as the gene expression of transforming growth factor beta-1 (TGF-β1) and Dishevelled-2 (Dvl2). Histopathological and immunohistochemical analyses of alpha smooth muscle actin α-SMA were performed. Serum alanine transaminase (ALT), aspartate transaminase (AST), and total bilirubin were measured. RESULTS The group of niclosamide-and-CCl4-treated rats showed a significant decrease in total bilirubin, ALT and AST, β-catenin, l-hydroxyproline, l-glutaminase activity, and gene expression of TGF-β1 and Dvl2. Moreover, the liver tissue in this group of rats showed mild α-SMA reactivity compared with the rats treated with CCl4 only (fibrosis group). On the other hand, lithium chloride-and-CCl4-treated rats showed a significant increase in liver indices, TGF-β1 expression, β-catenin, l-hydroxyproline, and l-glutaminase activity with severe α-SMA reactivity and apoptosis in the liver tissue. CONCLUSIONS Niclosamide protected rats against liver fibrosis by inhibiting the Wnt/β-catenin pathway and glutaminolysis.
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Affiliation(s)
- Nahla E El-Ashmawy
- Department of Biochemistry, Faculty of Pharmacy, Tanta University, Postal code: 31527, Egypt
| | - Ghada M Al-Ashmawy
- Department of Biochemistry, Faculty of Pharmacy, Tanta University, Postal code: 31527, Egypt
| | - Hoda E Fakher
- Department of Biochemistry, Faculty of Pharmacy, Menoufia University, Postal code: 32511, Egypt.
| | - Naglaa F Khedr
- Department of Biochemistry, Faculty of Pharmacy, Tanta University, Postal code: 31527, Egypt
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20
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Thamm K, Möbus K, Towers R, Segeletz S, Wetzel R, Bornhäuser M, Zhang Y, Wobus M. A Novel Synthetic, Xeno‐Free Biomimetic Surface for Serum‐Free Expansion of Human Mesenchymal Stromal Cells. ACTA ACUST UNITED AC 2020; 4:e2000008. [DOI: 10.1002/adbi.202000008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 06/05/2020] [Indexed: 12/27/2022]
Affiliation(s)
| | - Kristin Möbus
- University Hospital Carl Gustav Carus der Technischen Universität Dresden Medizinische Klinik und Poliklinik 1 Fetscherstraße 74 Dresden 01307 Germany
| | - Russell Towers
- University Hospital Carl Gustav Carus der Technischen Universität Dresden Medizinische Klinik und Poliklinik 1 Fetscherstraße 74 Dresden 01307 Germany
| | | | | | - Martin Bornhäuser
- University Hospital Carl Gustav Carus der Technischen Universität Dresden Medizinische Klinik und Poliklinik 1 Fetscherstraße 74 Dresden 01307 Germany
| | - Yixin Zhang
- Technische Universität Dresden Tatzberg 41 Dresden 01307 Germany
| | - Manja Wobus
- University Hospital Carl Gustav Carus der Technischen Universität Dresden Medizinische Klinik und Poliklinik 1 Fetscherstraße 74 Dresden 01307 Germany
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21
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Khalil MR, El-Demerdash RS, Elminshawy HH, Mehanna ET, Mesbah NM, Abo-Elmatty DM. Therapeutic effect of bone marrow mesenchymal stem cells in a rat model of carbon tetrachloride induced liver fibrosis. Biomed J 2020; 44:598-610. [PMID: 32389821 PMCID: PMC8640564 DOI: 10.1016/j.bj.2020.04.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 10/30/2019] [Accepted: 04/29/2020] [Indexed: 02/07/2023] Open
Abstract
Background Liver fibrosis is a major medical problem with high mortality and morbidity rates where the formation of regenerative nodules and cirrhosis leads to loss of liver function and may result in the development of hepatocellular carcinoma. bone marrow mesenchymal stem cells (BM-MSCs) have drawn attention as a novel approach for treatment of liver fibrosis. This study aimed to evaluate the therapeutic effect of BM-MSCs on the liver structure in carbon tetrachloride (CCl4) induced liver fibrosis in male rats relative to resveratrol and Silybum marianum as standard drugs derived from herbal plants. Methods Fifty adult male albino rats (Sprague Dawley strain; 180–220 g mean body weight) were purchased from the Laboratory Animal Unit in the Nile Center of Experimental Research, Mansoura, Egypt. Liver function were determined, isolation and preparation of BM- MSCs and detection of cell-surface markers by flow cytometry. Results Animals exposed to CCl4 developed liver injury characterized by significant increase of liver enzymes, malondialdehyde (MDA), tumor necrosis factor alpha (TNFα), and CYP450, inhibition of antioxidant enzymes, and decreased albumin. Treatment with stem cells enhanced liver state more effectively than resveratrol and S. marianum. It significantly decreased AST, ALT, ALP, MDA, TNF-α, and CYP450 and increased albumin, SOD, GSH, GST, and CAT. Histopathological study and atomic force microscope results confirmed the therapeutic effects of MSCs. Conclusions BM-MSCs could restore liver structure and function in CCL4 induced liver fibrosis rat model, ameliorating the toxicity of CCl4 and improving liver function tests.
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Affiliation(s)
- Mohammed R Khalil
- Department of Biochemistry, Faculty of Pharmacy, Delta University, Damietta, Egypt
| | - Reda S El-Demerdash
- Department of Clinical Pathology, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
| | - Hazem H Elminshawy
- Department of Internal Medicine, Specialized Medical Hospital, Mansoura University, Mansoura, Egypt
| | - Eman T Mehanna
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.
| | - Noha M Mesbah
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt
| | - Dina M Abo-Elmatty
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt
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22
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Eissa M, Elarabany N, Hyder A. In vitro efficacy of liver microenvironment in bone marrow mesenchymal stem cell differentiation. In Vitro Cell Dev Biol Anim 2020; 56:341-348. [PMID: 32270392 DOI: 10.1007/s11626-020-00436-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Accepted: 02/08/2020] [Indexed: 12/31/2022]
Abstract
Bone marrow-derived mesenchymal stem cells (BM-MSCs) represent an interesting alternative to liver or hepatocyte transplantation to treat liver injuries. Many studies have reported that MSCs can treat several diseases, including liver damage, just by injection into the bloodstream, without evidence of differentiation. The improvements were attributed to the organotrophic factors, low immunogenicity, immunomodulatory, and anti-inflammatory effects of MSCs, rather than their differentiation. The aim of the present study was to answer the question of whether the presence of BM-MSCs in the hepatic microenvironment will lead to their differentiation to functional hepatocyte-like cells. The hepatic microenvironment was mimicked in vitro by culture for 21 d with liver extract. The resulted cells expressed marker genes of the hepatic lineage including AFP, CK18, and Hnf4a. Functionally, they were able to detoxify ammonia into urea, to store glycogen as observed by PAS staining, and to synthesize glucose from pyruvate/lactate mixture. Phenotypically, the expression of MSC surface markers CD90 and CD105 decreased by differentiation. This evidenced differentiation into hepatocyte-like cells was accompanied by a downregulation of the stem cell marker genes sox2 and Nanog and the cell cycle regulatory genes ANAPC2, CDC2, Cyclin A1, and ABL1. The present results suggest a clear differentiation of BM-MSCs into functional hepatocyte-like cells by the extracted liver microenvironment. This differentiation is confirmed by a decrease in the stemness and mitotic activities. Tracking transplanted BM-MSCs and proving their in vivo differentiation remains to be elucidated.
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Affiliation(s)
- Manar Eissa
- Faculty of Science, Damietta University, New Damietta, 34517, Egypt
| | - Naglaa Elarabany
- Faculty of Science, Damietta University, New Damietta, 34517, Egypt
| | - Ayman Hyder
- Faculty of Science, Damietta University, New Damietta, 34517, Egypt.
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23
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Sun T, Li H, Bai Y, Bai M, Gao F, Yu J, Wu R, Du L, Li F. Ultrasound-targeted microbubble destruction optimized HGF-overexpressing bone marrow stem cells to repair fibrotic liver in rats. Stem Cell Res Ther 2020; 11:145. [PMID: 32245503 PMCID: PMC7119295 DOI: 10.1186/s13287-020-01655-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 03/11/2020] [Accepted: 03/17/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND/AIMS Bone marrow mesenchymal stem cells (BMSCs) have shown their therapeutic potential in cytotherapy for liver fibrosis. However, the insufficient homing of BMSCs and undefined proliferation of BMSCs represent a significant challenge and largely limit the effective implementation. The aims of the present study were to determine whether stable expression of hepatic growth factor (HGF) in BMSCs coupled with ultrasound-targeted microbubble destruction (UTMD) technique could effectively and definitely alleviating carbon tetrachloride (CCl4)-induced liver fibrosis in rats. MATERIALS AND METHODS A rat model of liver fibrosis was acquired by injection of carbon tetrachloride (CCl4). The experimental rats were randomly assigned to the four groups: normal, CCl4, BMSCs-HGF/US, and BMSCs-HGF/UTMD groups. The BMSCs, transfected by recombinant adeno-associated virus vector encoding human genome sequence of HGF (BMSCs-HGF), were transplanted in rat via the tail vein. The homing efficiency of BMSCs was observed by immunofluorescence staining. The liver function and its morphological changes were analyzed by biochemical tests and liver histology. The expression of liver fibrosis markers including α-smooth muscle actin (α-SMA), collagen I, and vimentin were examined by immunohistochemistry and quantitative real-time polymerase chain reaction. RESULTS The homing efficiency of BMSCs in the fibrotic liver was significantly greater with the application of UTMD. The biochemical markers of liver function and histopathological results showed significantly better improvement in BMSCs-HGF/UTMD group than the other groups, and the serum levels of biochemical markers returned to normal ranges in 12 weeks in this group. Furthermore, the expression levels of liver fibrosis markers (α-SMA, collagen I, and Vimentin) were all significantly lower in BMSCs-HGF/UTMD group in comparison with other groups. CONCLUSIONS Our findings have demonstrated that stable expression of HGF in BMSCs and application of the UTMD technique facilitate the homing of BMSCs, and more importantly, which could further improve their alleviation of liver fibrosis. Therefore, these findings have an important clinical implication that AAV-BMSCs-HGF and UTMD hold promise as a novel therapeutic approach for liver fibrosis.
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Affiliation(s)
- Ting Sun
- Department of Medical Ultrasound, Qingdao Municipal Hospital (Group), Qingdao, 266000, Shandong, China.,Department of Medical Ultrasound, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Rd., Shanghai, 200080, China
| | - Hualin Li
- Department of Medical Ultrasound, Zibo Maternal and Child Health Hospital, Zibo, 255029, Shandong, China
| | - Yun Bai
- Department of Medical Ultrasound, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Rd., Shanghai, 200080, China
| | - Min Bai
- Department of Medical Ultrasound, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Rd., Shanghai, 200080, China
| | - Feng Gao
- Department of Medical Ultrasound, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Rd., Shanghai, 200080, China
| | - Jie Yu
- Department of Medical Ultrasound, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Rd., Shanghai, 200080, China
| | - Rong Wu
- Department of Medical Ultrasound, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Rd., Shanghai, 200080, China
| | - Lianfang Du
- Department of Medical Ultrasound, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Rd., Shanghai, 200080, China.
| | - Fan Li
- Department of Medical Ultrasound, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Rd., Shanghai, 200080, China.
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24
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Sabry D, Mohamed A, Monir M, Ibrahim HA. The Effect of Mesenchymal Stem Cells Derived Microvesicles on the Treatment of Experimental CCL4 Induced Liver Fibrosis in Rats. Int J Stem Cells 2019; 12:400-409. [PMID: 31474025 PMCID: PMC6881047 DOI: 10.15283/ijsc18143] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Revised: 06/22/2019] [Accepted: 07/01/2019] [Indexed: 12/14/2022] Open
Abstract
Background and Objectives The release of microvesicles (MVs) from mesenchymal stem cells (MSCs) has been implicated in intercellular communication, and may contribute to beneficial paracrine effects of stem cell-based therapies. We investigated the effect of administration of MSC-MVs on the therapeutic potential of carbon tetrachloride (CCL4) induced liver fibrosis in rats. Methods Our work included: isolation and further identification of bone marrow MSC-MVs by transmission electron microscopy (TEM). Liver fibrosis was induced in rats by CCl4 followed by injection of prepared MSC-MVs in injured rats. The effects of MSC-MVs were evaluated by biochemical analysis of liver functions, RNA gene expression quantitation for collagen-1α, transforming growth factor β (TGF-β), interleukin-1β (IL-1β), vascular endothelial growth factor (VEGF) by real time reverse transcription PCR (RT-PCR) techniques. Finally histopathological examination of the liver tissues was assessed for all studied groups. Results BM-MSC-MVs treated group showed significant increase in serum albumin levels, VEGF quantitative gene expression (p<0.05), while it showed a significant decrease in serum alanine transaminase (ALT) enzyme levels, quantitative gene expression of TGF-β, collagen-1α, IL-1β compared to CCL4 fibrotic group (p<0.05). Additionally, the histopathological assessment of the liver tissues of BM-MSC-MVs treated group showed marked decrease in the collagen deposition & improvement of histopathological picture in comparison with CCL4 fibrotic group. Conclusions Our study demonstrates that BM-MSC-MVs possess anti-fibrotic, anti-inflammatory, and pro-angiogenic properties which can promote the resolution of CCL4 induced liver fibrosis in rats.
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Affiliation(s)
- Dina Sabry
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Abbas Mohamed
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Manar Monir
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Heba A Ibrahim
- Department of Pathology, Faculty of Medicine, Cairo University, Giza, Egypt
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25
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Khalifa YH, Mourad GM, Stephanos WM, Omar SA, Mehanna RA. Bone Marrow-Derived Mesenchymal Stem Cell Potential Regression of Dysplasia Associating Experimental Liver Fibrosis in Albino Rats. BIOMED RESEARCH INTERNATIONAL 2019; 2019:5376165. [PMID: 31781620 PMCID: PMC6874956 DOI: 10.1155/2019/5376165] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Revised: 09/25/2019] [Accepted: 10/08/2019] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Assessing the therapeutic efficacy of superparamagnetic iron oxide nanoparticles (SPIO) labeled bone marrow-derived mesenchymal stem cells (BM-MSCs) on experimental liver fibrosis and associated dysplasia. MATERIALS AND METHODS MSCs were obtained from 10 male Sprague-Dawley rats while 50 female rats were divided into control (CG), liver fibrosis (CCL4, intraperitoneal injection of CCl4 for 8 weeks), and CCL4 rats treated with SPIO-labeled MSCs (MSCs/CCl4) with and without continuing CCL4 injection for another 8 weeks. Assessment included liver histopathology, liver function tests, transmission electron microscopic tracing for homing of SPIO-MSCs, immunofluorescence histochemistry for fibrosis and dysplasia markers (transforming growth factor-beta (TGF-β1), proliferation nuclear antigen (PCNA), glypican 3)), and quantitative gene expression analysis for matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1). RESULTS SPIO-labeled MSCs were engrafted in the fibrotic liver and the BM/MSCs demonstrated regression for fibrous tissue deposition and inhibition progression of dysplastic changes in the liver of CCl4-treated rats on both the histological and molecular levels. CONCLUSION BM-MSCs possess regenerative and antidysplastic potentials.
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Affiliation(s)
- Yasmine H. Khalifa
- Histology and Cell Biology Department, Faculty of Medicine, Alexandria University, Dr. Fahmi Abdel Meguid Street, Mowassat Building, El Shatby, Alexandria 21561, Egypt
| | - Ghada M. Mourad
- Histology and Cell Biology Department, Faculty of Medicine, Alexandria University, Dr. Fahmi Abdel Meguid Street, Mowassat Building, El Shatby, Alexandria 21561, Egypt
- Center of Excellence for Research in Regenerative Medicine and Applications (CERRMA), Faculty of Medicine, Alexandria University, Alexandria 21514, Egypt
| | - Wahid M. Stephanos
- Histology and Cell Biology Department, Faculty of Medicine, Alexandria University, Dr. Fahmi Abdel Meguid Street, Mowassat Building, El Shatby, Alexandria 21561, Egypt
| | - Sahar A. Omar
- Histology and Cell Biology Department, Faculty of Medicine, Alexandria University, Dr. Fahmi Abdel Meguid Street, Mowassat Building, El Shatby, Alexandria 21561, Egypt
| | - Radwa A. Mehanna
- Center of Excellence for Research in Regenerative Medicine and Applications (CERRMA), Faculty of Medicine, Alexandria University, Alexandria 21514, Egypt
- Medical Physiology Department, Faculty of Medicine, Alexandria University, Dr. Fahmi Abdel Meguid Street, Mowassat Building, El Shatby, Alexandria 21561, Egypt
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26
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Zhang L, Zhou D, Li J, Yan X, Zhu J, Xiao P, Chen T, Xie X. Effects of Bone Marrow-Derived Mesenchymal Stem Cells on Hypoxia and the Transforming Growth Factor beta 1 (TGFβ-1) and SMADs Pathway in a Mouse Model of Cirrhosis. Med Sci Monit 2019; 25:7182-7190. [PMID: 31550244 PMCID: PMC6775794 DOI: 10.12659/msm.916428] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Accepted: 05/09/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The role of bone marrow-derived mesenchymal stem cells (BM-MSCs) in liver fibrosis remains poorly understood. This study aimed to use a mouse model of carbon tetrachloride (CCL₄)-induced liver fibrosis to investigate the effects of BM-MSCs during liver hypoxia and the involvement of the transforming growth factor beta 1 (TGF-ß1) and SMADs pathway. MATERIAL AND METHODS Thirty C57BL/6 mice were randomly divided into the control group (n=10), the model group (n=10), and the BM-MSC-treated model group (n=10). In the model group, liver fibrosis was induced by intraperitoneal injection of CCl₄. BM-MSCs were transplanted after 12 weeks of CCl₄ treatment. The serum biochemical parameters and histological changes in the liver, using histochemical stains, were investigated. The expression of collagen type I (collagen I), alpha-smooth muscle actin (alpha-SMA), TGF-ß1, SMAD3, SMAD7, hypoxia-inducible factor 1 alpha (HIF-1alpha), and vascular endothelial grow factor (VEGF) were assessed by immunohistochemistry and quantitative real-time polymerase chain (RT-qPCR) reaction. RESULTS Treatment with BM-MSCs reduced the expression of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) compared with the model group, and reduced liver fibrosis determined histologically using hematoxylin and eosin (H&E) and Masson's trichrome staining compared with the model group. The area of liver fibrosis decreased after BM-MSCs treatment (p<0.05). Protein expression of HIF-1alpha and VEGF were decreased after BM-MSCs treatment (p<0.05). Transplantation of BM-MSCs reduced the mRNA expression of TGF-ß1, collagen I, alpha-SMA, and SMAD3 (p<0.05). CONCLUSIONS BM-MSC transplantation reduced CCl₄-induced murine liver fibrosis, indicating that in a hypoxic microenvironment, BM-MSCs may inhibit the TGFß-1/SMADs pathway.
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Affiliation(s)
- Liting Zhang
- State Key Laboratory of Cryospheric Science, Northwest Institute of Eco-Environmental and Resources, Chinese Academy of Sciences, Lanzhou, Gansu, P.R. China
- Department of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou, Gansu, P.R. China
| | - Dan Zhou
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu, P.R. China
| | - Junfeng Li
- Institute of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou, Gansu, P.R. China
| | - Xiaoming Yan
- The 4 People’s Hospital of Qinghai Province, Xining, Qinghai, P.R. China
| | - Jun Zhu
- Department of Pathology of Donggang Branch, The First Hospital of Lanzhou University, Lanzhou, Gansu, P.R. China
| | - Ping Xiao
- Institute of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou, Gansu, P.R. China
| | - Tuo Chen
- State Key Laboratory of Cryospheric Science, Northwest Institute of Eco-Environmental and Resources, Chinese Academy of Sciences, Lanzhou, Gansu, P.R. China
| | - Xiaodong Xie
- Institute of Medical Genetics, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, P.R. China
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27
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Khan RS, Newsome PN. A Comparison of Phenotypic and Functional Properties of Mesenchymal Stromal Cells and Multipotent Adult Progenitor Cells. Front Immunol 2019; 10:1952. [PMID: 31555259 PMCID: PMC6724467 DOI: 10.3389/fimmu.2019.01952] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 08/02/2019] [Indexed: 12/15/2022] Open
Abstract
Both Multipotent Adult Progenitor Cells and Mesenchymal Stromal Cells are bone-marrow derived, non-haematopoietic adherent cells, that are well-known for having immunomodulatory and pro-angiogenic properties, whilst being relatively non-immunogenic. However, they are phenotypically and functionally distinct cell types, which has implications for their efficacy in different settings. In this review we compare the phenotypic and functional properties of these two cell types, to help in determining which would be the superior cell type for different applications.
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Affiliation(s)
- Reenam S Khan
- National Institute for Health Research (NIHR), Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, United Kingdom.,Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Philip N Newsome
- National Institute for Health Research (NIHR), Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, United Kingdom.,Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
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28
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Mitra A, Yan J, Zhang L, Li S. A small molecule Hedgehog agonist HhAg1.5 mediated reprogramming breaks the quiescence of noninjured liver stem cells for rescuing liver failure. Transl Res 2019; 205:44-50. [PMID: 30399369 PMCID: PMC6372324 DOI: 10.1016/j.trsl.2018.10.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 10/07/2018] [Accepted: 10/11/2018] [Indexed: 02/07/2023]
Abstract
Liver is the second most transplanted organ according to United network for organ sharing. Due to shortage of compatible donors, surgical difficulties, immunological hindrance, and high postoperative cost, stem cell therapy is an attractive substitute of liver transplant for millions of patients suffering from hepatic failure. Due to several technical limitations such as viral integration, inefficient differentiation, and adult phenotypes and epigenetic memory of fibroblasts, induced pluripotent stem cells, mesenchymal stem cells, or induced hepatocyte may not present a great clinical substitute for liver transplant. We pioneered a novel technology for robust expansion of quiescent liver stem cells (LSCs) from mice via utilizing of Hedgehog agonist HhAg1.5 for 3 weeks. These expanded LSCs retained stem-like properties after multiple passaging and differentiated to hepatocytes and cholangiocytes. Grafting of ex vivo expanded LSCs in Fah-/- Rag2-/- Il2rg-/- knockout mice, significantly increased life span compared to control group (P < 0.001). Thus in this study, we provide a promising viable substitute for primary hepatocytes for regenerative medicine and for life-threatening metabolic liver diseases.
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Affiliation(s)
- Abhisek Mitra
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jun Yan
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Liangfang Zhang
- Department of Nanoengineering, University of California, San Diego, La Jolla, California
| | - Shulin Li
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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29
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Hu C, Zhao L, Duan J, Li L. Strategies to improve the efficiency of mesenchymal stem cell transplantation for reversal of liver fibrosis. J Cell Mol Med 2019; 23:1657-1670. [PMID: 30635966 PMCID: PMC6378173 DOI: 10.1111/jcmm.14115] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 12/06/2018] [Accepted: 12/06/2018] [Indexed: 12/12/2022] Open
Abstract
End‐stage liver fibrosis frequently progresses to portal vein thrombosis, formation of oesophageal varices, hepatic encephalopathy, ascites, hepatocellular carcinoma and liver failure. Mesenchymal stem cells (MSCs), when transplanted in vivo, migrate into fibrogenic livers and then differentiate into hepatocyte‐like cells or fuse with hepatocytes to protect liver function. Moreover, they can produce various growth factors and cytokines with anti‐inflammatory effects to reverse the fibrotic state of the liver. In addition, only a small number of MSCs migrate to the injured tissue after cell transplantation; consequently, multiple studies have investigated effective strategies to improve the survival rate and activity of MSCs for the treatment of liver fibrosis. In this review, we intend to arrange and analyse the current evidence related to MSC transplantation in liver fibrosis, to summarize the detailed mechanisms of MSC transplantation for the reversal of liver fibrosis and to discuss new strategies for this treatment. Finally, and most importantly, we will identify the current problems with MSC‐based therapies to repair liver fibrosis that must be addressed in order to develop safer and more effective routes for MSC transplantation. In this way, it will soon be possible to significantly improve the therapeutic effects of MSC transplantation for liver regeneration, as well as enhance the quality of life and prolong the survival time of patients with liver fibrosis.
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Affiliation(s)
- Chenxia Hu
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Lingfei Zhao
- Kidney Disease Center, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, Zhejiang, PR China.,Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Jinfeng Duan
- The Key Laboratory of Mental Disorder Management of Zhejiang Province, Department of Psychiatry, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Lanjuan Li
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, PR China
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30
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Mansour HM, Salama AAA, Abdel-Salam RM, Ahmed NA, Yassen NN, Zaki HF. The anti-inflammatory and anti-fibrotic effects of tadalafil in thioacetamide-induced liver fibrosis in rats. Can J Physiol Pharmacol 2018; 96:1308-1317. [PMID: 30398909 DOI: 10.1139/cjpp-2018-0338] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Liver fibrosis is a health concern that leads to organ failure mediated via production of inflammatory cytokines and fibrotic biomarkers. This study aimed to explore the protective effect of tadalafil, a phosphodiesterase-5 inhibitor, against thioacetamide (TAA)-induced liver fibrosis. Fibrosis was induced by administration of TAA (200 mg/kg, i.p.) twice weekly for 6 weeks. Serum transaminases activities, liver inflammatory cytokines, fibrotic biomarkers, and liver histopathology were assessed. TAA induced marked histopathological changes in liver tissues coupled with elevations in serum transaminases activities. Furthermore, hepatic content of nitric oxide and tumor necrosis factor-alpha, interleukin-6, and interleukin-1 beta were elevated, together with a reduction of interleukin-10 in the liver. In addition, TAA increased hepatic contents of transforming growth factor-beta, hydroxyproline, alpha-smooth muscle actin, and gene expression of collagen-1. Pretreatment with tadalafil protected against TAA-induced liver fibrosis, in a dose-dependent manner, as proved by the alleviation of inflammatory and fibrotic biomarkers. The effects of tadalafil were comparable with that of silymarin, a natural antioxidant, and could be assigned to its anti-inflammatory and anti-fibrotic properties.
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Affiliation(s)
- Heba M Mansour
- a Pharmacology & Toxicology Department, Faculty of Pharmacy, Misr University for Science and Technology, Giza, Egypt
| | - Abeer A A Salama
- b Pharmacology Department, National Research Centre, Giza, Egypt
| | - Rania M Abdel-Salam
- c Pharmacology & Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Naglaa A Ahmed
- a Pharmacology & Toxicology Department, Faculty of Pharmacy, Misr University for Science and Technology, Giza, Egypt
| | - Noha N Yassen
- d Pathology Department, National Research Centre, Giza, Egypt
| | - Hala F Zaki
- c Pharmacology & Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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31
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Mesenchymal stromal cells prevent progression of liver fibrosis in a novel zebrafish embryo model. Sci Rep 2018; 8:16005. [PMID: 30375438 PMCID: PMC6207680 DOI: 10.1038/s41598-018-34351-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 10/12/2018] [Indexed: 12/22/2022] Open
Abstract
Chronic liver damage leads to the onset of fibrogenesis. Rodent models for liver fibrosis have been widely used, but are less suitable for screening purposes. Therefore the aim of our study was to design a novel model for liver fibrosis in zebrafish embryos, suitable for high throughput screening. Furthermore, we evaluated the efficacy of mesenchymal stromal cells (MSCs) to inhibit the fibrotic process and thereby the applicability of this model to evaluate therapeutic responses. Zebrafish embryos were exposed to TAA or CCL4 and mRNA levels of fibrosis-related genes (Collagen-1α1, Hand-2, and Acta-2) and tissue damage-related genes (TGF-β and SDF-1a, SDF-1b) were determined, while Sirius-red staining was used to estimate collagen deposition. Three days after start of TAA exposure, MSCs were injected after which the fibrotic response was determined. In contrast to CCL4, TAA resulted in an upregulation of the fibrosis-related genes, increased extracellular matrix deposition and decreased liver sizes suggesting the onset of fibrosis. The applicability of this model to evaluate therapeutic responses was shown by local treatment with MSCs which resulted in decreased expression of the fibrosis-related RNA markers. In conclusion, TAA induces liver fibrosis in zebrafish embryos, thereby providing a promising model for future mechanistic and therapeutic studies.
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32
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Farouk S, Sabet S, Abu Zahra FA, El-Ghor AA. Bone marrow derived-mesenchymal stem cells downregulate IL17A dependent IL6/STAT3 signaling pathway in CCl4-induced rat liver fibrosis. PLoS One 2018; 13:e0206130. [PMID: 30346985 PMCID: PMC6197688 DOI: 10.1371/journal.pone.0206130] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Accepted: 10/08/2018] [Indexed: 12/20/2022] Open
Abstract
Therapeutic potential of bone marrow–derived mesenchymal stem cells (BM-MSCs) has been reported in several animal models of liver fibrosis. Interleukin (IL) 17A, IL6 and Stat3 have been described to play crucial roles in chronic liver injury. However, the modulatory effect of MSCs on these markers was controversial in different diseases. BM-MSCs might activate the IL6/STAT3 signaling pathway and promote cell invasion in hepatocellular carcinoma, but the immunomodulatory role of BM-MSCs on IL17A/IL6/STAT3 was not fully elucidated in liver fibrosis. In the present study, we evaluated the capacity of the BM-MSCs in the modulation of cytokines milieu and signal transducers, based on unique inflammatory genes Il17a and Il17f and their receptors Il17rc and their effect on the IL6/STAT3 pathway in CCl4-induced liver fibrosis in rats. A single dose of BM-MSCs was administered to the group with induced liver fibrosis, and the genes and proteins of interest were evaluated along six weeks after treatment. Our results showed a significant downregulation of Il17a, Il17ra, il17f and Il17rc genes. In accordance, BM-MSCs administration declined IL17, IL2 and IL6 serum proteins and downregulated IL17A and IL17RA proteins in liver tissue. Interestingly, BM-MSCs downregulated both Stat3 mRNA expression and p-STAT3, while Stat5a gene was downregulated and p-STAT5 protein was elevated. Also P-SMAD3 and TGFβR2 proteins were downregulated in response to BM-MSCs treatment. Collectively, we suggest that BM-MSCs might play an immunomodulatory role in the treatment of liver fibrosis through downregulation of IL17A affecting IL6/STAT3 signaling pathway.
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Affiliation(s)
- Shimaa Farouk
- Department of Biology and Biotechnologies, Faculty of Science & Technology, AL-Neelain University, Khartoum, Sudan
| | - Salwa Sabet
- Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt
- * E-mail:
| | - Fatma A. Abu Zahra
- Medical Research Center, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Akmal A. El-Ghor
- Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt
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33
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Decorin-Modified Umbilical Cord Mesenchymal Stem Cells (MSCs) Attenuate Radiation-Induced Lung Injuries via Regulating Inflammation, Fibrotic Factors, and Immune Responses. Int J Radiat Oncol Biol Phys 2018; 101:945-956. [PMID: 29976507 DOI: 10.1016/j.ijrobp.2018.04.007] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Revised: 03/01/2018] [Accepted: 04/03/2018] [Indexed: 12/17/2022]
Abstract
PURPOSE To evaluate the therapeutic effects of decorin (DCN)-modified mesenchymal stem cells (MSCs) on radiation-induced lung injuries (RILIs) and to clarify the underlying mechanisms. METHODS AND MATERIALS Umbilical cord-derived mesenchymal stem cells (MSCs) were modified with Ad(E1-).DCN to generate DCN-expressing MSCs (DCN-modified MSCs [MSCs.DCN]). In an experimental mouse model of RILI, MSCs.DCN and MSCs.Null [MSCs modified with Ad(E1-).Null] were intravenously engrafted at 6 hours or 28 days after irradiation. The therapeutic effects on lung inflammation and fibrosis were evaluated by histopathologic analysis at 28 days and 3 months after irradiation. Inflammatory cytokines and chemokines were analyzed in both sera and lung tissues, and subtypes of T lymphocytes including regulatory T cells (Tregs) were analyzed in the peripheral blood and spleen. RESULTS Both MSC treatments could alleviate histopathologic injuries by reducing lymphocyte infiltration, decreasing apoptosis, increasing proliferation of epithelial cells, and inhibiting fibrosis in the later phase. However, treatment with MSCs.DCN resulted in much more impressive therapeutic effects. Moreover, we discovered that MSC treatment reduced the expression of chemokines and inflammatory cytokines and increased the expression of anti-inflammatory cytokines in both the peripheral blood and local pulmonary tissues. An important finding was that MSCs.DCN were much more effective in inducing interferon-γ expression, inhibiting collagen type III α1 expression in pulmonary tissues, and decreasing the proportion of Tregs. Furthermore, our data suggested that treatment during the acute phase (6 hours) after irradiation evoked much stronger responses both in attenuating inflammation and in inhibiting fibrosis than in the later phase (28 days). CONCLUSIONS MSCs.DCN could attenuate acute inflammation after irradiation and significantly inhibit later fibrosis. Likewise, DCN enhanced the functions of MSCs by targeting profibrotic factors and Tregs.
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Zhang Y, Li Y, Zhang L, Li J, Zhu C. Mesenchymal stem cells: potential application for the treatment of hepatic cirrhosis. Stem Cell Res Ther 2018; 9:59. [PMID: 29523186 PMCID: PMC5845383 DOI: 10.1186/s13287-018-0814-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Nowadays, orthotopic liver transplantation is considered the most efficient approach to the end stage of chronic hepatic cirrhosis. Because of the limitations of orthotopic liver transplantation, stem cells are an attractive therapeutic option. Mesenchymal stem cells (MSCs) especially show promise as an alternative treatment for hepatic cirrhosis in animal models and during clinical trials. Nevertheless, the homing of transplanted MSCs to the liver occurs in limited numbers. Therefore, we review the strategies for enhancing the homing of MSCs, mainly via the delivery routes, optimizing cell culture conditions, stimulating the target sites, and genetic modification.
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Affiliation(s)
- Yongting Zhang
- Department of Infectious Disease, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Yuwen Li
- Department of Pediatrics, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Lili Zhang
- Department of Infectious Disease, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Jun Li
- Department of Infectious Disease, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Chuanlong Zhu
- Department of Infectious Disease, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China
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Jang YO, Kim SH, Cho MY, Kim KS, Park KS, Cha SK, Kim MY, Chang SJ, Baik SK. Synergistic effects of simvastatin and bone marrow-derived mesenchymal stem cells on hepatic fibrosis. Biochem Biophys Res Commun 2018; 497:264-271. [PMID: 29428718 DOI: 10.1016/j.bbrc.2018.02.067] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 02/07/2018] [Indexed: 12/16/2022]
Abstract
The beneficial effects of simvastatin on fibrosis in various organs have been reported. In addition, bone marrow (BM)-derived mesenchymal stem cells (MSCs) have been suggested as an effective therapy for hepatic fibrosis and cirrhosis. Recent evidence suggests that pharmacological treatment devoted to regulating stem cell function is a potential new therapeutic strategy that is drawing nearer to clinical practice. The aim of this study was to determine whether the combination treatment of simvastatin plus MSCs (Sim-MSCs) could have a synergistic effect on hepatic fibrosis in a thioacetamide (TAA)-induced cirrhotic rat model and hepatic stellate cells (HSCs). Cirrhotic livers from rats treated with Sim-MSCs exhibited histological improvement compared to those treated with simvastatin alone. Sim-MSCs combination treatment decreased hepatic collagen distribution, lowered the hydroxyproline content, and rescued liver function impairment in rats with TAA-induced cirrhosis. These protective effects were more potent with Sim-MSCs than with simvastatin alone. The upregulation of collagen-1, α-smooth muscle actin (α-SMA), transforming growth factor (TGF)-β1, and phospho-Smad3 in cirrhotic livers was prevented by the administration of Sim-MSCs. Intriguingly, Sim-MSCs inhibited both TGF-β/Smad3 signaling and α-SMA in HSCs. The Sim-MSCs combination treatment exerted strong protective effects against hepatic fibrosis by suppressing TGF-β/Smad signaling. Simvastatin could act synergistically with MSCs as an efficient therapeutic approach for intractable cirrhosis.
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Affiliation(s)
- Yoon Ok Jang
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea; Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Sung Hoon Kim
- Department of Surgery, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Mee-Yon Cho
- Department of Pathology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Kyung Sik Kim
- Department of Surgery, Yonsei University College of Medicine, The Liver Cancer Clinic & Pancreatobiliary Cancer Clinic, Severance Hospital, Seoul, Republic of Korea
| | - Kyu-Sang Park
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Seung-Kuy Cha
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Moon Young Kim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Sei Jin Chang
- Department of Preventive Medicine and Institute of Occupational Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Soon Koo Baik
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea; Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea; Institute of Evidence Based Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.
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Current Perspectives Regarding Stem Cell-Based Therapy for Liver Cirrhosis. Can J Gastroenterol Hepatol 2018; 2018:4197857. [PMID: 29670867 PMCID: PMC5833156 DOI: 10.1155/2018/4197857] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 01/16/2018] [Indexed: 12/12/2022] Open
Abstract
Liver cirrhosis is a major cause of mortality and a common end of various progressive liver diseases. Since the effective treatment is currently limited to liver transplantation, stem cell-based therapy as an alternative has attracted interest due to promising results from preclinical and clinical studies. However, there is still much to be understood regarding the precise mechanisms of action. A number of stem cells from different origins have been employed for hepatic regeneration with different degrees of success. The present review presents a synopsis of stem cell research for the treatment of patients with liver cirrhosis according to the stem cell type. Clinical trials to date are summarized briefly. Finally, issues to be resolved and future perspectives are discussed with regard to clinical applications.
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Kim D, Cho GS, Han C, Park DH, Park HK, Woo DH, Kim JH. Current Understanding of Stem Cell and Secretome Therapies in Liver Diseases. Tissue Eng Regen Med 2017; 14:653-665. [PMID: 30603518 PMCID: PMC6171672 DOI: 10.1007/s13770-017-0093-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2017] [Revised: 10/23/2017] [Accepted: 10/29/2017] [Indexed: 12/14/2022] Open
Abstract
Liver failure is one of the main risks of death worldwide, and it originates from repetitive injuries and inflammations of liver tissues, which finally leads to the liver cirrhosis or cancer. Currently, liver transplantation is the only effective treatment for the liver diseases although it has a limitation due to donor scarcity. Alternatively, cell therapy to regenerate and reconstruct the damaged liver has been suggested to overcome the current limitation of liver disease cures. Several transplantable cell types could be utilized for recovering liver functions in injured liver, including bone marrow cells, mesenchymal stem cells, hematopoietic stem cells, macrophages, and stem cell-derived hepatocytes. Furthermore, paracrine effects of transplanted cells have been suggested as a new paradigm for liver disease cures, and this application would be a new strategy to cure liver failures. Therefore, here we reviewed the current status and challenges of therapy using stem cells for liver disease treatments.
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Affiliation(s)
- Dongkyu Kim
- Laboratory of Stem Cells, NEXEL Co., Ltd., 9th Floor, 21 Wangsan-ro, Dongdaemun-gu, Seoul, 02580 Korea
| | - Gun-Sik Cho
- Laboratory of Stem Cells, NEXEL Co., Ltd., 9th Floor, 21 Wangsan-ro, Dongdaemun-gu, Seoul, 02580 Korea
| | - Choongseong Han
- Laboratory of Stem Cells, NEXEL Co., Ltd., 9th Floor, 21 Wangsan-ro, Dongdaemun-gu, Seoul, 02580 Korea
- Department of Oral Medicine and Oral Diagnosis, School of Dentistry and Dental Research Institute, Seoul National University, #101 Daehak-ro, Jongro-gu, Seoul, 03080 Korea
| | - Dong-Hyuk Park
- Department of Neurosurgery, Korea University Medical Center, Anam Hospital, Korea University College of Medicine, 73 Inchonro, Sungbuk-gu, Seoul, 02841 Korea
| | - Hee-Kyung Park
- Department of Oral Medicine and Oral Diagnosis, School of Dentistry and Dental Research Institute, Seoul National University, #101 Daehak-ro, Jongro-gu, Seoul, 03080 Korea
| | - Dong-Hun Woo
- Laboratory of Stem Cells, NEXEL Co., Ltd., 9th Floor, 21 Wangsan-ro, Dongdaemun-gu, Seoul, 02580 Korea
| | - Jong-Hoon Kim
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Science Campus, Korea University, 145 Anam-ro, Seongbu-gu, Seoul, 02841 Korea
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Wang X, Gao JL, Zhao MM, Zhu HX, Tian YX, Li R, Jiang XH, Yu L, Tian JR, Cui JZ. Therapeutic effects of conditioned medium from bone marrow-derived mesenchymal stem cells on epithelial-mesenchymal transition in A549 cells. Int J Mol Med 2017; 41:659-668. [PMID: 29207055 PMCID: PMC5752235 DOI: 10.3892/ijmm.2017.3284] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 10/04/2017] [Indexed: 01/07/2023] Open
Abstract
Pulmonary fibrosis (PF) is a chronic lung disease. The transforming growth factor-β1 (TGF-β1)/Smad3 signaling pathway plays an important role in the pathogenesis of pulmonary fibrosis. Bone marrow-derived mesenchymal stem cells (BMSCs) have been shown to be a modulator of the molecular aspects of the fibrosis pathway. However, it is still unknown as to whether the conditioned medium from BMSCs (BMSCs-CM) inhibits the epithelial-mesenchymal transition (EMT) process. This study confirmed the hypothesis that BMSCs-CM exerts an anti-fibrotic effect on human type II alveolar epithelial cells (A549) by suppressing the phosphorylation of Smad3. We used the A549 cells in vitro to detect morphological evidence of EMT by phase-contrast microscopy. These cells were randomly divided into 4 groups as follows: the control group, the TGF-β1 group, the SIS3 (specific inhibitor of Smad3) group and the BMSCs-CM group. The immunofluorescence method was used to determined the location of E-cadherin (E-calcium mucins; E-cad), α-smooth muscle actin (α-SMA) and p-Smad3. The expression levels of E-cad, CK8, α-SMA, vimentin, p-Smad3, Snail1, collagen I (COLI) and collagen III (COLIII) were detected by western blot analysis. Following exposure to TGF-β1, the A549 cells displayed a spindle-shaped fibroblast-like morphology. In accordance with these morphological changes, the expression levels of E-cad and CK8 were downregulated, while the expression levels of α-SMA and vimentin were upregulated. Along with this process, the expression levels of p-Smad3, Snail1, COLI and COLIII were increased. However, the cells in the BMSCs-CM group and SIS3 group exhibited a decrease in the levels of α-SMA and vimentin (which had been upregulated by TGF-β1), and an increase in the levels of E-cad and CK8 expression (which had been downregulated by TGF-β1). On the whole, these results indicated that BMSCs-CM suppressed the EMT which might be associated with TGF-β1/Smad3. This study provides the theoretical basis for the research of the mechanisms responsible for pulmonary disease.
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Affiliation(s)
- Xin Wang
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, P.R. China
| | - Jun-Ling Gao
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, P.R. China
| | - Man-Man Zhao
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, P.R. China
| | - Hui-Xing Zhu
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, P.R. China
| | - Yan-Xia Tian
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, P.R. China
| | - Ran Li
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, P.R. China
| | - Xiao-Hua Jiang
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, P.R. China
| | - Lei Yu
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, P.R. China
| | - Jing-Rui Tian
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, P.R. China
| | - Jian-Zhong Cui
- Department of Neurosurgery, Tangshan Workers' Hospital, Tangshan, Hebei 063000, P.R. China
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Kang SH, Kim MY, Baik SK. Novelties in the pathophysiology and management of portal hypertension: new treatments on the horizon. Hepatol Int 2017; 12:112-121. [DOI: 10.1007/s12072-017-9806-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 06/08/2017] [Indexed: 02/06/2023]
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Guo Y, Chen B, Chen LJ, Zhang CF, Xiang C. Current status and future prospects of mesenchymal stem cell therapy for liver fibrosis. J Zhejiang Univ Sci B 2017; 17:831-841. [PMID: 27819130 DOI: 10.1631/jzus.b1600101] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Liver fibrosis is the end-stage of many chronic liver diseases and is a significant health threat. The only effective therapy is liver transplantation, which still has many problems, including the lack of donor sources, immunological rejection, and high surgery costs, among others. However, the use of cell therapy is becoming more prevalent, and mesenchymal stem cells (MSCs) seem to be a promising cell type for the treatment of liver fibrosis. MSCs have multiple differentiation abilities, allowing them to migrate directly into injured tissue and differentiate into hepatocyte-like cells. Additionally, MSCs can release various growth factors and cytokines to increase hepatocyte regeneration, regress liver fibrosis, and regulate inflammation and immune responses. In this review, we summarize the current uses of MSC therapies for liver fibrosis and suggest potential future applications.
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Affiliation(s)
- Yang Guo
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Bo Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Li-Jun Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Chun-Feng Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Charlie Xiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
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El Baz H, Demerdash Z, Kamel M, Atta S, Salah F, Hassan S, Hammam O, Khalil H, Meshaal S, Raafat I. Transplant of Hepatocytes, Undifferentiated Mesenchymal Stem Cells, and In Vitro Hepatocyte-Differentiated Mesenchymal Stem Cells in a Chronic Liver Failure Experimental Model: A Comparative Study. EXP CLIN TRANSPLANT 2017; 16:81-89. [PMID: 28585911 DOI: 10.6002/ect.2016.0226] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Liver transplant is the cornerstone line of treatment for chronic liver diseases; however, the long list of complications and obstacles stand against this operation. Searching for new modalities for treatment of chronic liver illness is a must. In the present research, we aimed to compare the effects of transplant of undifferentiated human mesenchymal stem cells, in vitro differentiated mesenchymal stem cells, and adult hepatocytes in an experimental model of chronic liver failure. MATERIALS AND METHODS Undifferentiated human cord blood mesenchymal stem cells were isolated, pro-pagated, and characterized by morphology, gene expression analysis, and flow cytometry of surface markers and in vitro differentiated into hepatocyte-like cells. Rat hepatocytes were isolated by double perfusion technique. An animal model of chronic liver failure was developed, and undifferentiated human cord blood mesenchymal stem cells, in vitro hepato-genically differentiated mesenchymal stem cells, or freshly isolated rat hepatocytes were transplanted into a CCL4 cirrhotic experimental model. Animals were killed 3 months after transplant, and liver functions and histopathology were assessed. RESULTS Compared with the cirrhotic control group, the 3 cell-treated groups showed improved alanine aminotransferase, aspartate aminotransferase, albumin, and bilirubin levels, with best results shown in the hepatocyte-treated group. Histopathologic examination of the treated groups showed improved fibrosis, with best results obtained in the undifferentiated mesenchymal stem cell-treated group. CONCLUSIONS Both adult hepatocytes and cord blood mesenchymal stem cells proved to be promising candidates for cell-based therapy in liver regeneration on an experimental level. Improved liver function was evident in the hepatocyte-treated group, and fibrosis control was more evident in the undifferentiated mesenchymal stem cell-treated group.
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Affiliation(s)
- Hanan El Baz
- From the Immunology Department, Theodor Bilharz Research Institute, Imbaba, Giza, Egypt
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Yu J, Hao G, Wang D, Liu J, Dong X, Sun Y, Pan Q, Li Y, Shi X, Li L, Cao H. Therapeutic Effect and Location of GFP-Labeled Placental Mesenchymal Stem Cells on Hepatic Fibrosis in Rats. Stem Cells Int 2017; 2017:1798260. [PMID: 28491093 PMCID: PMC5405597 DOI: 10.1155/2017/1798260] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 03/08/2017] [Indexed: 02/07/2023] Open
Abstract
Background. Liver fibrosis is a chronic progressive liver disease, but no established effective treatment exists except for liver transplantation. The present study was designed to investigate the effect of human placenta mesenchymal stem cells (hPMSCs) expressing green fluorescent protein (GFP) on carbon tetrachloride- (CCl4-) induced liver fibrosis in rats. Methods. Liver fibrosis was induced by subcutaneous injection with CCl4; hPMSCs were directly transplanted into rats through the caudal vein. The therapeutic efficacy of hPMSCs on liver fibrosis was measured by liver function tests, liver elastography, histopathology, Masson's trichrome and Sirius red staining, and immunohistochemical studies. The expression levels of fibrotic markers, transforming growth factor β1 (TGF-β1) and α-smooth muscle actin (α-SMA), were assessed using real-time polymerase chain reaction. Results. We demonstrated that liver fibrosis was significantly dampened in the hPMSC transplantation group according to the Laennec fibrosis scoring system and histological data. The Sirius red-stained collagen area and the elastography score were significantly reduced in the hPMSC-treated group. Meanwhile, hPMSC administration significantly decreased TGF-β1 and α-SMA expression and enhanced liver functions in CCl4-induced fibrotic rats. Conclusion. This study indicates that transplantation of hPMSCs could repair liver fibrosis induced by CCl4 in rats, which may serve as a valuable therapeutic approach to treat liver diseases.
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Affiliation(s)
- Jiong Yu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79 Qingchun Road, Hangzhou 310003, China
| | - Guangshu Hao
- Gansu Provincial Maternity and Child-Care Hospital, 143 Qilihe North Street, Lanzhou 730050, China
| | - Dan Wang
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79 Qingchun Road, Hangzhou 310003, China
| | - Jingqi Liu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79 Qingchun Road, Hangzhou 310003, China
| | - Xiaotian Dong
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79 Qingchun Road, Hangzhou 310003, China
| | - Yanni Sun
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79 Qingchun Road, Hangzhou 310003, China
| | - Qiaoling Pan
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79 Qingchun Road, Hangzhou 310003, China
| | - Yang Li
- Obstetrical Department, First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, China
| | - Xiaowei Shi
- Chu Kochen Honors College, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China
| | - Lanjuan Li
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79 Qingchun Road, Hangzhou 310003, China
| | - Hongcui Cao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79 Qingchun Road, Hangzhou 310003, China
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An SY, Jang YJ, Lim HJ, Han J, Lee J, Lee G, Park JY, Park SY, Kim JH, Do BR, Han C, Park HK, Kim OH, Song MJ, Kim SJ, Kim JH. Milk Fat Globule-EGF Factor 8, Secreted by Mesenchymal Stem Cells, Protects Against Liver Fibrosis in Mice. Gastroenterology 2017; 152:1174-1186. [PMID: 27956229 DOI: 10.1053/j.gastro.2016.12.003] [Citation(s) in RCA: 134] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 11/16/2016] [Accepted: 12/03/2016] [Indexed: 01/10/2023]
Abstract
BACKGROUND & AIMS Mesenchymal stem cells (MSCs) mediate tissue repair and might be used to prevent or reduce liver fibrosis. However, little is known about the anti-fibrotic factors secreted from MSCs or their mechanisms. METHODS Umbilical cord-derived MSCs (UCMSCs) were differentiated into hepatocyte-like cells (hpUCMSCs), medium was collected, and secretome proteins were identified and quantified using nanochip-liquid chromatography/quadrupole time-of-flight mass spectrometry. Liver fibrosis was induced in mice by intraperitoneal injection of thioacetamide or CCl4; some mice were then given injections of secretomes or proteins. Liver tissues were collected and analyzed by histology or polymerase chain reaction array to analyze changes in gene expression patterns. We analyzed the effects of MSC secretomes and potential anti-fibrotic proteins on transforming growth factor β 1 (TGFβ1)-mediated activation of human hepatic stellate cell (HSC) lines (hTert-HSC and LX2) and human primary HSCs. Liver tissues were collected from 16 patients with liver cirrhosis and 16 individuals without cirrhosis (controls) in Korea and analyzed by immunohistochemistry and immunoblots. RESULTS In mice with fibrosis, accumulation of extracellular matrix proteins was significantly reduced 3 days after injecting secretomes from UCMSCs, and to a greater extent from hpUCMSCs; numbers of activated HSCs that expressed the myogenic marker α-smooth muscle actin (α-SMA, encoded by ACTA2 [actin, alpha 2, smooth muscle]) were also reduced. Secretomes from UCMSCs, and to a greater extent from hpUCMSCs, reduced liver expression of multiple fibrotic factors, collagens, metalloproteinases, TGFβ, and Smad proteins in the TGFβ signaling pathways. In HSC cell lines and primary HSCs, TGFβ1-stimulated upregulation of α-SMA was significantly inhibited (and SMAD2 phosphorylation reduced) by secretomes from UCMSCs, and to a greater extent from hpUCMSCs. We identified 32 proteins in secretomes of UCMSCs that were more highly concentrated in secretomes from hpUCMSCs and inhibited TGFβ-mediated activation of HSCs. One of these, milk fat globule-EGF factor 8 (MFGE8), was a strong inhibitor of activation of human primary HSCs. We found MFGE8 to down-regulate expression of TGFβ type I receptor by binding to αvβ3 integrin on HSCs and to be secreted by MSCs from umbilical cord, teeth, and bone marrow. In mice, injection of recombinant human MFGE8 had anti-fibrotic effects comparable to those of the hpUCMSC secretome, reducing extracellular matrix deposition and HSC activation. Co-injection of an antibody against MFGE8 reduced the anti-fibrotic effects of the hpUCMSC secretome in mice. Levels of MFGE8 were reduced in cirrhotic liver tissue from patients compared with controls. CONCLUSIONS MFGE8 is an anti-fibrotic protein in MSC secretomes that strongly inhibits TGFβ signaling and reduces extracellular matrix deposition and liver fibrosis in mice.
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Affiliation(s)
- Su Yeon An
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Yu Jin Jang
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Hee-Joung Lim
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Jiyou Han
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Jaehun Lee
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Gyunggyu Lee
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Ji Young Park
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Seo-Young Park
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Ji Hyang Kim
- Biotechnology Research Institute, HurimBioCell Inc., Seoul, Republic of Korea
| | - Byung-Rok Do
- Biotechnology Research Institute, HurimBioCell Inc., Seoul, Republic of Korea
| | - Choongseong Han
- Department of Oral Medicine and Oral Diagnosis, Seoul National University Dental Hospital, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Republic of Korea; Nexel, Co., Ltd, Seoul, Republic of Korea
| | - Hee-Kyung Park
- Department of Oral Medicine and Oral Diagnosis, Seoul National University Dental Hospital, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Republic of Korea
| | - Ok-Hee Kim
- Department of Surgery, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon, Republic of Korea
| | - Myeong Jun Song
- Division of Hepatology, Department of Internal Medicine, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon, Republic of Korea
| | - Say-June Kim
- Department of Surgery, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon, Republic of Korea
| | - Jong-Hoon Kim
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
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Zorzopulos J, Opal SM, Hernando-Insúa A, Rodriguez JM, Elías F, Fló J, López RA, Chasseing NA, Lux-Lantos VA, Coronel MF, Franco R, Montaner AD, Horn DL. Immunomodulatory oligonucleotide IMT504: Effects on mesenchymal stem cells as a first-in-class immunoprotective/immunoregenerative therapy. World J Stem Cells 2017; 9:45-67. [PMID: 28396715 PMCID: PMC5368622 DOI: 10.4252/wjsc.v9.i3.45] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 10/12/2016] [Accepted: 12/19/2016] [Indexed: 02/06/2023] Open
Abstract
The immune responses of humans and animals to insults (i.e., infections, traumas, tumoral transformation and radiation) are based on an intricate network of cells and chemical messengers. Abnormally high inflammation immediately after insult or abnormally prolonged pro-inflammatory stimuli bringing about chronic inflammation can lead to life-threatening or severely debilitating diseases. Mesenchymal stem cell (MSC) transplant has proved to be an effective therapy in preclinical studies which evaluated a vast diversity of inflammatory conditions. MSCs lead to resolution of inflammation, preparation for regeneration and actual regeneration, and then ultimate return to normal baseline or homeostasis. However, in clinical trials of transplanted MSCs, the expectations of great medical benefit have not yet been fulfilled. As a practical alternative to MSC transplant, a synthetic drug with the capacity to boost endogenous MSC expansion and/or activation may also be effective. Regarding this, IMT504, the prototype of a major class of immunomodulatory oligonucleotides, induces in vivo expansion of MSCs, resulting in a marked improvement in preclinical models of neuropathic pain, osteoporosis, diabetes and sepsis. IMT504 is easily manufactured and has an excellent preclinical safety record. In the small number of patients studied thus far, IMT504 has been well-tolerated, even at very high dosage. Further clinical investigation is necessary to demonstrate the utility of IMT504 for resolution of inflammation and regeneration in a broad array of human diseases that would likely benefit from an immunoprotective/immunoregenerative therapy.
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Mesenchymal Stem Cells Transplantation following Partial Hepatectomy: A New Concept to Promote Liver Regeneration-Systematic Review of the Literature Focused on Experimental Studies in Rodent Models. Stem Cells Int 2017; 2017:7567958. [PMID: 28386285 PMCID: PMC5366767 DOI: 10.1155/2017/7567958] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2016] [Revised: 02/09/2017] [Accepted: 02/14/2017] [Indexed: 02/08/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are an attractive source for regenerative medicine because they are easily accessible through minimally invasive methods and have the potential to enhance liver regeneration (LG) and improve liver function, following partial hepatectomy (PH) and acute or chronic liver injury. A systematic review of the literature was conducted for articles published up to September 1st, 2016, using the MEDLINE database. The keywords that were used in various combinations were as follows: “Mesenchymal stem cells”, “transplantation”, “stem cells”, “adipose tissue derived stem cells”, “bone marrow-derived stem cells”, “partial hepatectomy”, “acute liver failure”, “chronic liver failure”, “liver fibrosis”, “liver cirrhosis”, “rats”, “mice”, and “liver regeneration”. All introduced keywords were searched for separately in MeSH Database to control relevance and terminological accuracy and validity. A total of 41 articles were identified for potential inclusion and reviewed in detail. After a strict selection process, a total of 28 articles were excluded, leaving 13 articles to form the basis of this systematic review. MSCs transplantation promoted LG and improved liver function. Furthermore, MSCs had the ability to differentiate in hepatocyte-like cells, increase survival, and protect hepatocytes by paracrine mechanisms. MSCs transplantation may provide beneficial effects in the process of LG after PH and acute or chronic liver injury. They may represent a new therapeutic option to treat posthepatectomy acute liver failure.
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Liang J, Zhang H, Zhao C, Wang D, Ma X, Zhao S, Wang S, Niu L, Sun L. Effects of allogeneic mesenchymal stem cell transplantation in the treatment of liver cirrhosis caused by autoimmune diseases. Int J Rheum Dis 2017; 20:1219-1226. [PMID: 28217916 DOI: 10.1111/1756-185x.13015] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Jun Liang
- Department of Rheumatology and Immunology; The Affiliated Drum Tower Hospital of Nanjing University Medical School; Nanjing Jiangsu China
| | - Huayong Zhang
- Department of Rheumatology and Immunology; The Affiliated Drum Tower Hospital of Nanjing University Medical School; Nanjing Jiangsu China
| | - Cheng Zhao
- Department of Rheumatology and Immunology; The Affiliated Drum Tower Hospital of Nanjing University Medical School; Nanjing Jiangsu China
| | - Dandan Wang
- Department of Rheumatology and Immunology; The Affiliated Drum Tower Hospital of Nanjing University Medical School; Nanjing Jiangsu China
| | - Xiaolei Ma
- Department of Rheumatology and Immunology; The Affiliated Drum Tower Hospital of Nanjing University Medical School; Nanjing Jiangsu China
| | - Shengnan Zhao
- Department of Rheumatology and Immunology; The Affiliated Drum Tower Hospital of Nanjing University Medical School; Nanjing Jiangsu China
| | - Shiying Wang
- Department of Rheumatology and Immunology; The Affiliated Drum Tower Hospital of Nanjing University Medical School; Nanjing Jiangsu China
| | - Lingying Niu
- Department of Rheumatology and Immunology; The Affiliated Drum Tower Hospital of Nanjing University Medical School; Nanjing Jiangsu China
| | - Lingyun Sun
- Department of Rheumatology and Immunology; The Affiliated Drum Tower Hospital of Nanjing University Medical School; Nanjing Jiangsu China
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Xuan J, Feng W, An ZT, Yang J, Xu HB, Li J, Zhao ZF, Wen W. Anti-TGFβ-1 receptor inhibitor mediates the efficacy of the human umbilical cord mesenchymal stem cells against liver fibrosis through TGFβ-1/Smad pathway. Mol Cell Biochem 2017; 429:113-122. [DOI: 10.1007/s11010-017-2940-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Accepted: 01/16/2017] [Indexed: 12/15/2022]
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Status of and candidates for cell therapy in liver cirrhosis: overcoming the "point of no return" in advanced liver cirrhosis. J Gastroenterol 2017; 52:129-140. [PMID: 27631592 DOI: 10.1007/s00535-016-1258-1] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Accepted: 08/26/2016] [Indexed: 02/07/2023]
Abstract
The treatment of liver cirrhosis is currently being standardized and developed specifically to reduce activation of hepatic stellate cells (HSCs), inhibit fibrosis, increase degradation of matrix components, and reduce activated myofibroblasts. Cell therapy can be applied in the treatment of liver cirrhosis; however, the characteristic features of this therapy differ from those of other treatments because of the involvement of a living body origin and production of multiple cytokines, chemokines, matrix metalloproteinases (MMPs), and growth factors. Thus, cell therapies can potentially have multiple effects on the damaged liver, including alleviating liver cirrhosis and stimulating liver regeneration with affecting the host cells. Cell therapies initially involved autologous bone marrow cell infusion, and have recently developed to include the use of specific cells such as mesenchymal stem cells and macrophages. The associated molecular mechanisms, routes of administration, possibility of allogeneic cell therapy, and host conditions appropriate for cell therapies are now being extensively analyzed. In this review, we summarize the status and future prospects of cell therapy for liver cirrhosis.
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Suk KT, Yoon JH, Kim MY, Kim CW, Kim JK, Park H, Hwang SG, Kim DJ, Lee BS, Lee SH, Kim HS, Jang JY, Lee CH, Kim BS, Jang YO, Cho MY, Jung ES, Kim YM, Bae SH, Baik SK. Transplantation with autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: Phase 2 trial. Hepatology 2016; 64:2185-2197. [PMID: 27339398 DOI: 10.1002/hep.28693] [Citation(s) in RCA: 205] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2016] [Revised: 05/30/2016] [Accepted: 06/21/2016] [Indexed: 12/12/2022]
Abstract
UNLABELLED Bone marrow-derived mesenchymal stem cell (BM-MSC) transplantation has been suggested as an effective therapy for liver cirrhosis. The efficacy and safety of autologous BM-MSC transplantation in the treatment of alcoholic cirrhosis were investigated. Seventy-two patients with baseline biopsy-proven alcoholic cirrhosis who had been alcohol-abstinent for more than 6 months underwent a multicenter, randomized, open-label, phase 2 trial. Patients were randomly assigned to three groups: one control group and two autologous BM-MSC groups that underwent either one-time or two-time hepatic arterial injections of 5 × 107 BM-MSCs 30 days after BM aspiration. A follow-up biopsy was performed 6 months after enrollment, and adverse events were monitored for 12 months. The primary endpoint was improvement in fibrosis quantification based on picrosirius red staining. The secondary endpoints included liver function tests, Child-Pugh score, and Model for End-stage Liver Disease score. Outcomes were analyzed by per-protocol analysis. In terms of fibrosis quantification (before versus after), the one-time and two-time BM-MSC groups were associated with 25% (19.5 ± 9.5% versus 14.5 ± 7.1%) and 37% (21.1 ± 8.9% versus 13.2 ± 6.7%) reductions in the proportion of collagen, respectively (P < 0.001). In the intergroup comparison, two-time BM-MSC transplantation in comparison with one-time BM-MSC transplantation was not associated with improved results in fibrosis quantification (P > 0.05). The Child-Pugh scores of both BM-MSC groups (one-time 7.6 ± 1.0 versus 6.3 ± 1.3 and two-time 7.8 ± 1.2 versus 6.8 ± 1.6) were also significantly improved following BM-MSC transplantation (P < 0.05). The proportion of patients with adverse events did not differ among the three groups. CONCLUSION Autologous BM-MSC transplantation safely improved histologic fibrosis and liver function in patients with alcoholic cirrhosis. (Hepatology 2016;64:2185-2197).
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Affiliation(s)
- Ki Tae Suk
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, South Korea
| | - Jung-Hwan Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Moon Young Kim
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University, Wonju College of Medicine, Wonju, South Korea
| | - Chang Wook Kim
- Department of Internal Medicine, Uijeongbu St Mary's Hospital College of Medicine, The Catholic University, Uijeongbu, South Korea
| | - Ja Kyung Kim
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University Health System, Yonsei University College of Medicine, Seoul, South Korea
| | - Hana Park
- Department of Internal Medicine, Bundang CHA Medical Center, CHA University, Seongnam, South Korea
| | - Seong Gyu Hwang
- Department of Internal Medicine, Bundang CHA Medical Center, CHA University, Seongnam, South Korea
| | - Dong Joon Kim
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, South Korea
| | - Byung Seok Lee
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, South Korea
| | - Sae Hwan Lee
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, South Korea
| | - Hong Soo Kim
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, South Korea
| | - Jae Young Jang
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul, South Korea
| | - Chang-Hyeong Lee
- Department of Internal Medicine, College of Medicine & Hospital, Catholic University of Daegu, Daegu, South Korea
| | - Byung Seok Kim
- Department of Internal Medicine, College of Medicine & Hospital, Catholic University of Daegu, Daegu, South Korea
| | - Yoon Ok Jang
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University, Wonju College of Medicine, Wonju, South Korea
| | - Mee Yon Cho
- Department of Pathology, Wonju Severance Christian Hospital, Yonsei University, Wonju College of Medicine, Wonju, South Korea
| | - Eun Sun Jung
- Department of Pathology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University, Seoul, South Korea
| | | | - Si Hyun Bae
- Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University, Seoul, South Korea
| | - Soon Koo Baik
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University, Wonju College of Medicine, Wonju, South Korea
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Haldar D, Henderson NC, Hirschfield G, Newsome PN. Mesenchymal stromal cells and liver fibrosis: a complicated relationship. FASEB J 2016; 30:3905-3928. [DOI: 10.1096/fj.201600433r] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Accepted: 08/15/2016] [Indexed: 12/17/2022]
Affiliation(s)
- Debashis Haldar
- National Institute for Health ResearchBirmingham Liver Biomedical Research Unit and Centre for Liver Research University of Birmingham Birmingham United Kingdom
- Liver UnitUniversity Hospital Birmingham National Health Service (NHS) Foundation Trust Birmingham United Kingdom
| | - Neil C. Henderson
- Medical Research Council (MRC) Centre for Inflammation ResearchQueens Medical Research Institute University of Edinburgh Edinburgh United Kingdom
| | - Gideon Hirschfield
- National Institute for Health ResearchBirmingham Liver Biomedical Research Unit and Centre for Liver Research University of Birmingham Birmingham United Kingdom
- Liver UnitUniversity Hospital Birmingham National Health Service (NHS) Foundation Trust Birmingham United Kingdom
| | - Philip N. Newsome
- National Institute for Health ResearchBirmingham Liver Biomedical Research Unit and Centre for Liver Research University of Birmingham Birmingham United Kingdom
- Liver UnitUniversity Hospital Birmingham National Health Service (NHS) Foundation Trust Birmingham United Kingdom
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