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Xu Y, Wang XS, Zhou XL, Lu WM, Tang XK, Jin Y, Ye JS. Mesenchymal stem cell therapy for liver fibrosis need "partner": Results based on a meta-analysis of preclinical studies. World J Gastroenterol 2024; 30:3766-3782. [PMID: 39221071 PMCID: PMC11362880 DOI: 10.3748/wjg.v30.i32.3766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 06/22/2024] [Accepted: 08/06/2024] [Indexed: 08/26/2024] Open
Abstract
BACKGROUND The efficacy of mesenchymal stem cells (MSCs) in treating liver fibrosis has been demonstrated in several clinical studies. However, their low survival and liver implantation rates remain problematic. In recent years, a large number of studies in animal models of liver fibrosis have shown that MSCs combined with drugs can improve the efficacy of MSCs in the treatment of liver fibrosis alone and inhibit its progression to end-stage liver disease. This has inspired new ways of thinking about treating liver fibrosis. AIM To investigate the effectiveness and mechanisms of MSCs combined with drugs in treating liver fibrosis. METHODS Data sources included four electronic databases and were constructed until January 2024. The subjects, interventions, comparators, outcomes, and study design principle were used to screen the literature, and the quality of the literature was evaluated to assess the risk of bias. Relevant randomised controlled trials were selected, and the final 13 studies were included in the final study. RESULTS A total of 13 studies were included after screening. Pooled analysis showed that MSCs combined with drug therapy significantly improved liver function, promoted the repair of damaged liver tissues, reduced the level of liver fibrosis-related indexes, and effectively ameliorated hepatic fibrosis by modulating the hepatic inflammatory microenvironment, promoting the homing of MSCs, and regulating the relevant signaling pathways, and the treatment efficacy was superior to MSCs alone. However, the combined treatment statistics showed no ame-lioration in serum albumin levels (standardized mean difference = 0.77, 95% confidence interval: -0.13 to 1.68, P = 0.09). CONCLUSION In conclusion, MSCs combined with drugs for treating liver fibrosis effectively make up for the shortcomings of MSCs in their therapeutic effects. However, due to the different drugs, the treatment mechanism and effect also differ. Therefore, more randomized controlled trials are needed to compare the therapeutic efficacy of different drugs in combination with MSCs, aiming to select the "best companion" of MSCs in treating hepatic fibrosis.
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Affiliation(s)
- Yan Xu
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Xue-Song Wang
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Xiao-Lei Zhou
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Wen-Ming Lu
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Xing-Kun Tang
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
- Department of Medical Genetics, School of Medicine, Tongji University, Shanghai 200092, China
| | - Yu Jin
- School of Rehabilitation Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Jun-Song Ye
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cere-brovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
- Jiangxi Provincal Key Laboratory of Tissue Engineering, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
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Xu Y, Zhou X, Wang X, Jin Y, Zhou L, Ye J. Progress of mesenchymal stem cells (MSCs) & MSC-Exosomes combined with drugs intervention in liver fibrosis. Biomed Pharmacother 2024; 176:116848. [PMID: 38834005 DOI: 10.1016/j.biopha.2024.116848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 05/20/2024] [Accepted: 05/27/2024] [Indexed: 06/06/2024] Open
Abstract
Liver fibrosis is an intrahepatic chronic damage repair response caused by various reasons such as alcoholic liver, fatty liver, viral hepatitis, autoimmune diseases, etc., and is closely related to the progression of liver disease. Currently, the mechanisms of liver fibrosis and its treatment are hot research topics in the field of liver disease remedy. Mesenchymal stem cells (MSCs) are a class of adult stem cells with self-renewal and multidirectional differentiation potential, which can ameliorate fibrosis through hepatic-directed differentiation, paracrine effects, and immunomodulation. However, the low inner-liver colonization rate, low survival rate, and short duration of intervention after stem cell transplantation have limited their wide clinical application. With the intensive research on liver fibrosis worldwide, it has been found that MSCs and MSCs-derived exosomes combined with drugs have shown better intervention efficiency than utilization of MSCs alone in many animal models of liver fibrosis. In this paper, we review the interventional effects and mechanisms of mesenchymal stem cells and their exosomes combined with drugs to alleviate hepatic fibrosis in vivo in animal models in recent years, which will provide new ideas to improve the efficacy of mesenchymal stem cells and their exosomes in treating hepatic fibrosis in the clinic.
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Affiliation(s)
- Yan Xu
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Jiangxi, China; School of Rehabilitation Medicine, Gannan Medical University, Jiangxi, China
| | - Xiaolei Zhou
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Jiangxi, China; School of Rehabilitation Medicine, Gannan Medical University, Jiangxi, China
| | - Xuesong Wang
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Jiangxi, China; School of Rehabilitation Medicine, Gannan Medical University, Jiangxi, China
| | - Yu Jin
- School of Rehabilitation Medicine, Gannan Medical University, Jiangxi, China
| | - Lin Zhou
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Jiangxi, China; School of Rehabilitation Medicine, Gannan Medical University, Jiangxi, China; Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Jiangxi, China; Jiangxi Provincal Key Laboratory of Tissue Engineering, Gannan Medical University, Jiangxi, China; Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Jiangxi, China
| | - Junsong Ye
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Jiangxi, China; School of Rehabilitation Medicine, Gannan Medical University, Jiangxi, China; Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Jiangxi, China; Jiangxi Provincal Key Laboratory of Tissue Engineering, Gannan Medical University, Jiangxi, China; Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Jiangxi, China.
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Salama YA, Hassan HM, El-Gayar AM, Abdel-Rahman N. Combined quercetin and simvastatin attenuate hepatic fibrosis in rats by modulating SphK1/NLRP3 pathways. Life Sci 2024; 337:122349. [PMID: 38128755 DOI: 10.1016/j.lfs.2023.122349] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 12/05/2023] [Accepted: 12/09/2023] [Indexed: 12/23/2023]
Abstract
Liver fibrosis involves several signalling pathways working in concert regulating the deposition of extracellular matrix. In this study, we evaluated the effect of quercetin and simvastatin alone and their combination on the treatment of experimentally induced hepatic fibrosis in rats. To decipher the potential mechanisms involved, liver fibrosis was induced in rats by administration of 40 % carbon tetrachloride (CCl4) (1 μl/g rat, i.p., twice weekly) for 6 weeks. Quercetin (50 mg/kg, orally), simvastatin (40 mg/kg, orally) either individually or combined were administered for another 4 weeks. The three treatment groups ameliorated hepatic dysfunction and altered parameters of sphingolipid and pyroptosis pathways. Yet, the combined group showed a more pronounced effect. Treatments lowered serum levels of GOT, GPT, ALP and elevated albumin and total protein levels. Histopathological and electron microscope examination of liver tissue revealed diminished fibrosis and inflammation. Protein expression levels of α-SMA, IL-1β, PPAR-γ, TGF-β1, caspase-1 and caspase-3 expression in liver tissues were reduced. Additionally, hepatic mRNA levels of SphK1 and NLRP3 decreased after treatment. Furthermore, the three groups lowered MDA levels and elevated total antioxidant capacity, GSH and Nrf2 expression levels. Treatments downregulated sphingolipid pathway and NLRP3-mediated pyroptosis and stimulated an anti-apoptotic, anti-proliferative and antioxidant activity. This suggests that targeting the SphK1/NLRP3 pathway could be a prospective therapeutic strategy against liver fibrosis.
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Affiliation(s)
- Yasmin A Salama
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, 35516, Egypt; Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt
| | - Hanan M Hassan
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt
| | - Amal M El-Gayar
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, 35516, Egypt
| | - Noha Abdel-Rahman
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, 35516, Egypt.
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Chang CH, Lin CP, Chen YK, Hsiao YF, Wang YH. Simvastatin Attenuates Areca Nut Extract-Induced Subdermal Fibrosis in Mice by Targeting TGF-β Signaling Pathways. Curr Issues Mol Biol 2023; 45:8622-8632. [PMID: 37998719 PMCID: PMC10670689 DOI: 10.3390/cimb45110542] [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: 10/06/2023] [Revised: 10/20/2023] [Accepted: 10/24/2023] [Indexed: 11/25/2023] Open
Abstract
Oral submucous fibrosis (OSMF) is a chronic inflammatory disease and a potentially malignant oral disorder, characterized by fibrosis of the oral mucosa. TGF-β signaling pathways have been implicated in the development of OSMF, with areca nut extract (ANE) contributing to the disease progression. Simvastatin, a statin drug, has demonstrated anti-fibrotic properties in various fibrotic conditions. However, its therapeutic potential in treating OSMF remains unclear. In this study, 8-week-old male BALB/c mice were randomly divided into three groups based on different time points. Each mouse was then treated with four different drug formulations. Post-treatment, specimens were collected for histopathological examination and staining to assess skin thickness, fibrosis, and collagen deposition. ANE treatment alone significantly increased skin thickness and collagen deposition compared to the control group after the 4-week time point. The combined administration of ANE and simvastatin, resulted in a notable reduction in skin thickness and collagen deposition. Western blot analysis revealed that simvastatin effectively suppressed the expression of fibrosis-related proteins, including CTGF, and α-SMA, in ANE-induced subdermal fibrosis. These results suggest that simvastatin has potential therapeutic effects on ANE-induced subdermal fibrosis, providing a foundation for future studies and possible clinical applications.
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Affiliation(s)
- Chi-Hua Chang
- Division of Oral and Maxillofacial Surgery, Department of Dentistry, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan;
| | - Ching-Ping Lin
- Division of Periodontology, Department of Dentistry, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan;
| | - Yuk-Kwan Chen
- School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Division of Oral Pathology and Maxillofacial Radiology, Department of Dentistry, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Oral & Maxillofacial Imaging Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Yu-Fang Hsiao
- College of Medicine, Orthopaedic Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Yan-Hsiung Wang
- School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- College of Medicine, Orthopaedic Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
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Dolivo DM, Reed CR, Gargiulo KA, Rodrigues AE, Galiano RD, Mustoe TA, Hong SJ. Anti-fibrotic effects of statin drugs: a review of evidence and mechanisms. Biochem Pharmacol 2023:115644. [PMID: 37321414 DOI: 10.1016/j.bcp.2023.115644] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 06/05/2023] [Accepted: 06/07/2023] [Indexed: 06/17/2023]
Abstract
Fibrosis is a pathological repair process common among organs, that responds to damage by replacement of tissue with non-functional connective tissue. Despite the widespread prevalence of tissue fibrosis, manifesting in numerous disease states across myriad organs, therapeutic modalities to prevent or alleviate fibrosis are severely lacking in quantity and efficacy. Alongside development of new drugs, repurposing of existing drugs may be a complementary strategy to elect anti-fibrotic compounds for pharmacologic treatment of tissue fibrosis. Drug repurposing can provide key advantages to de novo drug discovery, harnessing the benefits of previously elucidated mechanisms of action and already existing pharmacokinetic profiles. One class of drugs a wealth of clinical data and extensively studied safety profiles is the statins, a class of antilipidemic drugs widely prescribed for hypercholesterolemia. In addition to these widely utilized lipid-lowering effects, increasing data from cellular, pre-clinical mammalian, and clinical human studies have also demonstrated that statins are able to alleviate tissue fibrosis originating from a variety of pathological insults via lesser-studied, pleiotropic effects of these drugs. Here we review literature demonstrating evidence for direct effects of statins antagonistic to fibrosis, as well as much of the available mechanistic data underlying these effects. A more complete understanding of the anti-fibrotic effects of statins may enable a clearer picture of their anti-fibrotic potential for various clinical indications. Additionally, more lucid comprehension of the mechanisms by which statins exert anti-fibrotic effects may aid in development of novel therapeutic agents that target similar pathways but with greater specificity or efficacy.
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Affiliation(s)
- David M Dolivo
- Department of Surgery-Northwestern University Feinberg School of Medicine, United States.
| | - Charlotte R Reed
- Department of Surgery-Northwestern University Feinberg School of Medicine, United States
| | - Kristine A Gargiulo
- Department of Surgery-Northwestern University Feinberg School of Medicine, United States
| | - Adrian E Rodrigues
- Department of Surgery-Northwestern University Feinberg School of Medicine, United States
| | - Robert D Galiano
- Department of Surgery-Northwestern University Feinberg School of Medicine, United States
| | - Thomas A Mustoe
- Department of Surgery-Northwestern University Feinberg School of Medicine, United States
| | - Seok Jong Hong
- Department of Surgery-Northwestern University Feinberg School of Medicine, United States.
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6
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Opo FDM, Moulay M, Alrefaei GI, Alsubhi NH, Alkarim S, Rahman MM. Effect of Co-culturing both placenta-derived mesenchymal stem cells and their condition medium in the cancer cell (HepG2) migration, damage through apoptosis and cell cycle arrest. Saudi J Biol Sci 2023; 30:103519. [PMID: 36561333 PMCID: PMC9763848 DOI: 10.1016/j.sjbs.2022.103519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/28/2022] [Accepted: 11/25/2022] [Indexed: 12/03/2022] Open
Abstract
Human placental-derived mesenchymal stem cells (hPMSCs) are a promising candidate to inhibit the proliferation of hepatocellular carcinoma (HCC) cell lines such as HepG2. The effects of hPMSCs and their conditioned media on HepG2 are, however, still a mystery. As a result, the goal of this study was to look into the effects of hPMSCs and their conditioned media on HepG2 and figure out what was going on. Fluorescence-activated cell sorting and the MTT test were used to determine the percentage of cells that died (early apoptosis, late apoptosis). The DIO and DID colors were used to detect cell fusion and cell death in both cells. HepG2 cells were co-treated with hPMSCs or hPMSCs-conditioned medium (hPMSCs-CM) to reduce growth and promote apoptosis. Morphological changes were also seen in the 30 percent, 50 percent, and 60 percent cases. The secretion of cytokine was determined by the ELISA. Flow cytometry, caspase 9 immunofluorescence, qPCR (detection of Bax, Bcl-2, and β-catenin genes), western blot, and immunophenotyping revealed that treatment with hPMSCs or hPMSCs-CM caused HepG2 cell death through apoptosis (detection of caspase 9, caspase 3 protein). HepG2 cell cycle arrest could be induced by hPMSCs and hPMSCs-CM. Following treatment with hPMSCs or hPMSCs-CM, HepG2 cell development was stopped in the G0/G1 phase. These treatments also inhibited HepG2 cells from migrating, with the greatest effect when the highest ratio/concentration of hPMSCs (70%) and hPMSCs-CM were used (90%). Our findings indicated that hPMSCs and hPMSCs-CM could be promising treatment options for liver cancer. To elucidate the proper effect, more research on liver cancer-induced rat/mice is needed.
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Key Words
- 30H, 30% HepG2
- 30P, 30% placenta
- 50H, 50% HepG2
- 50P, 50% placenta
- 70H, 70% HepG2
- 70P, 70% placenta
- AFP, Alfa Feto Protein
- Apoptosis
- Conditioned medium
- Differentiation
- HCC, Hepatocellular Carcinoma
- HepG2
- IL, Interleukin
- Morphology
- PVDF, Polyvinylidene Fluoride
- TBST, Tris-Buffered Saline with 0.1% Tween 20 detergent.
- hP-MSCs, human Placenta derived Mesenchymal Stem Cells
- hPMSCs
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Affiliation(s)
- F.A. Dain Md Opo
- Department of Biological Science, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia,Embryonic Stem Cell Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Mohammed Moulay
- Embryonic Stem Cell Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia,Embryonic and Cancer Stem Cell Research Group, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia,Corresponding authors at: Embryonic Stem Cell Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia (M. Moulay).
| | - Ghadeer I. Alrefaei
- Department of Biology, College of Science, University of Jeddah, Jeddah 21589, Saudi Arabia,Embryonic and Cancer Stem Cell Research Group, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Nouf H. Alsubhi
- Biological Sciences Department, College of Science & Arts, King Abdulaziz University, Rabigh 21911, Saudi Arabia,Embryonic and Cancer Stem Cell Research Group, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Saleh Alkarim
- Department of Biological Science, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia,Embryonic Stem Cell Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia,Embryonic and Cancer Stem Cell Research Group, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Mohammed M. Rahman
- Department of Chemistry, King Abdulaziz University, Jeddah 21589, Saudi Arabia,Corresponding authors at: Embryonic Stem Cell Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia (M. Moulay).
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Abo-Aziza FAM, Albarrak SM, Zaki AKA, El-Shafey SE. Tumor necrosis factor-alpha antibody labeled-polyethylene glycol-coated nanoparticles: A mesenchymal stem cells-based drug delivery system in the rat model of cisplatin-induced nephrotoxicity. Vet World 2022; 15:2475-2490. [DOI: 10.14202/vetworld.2022.2475-2490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 09/12/2022] [Indexed: 11/16/2022] Open
Abstract
Background and Aim: A delivery system consisting of bone marrow mesenchymal stem cells (MSCs) loaded with polyethylene glycol (PEG) coated superparamagnetic iron oxide nanoparticles (SPIONs) was constructed to treat a rat model of cisplatin (Cis)-induced nephrotoxicity with 1/10 of the common dose of anti-tumor necrosis factor-alpha (TNF-α) antibodies (infliximab).
Materials and Methods: Morphology, size, crystallinity, molecular structure, and magnetic properties of uncoated and PEG-coated SPIONs were analyzed. A delivery system consisting of MSCs containing infliximab-labeled PEG-coated SPIONs (Infliximab-PEG-SPIONs-MSCs) was generated and optimized before treatment. Fifty female Wistar rats were divided into five equal groups: Group 1: Untreated control; Group 2 (Cis): Rats were administered Cis through intraperitoneal (i.p.) injection (8 mg/kg) once a week for 4 weeks; Group 3 (Infliximab): Rats were injected once with infliximab (5 mg/kg), i.p. 3 days before Cis administration; Group 4 (Cis + MSCs): Rats were injected with Cis followed by an injection of 2 × 106 MSCs into the tail vein twice at a 1-week interval; and Group 5 (Cis + Infliximab (500 μg/kg)-PEG-SPIONs-MSCs): Rats were injected with the delivery system into the tail vein twice at a 1-week interval. Besides histological examination of the kidney, the Doppler ultrasound scanner was used to scan the kidney with the Gray-color-spectral mode.
Results: In vivo, intra-renal iron uptake indicates the traffic of the delivery system from venous blood to renal tissues. Cis-induced nephrotoxicity resulted in a significant increase in TNF-α and malondialdehyde (MDA) (p < 0.05), bilirubin, creatinine, and uric acid (p < 0.01) levels compared with the untreated control group. The different treatments used in this study resulted in the amelioration of some renal parameters. However, TNF-α levels significantly decreased in Cis + Infliximab and Cis + MSCs (p < 0.05) groups. The serum levels of MDA significantly decreased in Cis + Infliximab (p < 0.05), Cis + MSCs (p < 0.05), and Cis + Infliximab-PEG-SPIONs-MSCs (p < 0.01). Furthermore, the serum activities of antioxidant enzymes were significantly elevated in the Cis + MSCs and Cis + Infliximab-PEG-SPIONs-MSCs groups (p < 0.05) compared to the Cis-induced nephrotoxicity rat model.
Conclusion: With the support of the constructed MSCs-SPIONs infliximab delivery system, it will be possible to track and monitor cell homing after therapeutic application. This infliximab-loading system may help overcome some challenges regarding drug delivery to the target organ, optimize therapeutics' efficacy, and reduce the dose. The outcomes of the current study provide a better understanding of the potential of combining MSCs and antibodies-linked nanoparticles for the treatment of nephrotoxicity. However, further investigation is recommended using different types of other drugs. For new approaches development, we should evaluate whether existing toxicity analysis and risk evaluation strategies are reliable and enough for the variety and complexity of nanoparticles.
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Affiliation(s)
- Faten A. M. Abo-Aziza
- Department of Parasitology and Animal Diseases, Veterinary Research Institute, National Research Centre, Cairo, Egypt
| | - Saleh M. Albarrak
- Department of Veterinary Medicine, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah, Saudi Arabia
| | - Abdel-Kader A. Zaki
- Department of Veterinary Medicine, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah, Saudi Arabia; Department of Physiology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
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8
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Li WQ, Liu WH, Qian D, Liu J, Zhou SQ, Zhang L, Peng W, Su L, Zhang H. Traditional Chinese medicine: An important source for discovering candidate agents against hepatic fibrosis. Front Pharmacol 2022; 13:962525. [PMID: 36081936 PMCID: PMC9445813 DOI: 10.3389/fphar.2022.962525] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 07/28/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatic fibrosis (HF) refers to the pathophysiological process of connective tissue dysplasia in the liver caused by various pathogenic factors. Nowadays, HF is becoming a severe threat to the health of human being. However, the drugs available for treating HF are limited. Currently, increasing natural agents derived from traditional Chinese medicines (TCMs) have been found to be beneficial for HF. A systemic literature search was conducted from PubMed, GeenMedical, Sci-Hub, CNKI, Google Scholar and Baidu Scholar, with the keywords of "traditional Chinese medicine," "herbal medicine," "natural agents," "liver diseases," and "hepatic fibrosis." So far, more than 76 natural monomers have been isolated and identified from the TCMs with inhibitory effect on HF, including alkaloids, flavones, quinones, terpenoids, saponins, phenylpropanoids, and polysaccharides, etc. The anti-hepatic fibrosis effects of these compounds include hepatoprotection, inhibition of hepatic stellate cells (HSC) activation, regulation of extracellular matrix (ECM) synthesis & secretion, regulation of autophagy, and antioxidant & anti-inflammation, etc. Natural compounds and extracts from TCMs are promising agents for the prevention and treatment of HF, and this review would be of great significance to development of novel drugs for treating HF.
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Affiliation(s)
- Wen-Qing Li
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wen-Hao Liu
- Department of Pharmacy, Tenth People’s Hospital of Tongji University, Shanghai, China
| | - Die Qian
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jia Liu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shi-Qiong Zhou
- Hospital of Nursing, The Second Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Lei Zhang
- Department of Vascular Surgery, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wei Peng
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Li Su
- Institute of Translational Medicine, Shanghai University, Shanghai, China
| | - Hong Zhang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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9
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Shokravi S, Borisov V, Zaman BA, Niazvand F, Hazrati R, Khah MM, Thangavelu L, Marzban S, Sohrabi A, Zamani A. Mesenchymal stromal cells (MSCs) and their exosome in acute liver failure (ALF): a comprehensive review. Stem Cell Res Ther 2022; 13:192. [PMID: 35527304 PMCID: PMC9080215 DOI: 10.1186/s13287-022-02825-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 02/28/2022] [Indexed: 12/13/2022] Open
Abstract
Recently, mesenchymal stromal cells (MSCs) and their derivative exosome have become a promising approach in the context of liver diseases therapy, in particular, acute liver failure (ALF). In addition to their differentiation into hepatocytes in vivo, which is partially involved in liver regeneration, MSCs support liver regeneration as a result of their appreciated competencies, such as antiapoptotic, immunomodulatory, antifibrotic, and also antioxidant attributes. Further, MSCs-secreted molecules inspire hepatocyte proliferation in vivo, facilitating damaged tissue recovery in ALF. Given these properties, various MSCs-based approaches have evolved and resulted in encouraging outcomes in ALF animal models and also displayed safety and also modest efficacy in human studies, providing a new avenue for ALF therapy. Irrespective of MSCs-derived exosome, MSCs-based strategies in ALF include administration of native MSCs, genetically modified MSCs, pretreated MSCs, MSCs delivery using biomaterials, and also MSCs in combination with and other therapeutic molecules or modalities. Herein, we will deliver an overview regarding the therapeutic effects of the MSCs and their exosomes in ALF. As well, we will discuss recent progress in preclinical and clinical studies and current challenges in MSCs-based therapies in ALF, with a special focus on in vivo reports.
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Affiliation(s)
- Samin Shokravi
- Department of Research and Academic Affairs, Larkin Community Hospital, Miami, FL USA
| | - Vitaliy Borisov
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation
| | - Burhan Abdullah Zaman
- Basic Sciences Department, College of Pharmacy, University of Duhok, Duhok, Kurdistan Region Iraq
| | - Firoozeh Niazvand
- School of Medicine, Abadan University of Medical Sciences, Abadan, Iran
| | - Raheleh Hazrati
- Department of Medicinal Chemistry, Pharmacy Faculty, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Meysam Mohammadi Khah
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Lakshmi Thangavelu
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Science, Saveetha University, Chennai, India
| | - Sima Marzban
- Department of Research and Academic Affairs, Larkin Community Hospital, Miami, FL USA
| | - Armin Sohrabi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Zamani
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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10
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Lai J, Jiang S, Shuai L, Zhang Y, Xia R, Chen Q, Bai L. Comparison of the biological and functional characteristics of mesenchymal stem cells from intrahepatic and identical bone marrow. Stem Cell Res 2021; 55:102477. [PMID: 34343826 DOI: 10.1016/j.scr.2021.102477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 07/11/2021] [Accepted: 07/21/2021] [Indexed: 02/07/2023] Open
Abstract
In our privious work, our reseach group characterized a population of hepatic-sourced mesenchymal stem cells (MSCs) called MLpvNG2+ cells. In the present study, we compared the biological and functional characteristics of naïve MLpvNG2 cells with identical bone marrow-derived MSCs (niBM-MSCs) using in vitro (conditioned media) and in vivo (a well-set diethylnitrosamine (DEN)-induced liver fibrotic/cirrhotic murine model) procedures. The intrahepatic-sourced mesodermal MLpvNG2+ cells exhibited some biological characteristics (e.g., a set of surface markers) similar to those of extrahepatic niBM-MSCs. In responsed to signals of pathological conditions, such as singals of fibrotic/cirrhotic liver, MLpvNG2+ cells showed higher survival and favored differentiation into ALB(+) and G6Pc(+) hepatocytes, whereas niBM-MSCs predominantly differentiated into CK/KRT19(+) cholangiocytes. We identified C/EBPα/β expression as a biological characteristic differentiating these two populations of MSCs, wherein MLpvNG2+ cells are likely regulated by C/EBPβ transcriptional signaling, whereas niBM-MSCs are likely controlled by C/EBPα transcriptional signaling. Notably, although C/EBPα and C/EBPβ transcriptional signaling regulate hepatocyte and cholangiocyte fate, respectively, the expression of these proteins in MLpvNG2+ cells is, to our knowledge, reported for the first time in the present study. We used anti-C/EBP neutralizing antibodies (Abs) both in vitro and in vivo to determine the functional characteristics of these proteins. We conclude that the biological characteristics of these two populations of MSCs depend on their differential C/EBPα/β expression patterns.
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Affiliation(s)
- Jiejuan Lai
- Hepatobiliary Institute, Southwest Hospital, the Army Medical University, No 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China
| | - Shifang Jiang
- Hepatobiliary Institute, Southwest Hospital, the Army Medical University, No 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China
| | - Ling Shuai
- Hepatobiliary Institute, Southwest Hospital, the Army Medical University, No 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China
| | - Yujun Zhang
- Hepatobiliary Institute, Southwest Hospital, the Army Medical University, No 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China
| | - Renpei Xia
- Hepatobiliary Institute, Southwest Hospital, the Army Medical University, No 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China
| | - Quanyu Chen
- Hepatobiliary Institute, Southwest Hospital, the Army Medical University, No 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China; Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Laboratory of Molecular Developmental Biology, School of Life Sciences, Southwest University, Beibei, Chongqing 400715, China
| | - Lianhua Bai
- Hepatobiliary Institute, Southwest Hospital, the Army Medical University, No 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China.
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11
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Increased Myocardial Retention of Mesenchymal Stem Cells Post-MI by Pre-Conditioning Exercise Training. Stem Cell Rev Rep 2021; 16:730-741. [PMID: 32306279 DOI: 10.1007/s12015-020-09970-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Stem cell (SC) therapy is a promising approach to improve post-myocardial infarction (MI) cardiac remodeling, but the proinflammatory microenvironment may lead to SC loss and, therefore, may have a negative impact on therapy. It appears that exercise training (ET) improves myocardial microenvironment for SC transplantation. Therefore, we tested the effect of ET on post-infarction retention of adipose-derived SCs (ADSCs) and its combined effects on the inflammatory microenvironment. Fischer-344 female rats were randomized to one of the following groups: Sham; sedentary coronary occlusion who did not receive ADSCs (sMI); sedentary coronary occlusion who received ADSCs; exercise coronary occlusion who received ADSCs. Rats were trained nine weeks prior to MI, followed by ADSCs transplantation. The MI led to left ventricle (LV) dilation and dysfunction, myocardial hypertrophy and fibrosis, and increased proinflammatory profile compared to Sham rats. Conversely, ADSCs transplanted rats exhibited, better morphological and functional LV parameters; inhibition of myocardial hypertrophy and fibrosis; and attenuation of proinflammatory cytokines (interleukins 1β and 10, tumor necrosis factor α, and transforming growth factor β) in the myocardium compared to sMI rats. Interestingly, ET enhanced the effect of ADSCs on interleukin 10 expression. There was a correlation between cytokine expression and myocardial ADSCs retention. The. ET enhanced the beneficial effects of ADSCs in infarcted myocardium, which was associated with higher ADSCs retention. These findings highlight the importance of ET in myocardial retention of ADSCs and attenuation of cardiac remodeling post-infarction. Cytokine analysis suggests improvement in ET-linked myocardial microenvironment based on its anti-inflammatory action.
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12
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Sanz-García C, Fernández-Iglesias A, Gracia-Sancho J, Arráez-Aybar LA, Nevzorova YA, Cubero FJ. The Space of Disse: The Liver Hub in Health and Disease. LIVERS 2021; 1:3-26. [DOI: 10.3390/livers1010002] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Since it was first described by the German anatomist and histologist, Joseph Hugo Vincenz Disse, the structure and functions of the space of Disse, a thin perisinusoidal area between the endothelial cells and hepatocytes filled with blood plasma, have acquired great importance in liver disease. The space of Disse is home for the hepatic stellate cells (HSCs), the major fibrogenic players in the liver. Quiescent HSCs (qHSCs) store vitamin A, and upon activation they lose their retinol reservoir and become activated. Activated HSCs (aHSCs) are responsible for secretion of extracellular matrix (ECM) into the space of Disse. This early event in hepatic injury is accompanied by loss of the pores—known as fenestrations—of the endothelial cells, triggering loss of balance between the blood flow and the hepatocyte, and underlies the link between fibrosis and organ dysfunction. If the imbalance persists, the expansion of the fibrotic scar followed by the vascularized septae leads to cirrhosis and/or end-stage hepatocellular carcinoma (HCC). Thus, researchers have been focused on finding therapeutic targets that reduce fibrosis. The space of Disse provides the perfect microenvironment for the stem cells niche in the liver and the interchange of nutrients between cells. In the present review article, we focused on the space of Disse, its components and its leading role in liver disease development.
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Affiliation(s)
- Carlos Sanz-García
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain
| | - Anabel Fernández-Iglesias
- Liver Vascular Biology Research Group, IDIBAPS, 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain
| | - Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, IDIBAPS, 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain
- Hepatology, Department of Biomedical Research, University of Bern, 3012 Bern, Switzerland
| | - Luis Alfonso Arráez-Aybar
- Department of Anatomy and Embriology, Complutense University School of Medicine, 28040 Madrid, Spain
| | - Yulia A. Nevzorova
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain
- Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany
- 12 de Octubre Health Research Institute (imas12), 28040 Madrid, Spain
| | - Francisco Javier Cubero
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain
- 12 de Octubre Health Research Institute (imas12), 28040 Madrid, Spain
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13
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Rostom DM, Attia N, Khalifa HM, Abou Nazel MW, El Sabaawy EA. The Therapeutic Potential of Extracellular Vesicles Versus Mesenchymal Stem Cells in Liver Damage. Tissue Eng Regen Med 2020; 17:537-552. [PMID: 32506351 DOI: 10.1007/s13770-020-00267-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 04/05/2020] [Accepted: 04/15/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The extracellular vesicles (EVs) secreted by bone marrow-derived mesenchymal stem cells (MSCs) hold significant potential as a novel alternative to whole-cell therapy. We herein compare the therapeutic potential of BM-MSCs versus their EVs (MSC-EVs) in an experimental Carbon tetrachloride (CCl4)-induced liver damage rat model. METHODS Rats with liver damage received a single IV injection of MSC-EVs, 1 million MSCs, or 3 million MSCs. The therapeutic efficacy of each treatment was assessed using liver histopathology, liver function tests and immunohistochemistry for liver fibrosis and hepatocellular injury. RESULTS Animals that received an injection of either MSCs-EVs or 3 million MSCs depicted significant regression of collagen deposition in the liver tissue and marked attenuation of hepatocellular damage, both structurally and functionally. CONCLUSION Similar to high doses of MSC-based therapy (3 million MSCs), MSC-EVs mitigated the fibrogenesis and hepatocellular injury in a rat model of CCl4-induced liver fibrosis. The anti-fibrinogenic effect was induced by attenuating hepatic stellate cell activation. Therefore, the administration of MSC-EVs could be considered as a candidate cell-free therapeutic strategy for liver fibrosis and hepatocellular damage.
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Affiliation(s)
- Dina M Rostom
- Department of Medical Histology and Cell Biology, Faculty of Medicine, University of Alexandria, Dr. Fahmi Abdelmeguid St., Mowassah Campus, Alexandria, 21561, Egypt
| | - Noha Attia
- Department of Medical Histology and Cell Biology, Faculty of Medicine, University of Alexandria, Dr. Fahmi Abdelmeguid St., Mowassah Campus, Alexandria, 21561, Egypt. .,Department of Basic Sciences, The American University of Antigua - College of Medicine, University Park, Jabberwock Beach Road, P.O. Box 1451, Coolidge, Antigua and Barbuda.
| | - Hoda M Khalifa
- Department of Medical Histology and Cell Biology, Faculty of Medicine, University of Alexandria, Dr. Fahmi Abdelmeguid St., Mowassah Campus, Alexandria, 21561, Egypt
| | - Maha W Abou Nazel
- Department of Medical Histology and Cell Biology, Faculty of Medicine, University of Alexandria, Dr. Fahmi Abdelmeguid St., Mowassah Campus, Alexandria, 21561, Egypt
| | - Eshrak A El Sabaawy
- Department of Medical Histology and Cell Biology, Faculty of Medicine, University of Alexandria, Dr. Fahmi Abdelmeguid St., Mowassah Campus, Alexandria, 21561, Egypt
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14
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Fathy M, Okabe M, M. Othman E, Saad Eldien HM, Yoshida T. Preconditioning of Adipose-Derived Mesenchymal Stem-Like Cells with Eugenol Potentiates Their Migration and Proliferation In Vitro and Therapeutic Abilities in Rat Hepatic Fibrosis. Molecules 2020; 25:molecules25092020. [PMID: 32357508 PMCID: PMC7248858 DOI: 10.3390/molecules25092020] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 04/18/2020] [Accepted: 04/24/2020] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have considerable therapeutic abilities in various disorders, including hepatic fibrosis. They may be affected with different culture conditions. This study investigated, on molecular basics, the effect of pretreatment with eugenol on the characteristics of adipose tissue-derived MSCs (ASCs) in vitro and the implication of eugenol preconditioning on the in vivo therapeutic abilities of ASCs against CCl4-induced hepatic fibrosis in rats. The effect of eugenol on ASCs was assessed using viability, scratch migration and sphere formation assays. Expressions of genes and proteins were estimated by immunofluorescence or qRT-PCR. For the in vivo investigations, rats were divided into four groups: the normal control group, fibrotic (CCl4) group, CCl4+ASCs group and CCl4 + eugenol-preconditioned ASCs (CCl4+E-ASCs) group. Eugenol affected the viability of ASCs in a concentration- and time-dependent manner. Eugenol improved their self-renewal, proliferation and migration abilities and significantly increased their expression of c-Met, reduced expression 1 (Rex1), octamer-binding transcription factor 4 (Oct4) and nanog genes. Furthermore, E-ASCs showed more of a homing ability than ASCs and improved the serum levels of ALT, AST, albumin, total bilirubin and hyaluronic acid more efficient than ASCs in treating CCl4-induced hepatic fibrosis, which was confirmed with histopathology. More interestingly, compared to the CCl4+ASCs group, CCl4+E-ASCs group showed a lower expression of inducible nitric oxide synthase (iNOS), monocyte chemoattractant protein-1 (MCP-1), cluster of differentiation 163 (CD163) and tumor necrosis factor-α (TNF-α) genes and higher expression of matrix metalloproteinase (MMP)-9 and MMP-13 genes. This study, for the first time, revealed that eugenol significantly improved the self-renewal, migration and proliferation characteristics of ASCs, in vitro. In addition, we demonstrated that eugenol-preconditioning significantly enhanced the therapeutic abilities of the injected ASCs against CCl4-induced hepatic fibrosis.
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MESH Headings
- Animals
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Antigens, Differentiation, Myelomonocytic/genetics
- Antigens, Differentiation, Myelomonocytic/metabolism
- Bilirubin/blood
- Carbon Tetrachloride/toxicity
- Cell Movement/drug effects
- Cell Proliferation/drug effects
- Cell Survival/drug effects
- Cells, Cultured
- Chemokine CCL2/genetics
- Chemokine CCL2/metabolism
- Eugenol/pharmacology
- Gene Expression Regulation/drug effects
- Hyaluronic Acid/blood
- Kruppel-Like Transcription Factors/genetics
- Kruppel-Like Transcription Factors/metabolism
- Liver Cirrhosis/chemically induced
- Liver Cirrhosis/pathology
- Liver Cirrhosis/therapy
- Male
- Matrix Metalloproteinase 13/genetics
- Matrix Metalloproteinase 13/metabolism
- Matrix Metalloproteinase 9/genetics
- Matrix Metalloproteinase 9/metabolism
- Mesenchymal Stem Cell Transplantation/methods
- Mesenchymal Stem Cells/cytology
- Mesenchymal Stem Cells/drug effects
- Mesenchymal Stem Cells/enzymology
- Mesenchymal Stem Cells/metabolism
- Nanog Homeobox Protein/genetics
- Nanog Homeobox Protein/metabolism
- Nitric Oxide Synthase Type II/genetics
- Nitric Oxide Synthase Type II/metabolism
- Octamer Transcription Factor-3/genetics
- Octamer Transcription Factor-3/metabolism
- Proto-Oncogene Proteins c-met/genetics
- Proto-Oncogene Proteins c-met/metabolism
- Rats
- Rats, Sprague-Dawley
- Receptors, Cell Surface/genetics
- Receptors, Cell Surface/metabolism
- Tumor Necrosis Factor-alpha/genetics
- Tumor Necrosis Factor-alpha/metabolism
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Affiliation(s)
- Moustafa Fathy
- Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan; (M.F.); (M.O.)
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt;
| | - Motonori Okabe
- Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan; (M.F.); (M.O.)
| | - Eman M. Othman
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt;
- Department of Bioinformatics, Biocenter, University of Würzburg, Am Hubland, 97074 Wuerzburg, Germany
| | - Heba M. Saad Eldien
- Department of Anatomy, College of Medicine, Jouf University, Jouf, Saudi Arabia;
| | - Toshiko Yoshida
- Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan; (M.F.); (M.O.)
- Correspondence: ; Tel.: +81-76-434-7211
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15
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Chitosan Coated Microparticles Enhance Simvastatin Colon Targeting and Pro-Apoptotic Activity. Mar Drugs 2020; 18:md18040226. [PMID: 32344610 PMCID: PMC7231066 DOI: 10.3390/md18040226] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 04/13/2020] [Accepted: 04/21/2020] [Indexed: 02/07/2023] Open
Abstract
This work aimed at improving the targeting and cytotoxicity of simvastatin (SMV) against colon cancer cells. SMV was encapsulated in chitosan polymers, followed by eudragit S100 microparticles. The release of SMV double coated microparticles was dependent on time and pH. At pH 7.4 maximum release was observed for 6 h. The efficiency of the double coat to target colonic tissues was confirmed using real-time X-ray radiography of iohexol dye. Entrapment efficiency and particle size were used in the characterization of the formula. Cytotoxicity of SMV microparticles against HCT-116 colon cancer cells was significantly improved as compared to raw SMV. Cell cycle analysis by flow cytomeric technique indicated enhanced accumulation of colon cancer cells in the G2/M phase. Additionally, a significantly higher cell fraction was observed in the pre-G phase, which highlighted enhancement of the proapoptotic activity of SMV prepared in the double coat formula. Assessment of annexin V staining was used for confirmation. Cell fraction in early, late and total cell death were significantly elevated. This was accompanied by a significant elevation of cellular caspase 3 activity. In conclusion, SMV-loaded chitosan coated with eudragit S100 formula exhibited improved colon targeting and enhanced cytotoxicity and proapoptotic activity against HCT-116 colon cancer cells.
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16
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Li G, Lin J, Peng Y, Qin K, Wen L, Zhao T, Feng Q. Curcumol may reverse early and advanced liver fibrogenesis through downregulating the uPA/uPAR pathway. Phytother Res 2020; 34:1421-1435. [PMID: 31989700 DOI: 10.1002/ptr.6616] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Revised: 12/10/2019] [Accepted: 01/05/2020] [Indexed: 01/18/2023]
Abstract
Previous studies have suggested strong antifibrotic activity of curcumol in the liver; the underlying mechanisms of which, however, remain largely unknown. Aiming to investigate the role of curcumol in regulating early and advanced liver fibrosis, we designed a rat model with advanced liver fibrosis and cell model with an initial fibrotic stage. Model rats induced by CCl4 and alcohol presented advanced liver fibrosis with complete fibrous septa. The administration of curcumol (25 mg/kg or 50 mg/kg) resulted in reversal of liver fibrosis. Leptin-administrated liver sinusoidal endothelial cells presented defenestration and basement membrane components deposition, including laminin (LN) and type IV collagen (Col IV), the characteristics of capillarization by scanning electron microscopy and immunofluorescence assays. After treatment with curcumol (12.5, 25, or 50 mg/L), defenestration was restored and the levels of LN and Col IV were decreased, consistent with the rat model. Quantitative polymerase chain reaction and Western blot results revealed that increased levels of urokinase plasminogen activator (uPA)/ uPA receptor (uPAR) were observed both in vivo and in vitro, curcumol significantly reduced uPA/uPAR at both the mRNA and protein levels. Reduction of uPA/uPAR may be synergistic with matrix metallopeptidase 13 to reverse liver fibrogenesis. In conclusion, curcumol protects liver from phenotypic changes in the early and advanced fibrogenesis, possibly through uPA/uPAR pathway.
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Affiliation(s)
- Guiyu Li
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.,Department of Physiology, Faculty of Basic Medicine, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Jiyong Lin
- Traditional Chinese Medicine Department, Shenzhen Center for Chronic Disease Control, Shenzhen, Guangdong, China
| | - Yue Peng
- Department of Physiology, Faculty of Basic Medicine, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Kefeng Qin
- Department of Neurology, University of Chicago, Chicago, Illinois, USA
| | - Li Wen
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Tiejian Zhao
- Department of Physiology, Faculty of Basic Medicine, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Quansheng Feng
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
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17
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Mohamed Y, Basyony MA, El-Desouki NI, Abdo WS, El-Magd MA. The potential therapeutic effect for melatonin and mesenchymal stem cells on hepatocellular carcinoma. Biomedicine (Taipei) 2019; 9:24. [PMID: 31724939 PMCID: PMC6855194 DOI: 10.1051/bmdcn/2019090424] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 06/25/2019] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND/AIM Herein, we investigated the potential therapeutic effect of Melatonin (Mel) and/or mesenchymal stem cells (MSCs) on rat model of HCC. MATERIALS AND METHODS Female mature rats were divided into 5 groups (n = 10/group): normal (Nor), HCC group intraperitoneally injected with 200 mg/kg DEN, and 3 treated groups; HCC + Mel (Mel) group given Mel intraperitoneally 20 mg/kg, twice a week, HCC + MSCs (MSCs) group intravenously injected by 1 × 106 cells, and HCC + MSCs (Mel +MSCs) group. RESULTS Rats in HCC group showed most deteriorated effect in form of increased mortality and relative liver weight, elevated serum levels of ALT, AST, ALP, AFP and GGT in addition to increased pre-neoplastic nodules in liver tissues. Liver tissues of HCC group also exhibited lower level of apoptosis as indicated by decreased DNA fragmentation and expression of p53 caspase 9 and caspase 3 genes and increased PCNA immunoreactivity. Moreover, in this group the expression of IL6 and TGFβ1 genes was significantly upregulated. All these deleterious effects induced by DEN were reversed after administration of Mel and/ or MSCs with best improvement for the combined group (MSCs + Mel). CONCLUSIONS These findings reveal a better therapeutic effect for MSCs when given with Mel and we attribute this beneficial effect, at least in part, to triggering apoptosis and targeting inflammation in HCC. Therefore, combined treatment with Mel and MSCs is recommended to enhance the therapeutic potential against HCC.
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Affiliation(s)
- Yasser Mohamed
- Department of Zoology, Faculty of Science, Tanta University, Tanta 31527, Egypt
| | - Mohamed A Basyony
- Department of Zoology, Faculty of Science, Tanta University, Tanta 31527, Egypt
| | - Nabila I El-Desouki
- Department of Zoology, Faculty of Science, Tanta University, Tanta 31527, Egypt
| | - Walied S Abdo
- Department of Pathology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
| | - Mohammed A El-Magd
- Department of Anatomy, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
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18
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Chen TS, Lai CH, Shen CY, Pai PY, Chen RJ, PadmaViswanadha V, Yang CK, Chen MC, Lin YM, Huang CY. Orally administered resveratrol enhances the therapeutic effect of autologous transplanted adipose-derived stem cells on rats with diabetic hepatopathy. Biotech Histochem 2019; 95:37-45. [PMID: 31423853 DOI: 10.1080/10520295.2019.1631481] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Stem cell therapy is a promising treatment for hepatopathy due to diabetes mellitus (DM); oral resveratrol treatment exhibits protective effects. We investigated whether protective effects could be produced in liver of diabetic rats receiving autologous adipose-derived stem cell transplantation (ADSC) plus oral resveratrol administration. Male rats were divided into four groups: sham group; streptozotocin induced DM group; DM + ADSC group, in which DM rats were treated with 106 stem cells/rat; and DM + R + ADSC group, in which DM rats were treated with ADSC and oral resveratrol. The DM group exhibited apoptosis, inflammation and fibrosis, whereas Sirt-1 and survival signaling were suppressed. Pathological conditions other than survival signaling were improved in the DM + ADSC group. All pathological conditions were improved in the DM + R + ADSC group. Also, the oxidative stress level in the blood was reduced in the DM + R + ADSC group compared to the sham group. Oral resveratrol administration appears to reduce oxidative damage and enhances survival signaling in diabetic liver. The therapeutic response in the DM + R + ADSC group was better than in the DM + ADSC group.
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Affiliation(s)
- T-S Chen
- School of Life Science, National Taiwan Normal University, Taipei, Taiwan
| | - C-H Lai
- Division of Cardiology, Department of Internal Medicine, Armed Force Taichung General Hospital, Taichung, Taiwan
| | - C-Y Shen
- Department of Nursing, Meiho University, Pingtung, Taiwan
| | - P-Y Pai
- Division of Cardiology, China Medical University Hospital, Taichung, Taiwan
| | - R-J Chen
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - V PadmaViswanadha
- Department of Biotechnology, Bharathiar University, Coimbatore, India
| | - C-K Yang
- Division of Colorectal Surgery, Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan
| | - M-C Chen
- Division of Colorectal Surgery, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Y-M Lin
- Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan.,Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan
| | - C-Y Huang
- Medical Research Center for Exosome and Mitochondria Related Diseases, China Medical University and Hospital, Taichung, Taiwan.,Department of Biotechnology, Asia University, Taichung, Taiwan.,Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan.,College of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien, Taiwan
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19
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Abdelmonem M, Shahin NN, Rashed LA, Amin HAA, Shamaa AA, Shaheen AA. Hydrogen sulfide enhances the effectiveness of mesenchymal stem cell therapy in rats with heart failure: In vitro preconditioning versus in vivo co-delivery. Biomed Pharmacother 2019; 112:108584. [DOI: 10.1016/j.biopha.2019.01.045] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Revised: 01/09/2019] [Accepted: 01/16/2019] [Indexed: 12/13/2022] Open
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20
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El-Magd MA, Mohamed Y, El-Shetry ES, Elsayed SA, Abo Gazia M, Abdel-Aleem GA, Shafik NM, Abdo WS, El-Desouki NI, Basyony MA. Melatonin maximizes the therapeutic potential of non-preconditioned MSCs in a DEN-induced rat model of HCC. Biomed Pharmacother 2019; 114:108732. [PMID: 30925457 DOI: 10.1016/j.biopha.2019.108732] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 02/22/2019] [Accepted: 02/22/2019] [Indexed: 12/21/2022] Open
Abstract
Pretreatment of mesenchymal stem cells (MSCs) with melatonin (Mel) improves their potential therapeutic effect on chronic diseases and cancers. However, this preconditioning strategy may direct the effect of Mel toward MSCs alone and deprive cancer cells of the oncostatic effect of Mel. Herein, we hypothesized that Mel given before transplantation of non-preconditioned MSCs may maximize the therapeutic outcome via the oncostatic effect of Mel by preparing a suitable tumor microenvironment for MSCs. Female rats (n = 60) were equally divided into 6 groups; normal control, diethylnitrosamine (DEN), DEN + Mel, DEN + MSCs, DEN + MSCs preconditioned with Mel, and DEN + MSCs + Mel. The obtained data revealed that administration of Mel before MSCs treatment without preconditioning yielded a better ameliorative effect against DEN-induced hepatocellular carcinoma (HCC) as evidenced by: 1) reduced serum levels of alpha fetoprotein and gamma-glutamyl transferase; 2) decreased number and area of glutathione S-transferase placental positive foci; 3) induced apoptosis (as indicated by increased cleaved caspase-3 activity, upregulated expression of proapoptotic genes Bax and caspase 3 and downregulated expression of anti-apoptotic genes Bcl2, survivin); 4) decreased malondialdehyde level and increased activities of superoxide dismutase, catalase, and glutathione peroxidase enzymes; and 5) reduced inflammation, angiogenesis and metastasis as indicated by downregulated expression of interleukin 1 beta, nuclear factor kappa B, vascular endothelial growth factor, and matrix metallopeptidase 9 genes and upregulated expression of metalloproteinase inhibitor 1 gene. Thus, administration of Mel before MSCs (without preconditioning) fostered the survival and therapeutic potential of MSCs in HCC, possibly through induction of apoptosis and inhibition of inflammation and oxidative stress. This new strategy showed better therapeutic outcomes and may improve MSC-based therapies for HCC.
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Affiliation(s)
- Mohammed A El-Magd
- Department of Anatomy, Faculty of Veterinary Medicine, Kafrelsheikh University, Egypt.
| | - Yasser Mohamed
- Department of Zoology, Faculty of Science, Tanta University, Egypt
| | - Eman S El-Shetry
- Department of Anatomy, Faculty of Medicine, Zagazig University, Egypt
| | - Shafika A Elsayed
- Department of Histology and Cytology, Faculty of Veterinary Medicine, Zagazig University, Egypt
| | - Maha Abo Gazia
- Department of Histology, Faculty of Medicine, Kafrelsheikh University, Egypt
| | - Ghada A Abdel-Aleem
- Department of Medical Biochemistry, Faculty of Medicine, Tanta University, Egypt
| | - Noha M Shafik
- Department of Medical Biochemistry, Faculty of Medicine, Tanta University, Egypt
| | - Walied S Abdo
- Department of Pathology, Faculty of Veterinary Medicine, Kafrelsheikh University, Egypt
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Snarska A, Wysocka D, Rytel L. Effect of Simvastatin on Thrombopoiesis in Porcine Bone Marrow. J Vet Res 2019; 63:117-121. [PMID: 30989143 PMCID: PMC6458551 DOI: 10.2478/jvetres-2019-0007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2018] [Accepted: 02/12/2019] [Indexed: 11/25/2022] Open
Abstract
INTRODUCTION Statins are pharmacological agents commonly used to lower serum cholesterol level. The aim of the experiment was to investigate the effect of the statin simvastatin on thrombopoiesis in the porcine model because it is the closest to the human one regarding physiological and genetic similarities. MATERIAL AND METHODS The study was conducted on a group of 32 pigs randomly divided into two equal groups: control and experimental. The pigs were treated for 28 and 56 days with simvastatin in a dose of 40 mg per day per animal. Cytological evaluation of bone marrow smears was performed to assess the average number of all types of cells during thrombopoiesis as was analysis of haematological parameters to assess PLT and MPV. RESULTS During the course of the experiment statistically significant changes in the number of promegakaryocytes were observed. Other parameters also showed some fluctuations during the study. However, these changes were not statistically significant. CONCLUSION The obtained results clearly indicate a toxic influence of simvastatin on the process of thrombopoiesis and prove that statins reduce mean platelet volume, thus affecting the process of clot formation through the period of administration in a duration-dependent manner.
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Affiliation(s)
- Anna Snarska
- Department and Clinic of Internal Diseases, Faculty of Veterinary Medicine, University of Warmia and Mazury, 10-719Olsztyn, Poland
| | - Dominika Wysocka
- Department and Clinic of Internal Diseases, Faculty of Veterinary Medicine, University of Warmia and Mazury, 10-719Olsztyn, Poland
| | - Liliana Rytel
- Department and Clinic of Internal Diseases, Faculty of Veterinary Medicine, University of Warmia and Mazury, 10-719Olsztyn, Poland
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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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Brückner S, Zipprich A, Hempel M, Thonig A, Schwill F, Roderfeld M, Roeb E, Christ B. Improvement of portal venous pressure in cirrhotic rat livers by systemic treatment with adipose tissue–derived mesenchymal stromal cells. Cytotherapy 2017; 19:1462-1473. [DOI: 10.1016/j.jcyt.2017.09.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 09/01/2017] [Accepted: 09/05/2017] [Indexed: 02/07/2023]
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Uder C, Brückner S, Winkler S, Tautenhahn HM, Christ B. Mammalian MSC from selected species: Features and applications. Cytometry A 2017; 93:32-49. [PMID: 28906582 DOI: 10.1002/cyto.a.23239] [Citation(s) in RCA: 120] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Mesenchymal stromal/stem cells (MSC) are promising candidates for cellular therapy of different diseases in humans and in animals. Following the guidelines of the International Society for Cell Therapy, human MSC may be identified by expression of a specific panel of cell surface markers (CD105+, CD73+, CD90+, CD34-, CD14-, or CD11b-, CD79- or CD19-, HLA-DR-). In addition, multiple differentiation potential into at least the osteogenic, adipogenic, and chondrogenic lineage is a main criterion for MSC definition. Human MSC and MSC of a variety of mammals isolated from different tissues meet these criteria. In addition to the abovementioned, they express many more cell surface markers. Yet, these are not uniquely expressed by MSC. The gross phenotypic appearance like marker expression and differentiation potential is similar albeit not identical for MSC from different tissues and species. Similarly, MSC may feature different biological characteristics depending on the tissue source and the isolation and culture procedures. Their versatile biological qualities comprising immunomodulatory, anti-inflammatory, and proregenerative capacities rely largely on the migratory and secretory capabilities of MSC. They are attracted to sites of tissue lesion and secrete factors to promote self-repair of the injured tissue. This is a big perspective for clinical MSC applications in both veterinary and human medicine. Phase I/II clinical trials have been initiated to assess safety and feasibility of MSC therapies in acute and chronic disease settings. Yet, since the mode of MSC action in a specific disease environment is still unknown at large, it is mandatory to unravel the response of MSC from a given source onto a specific disease environment in suitable animal models prior to clinical applications. © 2017 International Society for Advancement of Cytometry.
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Affiliation(s)
- Christiane Uder
- Department of Visceral, Transplantation, Thoracic and Vascular Surgery, Applied Molecular Hepatology Laboratory, University Hospital of Leipzig, Liebigstraße 21, Leipzig D-04103, Germany
| | - Sandra Brückner
- Department of Visceral, Transplantation, Thoracic and Vascular Surgery, Applied Molecular Hepatology Laboratory, University Hospital of Leipzig, Liebigstraße 21, Leipzig D-04103, Germany
| | - Sandra Winkler
- Department of Visceral, Transplantation, Thoracic and Vascular Surgery, Applied Molecular Hepatology Laboratory, University Hospital of Leipzig, Liebigstraße 21, Leipzig D-04103, Germany
| | - Hans-Michael Tautenhahn
- Department of Visceral, Transplantation, Thoracic and Vascular Surgery, Applied Molecular Hepatology Laboratory, University Hospital of Leipzig, Liebigstraße 21, Leipzig D-04103, Germany
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25
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Maerz T, Fleischer M, Newton MD, Davidson A, Salisbury M, Altman P, Kurdziel MD, Anderson K, Bedi A, Baker KC. Acute mobilization and migration of bone marrow-derived stem cells following anterior cruciate ligament rupture. Osteoarthritis Cartilage 2017; 25:1335-1344. [PMID: 28284998 DOI: 10.1016/j.joca.2017.03.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Revised: 02/21/2017] [Accepted: 03/01/2017] [Indexed: 02/02/2023]
Abstract
OBJECTIVE Little is known regarding acute local and systemic processes following anterior cruciate ligament (ACL) rupture. No study has elucidated whether bone marrow-derived mesenchymal stem cells (MSCs) are mobilized into circulation and recruited to the injured joint. METHODS In Part 1, Lewis rats were randomized to noninvasive ACL rupture (Rupture) or non-injured (Control) (n = 6/group). After 72 h, whole blood MSC concentration was assessed using flow cytometry. Synovial fluid and serum were assayed for stromal cell-derived factor (SDF)-1α and cartilage degeneration biomarkers, respectively. In Part 2, 12 additional rats were randomized and intravenously-injected with fluorescently-labeled allogenic MSCs. Cell tracking was performed using longitudinal, in vivo and ex vivo near-infrared (NIR) imaging and histology. Synovium SDF-1α and interleukin (IL)-17A immunostaining was performed. Serum was assayed for SDF-1α and 29 other cytokines. RESULTS In Part 1, there was a significant increase in MSC concentration and synovial fluid SDF-1α in Rupture. No differences in cartilage biomarkers were observed. In Part 2, Rupture had significantly higher NIR signal at 24, 48, and 72 h, indicating active recruitment of MSCs to the injured joint. Ex vivo cell tracking demonstrated MSC localization in the synovium and myotendinous junction (MTJ) of the quadriceps. Injured synovia exhibited increased synovitis grade and higher degree of IL-17A and SDF-1α immunostaining. CONCLUSION ACL rupture induced peripheral blood mobilization of MSCs and migration of intravenously-injected allogenic MSCs to the injured joint, where they localized in the synovium and quadriceps MTJ.
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Affiliation(s)
- T Maerz
- Orthopaedic Research Laboratory, Beaumont Health, Royal Oak, MI, USA; Department of Orthopaedic Surgery, Oakland University - William Beaumont School of Medicine, Rochester, MI, USA
| | - M Fleischer
- Orthopaedic Research Laboratory, Beaumont Health, Royal Oak, MI, USA
| | - M D Newton
- Orthopaedic Research Laboratory, Beaumont Health, Royal Oak, MI, USA
| | - A Davidson
- Orthopaedic Research Laboratory, Beaumont Health, Royal Oak, MI, USA
| | - M Salisbury
- Orthopaedic Research Laboratory, Beaumont Health, Royal Oak, MI, USA
| | - P Altman
- Department of Orthopaedic Surgery, Beaumont Health, Royal Oak, MI, USA
| | - M D Kurdziel
- Orthopaedic Research Laboratory, Beaumont Health, Royal Oak, MI, USA; Department of Orthopaedic Surgery, Oakland University - William Beaumont School of Medicine, Rochester, MI, USA
| | - K Anderson
- Department of Orthopaedic Surgery, Oakland University - William Beaumont School of Medicine, Rochester, MI, USA; Department of Orthopaedic Surgery, Beaumont Health, Royal Oak, MI, USA
| | - A Bedi
- MedSport and Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - K C Baker
- Orthopaedic Research Laboratory, Beaumont Health, Royal Oak, MI, USA; Department of Orthopaedic Surgery, Oakland University - William Beaumont School of Medicine, Rochester, MI, USA.
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Mortezaee K, Khanlarkhani N, Sabbaghziarani F, Nekoonam S, Majidpoor J, Hosseini A, Pasbakhsh P, Kashani IR, Zendedel A. Preconditioning with melatonin improves therapeutic outcomes of bone marrow-derived mesenchymal stem cells in targeting liver fibrosis induced by CCl4. Cell Tissue Res 2017; 369:303-312. [PMID: 28413861 DOI: 10.1007/s00441-017-2604-1] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Accepted: 03/03/2017] [Indexed: 01/14/2023]
Abstract
Preconditioning of mesenchymal stem cells (MSCs) with melatonin (MT) has shown promising results in animal models of myocardial infarction, renal ischemia and cerebral ischemia. Here, we use this strategy in the liver fibrosis induced by CCl4. There were five groups: normal, CCl4, CCl4 + vehicle, CCl4 + BMMSCs and CCl4 + MT-bone marrow (BM)-derived MSCs (MT-BMMSCs). CCl4 was injected twice weekly for 8 weeks and treatment either with cells or vehicle was performed at the beginning of week 5 with a single dose. BMMSCs were preconditioned with MT for 24 h before injection. MT-BMMSCs had a high ability of homing into the injured liver (P ≤ 0.05 vs. BMMSCs). The CCl4 + MT-BMMSCs group showed higher percentage of glycogen storage but lower percentage of collagen and lipid accumulation (P ≤ 0.05 vs. CCl4 + BMMSCs). The CCl4 + MT-BMMSCs group showed lower expressions of transforming growth factor-β1 (TGF-β1) and Bax and lower content of sera alanine aminotransferase (ALT) but higher expressions of matrix metalloproteinases (MMPs) and Bcl2 compared with the BMMSCs group (P ≤ 0.05). The results showed the better therapeutic outcomes of MT preconditioning by probably improving cell homing and also better maintenance of the balance between matrix degrading and accumulating factors.
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Affiliation(s)
- Keywan Mortezaee
- Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Neda Khanlarkhani
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Sabbaghziarani
- Department of Anatomy, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Saeid Nekoonam
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Jamal Majidpoor
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Amir Hosseini
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Parichehr Pasbakhsh
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Iraj Ragerdi Kashani
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Adib Zendedel
- Institute of Neuroanatomy, School of Medicine, RWTH Aachen University, 52074, Aachen, Germany
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Sadik NAH, Metwally NS, Shaker OG, Soliman MS, Mohamed AA, Abdelmoaty MM. Local renin-angiotensin system regulates the differentiation of mesenchymal stem cells into insulin-producing cells through angiotensin type 2 receptor. Biochimie 2017; 137:132-138. [PMID: 28288872 DOI: 10.1016/j.biochi.2017.03.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2016] [Accepted: 03/08/2017] [Indexed: 12/11/2022]
Abstract
Differentiation of stem cells into insulin-producing cells (IPCs) suitable for therapeutic transplantation offers a desperately needed approach for the diabetic patients. Elucidation of the molecular mechanisms during the differentiation of mesenchymal stem cells (MSCs) into IPCs assists the successful production of IPCs and provides an important insight into the improvement of the role of MSCs as a therapeutic tool for diabetes mellitus (DM). The present study aimed to investigate the role of local renin-angiotensin system (RAS) on MSCs differentiation into IPCs by measuring the expression of local RAS in MSCs during the differentiation into IPCs and assessing the effect of angiotensin type 1 receptor (AT1R) blocker and angiotensin type 2 receptor (AT2R) blocker on the differentiation process. Our data showed that the differentiation of MSCs into IPCs was associated with an increase in cellular angiotensinogen, angiotensin-converting enzyme (ACE), renin, and AT2R expression and undetectable expression of AT1R. The net effect was an increase in cellular angiotensin II (Ang II) during the differentiation process. AT1R blockade allowed the differentiation of MSCs into IPCs, whereas AT2R blockade alone and blockade of both AT1R and AT2R inhibited the differentiation of MSCs into IPCs. Our data demonstrated an important role of local RAS in the regulation of MSCs differentiation into IPCs and that Ang II mainly orchestrates this role through AT2R activation.
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Affiliation(s)
- Nermin Abdel-Hamid Sadik
- Biochemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Einy St., Cairo, 11562, Egypt.
| | - Nadia Said Metwally
- Therapeutic Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, El-buhouth St., Dokki, Giza, 12622, Egypt.
| | - Olfat Gamil Shaker
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Kasr El-Einy St., Cairo, Egypt.
| | - Mahmoud Sanad Soliman
- Therapeutic Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, El-buhouth St., Dokki, Giza, 12622, Egypt.
| | | | - Mai Mohamed Abdelmoaty
- Therapeutic Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, El-buhouth St., Dokki, Giza, 12622, Egypt.
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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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Yang JJ, Tao H, Deng ZY, Lu C, Li J. Non-coding RNA-mediated epigenetic regulation of liver fibrosis. Metabolism 2015; 64:1386-94. [PMID: 26362725 DOI: 10.1016/j.metabol.2015.08.004] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Revised: 07/06/2015] [Accepted: 08/08/2015] [Indexed: 12/27/2022]
Abstract
Hepatic stellate cells (HSC) activation plays a key role in liver fibrosis. Numerous studies have indicated that non-coding RNAs (ncRNAs) control liver fibrosis and fibroblasts proliferation. Greater knowledge of the role of the ncRNAs-mediated epigenetic mechanism in liver fibrosis could improve understanding of the liver fibrosis pathogenesis. The aim of this review is to describe the present knowledge about the ncRNAs significantly participating in liver fibrosis and HSC activation, and look ahead on new perspectives of ncRNAs-mediated epigenetic mechanism research. Moreover, we will discuss examples of non-coding RNAs that interact with histone modification or DNA methylation to regulate gene expression in liver fibrosis. Diverse classes of ncRNAs, ranging from microRNAs (miRs) to long non-coding RNAs (LncRNAs), have emerged as key regulators of several important aspects of function, including cell proliferation, activation, etc. In addition, recent advances suggest the important role of ncRNAs transcripts in epigenetic gene regulation. Targeting the miRs and LncRNAs can be a promising direction in liver fibrosis treatment. We discuss new perspectives of miRs and LncRNAs in liver fibrosis and HSC activation, mainly including interaction with histone modification or DNA methylation to regulate gene expression. These epigenetic mechanisms form powerful ncRNAs surveillance systems that may represent new targets for liver fibrosis therapeutic intervention.
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Affiliation(s)
- Jing-Jing Yang
- Department of Pharmacology, The Second Hospital of Anhui Medical University, Hefei, China, 230601
| | - Hui Tao
- Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Hefei, China, 230601
| | - Zi-Yu Deng
- Department of Scientific and Educational, The Second Hospital of Anhui Medical University, Hefei, China, 230601.
| | - Chao Lu
- Department of Scientific and Educational, The Second Hospital of Anhui Medical University, Hefei, China, 230601
| | - Jun Li
- School of Pharmacy, Anhui Medical University, Hefei, China, 230032.
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Raafat N, Abdel Aal SM, Abdo FK, El Ghonaimy NM. Mesenchymal stem cells: In vivo therapeutic application ameliorates carbon tetrachloride induced liver fibrosis in rats. Int J Biochem Cell Biol 2015; 68:109-18. [PMID: 26369870 DOI: 10.1016/j.biocel.2015.09.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Revised: 08/20/2015] [Accepted: 09/09/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND Egypt has the highest prevalence of hepatitis C virus in the world with infection rate up to 60%, for which liver fibrosis or hepatic carcinoma is the final outcome. Stem cell therapy provides a new hope for hepatic repair instead of traditional treatment, liver transplantation, as it is safer, gives long term engraftment and avoid expensive immunosuppressive drugs and unexpected hazardous effects. AIM This work aimed at determining the therapeutic potential of mesenchymal stem cells (MSC) in hepatic repair as a new line of therapy for liver fibrosis. METHODS 33 female albino rats were divided into three groups: Group I: 10 rats injected subcutaneously with olive oil, Group II: 13 rats injected with carbon tetrachloride (CCl4) and Group III: 10 rats injected with CCl4 then bone marrow derived MSC from male rats. Blood and liver tissue samples were taken from all rats for biochemical and histological study. RESULTS Liver functions for group II rats showed significant deterioration in response to CCl4 in addition to significant histological changes in liver lobules and portal areas. Those parameters tend to be normal in MSC-treated group. Group III rats revealed normalized liver function and histological picture. Meanwhile, most of the pathological lesions were still detected in rats of second group. CONCLUSION Undifferentiated MSCs have the ability to ameliorate CCl4 induced liver injury in albino rats in terms of liver functions and histological features. So, stem cell therapy can be considered clinically to offer a hope for patients suffering from liver fibrosis.
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Affiliation(s)
- Nermin Raafat
- Medical Biochemistry & Molecular Biology Department, Faculty of Medicine, Zagazig University, Egypt.
| | - Sara M Abdel Aal
- Histology & Cell Biology Department, Faculty of Medicine, Zagazig University, Egypt
| | - Fadia K Abdo
- Histology & Cell Biology Department, Faculty of Medicine, Zagazig University, Egypt
| | - Nabila M El Ghonaimy
- Histology & Cell Biology Department, Faculty of Medicine, Zagazig University, Egypt
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31
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Marrone G, Maeso-Díaz R, García-Cardena G, Abraldes JG, García-Pagán JC, Bosch J, Gracia-Sancho J. KLF2 exerts antifibrotic and vasoprotective effects in cirrhotic rat livers: behind the molecular mechanisms of statins. Gut 2015; 64:1434-43. [PMID: 25500203 DOI: 10.1136/gutjnl-2014-308338] [Citation(s) in RCA: 148] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Accepted: 11/07/2014] [Indexed: 12/11/2022]
Abstract
OBJECTIVE In the liver, the transcription factor, Kruppel-like factor 2 (KLF2), is induced early during progression of cirrhosis to lessen the development of vascular dysfunction; nevertheless, its endogenous expression results insufficient to attenuate establishment of portal hypertension and aggravation of cirrhosis. Herein, we aimed to explore the effects and the underlying mechanisms of hepatic KLF2 overexpression in in vitro and in vivo models of liver cirrhosis. DESIGN Activation phenotype was evaluated in human and rat cirrhotic hepatic stellate cells (HSC) treated with the pharmacological inductor of KLF2 simvastatin, with adenovirus codifying for this transcription factor (Ad-KLF2), or vehicle, in presence/absence of inhibitors of KLF2. Possible paracrine interactions between parenchymal and non-parenchymal cells overexpressing KLF2 were studied. Effects of in vivo hepatic KLF2 overexpression on liver fibrosis and systemic and hepatic haemodynamics were assessed in cirrhotic rats. RESULTS KLF2 upregulation profoundly ameliorated HSC phenotype (reduced α-smooth muscle actin, procollagen I and oxidative stress) partly via the activation of the nuclear factor (NF)-E2-related factor 2 (Nrf2). Coculture experiments showed that improvement in HSC phenotype paracrinally ameliorated liver sinusoidal endothelial cells probably through a vascular endothelial growth factor-mediated mechanism. No paracrine interactions between hepatocytes and HSC were observed. Cirrhotic rats treated with simvastatin or Ad-KLF2 showed hepatic upregulation in the KLF2-Nrf2 pathway, deactivation of HSC and prominent reduction in liver fibrosis. Hepatic KLF2 overexpression was associated with lower portal pressure (-15%) due to both attenuations in the increased portal blood flow and hepatic vascular resistance, together with a significant improvement in hepatic endothelial dysfunction. CONCLUSIONS Exogenous hepatic KLF2 upregulation improves liver fibrosis, endothelial dysfunction and portal hypertension in cirrhosis.
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Affiliation(s)
- Giusi Marrone
- Barcelona Hepatic Hemodynamic Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Centro de Investigaciones Biomédicas en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Raquel Maeso-Díaz
- Barcelona Hepatic Hemodynamic Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Centro de Investigaciones Biomédicas en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Guillermo García-Cardena
- Departments of Pathology, Brigham and Women's Hospital & Harvard Medical School, Boston, Massachusetts, USA
| | - Juan G Abraldes
- Barcelona Hepatic Hemodynamic Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Centro de Investigaciones Biomédicas en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Juan Carlos García-Pagán
- Barcelona Hepatic Hemodynamic Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Centro de Investigaciones Biomédicas en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Jaime Bosch
- Barcelona Hepatic Hemodynamic Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Centro de Investigaciones Biomédicas en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Jordi Gracia-Sancho
- Barcelona Hepatic Hemodynamic Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Centro de Investigaciones Biomédicas en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
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Strategies to prevent and reverse liver fibrosis in humans and laboratory animals. Arch Toxicol 2015; 89:1727-50. [PMID: 25963329 DOI: 10.1007/s00204-015-1525-6] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Accepted: 04/28/2015] [Indexed: 02/07/2023]
Abstract
Liver fibrosis results from chronic damage to the liver in conjunction with various pathways and is mediated by a complex microenvironment. Based on clinical observations, it is now evident that fibrosis is a dynamic, bidirectional process with an inherent capacity for recovery and remodeling. The major mechanisms involved in liver fibrosis include the repetitive injury of hepatocytes, the activation of the inflammatory response after injury stimulation, and the activation and proliferation of hepatic stellate cells (HSCs), which represents the major extracellular matrix (ECM)-producing cells, stimulated by hepatocyte injury and inflammation. The microenvironment in the liver is synergistically regulated abnormal ECM deposition, scar formation, angiogenesis, and fibrogenesis. Moreover, recent studies have clarified novel mechanism in fibrosis such as epigenetic regulation of HSCs, the leptin and PPARγ pathways, the coagulation system, and even autophagy. Uncovering the mechanisms of liver fibrogenesis provides a basis to develop potential therapies to reverse and treat the fibrotic response, thereby improving the outcomes of patients with chronic liver disease. Although both scientific and clinical challenges remain, emerging studies attempt to reveal the ideal anti-fibrotic drug that could be easily delivered to the liver with high specificity and low toxicity. This review highlights the mechanisms, including novel pathways underlying fibrogenesis that may be translated into preventive and treatment strategies, reviews both current and novel agents that target specific pathways or multiple targets, and discusses novel drug delivery systems such as nanotechnology that can be applied in the treatment of liver fibrosis. In addition, we also discuss some current treatment strategies that are being applied in animal models and in clinical trials.
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Zhang J, Zhou S, Zhou Y, Feng F, Wang Q, Zhu X, Ai H, Huang X, Zhang X. Hepatocyte growth factor gene-modified adipose-derived mesenchymal stem cells ameliorate radiation induced liver damage in a rat model. PLoS One 2014; 9:e114670. [PMID: 25501583 PMCID: PMC4264768 DOI: 10.1371/journal.pone.0114670] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Accepted: 11/12/2014] [Indexed: 01/26/2023] Open
Abstract
Liver damage caused by radiotherapy is associated with a high mortality rate, but no established treatment exists. Adipose-derived mesenchymal stem cells (ADSCs) are capable of migration to injured tissue sites, where they aid in the repair of the damage. Hepatocyte growth factor (HGF) is critical for damage repair due to its anti-apoptotic, anti-fibrotic and cell regeneration-promoting effects. This study was performed to investigate the therapeutic effects of HGF-overexpressing ADSCs on radiation-induced liver damage (RILD). ADSCs were infected with a lentivirus encoding HGF and HGF-shRNA. Sprague-Dawley (SD) rats received 60Gy of irradiation to induce liver injury and were immediately given either saline, ADSCs, ADSCs + HGF or ADSCs + shHGF. Two days after irradiation, a significant reduction in apoptosis was observed in the HGF-overexpressing ADSC group compared with the RILD group, as assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Scanning electron microscopy showed chromatin condensation after irradiation, which was ameliorated in the group that received ADSCs and was reversed in the group that received HGF-overexpressing ADSCs. HGF-overexpressing ADSCs ameliorated radiation- induced liver fibrosis through down regulation of α-SMA and fibronectin. Hepatocyte regeneration was significantly improved in rats treated with ADSCs compared with rats from the RILD group), as assessed by Ki-67 immunohistochemistry. Rats that received HGF-overexpressing ADSCs showed an even greater level of hepatocyte regeneration. HGF-overexpressing ADSCs completely blocked the radiation-induced increase in the enzymes ALT and AST. The effect of mitigating RILD was compromised in the ADSC + shHGF group compared with the ADSC group. Altogether, these results suggest that HGF-overexpressing ADSCs can significantly improve RILD in a rat model, which may serve as a valuable therapeutic alternative.
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Affiliation(s)
- Jiamin Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, Xicheng District, Beijing, China
| | - Shiyuan Zhou
- Peking University People's Hospital, Peking University Institute of Hematology, Xicheng District, Beijing, China
| | - Yi Zhou
- Peking University People's Hospital, Peking University Institute of Hematology, Xicheng District, Beijing, China
| | - Feier Feng
- Peking University People's Hospital, Peking University Institute of Hematology, Xicheng District, Beijing, China
| | - Qianming Wang
- Peking University People's Hospital, Peking University Institute of Hematology, Xicheng District, Beijing, China
| | - Xiaolu Zhu
- Peking University People's Hospital, Peking University Institute of Hematology, Xicheng District, Beijing, China
| | - Huisheng Ai
- Department of Hematology, Affiliated Hospital to the Academy of Military Medicine Science, FengTai District, Beijing, China
| | - Xiaojun Huang
- Peking University People's Hospital, Peking University Institute of Hematology, Xicheng District, Beijing, China
- * E-mail: (X. Zhang); (XH)
| | - Xiaohui Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, Xicheng District, Beijing, China
- * E-mail: (X. Zhang); (XH)
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Yang JJ, Tao H, Li J. Hedgehog signaling pathway as key player in liver fibrosis: new insights and perspectives. Expert Opin Ther Targets 2014; 18:1011-21. [PMID: 24935558 DOI: 10.1517/14728222.2014.927443] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Activation of hepatic stellate cells (HSCs) is a pivotal cellular event in liver fibrosis. Therefore, improving our understanding of the molecular pathways that are involved in these processes is essential to generate new therapies for liver fibrosis. Greater knowledge of the role of the hedgehog signaling pathway in liver fibrosis could improve understanding of the liver fibrosis pathogenesis. AREAS COVERED The aim of this review is to describe the present knowledge about the hedgehog signaling pathway, which significantly participates in liver fibrosis and HSC activation, and look ahead on new perspectives of hedgehog signaling pathway research. Moreover, we will discuss the different interactions with hedgehog signaling pathway-regulated liver fibrosis. EXPERT OPINION The hedgehog pathway modulates several important aspects of function, including cell proliferation, activation and differentiation. Targeting the hedgehog pathway can be a promising direction in liver fibrosis treatment. We discuss new perspectives of hedgehog signaling pathway activation in liver fibrosis and HSC fate, including DNA methylation, methyl CpG binding protein 2, microRNA, irradiation and metabolism that influence hedgehog signaling pathway transduction. These findings identify the hedgehog pathway as a potentially important for biomarker development and therapeutic targets in liver fibrosis. Future studies are needed in order to find safer and more effective hedgehog-based drugs.
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Affiliation(s)
- Jing-Jing Yang
- The Second Hospital of Anhui Medical University, Department of Pharmacology , Hefei 230601 , China
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New therapy of skin repair combining adipose-derived mesenchymal stem cells with sodium carboxymethylcellulose scaffold in a pre-clinical rat model. PLoS One 2014; 9:e96241. [PMID: 24788779 PMCID: PMC4008527 DOI: 10.1371/journal.pone.0096241] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Accepted: 04/04/2014] [Indexed: 12/26/2022] Open
Abstract
Lesions with great loss of skin and extensive burns are usually treated with heterologous skin grafts, which may lead rejection. Cell therapy with mesenchymal stem cells is arising as a new proposal to accelerate the healing process. We tested a new therapy consisting of sodium carboxymethylcellulose (CMC) as a biomaterial, in combination with adipose-derived stem cells (ADSCs), to treat skin lesions in an in vivo rat model. This biomaterial did not affect membrane viability and induced a small and transient genotoxicity, only at the highest concentration tested (40 mg/mL). In a rat wound model, CMC at 10 mg/mL associated with ADSCs increased the rate of cell proliferation of the granulation tissue and epithelium thickness when compared to untreated lesions (Sham), but did not increase collagen fibers nor alter the overall speed of wound closure. Taken together, the results show that the CMC is capable to allow the growth of ADSCs and is safe for this biological application up to the concentration of 20 mg/mL. These findings suggest that CMC is a promising biomaterial to be used in cell therapy.
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