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Gantier M, Ménoret S, Fourrier A, Delbos F, Nguyen TH, Anegon I. Human pluripotent stem cell-derived hepatic progenitors exhibit a partially hypoimmunogenic phenotype and actively inhibit immune responses. Front Immunol 2025; 16:1507317. [PMID: 40070824 PMCID: PMC11893836 DOI: 10.3389/fimmu.2025.1507317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 02/03/2025] [Indexed: 03/14/2025] Open
Abstract
Introduction GStemHep cells are human cryopreserved hepatic progenitors derived from pluripotent of stem cells (GStem cells) using a cGMP-compliant protocol. They were highly effective in rescuing mice from acute liver failure. Methods The objective of this study was to analyze the immunogenicity and immunoregulatory properties of GStemHep cells. Results As compared to GStem cells, GStemHep cells showed complete loss of HLA-I (ABC) and they lacked of expression of HLA-II, HLA-G, HLA-E and PD-L1. GStemHep cells also showed increased expression of CD47, maintained high expression of indoleamine 2,3-dioxygenase (IDO) and heme oxygenase-1 (HO-1) and reduced expression of CD200. In comparison with GStem cells, GStemHep cultured in inflammatory conditions increased the expression of PD-L1, CD200, HO-1, HLA-E, CD47 and HLA-I (ABC) as well as maintained expression of IDO and were negative for HLA-II and HLA-G. GStemHep culture in basal or inflammatory conditions has a low or absent immunogenic activity on T cells, associated to a suppressive effect on proliferation partially mediated by IDO. We observed phagocytosis of GStemHep by macrophages that was partially inhibited by CD47 expression. NK cells were activated by resting GStemHep cells. Upon culture in inflammatory conditions that induced expression of HLA-I molecules in GStemHep cells NK cell activation was reduced. Thus, GStemHep cells are partially hypoimmune cells due to the expression of several immune checkpoint inhibitors and the absence of HLA-I molecules. In inflammatory conditions, the expression of several of these molecules was increased but also of HLA-I that could be immunogenic for T cells but it was inhibitory for NK cells. Discussion GStemHep cells show a favorable immunological profile for their use as allogeneic off-the shelf treatment of liver diseases with loss of hepatocyte function.
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Affiliation(s)
| | - Séverine Ménoret
- Nantes Université, Inserm, CNRS, SFR Santé, Inserm UMS 016 CNRS UMS 3556, Nantes, France
- Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | | | | | | | - Ignacio Anegon
- Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
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Liu Z, Ren J, Qiu C, Wang Y, Zhang T. Application of mesenchymal stem cells in liver fibrosis and regeneration. LIVER RESEARCH 2024; 8:246-258. [PMID: 39958916 PMCID: PMC11771278 DOI: 10.1016/j.livres.2024.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 11/20/2024] [Accepted: 11/22/2024] [Indexed: 02/18/2025]
Abstract
Liver transplantation remains the most effective treatment for end-stage liver disease (ESLD), but it is fraught with challenges such as immunosuppression, high risk and cost, and donor shortage. In recent years, stem cell transplantation has emerged as a promising new strategy for ESLD treatment, with mesenchymal stem cells (MSCs) gaining significant attention because of their unique properties. MSCs can regulate signaling pathways, including hepatocyte growth factor/c-Met, Wnt/beta (β)-catenin, Notch, transforming growth factor-β1/Smad, interleukin-6/Janus kinase/signal transducer and activator of transcription 3, and phosphatidylinositol 3-kinase/PDK/Akt, thereby influencing the progression of liver fibrosis and regeneration. As a promising stem cell type, MSCs offer numerous advantages in liver disease treatment, including low immunogenicity; ease of acquisition; unlimited proliferative ability; pluripotent differentiation potential; immunomodulatory function; and anti-inflammatory, antifibrotic, and antiapoptotic biological characteristics. This review outlines the mechanisms by which MSCs reverse liver fibrosis and promote liver regeneration. MSCs are crucial in reversing liver fibrosis and repairing liver damage through the secretion of growth factors, regulation of signaling pathways, and modulation of immune responses. MSCs have shown good therapeutic effects in preclinical and clinical studies, providing new strategies for liver disease treatment. However, challenges still exist in the clinical application of MSCs, including low differentiation efficiency and limited sources. This review provides a reference for MSC application in liver disease treatment. With the continuous progress in MSC research, MSCs are expected to achieve breakthroughs in liver disease treatment, thereby improving patient treatment outcomes.
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Affiliation(s)
- Zhenyu Liu
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Junkai Ren
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Cheng Qiu
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Ying Wang
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Tong Zhang
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, China
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Xiong X, Gao C, Meng X, Liu A, Gong X, Sun Y. Research progress in stem cell therapy for Wilson disease. Regen Ther 2024; 27:73-82. [PMID: 38525238 PMCID: PMC10959646 DOI: 10.1016/j.reth.2024.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 02/27/2024] [Accepted: 03/09/2024] [Indexed: 03/26/2024] Open
Abstract
Wilson disease (WD), also known as hepatolenticular degeneration, is an autosomal recessive disorder characterized by disorganized copper metabolism caused by mutations in the ATP7B gene. Currently, the main treatment options for WD involve medications such as d-penicillamine, trientine hydrochloride, zinc acetate, and liver transplantation. However, there are challenges that encompass issues of poor compliance, adverse effects, and limited availability of liver sources that persist. Stem cell therapy for WD is currently a promising area of research. Due to the advancement in stem cell directed differentiation technology in vitro and the availability of sufficient stem cell donors, it is expected to be a potential treatment option for the permanent correction of abnormal copper metabolism. This article discusses the research progress of stem cell therapy for WD from various sources, as well as the challenges and future prospects of the clinical application of stem cell therapy for WD.
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Affiliation(s)
- Xianlang Xiong
- Hospital of Hunan Guangxiu, Hunan Normal University, Changsha, 410205, China
- National Engineering and Research Center of Human Stem Cells, Changsha, 410205, China
| | - Ce Gao
- Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410008, China
- National Engineering and Research Center of Human Stem Cells, Changsha, 410205, China
| | - Xiangying Meng
- Hospital of Hunan Guangxiu, Hunan Normal University, Changsha, 410205, China
- National Engineering and Research Center of Human Stem Cells, Changsha, 410205, China
| | - Aihui Liu
- Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410008, China
- National Engineering and Research Center of Human Stem Cells, Changsha, 410205, China
| | - Xin Gong
- Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410008, China
- National Engineering and Research Center of Human Stem Cells, Changsha, 410205, China
| | - Yi Sun
- Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410008, China
- Hospital of Hunan Guangxiu, Hunan Normal University, Changsha, 410205, China
- National Engineering and Research Center of Human Stem Cells, Changsha, 410205, China
- Key Laboratory of Stem Cells and Reproductive Engineering, Ministry of Health, Changsha, 410008, China
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Alatas FS, Yamaza T, Matsuura T, Ongko L, Kadim M, Ohga S, Taguchi T, Tajiri T. Potential role of stem cells from human exfoliated deciduous teeth in inducing liver regeneration. J Gastroenterol Hepatol 2024; 39:2190-2196. [PMID: 38859685 DOI: 10.1111/jgh.16651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 04/11/2024] [Accepted: 05/28/2024] [Indexed: 06/12/2024]
Abstract
BACKGROUND AND AIM Even with advancement of medical technologies, liver transplantation still faces several major challenges. Hence, other treatment modalities are urgently needed for patients with end-stage liver disease. Stem cells from human exfoliated deciduous teeth (SHED) was discovered to have highly proliferative and pluripotent properties; including differentiation into hepatocyte-like cells. This study aims to investigate the capability of intrasplenic transplanted SHED and SHED-Hep cells in inducing proliferation of stem cells and native hepatocytes in order to accelerate liver regeneration in liver fibrosis mice models. METHODS Three carbon tetrachloride (CCl4)-injured male mice groups were used in this study. Two of those groups were transplanted with either SHED or SHED-Hep, while the other did not undergo transplantation. One age- and sex- matched healthy mice group was used as control. All specimens were immunohistochemically stained with anti-Ki-67 antibodies and anti-proliferating cell nuclear antigen (PCNA) antibodies before counter stained with hematoxylin-eosin. RESULTS Anti-Ki-67 antibodies staining: at both 8 and 12 weeks, proliferating activity was predominantly seen on both SHED- and SHED-Hep-transplanted CCl4-injured mice groups, while control and non-transplanted CCl4-injured mice group showed little to no sign of proliferation activity. Anti-PCNA staining: at both 8 and 12 weeks, significant proliferating activity was detected by PCNA staining, mainly on stem cells population area on SHED- and SHED-Hep-treated group. CONCLUSIONS In conclusion, this study has provided the evidence that transplantation of SHED or SHED-Hep on liver-injured mice induced proliferation of both transplanted stem cells and native liver cells in order to accelerate liver regeneration.
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Affiliation(s)
- Fatima Safira Alatas
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Child Health, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Takayoshi Yamaza
- Departments of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, Fukuoka, Japan
| | - Toshiharu Matsuura
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Lukito Ongko
- Department of Child Health, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Muzal Kadim
- Department of Child Health, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Shouichi Ohga
- Departments of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomoaki Taguchi
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Fukuoka College of Health Sciences, Fukuoka, Japan
| | - Tatsuro Tajiri
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Jin YX, Hu HQ, Zhang JC, Xin XY, Zhu YT, Ye Y, Li D. Mechanism of mesenchymal stem cells in liver regeneration: Insights and future directions. World J Stem Cells 2024; 16:842-845. [PMID: 39351263 PMCID: PMC11438733 DOI: 10.4252/wjsc.v16.i9.842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Revised: 08/08/2024] [Accepted: 08/26/2024] [Indexed: 09/24/2024] Open
Abstract
Mesenchymal stem cells (MSCs) are a prevalent source for stem cell therapy and play a crucial role in modulating both innate and adaptive immune responses. Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of triglycerides in liver cells and involves immune system activation, leading to histological changes, tissue damage, and clinical symptoms. A recent publication by Jiang et al, highlighted the potential of MSCs to mitigate in NAFLD progression by targeting various molecular pathways, including glycolipid metabolism, inflammation, oxidative stress, endoplasmic reticulum stress, and fibrosis. In this editorial, we comment on their research and discuss the efficacy of MSC therapy in treating NAFLD.
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Affiliation(s)
- Yu-Xin Jin
- Department of Traditional Chinese Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Hang-Qi Hu
- Department of Traditional Chinese Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Jia-Cheng Zhang
- Department of Traditional Chinese Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Xi-Yan Xin
- Department of Traditional Chinese Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Yu-Tian Zhu
- Department of Traditional Chinese Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Yang Ye
- Department of Traditional Chinese Medicine, Peking University Third Hospital, Beijing 100191, China.
| | - Dong Li
- Department of Traditional Chinese Medicine, Peking University Third Hospital, Beijing 100191, China
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Carvalho AM, Bansal R, Barrias CC, Sarmento B. The Material World of 3D-Bioprinted and Microfluidic-Chip Models of Human Liver Fibrosis. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2307673. [PMID: 37961933 DOI: 10.1002/adma.202307673] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 11/06/2023] [Indexed: 11/15/2023]
Abstract
Biomaterials are extensively used to mimic cell-matrix interactions, which are essential for cell growth, function, and differentiation. This is particularly relevant when developing in vitro disease models of organs rich in extracellular matrix, like the liver. Liver disease involves a chronic wound-healing response with formation of scar tissue known as fibrosis. At early stages, liver disease can be reverted, but as disease progresses, reversion is no longer possible, and there is no cure. Research for new therapies is hampered by the lack of adequate models that replicate the mechanical properties and biochemical stimuli present in the fibrotic liver. Fibrosis is associated with changes in the composition of the extracellular matrix that directly influence cell behavior. Biomaterials could play an essential role in better emulating the disease microenvironment. In this paper, the recent and cutting-edge biomaterials used for creating in vitro models of human liver fibrosis are revised, in combination with cells, bioprinting, and/or microfluidics. These technologies have been instrumental to replicate the intricate structure of the unhealthy tissue and promote medium perfusion that improves cell growth and function, respectively. A comprehensive analysis of the impact of material hints and cell-material interactions in a tridimensional context is provided.
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Affiliation(s)
- Ana Margarida Carvalho
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, Porto, 4050-313, Portugal
| | - Ruchi Bansal
- Translational Liver Research, Department of Medical Cell Biophysics, Technical Medical Center, Faculty of Science and Technology, University of Twente, Enschede, 7522 NB, The Netherlands
| | - Cristina C Barrias
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, Porto, 4050-313, Portugal
| | - Bruno Sarmento
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- IUCS - Instituto Universitário de Ciências da Saúde, CESPU, Rua Central de Gandra 1317, Gandra, 4585-116, Portugal
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Yadav P, Singh SK, Rajput S, Allawadhi P, Khurana A, Weiskirchen R, Navik U. Therapeutic potential of stem cells in regeneration of liver in chronic liver diseases: Current perspectives and future challenges. Pharmacol Ther 2024; 253:108563. [PMID: 38013053 DOI: 10.1016/j.pharmthera.2023.108563] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 11/04/2023] [Accepted: 11/15/2023] [Indexed: 11/29/2023]
Abstract
The deposition of extracellular matrix and hyperplasia of connective tissue characterizes chronic liver disease called hepatic fibrosis. Progression of hepatic fibrosis may lead to hepatocellular carcinoma. At this stage, only liver transplantation is a viable option. However, the number of possible liver donors is less than the number of patients needing transplantation. Consequently, alternative cell therapies based on non-stem cells (e.g., fibroblasts, chondrocytes, keratinocytes, and hepatocytes) therapy may be able to postpone hepatic disease, but they are often ineffective. Thus, novel stem cell-based therapeutics might be potentially important cutting-edge approaches for treating liver diseases and reducing patient' suffering. Several signaling pathways provide targets for stem cell interventions. These include pathways such as TGF-β, STAT3/BCL-2, NADPH oxidase, Raf/MEK/ERK, Notch, and Wnt/β-catenin. Moreover, mesenchymal stem cells (MSCs) stimulate interleukin (IL)-10, which inhibits T-cells and converts M1 macrophages into M2 macrophages, producing an anti-inflammatory environment. Furthermore, it inhibits the action of CD4+ and CD8+ T cells and reduces the activity of TNF-α and interferon cytokines by enhancing IL-4 synthesis. Consequently, the immunomodulatory and anti-inflammatory capabilities of MSCs make them an attractive therapeutic approach. Importantly, MSCs can inhibit the activation of hepatic stellate cells, causing their apoptosis and subsequent promotion of hepatocyte proliferation, thereby replacing dead hepatocytes and reducing liver fibrosis. This review discusses the multidimensional therapeutic role of stem cells as cell-based therapeutics in liver fibrosis.
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Affiliation(s)
- Poonam Yadav
- Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, Punjab 151401, India
| | - Sumeet Kumar Singh
- Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, Punjab 151401, India
| | - Sonu Rajput
- Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, Punjab 151401, India
| | - Prince Allawadhi
- Department of Pharmacy, Vaish Institute of Pharmaceutical Education and Research (VIPER), Pandit Bhagwat Dayal Sharma University of Health Sciences (Pt. B. D. S. UHS), Rohtak, Haryana 124001, India
| | - Amit Khurana
- Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, Punjab 151401, India; Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH Aachen University Hospital, Pauwelsstr. 30, D-52074 Aachen, Germany.
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH Aachen University Hospital, Pauwelsstr. 30, D-52074 Aachen, Germany.
| | - Umashanker Navik
- Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, Punjab 151401, India; Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH Aachen University Hospital, Pauwelsstr. 30, D-52074 Aachen, Germany.
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Dimachkie R, Hamadi R, Alameddine Z, Aridi H, Sakr F, Asmar S, Deeb L. Granulocyte-colony stimulating factor in decompensated liver cirrhosis: a meta-analysis of four randomized controlled trials. Eur J Gastroenterol Hepatol 2023; 35:1382-1388. [PMID: 37642669 PMCID: PMC10602212 DOI: 10.1097/meg.0000000000002637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Accepted: 08/01/2023] [Indexed: 08/31/2023]
Abstract
BACKGROUND Decompensated liver cirrhosis (DC) has high mortality, but liver transplantation is limited due to organ scarcity and contraindications for transplantation. Granulocyte-colony stimulating factor (GCSF) shows potential for liver disease treatment with its regenerative and immunomodulatory properties. To assess the controversial use of GCSF in DC, a meta-analysis of randomized controlled trials (RCTs) compared survival benefits in patients receiving GCSF plus standard medical therapy (SMT) versus SMT alone. METHODS A literature search was performed in four databases from data inception up to December 2022, and all registered randomized controlled (RCTs) evaluating GCSF-based therapies for cirrhotic patients were included. RESULTS A study combining four RCTs assessed the impact of GCSF with SMT in 595 patients with decompensated cirrhosis. The results indicated that GCSF + SMT led to higher odds of survival compared to SMT alone [risk ratio 1.28, 95% CI (1.08-1.5)]. Heterogeneity existed among the studies, but overall, GCSF showed potential in improving survival. The intervention group exhibited improved Child-Pugh-Turcotte scores [-2.51, CI (-4.33 to -0.70)], and increased CD34 levels, but no significant improvement in MELD scores. These findings suggest GCSF may benefit patients with decompensated cirrhosis in terms of survival and liver function. CONCLUSION These results suggest that the combination of GCSF and SMT may have a positive impact on the survival rate and improvement in CPT score in patients with DC. Further RCTs are needed to shed more light on this promising modality in end-stage liver disease.
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Affiliation(s)
- Reem Dimachkie
- Internal medicine department, Staten Island University Hospital
| | - Rachelle Hamadi
- Internal medicine department, Staten Island University Hospital
| | | | - Hussam Aridi
- Internal medicine department, Staten Island University Hospital
| | - Fouad Sakr
- Internal medicine department, Staten Island University Hospital
| | - Samer Asmar
- Internal medicine department, Staten Island University Hospital
| | - Liliane Deeb
- Internal medicine department, Staten Island University Hospital
- Gastroenterology and Hepatology department, Staten Island University Hospital, Staten Island, New York, USA
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Mohammad-Rafiei F, Khojini JY, Ghazvinian F, Alimardan S, Norioun H, Tahershamsi Z, Tajbakhsh A, Gheibihayat SM. Cell membrane biomimetic nanoparticles in drug delivery. Biotechnol Appl Biochem 2023; 70:1843-1859. [PMID: 37387120 DOI: 10.1002/bab.2487] [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: 09/02/2022] [Accepted: 06/05/2023] [Indexed: 07/01/2023]
Abstract
Despite the efficiency of nanoparticle (NP) therapy, in vivo investigations have shown that it does not perform as well as in vitro. In this case, NP confronts many defensive hurdles once they enter the body. The delivery of NP to sick tissue is inhibited by these immune-mediated clearance mechanisms. Hence, using a cell membrane to hide NP for active distribution offers up a new path for focused treatment. These NPs are better able to reach the disease's target location, leading to enhanced therapeutic efficacy. In this emerging class of drug delivery vehicles, the inherent relation between the NPs and the biological components obtained from the human body was utilized, which mimic the properties and activities of native cells. This new technology has shown the viability of using biomimicry to evade immune system-provided biological barriers, with an emphasis on restricting clearance from the body before reaching its intended target. Furthermore, by providing signaling cues and transplanted biological components that favorably change the intrinsic immune response at the disease site, the NPs would be capable interacting with immune cells regarding the biomimetic method. Thus, we aimed to provide a current landscape and future trends of biomimetic NPs in drug delivery.
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Affiliation(s)
- Fatemeh Mohammad-Rafiei
- Department of Medical Biotechnology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Javad Yaghmoorian Khojini
- Department of Medical Biotechnology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Fatemeh Ghazvinian
- Department of Life science and biotechnology, Faculty of Natural Sciences, University of Shahid Beheshti, Tehran, Iran
| | - Sajad Alimardan
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hamid Norioun
- Medical Genetics Department, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
| | - Zahra Tahershamsi
- Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Amir Tajbakhsh
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Mohammad Gheibihayat
- Department of Medical Biotechnology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Munich, Germany
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Kumari K, Tandon S, Ghosh S, Baligar P. Gelatin scaffold ameliorates proliferation & stem cell differentiation into the hepatic like cell and support liver regeneration in partial-hepatectomized mice model. Biomed Mater 2023; 18:065022. [PMID: 37860885 DOI: 10.1088/1748-605x/ad04fd] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Accepted: 10/19/2023] [Indexed: 10/21/2023]
Abstract
Stem cell-based tissue engineering is an emerging tool for developing functional tissues of choice. To understand pluripotency and hepatic differentiation of mouse embryonic stem cells (mESCs) on a three-dimensional (3D) scaffold, we established an efficient approach for generating hepatocyte-like cells (HLCs) from hepatoblast cells. We developed porous and biodegradable scaffold, which was stimulated with exogenous growth factors and investigated stemness and differentiation capacity of mESCs into HLCs on the scaffoldin-vitro. In animal studies, we had cultured mESCs-derived hepatoblast-like cells on the scaffold and then, transplanted them into the partially hepatectomized C57BL/6 male mice model to evaluate the effect of gelatin scaffold on hepatic regeneration. The 3D culture system allowed maintenance of stemness properties in mESCs. The step-wise induction of mESCs with differentiation factors leads to the formation of HLCs and expressed liver-specific genes, including albumin, hepatocyte nucleic factor 4 alpha, and cytokeratin 18. In addition, cells also expressed Ki67, indicating cells are proliferating. The secretome showed expression of albumin, urea, creatinine, alanine transaminase, and aspartate aminotransferase. However, the volume of the excised liver which aids regeneration has not been studied. Our results indicate that hepatoblast cells on the scaffold implanted in PH mouse indicates that these cells efficiently differentiate into HLCs and cholangiocytes, forming hepatic lobules with central and portal veins, and bile duct-like structures with neovascularization. The gelatin scaffold provides an efficient microenvironment for liver differentiation and regeneration bothin-vitroandin-vivo. These hepatoblasts cells would be a valuable source for 3D liver tissue engineering/transplantation in liver diseases.
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Affiliation(s)
- Kshama Kumari
- Amity Institute of Molecular Medicine & Stem Cell Research (AIMMSCR), Amity University, Noida, Uttar Pradesh, India
| | | | - Sourabh Ghosh
- Regenerative Engineering Laboratory, Department of Textile and Fibre Engineering, Indian Institute of Technology Delhi, New Delhi 110016, India
| | - Prakash Baligar
- Amity Institute of Molecular Medicine & Stem Cell Research (AIMMSCR), Amity University, Noida, Uttar Pradesh, India
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Han J, Li X, Liang B, Ma S, Pu Y, Yu F, Lu J, Ma Y, MacHugh DE, Jiang L. Transcriptome profiling of differentiating adipose-derived stem cells across species reveals new genes regulating adipogenesis. Biochim Biophys Acta Mol Cell Biol Lipids 2023; 1868:159378. [PMID: 37572997 DOI: 10.1016/j.bbalip.2023.159378] [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: 04/11/2023] [Revised: 07/31/2023] [Accepted: 08/02/2023] [Indexed: 08/14/2023]
Abstract
Adipose-derived stem cells (ADSCs) that are enriched in adipose tissue with multilineage differentiation potential have become an important tool in therapeutic research and tissue engineering. Certain breeds of sheep exhibit a unique fat tail trait such that tail tissue accounts for approximately 10 % of body weight and can provide an excellent source of ADSCs. Here, we describe isolation of primary ADSCs from ovine embryonic fat tail tissues that displayed high self-renewal capacity, multilineage differentiation and excellent adipogenic ability. Through transcriptome analysis covering ADSCs differentiating into adipocytes, 37 transcription factors were involved in early transcriptional events that initiate a regulatory cascade of adipogenesis; the entire adipogenic activity consists of a reduction in proliferation ability and upregulation of genes related to lipid generation and energy metabolism, as well as several genes associated with myogenesis. Furthermore, Comparative transcriptome analysis across species (sheep, human, and mouse) revealed enhanced basal metabolic ability in differentiating ovine ADSCs, which may relate to the excellent adipogenic capability of these cells. We also identified a small evolutionarily conserved gene set, consisting of 21 and 22 genes exhibiting increased and decreased expression, respectively. Almost half (20) of these genes have not previously been reported to regulate adipogenesis in mammals. In this study, we identified important regulators that trigger ovine adipocyte differentiation, main biological pathways involved in adipogenesis as well as the evolutionarily conserved genes governing adipogenic process across species. Our study provides a novel excellent biomaterial and novel genes regulating adipogenesis for cellular transplantation therapy and investigations of fat metabolism.
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Affiliation(s)
- Jiangang Han
- Laboratory of Animal Genetics Breeding and Reproduction, Ministry of Agriculture, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China; Animal Genomics Laboratory, UCD School of Agriculture and Food Science, UCD College of Health and Agricultural Sciences, University College Dublin, Belfield, Dublin D04 V1W8, Ireland
| | - Xiaojie Li
- Laboratory of Animal Genetics Breeding and Reproduction, Ministry of Agriculture, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China; National Germplasm Center of Domestic Animal Resources, Ministry of Technology, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China
| | - Benmeng Liang
- Laboratory of Animal Genetics Breeding and Reproduction, Ministry of Agriculture, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China; National Germplasm Center of Domestic Animal Resources, Ministry of Technology, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China
| | - Sijia Ma
- Laboratory of Animal Genetics Breeding and Reproduction, Ministry of Agriculture, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China; Agricultural College, Ningxia University, Yinchuan, Ningxia, China
| | - Yabin Pu
- Laboratory of Animal Genetics Breeding and Reproduction, Ministry of Agriculture, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China; National Germplasm Center of Domestic Animal Resources, Ministry of Technology, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China
| | - Fuqing Yu
- National Animal Husbandry Service, Beijing 100193, China
| | - Jian Lu
- National Animal Husbandry Service, Beijing 100193, China
| | - Yuehui Ma
- Laboratory of Animal Genetics Breeding and Reproduction, Ministry of Agriculture, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China; National Germplasm Center of Domestic Animal Resources, Ministry of Technology, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China
| | - David E MacHugh
- Animal Genomics Laboratory, UCD School of Agriculture and Food Science, UCD College of Health and Agricultural Sciences, University College Dublin, Belfield, Dublin D04 V1W8, Ireland; UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin D04 V1W8, Ireland.
| | - Lin Jiang
- Laboratory of Animal Genetics Breeding and Reproduction, Ministry of Agriculture, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China; National Germplasm Center of Domestic Animal Resources, Ministry of Technology, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China.
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12
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Zhu S, Cheng Y, Wang J, Liu G, Luo T, Li X, Yang S, Yang R. Biohybrid magnetic microrobots: An intriguing and promising platform in biomedicine. Acta Biomater 2023; 169:88-106. [PMID: 37572981 DOI: 10.1016/j.actbio.2023.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 07/19/2023] [Accepted: 08/03/2023] [Indexed: 08/14/2023]
Abstract
Biohybrid magnetic microrobots (BMMs) have emerged as an exciting class of microrobots and have been considered as a promising platform in biomedicine. Many microorganisms and body's own cells show intriguing properties, such as morphological characteristics, biosafety, and taxis abilities (e.g., chemotaxis, aerotaxis), which have made them attractive for the fabrication of microrobots. For remote controllability and sustainable actuation, magnetic components are usually incorporated onto these biological entities, and other functionalized non-biological components (e.g., therapeutic agents) are also included for specific applications. This review highlights the latest developments in BMMs with a focus on their biomedical applications. It starts by introducing the fundamental understanding of the propulsion system at the microscale in a magnetically driven manner, followed by a summary of diverse BMMs based on different microorganisms and body's own cells along with their relevant applications. Finally, the review discusses how BMMs contribute to the advancements of microrobots, the current challenges of using BMMs in practical clinical settings, and the future perspectives of this exciting field. STATEMENT OF SIGNIFICANCE: Biohybrid magnetic microrobots (BMMs), composed of biological entities and functional parts, hold great potential and serve as a novel and promising platform for biomedical applications such as targeted drug delivery. This review comprehensively summarizes the recent advancements in BMMs for biomedical applications, mainly focused on the representative propulsion modalities in a magnetically propelled manner and diverse designs of BMMs based on different biological entities, including microorganisms and body's own cells. We hope this review can provide ideas for the future design, development, and innovation of micro/nanorobots in the field of biomedicine.
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Affiliation(s)
- Shilu Zhu
- School of Biomedical Engineering, 3D-Printing and Tissue Engineering Center, Anhui Medical University, Hefei 230032, China
| | - Yifan Cheng
- School of Biomedical Engineering, 3D-Printing and Tissue Engineering Center, Anhui Medical University, Hefei 230032, China
| | - Jian Wang
- School of Biomedical Engineering, 3D-Printing and Tissue Engineering Center, Anhui Medical University, Hefei 230032, China
| | - Guangli Liu
- School of Biomedical Engineering, 3D-Printing and Tissue Engineering Center, Anhui Medical University, Hefei 230032, China
| | - Tingting Luo
- School of Biomedical Engineering, 3D-Printing and Tissue Engineering Center, Anhui Medical University, Hefei 230032, China.
| | - Xiaojian Li
- Department of Management, Hefei University of Technology, Hefei 230009, China.
| | - Shanlin Yang
- Key Laboratory of Process Optimization and Intelligent Decision-Making (Ministry of Education), Hefei University of Technology, Hefei 230009, China.
| | - Runhuai Yang
- School of Biomedical Engineering, 3D-Printing and Tissue Engineering Center, Anhui Medical University, Hefei 230032, China.
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13
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Chen L, Zhang N, Huang Y, Zhang Q, Fang Y, Fu J, Yuan Y, Chen L, Chen X, Xu Z, Li Y, Izawa H, Xiang C. Multiple Dimensions of using Mesenchymal Stem Cells for Treating Liver Diseases: From Bench to Beside. Stem Cell Rev Rep 2023; 19:2192-2224. [PMID: 37498509 DOI: 10.1007/s12015-023-10583-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/26/2023] [Indexed: 07/28/2023]
Abstract
Liver diseases impose a huge burden worldwide. Although hepatocyte transplantation has long been considered as a potential strategy for treating liver diseases, its clinical implementation has created some obvious limitations. As an alternative strategy, cell therapy, particularly mesenchymal stem cell (MSC) transplantation, is widely used in treating different liver diseases, including acute liver disease, acute-on-chronic liver failure, hepatitis B/C virus, autoimmune hepatitis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, alcoholic liver disease, liver fibrosis, liver cirrhosis, and hepatocellular carcinoma. Here, we summarize the status of MSC transplantation in treating liver diseases, focusing on the therapeutic mechanisms, including differentiation into hepatocyte-like cells, immunomodulating function with a variety of immune cells, paracrine effects via the secretion of various cytokines and extracellular vesicles, and facilitation of homing and engraftment. Some improved perspectives and current challenges are also addressed. In summary, MSCs have great potential in the treatment of liver diseases based on their multi-faceted characteristics, and more accurate mechanisms and novel therapeutic strategies stemming from MSCs will facilitate clinical practice.
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Affiliation(s)
- Lijun Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Ning Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Yuqi Huang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Qi Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Yangxin Fang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Jiamin Fu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Yin Yuan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Lu Chen
- Innovative Precision Medicine (IPM) Group, Hangzhou, Zhejiang, 311215, People's Republic of China
| | - Xin Chen
- Department of Hematology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310027, People's Republic of China
| | - Zhenyu Xu
- Innovative Precision Medicine (IPM) Group, Hangzhou, Zhejiang, 311215, People's Republic of China
| | - Yifei Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Hiromi Izawa
- Jingugaien Woman Life Clinic, Jingu-Gaien 3-39-5 2F, Shibuya-Ku, Tokyo, Japan
| | - Charlie Xiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China.
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China.
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14
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Barreto da Silva T, Dias EA, Cardoso LMDF, Gama JFG, Alves LA, Henriques-Pons A. Magnetic Nanostructures and Stem Cells for Regenerative Medicine, Application in Liver Diseases. Int J Mol Sci 2023; 24:ijms24119293. [PMID: 37298243 DOI: 10.3390/ijms24119293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 05/08/2023] [Accepted: 05/19/2023] [Indexed: 06/12/2023] Open
Abstract
The term "liver disease" refers to any hepatic condition that leads to tissue damage or altered hepatic function and can be induced by virus infections, autoimmunity, inherited genetic mutations, high consumption of alcohol or drugs, fat accumulation, and cancer. Some types of liver diseases are becoming more frequent worldwide. This can be related to increasing rates of obesity in developed countries, diet changes, higher alcohol intake, and even the coronavirus disease 2019 (COVID-19) pandemic was associated with increased liver disease-related deaths. Although the liver can regenerate, in cases of chronic damage or extensive fibrosis, the recovery of tissue mass is impossible, and a liver transplant is indicated. Because of reduced organ availability, it is necessary to search for alternative bioengineered solutions aiming for a cure or increased life expectancy while a transplant is not possible. Therefore, several groups were studying the possibility of stem cells transplantation as a therapeutic alternative since it is a promising strategy in regenerative medicine for treating various diseases. At the same time, nanotechnological advances can contribute to specifically targeting transplanted cells to injured sites using magnetic nanoparticles. In this review, we summarize multiple magnetic nanostructure-based strategies that are promising for treating liver diseases.
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Affiliation(s)
- Tatiane Barreto da Silva
- Laboratory of Cellular Communication, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21045-900, Brazil
| | - Evellyn Araújo Dias
- Laboratory of Cellular Communication, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21045-900, Brazil
| | | | - Jaciara Fernanda Gomes Gama
- Laboratory of Cellular Communication, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21045-900, Brazil
| | - Luiz Anastácio Alves
- Laboratory of Cellular Communication, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21045-900, Brazil
| | - Andrea Henriques-Pons
- Laboratory of Innovations in Therapies, Education, and Bioproducts, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21041-361, Brazil
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15
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Hu XH, Chen L, Wu H, Tang YB, Zheng QM, Wei XY, Wei Q, Huang Q, Chen J, Xu X. Cell therapy in end-stage liver disease: replace and remodel. Stem Cell Res Ther 2023; 14:141. [PMID: 37231461 DOI: 10.1186/s13287-023-03370-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 04/26/2023] [Indexed: 05/27/2023] Open
Abstract
Liver disease is prevalent worldwide. When it reaches the end stage, mortality rises to 50% or more. Although liver transplantation has emerged as the most efficient treatment for end-stage liver disease, its application has been limited by the scarcity of donor livers. The lack of acceptable donor organs implies that patients are at high risk while waiting for suitable livers. In this scenario, cell therapy has emerged as a promising treatment approach. Most of the time, transplanted cells can replace host hepatocytes and remodel the hepatic microenvironment. For instance, hepatocytes derived from donor livers or stem cells colonize and proliferate in the liver, can replace host hepatocytes, and restore liver function. Other cellular therapy candidates, such as macrophages and mesenchymal stem cells, can remodel the hepatic microenvironment, thereby repairing the damaged liver. In recent years, cell therapy has transitioned from animal research to early human studies. In this review, we will discuss cell therapy in end-stage liver disease treatment, especially focusing on various cell types utilized for cell transplantation, and elucidate the processes involved. Furthermore, we will also summarize the practical obstacles of cell therapy and offer potential solutions.
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Affiliation(s)
- Xin-Hao Hu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Lan Chen
- Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Hao Wu
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
| | - Yang-Bo Tang
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
| | - Qiu-Min Zheng
- Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China
| | - Xu-Yong Wei
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Qiang Wei
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Qi Huang
- Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Jian Chen
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
| | - Xiao Xu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
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16
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Sharma S, Rawal P, Kaur S, Puria R. Liver organoids as a primary human model to study HBV-mediated Hepatocellular carcinoma. A review. Exp Cell Res 2023; 428:113618. [PMID: 37142202 DOI: 10.1016/j.yexcr.2023.113618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 04/21/2023] [Accepted: 04/26/2023] [Indexed: 05/06/2023]
Abstract
Hepatitis B Virus (HBV) is the prevailing cause of chronic liver disease, which progresses to Hepatocellular carcinoma (HCC) in 75% of cases. It represents a serious health concern being the fourth leading cause of cancer-related mortality worldwide. Treatments available to date fail to provide a complete cure with high chances of recurrence and related side effects. The lack of reliable, reproducible, and scalable in vitro modeling systems that could recapitulate the viral life cycle and represent virus-host interactions has hindered the development of effective treatments so far. The present review provides insights into the current in-vivo and in-vitro models used for studying HBV and their major limitations. We highlight the use of three-dimensional liver organoids as a novel and suitable platform for modeling HBV infection and HBV-mediated HCC. HBV organoids can be expanded, genetically altered, patient-derived, tested for drug discovery, and biobanked. This review also provides the general guidelines for culturing HBV organoids and highlights their several prospects for HBV drug discovery and screening.
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Affiliation(s)
- Simran Sharma
- School of Biotechnology, Gautam Buddha University, Greater Noida, India
| | - Preety Rawal
- School of Biotechnology, Gautam Buddha University, Greater Noida, India
| | - Savneet Kaur
- Institute of Liver and Biliary Sciences, Delhi, India.
| | - Rekha Puria
- School of Biotechnology, Gautam Buddha University, Greater Noida, India.
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17
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Giuli L, Santopaolo F, Pallozzi M, Pellegrino A, Coppola G, Gasbarrini A, Ponziani FR. Cellular therapies in liver and pancreatic diseases. Dig Liver Dis 2023; 55:563-579. [PMID: 36543708 DOI: 10.1016/j.dld.2022.11.013] [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: 08/11/2022] [Revised: 10/21/2022] [Accepted: 11/22/2022] [Indexed: 04/29/2023]
Abstract
Over the past two decades, developments in regenerative medicine in gastroenterology have been greatly enhanced by the application of stem cells, which can self-replicate and differentiate into any somatic cell. The discovery of induced pluripotent stem cells has opened remarkable perspectives on tissue regeneration, including their use as a bridge to transplantation or as supportive therapy in patients with organ failure. The improvements in DNA manipulation and gene editing strategies have also allowed to clarify the physiopathology and to correct the phenotype of several monogenic diseases, both in vivo and in vitro. Further progress has been made with the development of three-dimensional cultures, known as organoids, which have demonstrated morphological and functional complexity comparable to that of a miniature organ. Hence, owing to its protean applications and potential benefits, cell and organoid transplantation has become a hot topic for the management of gastrointestinal diseases. In this review, we describe current knowledge on cell therapies in hepatology and pancreatology, providing insight into their future applications in regenerative medicine.
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Affiliation(s)
- Lucia Giuli
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Maria Pallozzi
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Antonio Pellegrino
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Gaetano Coppola
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Università Cattolica del Sacro Cuore, Rome, Italy.
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Università Cattolica del Sacro Cuore, Rome, Italy
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18
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Ma Y, Hu L, Tang J, Guo W, Feng Y, Liu Y, Tang F. Three-Dimensional Cell Co-Culture Liver Models and Their Applications in Pharmaceutical Research. Int J Mol Sci 2023; 24:ijms24076248. [PMID: 37047220 PMCID: PMC10094553 DOI: 10.3390/ijms24076248] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/14/2023] [Accepted: 03/22/2023] [Indexed: 03/29/2023] Open
Abstract
As the primary site for the biotransformation of drugs, the liver is the most focused on organ type in pharmaceutical research. However, despite being widely used in pharmaceutical research, animal models have inherent species differences, while two-dimensional (2D) liver cell monocultures or co-cultures and three-dimensional (3D) liver cell monoculture in vitro liver models do not sufficiently represent the complexity of the human liver’s structure and function, making the evaluation results from these tools less reliable. Therefore, there is a pressing need to develop more representative in vitro liver models for pharmaceutical research. Fortunately, an exciting new development in recent years has been the emergence of 3D liver cell co-culture models. These models hold great promise as in vitro pharmaceutical research tools, because they can reproduce liver structure and function more practically. This review begins by explaining the structure and main cell composition of the liver, before introducing the potential advantages of 3D cell co-culture liver models for pharmaceutical research. We also discuss the main sources of hepatocytes and the 3D cell co-culture methods used in constructing these models. In addition, we explore the applications of 3D cell co-culture liver models with different functional states and suggest prospects for their further development.
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Takashina T, Matsunaga A, Shimizu Y, Sakuma T, Okamura T, Matsuoka K, Yamamoto T, Ishizaka Y. Robust protein-based engineering of hepatocyte-like cells from human mesenchymal stem cells. Hepatol Commun 2023; 7:e0051. [PMID: 36848084 PMCID: PMC9974069 DOI: 10.1097/hc9.0000000000000051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 12/14/2022] [Indexed: 03/01/2023] Open
Abstract
BACKGROUND Cells of interest can be prepared from somatic cells by forced expression of lineage-specific transcription factors, but it is required to establish a vector-free system for their clinical use. Here, we report a protein-based artificial transcription system for engineering hepatocyte-like cells from human umbilical cord-derived mesenchymal stem cells (MSCs). METHODS MSCs were treated for 5 days with 4 artificial transcription factors (4F), which targeted hepatocyte nuclear factor (HNF)1α, HNF3γ, HNF4α, and GATA-binding protein 4 (GATA4). Then, engineered MSCs (4F-Heps) were subjected to epigenetic analysis, biochemical analysis and flow cytometry analysis with antibodies to marker proteins of mature hepatocytes and hepatic progenitors such as delta-like homolog 1 (DLK1) and trophoblast cell surface antigen 2 (TROP2). Functional properties of the cells were also examined by injecting them to mice with lethal hepatic failure. RESULTS Epigenetic analysis revealed that a 5-day treatment of 4F upregulated the expression of genes involved in hepatic differentiation, and repressed genes related to pluripotency of MSCs. Flow cytometry analysis detected that 4F-Heps were composed of small numbers of mature hepatocytes (at most 1%), bile duct cells (~19%) and hepatic progenitors (~50%). Interestingly, ~20% of 4F-Heps were positive for cytochrome P450 3A4, 80% of which were DLK1-positive. Injection of 4F-Heps significantly increased survival of mice with lethal hepatic failure, and transplanted 4F-Heps expanded to more than 50-fold of human albumin-positive cells in the mouse livers, well consistent with the observation that 4F-Heps contained DLK1-positive and/or TROP2-positive cells. CONCLUSION Taken together with observations that 4F-Heps were not tumorigenic in immunocompromised mice for at least 2 years, we propose that this artificial transcription system is a versatile tool for cell therapy for hepatic failures.
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Affiliation(s)
- Tomoki Takashina
- Department of Intractable Diseases, National Center for Global Health and Medicine, Tokyo, Japan
| | - Akihiro Matsunaga
- Department of Intractable Diseases, National Center for Global Health and Medicine, Tokyo, Japan
| | - Yukiko Shimizu
- Department of Laboratory Animal Medicine, National Center for Global Health and Medicine, Tokyo, Japan
- Department of Pediatrics, Juntendo University School of Medicine, Tokyo, Japan
| | - Tetsushi Sakuma
- Division of Integrated Sciences for Life, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan
| | - Tadashi Okamura
- Department of Laboratory Animal Medicine, National Center for Global Health and Medicine, Tokyo, Japan
| | - Kunie Matsuoka
- Deafness Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Takashi Yamamoto
- Division of Integrated Sciences for Life, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan
| | - Yukihito Ishizaka
- Department of Intractable Diseases, National Center for Global Health and Medicine, Tokyo, Japan
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20
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Zahmatkesh E, Khoshdel Rad N, Hossein-Khannazer N, Mohamadnejad M, Gramignoli R, Najimi M, Malekzadeh R, Hassan M, Vosough M. Cell and cell-derivative-based therapy for liver diseases: current approaches and future promises. Expert Rev Gastroenterol Hepatol 2023; 17:237-249. [PMID: 36692130 DOI: 10.1080/17474124.2023.2172398] [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] [Indexed: 01/25/2023]
Abstract
INTRODUCTION According to the recent updates from World Health Organization, liver diseases are the 12th most common cause of mortality. Currently, orthotopic liver transplantation (OLT) is the most effective and the only treatment for end-stage liver diseases. Owing to several shortcomings like finite numbers of healthy organ donors, lifelong immunosuppression, and complexity of the procedure, cell and cell-derivatives therapies have emerged as a potential therapeutic alternative for liver diseases. Various cell types and therapies have been proposed and their therapeutic effects evaluated in preclinical or clinical studies, including hepatocytes, hepatocyte-like cells (HLCs) derived from stem cells, human liver stem cells (HLSCs), combination therapies with various types of cells, organoids, and implantable cell-biomaterial constructs with synthetic and natural polymers or even decellularized extracellular matrix (ECM). AREAS COVERED In this review, we highlighted the current status of cell and cell-derivative-based therapies for liver diseases. Furthermore, we discussed future prospects of using HLCs, liver organoids, and their combination therapies. EXPERT OPINION Promising application of stem cell-based techniques including iPSC technology has been integrated into novel techniques such as gene editing, directed differentiation, and organoid technology. iPSCs offer promising prospects to represent novel therapeutic strategies and modeling liver diseases.
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Affiliation(s)
- Ensieh Zahmatkesh
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Niloofar Khoshdel Rad
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Nikoo Hossein-Khannazer
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Mohamadnejad
- Cell-Based Therapies Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Roberto Gramignoli
- Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Mustapha Najimi
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), Université Catholique de Louvain, Brussels, Belgium
| | - Reza Malekzadeh
- Digestive Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Moustapha Hassan
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
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21
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Li S, Tang H, Li C, Ma J, Ali M, Dong Q, Wu J, Hui Y, Sun C. Synthetic Biology Technologies And Genetically Engineering Strategies For Enhanced Cell Therapeutics. Stem Cell Rev Rep 2023; 19:309-321. [PMID: 36166137 PMCID: PMC9514184 DOI: 10.1007/s12015-022-10454-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/13/2022] [Indexed: 02/07/2023]
Abstract
Stem cell therapy mainly uses natural stem cells for transplantation, and the use of genetic engineering to optimize stem cell products is a very important process. This article reviews successful gene modification methods in the field of immune cell therapy and summarizes some attempts at stem cell gene editing in current research. Cell bridging is an innovative cutting-edge strategy that includes the specific recognition and signal transduction of artificial receptors. The "off-the-shelf" cell strategies mainly introduce the advantages of allogeneic cell therapy and how to overcome issues such as immunogenicity. Gene regulatory systems allow us to manipulate cells with small molecules to control cellular phenotypes. In addition, we also summarize some important genes that can provide a reference for cell genetic engineering. In conclusion, we summarize a variety of technical strategies for gene editing cells to provide useful ideas and experiences for future stem cell therapy research.
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Affiliation(s)
- Siyu Li
- Department of Biochemistry and Molecular Biology, Harbin Medical University, 157 BaoJian Road Nangang Dist, Harbin, 150086, People's Republic of China
| | - Hao Tang
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China
| | - Cheng Li
- Department of Biochemistry and Molecular Biology, Harbin Medical University, 157 BaoJian Road Nangang Dist, Harbin, 150086, People's Republic of China
| | - Jiajia Ma
- Department of Biochemistry and Molecular Biology, Harbin Medical University, 157 BaoJian Road Nangang Dist, Harbin, 150086, People's Republic of China
| | - Maqsood Ali
- Department of Biochemistry and Molecular Biology, Harbin Medical University, 157 BaoJian Road Nangang Dist, Harbin, 150086, People's Republic of China
| | - Qi Dong
- Department of Biochemistry and Molecular Biology, Harbin Medical University, 157 BaoJian Road Nangang Dist, Harbin, 150086, People's Republic of China
| | - Jiajia Wu
- Department of Biochemistry and Molecular Biology, Harbin Medical University, 157 BaoJian Road Nangang Dist, Harbin, 150086, People's Republic of China
| | - Yang Hui
- Department of Biochemistry and Molecular Biology, Harbin Medical University, 157 BaoJian Road Nangang Dist, Harbin, 150086, People's Republic of China.
- Basic Medical Institute of Heilongjiang Medical Science Academy, Harbin, China.
| | - Chongran Sun
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou City, Xihu District, 310058, People's Republic of China.
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22
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Ali FE, Abd El-Aziz MK, Sharab EI, Bakr AG. Therapeutic interventions of acute and chronic liver disorders: A comprehensive review. World J Hepatol 2023; 15:19-40. [PMID: 36744165 PMCID: PMC9896501 DOI: 10.4254/wjh.v15.i1.19] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 11/17/2022] [Accepted: 12/21/2022] [Indexed: 01/16/2023] Open
Abstract
Liver disorders are one of the most common pathological problems worldwide. It affects more than 1.5 billion worldwide. Many types of hepatic cells have been reported to be involved in the initiation and propagation of both acute and chronic liver diseases, including hepatocytes, Kupffer cells, sinusoidal endothelial cells, and hepatic stellate cells (HSCs). In addition, oxidative stress, cytokines, fibrogenic factors, microRNAs, and autophagy are also involved. Understanding the molecular mechanisms of liver diseases leads to discovering new therapeutic interventions that can be used in clinics. Recently, antioxidant, anti-inflammatory, anti-HSCs therapy, gene therapy, cell therapy, gut microbiota, and nanoparticles have great potential for preventing and treating liver diseases. Here, we explored the recent possible molecular mechanisms involved in the pathogenesis of acute and chronic liver diseases. Besides, we overviewed the recent therapeutic interventions that targeted liver diseases and summarized the recent studies concerning liver disorders therapy.
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Affiliation(s)
- Fares Em Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt.
| | | | - Elham I Sharab
- Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt
| | - Adel G Bakr
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt
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Banerjee A, Sriramulu S, Catanzaro R, He F, Chabria Y, Balakrishnan B, Hari S, Ayala A, Muñoz M, Pathak S, Marotta F. Natural Compounds as Integrative Therapy for Liver Protection against Inflammatory and Carcinogenic Mechanisms: From Induction to Molecular Biology Advancement. Curr Mol Med 2023; 23:216-231. [PMID: 35297348 DOI: 10.2174/1566524022666220316102310] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 10/20/2021] [Accepted: 12/25/2021] [Indexed: 02/08/2023]
Abstract
The liver is exposed to several harmful substances that bear the potential to cause excessive liver damage ranging from hepatitis and non-alcoholic fatty liver disease to extreme cases of liver cirrhosis and hepatocellular carcinoma. Liver ailments have been effectively treated from very old times with Chinese medicinal herbal formulations and later also applied by controlled trials in Japan. However, these traditional practices have been hardly well characterized in the past till in the last decades when more qualified studies have been carried out. Modern advances have given rise to specific molecular targets which are specifically good candidates for affecting the intricate mechanisms that play a role at the molecular level. These therapeutic regimens that mainly affect the progression of the disease by inhibiting the gene expression levels or by blocking essential molecular pathways or releasing cytokines may prove to play a vital role in minimizing the tissue damage. This review, therefore, tries to throw light upon the variation in the therapies for the treatment of benign and malignant liver disease from ancient times to the current date. Nonetheless, clinical research exploring the effectiveness of herbal medicines in the treatment of benign chronic liver diseases as well as prevention and treatment of HCC is still warranted.
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Affiliation(s)
- Antara Banerjee
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai 603103, India
| | - Sushmitha Sriramulu
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai 603103, India
| | - Roberto Catanzaro
- Dept of Clinical and Experimental Medicine, Section of Gastroenterology, University of Catania, Catania, Italy
| | - Fang He
- Dept of Nutrition, West China School of Public Health, Sichuan University, Chengdu, China
| | - Yashna Chabria
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai 603103, India
| | | | - Sruthi Hari
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai 603103, India
| | - Antonio Ayala
- Biochemistry and Clinical Biochemistry Department, Faculty of Pharmacy, University of Seville, Spain
| | - Mario Muñoz
- Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Portugal
| | - Surajit Pathak
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai 603103, India
| | - Francesco Marotta
- ReGenera R&D International for Aging Intervention, Milano, Italy and Vitality and Longevity Medical Science Commission, FEMTEC World Federation
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24
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Li H, Gu J, Sun X, Zuo Q, Li B, Gu X. Isolation of Swine Bone Marrow Lin-/CD45-/CD133 + Cells and Cardio-protective Effects of its Exosomes. Stem Cell Rev Rep 2023; 19:213-229. [PMID: 35925437 PMCID: PMC9822881 DOI: 10.1007/s12015-022-10432-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/19/2022] [Indexed: 01/29/2023]
Abstract
BACKGROUND The identification in murine bone marrow (BM) of CD133 + /Lin-/CD45- cells, possessing several features of pluripotent stem cells, encouraged us to investigate if similar population of cells could be also isolated from the swine BM. Heart failure is the terminal stage of many cardiovascular diseases, and its key pathological basis is cardiac fibrosis (CF). Research showed that stem cell derived exosomes may play a critical role in cardiac fibrosis. The effect of exosomes (Exos) on CF has remained unclear. OBJECTIVE To establish an isolation and amplification method of CD133 + /Lin-/CD45- cells from newbron swine BM in vitro, explore an highly efficient method to enrich swine bone marrow derived CD133 + /Lin-/CD45- cells and probe into their biological characteristics further. Furher more, to extract exosomes from it and explore its effect on CF. METHODS The mononuclear cells isolated from swine bone marrow by red blood cell (RBC) lysing buffer were coated by adding FcR blocking solution and coupled with CD133 antibody immunomagnetic beads, obtaining CD133 + cell group via Magnetic Activated Cell Sorting (MACS). In steps, the CD133 + /Lin-/CD45- cells were collected by fluorescence-activated cell sorting (FACS) labeled with CD133, Lin and CD45 antibodies, which were cultured and amplified in vitro. The biological features of CD133 + /Lin-/CD45- cells were studied in different aspects, including morphological trait observed with inverted microscope, ultrastructural characteristics observed under transmission electron microscope, expression of pluripotent markersidentified by immunofluorescent staining and Alkaline phosphatase staining. The Exos were extracted using a sequential centrifugation approach and its effects on CF were analyzed in Angiotensin II (Ang-II) induced-cardiac fibrosis in vivo. Rats in each group were treated for 4 weeks, and 2D echocardiography was adopted to evaluate the heart function. The degree of cardiac fibrosis was assessed by Hematoxylin-Eosin (HE) and Masson's trichrome staining. RESULTS The CD133 + /Lin-/CD45- cells accounted for about 0.2%-0.5% of the total mononuclear cells isolated from swine bone marrow. The combination of MACS and FACS to extract CD133 + /Lin-/CD45- cells could improved efficiency and reduced cell apoptosis. The CD133 + /Lin-/CD45- cells featured typical traits of pluripotent stem cells, the nucleus is large, mainly composed of euchromatin, with less cytoplasm and larger nucleoplasmic ratio, which expressed pluripotent markers (SSEA-1, Oct-4, Nanog and Sox-2) and alkaline phosphatase staining was positive.Animal experiment indicated that the cardiac injury related indexes (BNP、cTnI、CK-MB and TNF-α), the expression of key gene Smad3 and the degree of cardiac fibrosis in Exo treatment group were significantly reduced compared with the control group. 4 weeks after the treatment, cardiac ejection fraction (EF) value in the model group showed a remarkable decrease, indicating the induction of HF model. While Exo elevated the EF values, demonstrating cardio-protective effects. CONCLUSION The CD133 + /Lin-/CD45- cells derived from swine bone marrow were successfully isolated and amplified, laying a good foundation for further research on this promising therapeutic cell. The Exos may be a promising potential treatment strategy for CF.
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Affiliation(s)
- Hongxiao Li
- Medical College of Yangzhou University, Yangzhou, 225001, Jiangsu, China
- Department of Cardiology, Northern Jiangsu People's Hospital, Yangzhou, 225001, Jiangsu, China
| | - Jianjun Gu
- Medical College of Yangzhou University, Yangzhou, 225001, Jiangsu, China
- Department of Cardiology, Northern Jiangsu People's Hospital, Yangzhou, 225001, Jiangsu, China
| | - Xiaolin Sun
- Medical College of Yangzhou University, Yangzhou, 225001, Jiangsu, China
- Department of Cardiology, Northern Jiangsu People's Hospital, Yangzhou, 225001, Jiangsu, China
| | - Qisheng Zuo
- College of Animal Science and Technology, Yangzhou University, Yangzhou, 225001, Jiangsu, China
| | - Bichun Li
- College of Animal Science and Technology, Yangzhou University, Yangzhou, 225001, Jiangsu, China
| | - Xiang Gu
- Medical College of Yangzhou University, Yangzhou, 225001, Jiangsu, China.
- Department of Cardiology, Northern Jiangsu People's Hospital, Yangzhou, 225001, Jiangsu, China.
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25
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Han J, Lee C, Hur J, Jung Y. Current Therapeutic Options and Potential of Mesenchymal Stem Cell Therapy for Alcoholic Liver Disease. Cells 2022; 12:22. [PMID: 36611816 PMCID: PMC9818513 DOI: 10.3390/cells12010022] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/16/2022] [Accepted: 12/17/2022] [Indexed: 12/24/2022] Open
Abstract
Alcoholic liver disease (ALD) is a globally prevalent chronic liver disease caused by chronic or binge consumption of alcohol. The therapeutic efficiency of current therapies for ALD is limited, and there is no FDA-approved therapy for ALD at present. Various strategies targeting pathogenic events in the progression of ALD are being investigated in preclinical and clinical trials. Recently, mesenchymal stem cells (MSCs) have emerged as a promising candidate for ALD treatment and have been tested in several clinical trials. MSC-released factors have captured attention, as they have the same therapeutic function as MSCs. Herein, we focus on current therapeutic options, recently proposed strategies, and their limitations in ALD treatment. Also, we review the therapeutic effects of MSCs and those of MSC-related secretory factors on ALD. Although accumulating evidence suggests the therapeutic potential of MSCs and related factors in ALD, the mechanisms underlying their actions in ALD have not been well studied. Further investigations of the detailed mechanisms underlying the therapeutic role of MSCs in ALD are required to expand MSC therapies to clinical applications. This review provides information on current or possible treatments for ALD and contributes to our understanding of the development of effective and safe treatments for ALD.
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Affiliation(s)
- Jinsol Han
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
| | - Chanbin Lee
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
- Institute of Systems Biology, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
| | - Jin Hur
- Department of Convergence Medicine, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
- PNU GRAND Convergence Medical Science Education Research Center, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
| | - Youngmi Jung
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
- Department of Biological Sciences, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
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26
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Konda B, Mulay A, Yao C, Israely E, Beil S, Huynh CA, Tourtellotte WG, Rampolla R, Chen P, Carraro G, Stripp BR. Cryobanking of Human Distal Lung Epithelial Cells for Preservation of Their Phenotypic and Functional Characteristics. Am J Respir Cell Mol Biol 2022; 67:623-631. [PMID: 36036918 PMCID: PMC12042124 DOI: 10.1165/rcmb.2021-0507ma] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 08/26/2022] [Indexed: 11/24/2022] Open
Abstract
The epithelium lining airspaces of the human lung is maintained by regional stem cells, including basal cells of pseudostratified airways and alveolar type 2 (AT2) pneumocytes of the gas-exchange region. Despite effective techniques for long-term preservation of airway basal cells, procedures for efficient preservation of functional epithelial cell types of the distal gas-exchange region are lacking. Here we detail a method for cryobanking of epithelial cells from either mouse or human lung tissue for preservation of their phenotypic and functional characteristics. Flow cytometric profiling, epithelial organoid-forming efficiency, and single-cell transcriptomic analysis were used to compare cells recovered from cryobanked tissue with those of freshly dissociated tissue. AT2 cells within single-cell suspensions of enzymatically digested cryobanked distal lung tissue retained expression of the pan-epithelial marker CD326 and the AT2 cell surface antigen recognized by monoclonal antibody HT II-280, allowing antibody-mediated enrichment and downstream analysis. Isolated AT2 cells from cryobanked tissue were comparable with those of freshly dissociated tissue both in their single-cell transcriptome and their capacity for in vitro organoid formation in three-dimensional cultures. We conclude that the cryobanking method described herein allows long-term preservation of distal human lung tissue for downstream analysis of lung cell function and molecular phenotype and is ideally suited for the creation of an easily accessible tissue resource for the research community.
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Affiliation(s)
- Bindu Konda
- Lung Institute, Department of Medicine
- Regenerative Medicine Institute, and
| | - Apoorva Mulay
- Lung Institute, Department of Medicine
- Regenerative Medicine Institute, and
| | - Changfu Yao
- Lung Institute, Department of Medicine
- Regenerative Medicine Institute, and
| | - Edo Israely
- Lung Institute, Department of Medicine
- Regenerative Medicine Institute, and
| | - Stephen Beil
- Lung Institute, Department of Medicine
- Regenerative Medicine Institute, and
| | - Carissa A Huynh
- Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California
| | | | | | | | - Gianni Carraro
- Lung Institute, Department of Medicine
- Regenerative Medicine Institute, and
| | - Barry R Stripp
- Lung Institute, Department of Medicine
- Regenerative Medicine Institute, and
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27
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Lv W, Zhou H, Aazmi A, Yu M, Xu X, Yang H, Huang YYS, Ma L. Constructing biomimetic liver models through biomaterials and vasculature engineering. Regen Biomater 2022; 9:rbac079. [PMID: 36338176 PMCID: PMC9629974 DOI: 10.1093/rb/rbac079] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 09/19/2022] [Accepted: 10/08/2022] [Indexed: 04/04/2024] Open
Abstract
The occurrence of various liver diseases can lead to organ failure of the liver, which is one of the leading causes of mortality worldwide. Liver tissue engineering see the potential for replacing liver transplantation and drug toxicity studies facing donor shortages. The basic elements in liver tissue engineering are cells and biomaterials. Both mature hepatocytes and differentiated stem cells can be used as the main source of cells to construct spheroids and organoids, achieving improved cell function. To mimic the extracellular matrix (ECM) environment, biomaterials need to be biocompatible and bioactive, which also help support cell proliferation and differentiation and allow ECM deposition and vascularized structures formation. In addition, advanced manufacturing approaches are required to construct the extracellular microenvironment, and it has been proved that the structured three-dimensional culture system can help to improve the activity of hepatocytes and the characterization of specific proteins. In summary, we review biomaterials for liver tissue engineering, including natural hydrogels and synthetic polymers, and advanced processing techniques for building vascularized microenvironments, including bioassembly, bioprinting and microfluidic methods. We then summarize the application fields including transplant and regeneration, disease models and drug cytotoxicity analysis. In the end, we put the challenges and prospects of vascularized liver tissue engineering.
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Affiliation(s)
- Weikang Lv
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou 310058, China
- School of Mechanical Engineering, Zhejiang University, Hangzhou 310058, China
| | - Hongzhao Zhou
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou 310058, China
- School of Mechanical Engineering, Zhejiang University, Hangzhou 310058, China
| | - Abdellah Aazmi
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou 310058, China
- School of Mechanical Engineering, Zhejiang University, Hangzhou 310058, China
| | - Mengfei Yu
- The Affiliated Stomatologic Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Xiaobin Xu
- School of Materials Science and Engineering, Tongji University, Shanghai 201804, China
| | - Huayong Yang
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou 310058, China
- School of Mechanical Engineering, Zhejiang University, Hangzhou 310058, China
| | | | - Liang Ma
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou 310058, China
- School of Mechanical Engineering, Zhejiang University, Hangzhou 310058, China
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28
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Karmacharya MB, Hada B, Park SR, Kim KH, Choi BH. Granulocyte-macrophage colony-stimulating factor (GM-CSF) shows therapeutic effect on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. PLoS One 2022; 17:e0274126. [PMID: 36054162 PMCID: PMC9439244 DOI: 10.1371/journal.pone.0274126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 08/22/2022] [Indexed: 11/18/2022] Open
Abstract
This study was undertaken to investigate the inhibitory effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. Liver fibrosis was induced in Sprague-Dawley rats by injecting DMN intraperitoneally (at 10 mg/kg of body weight) daily for three consecutive days per week for 4 weeks. To investigate the effect of GM-CSF on disease onset, GM-CSF (50 μg/kg of body weight) was co-treated with DMN for 2 consecutive days per week for 4 weeks (4-week groups). To observe the effect of GM-CSF on the progression of liver fibrosis, GM-CSF was post-treated alone at 5–8 weeks after the 4 weeks of DMN injection (8-week groups). We found that DMN administration for 4 weeks produced molecular and pathological manifestations of liver fibrosis, that is, it increased the expressions of collagen type I, alpha-smooth muscle actin (α-SMA), and transforming growth factor-β1 (TGF-β1), and decreased peroxisome proliferator-activated receptor gamma (PPAR-γ) expression. In addition, elevated serum levels of aspartate aminotransferase (AST), total bilirubin level (TBIL), and decreased albumin level (ALB) were observed. In both the 4-week and 8-week groups, GM-CSF clearly improved the pathological liver conditions in the gross and histological observations, and significantly recovered DMN-induced increases in AST and TBIL and decreases in ALB serum levels to normal. GM-CSF also significantly decreased DMN-induced increases in collagen type I, α-SMA, and TGF-β1 and increased DMN-induced decreases in PPAR-γ expression. In the DMN groups, survival decreased continuously for 8 weeks after DMN treatment for the first 4 weeks. GM-CSF showed a survival benefit when co-treated for the first 4 weeks but a marginal effect when post-treated for 5–8 weeks. In conclusion, co-treatment of GM-CSF showed therapeutic effects on DMN-induced liver fibrosis and survival rates in rats, while post-treatment efficiently blocked liver fibrosis.
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Affiliation(s)
| | - Binika Hada
- Department of Biomedical Sciences, Inha University College of Medicine, Incheon, South Korea
| | - So Ra Park
- Department of Physiology and Biophysics, Inha University College of Medicine, Incheon, South Korea
| | - Kil Hwan Kim
- Veterans Medical Research Institute, Veterans Health Service Medical Center, Seoul, South Korea
- * E-mail: (BHC); (KHK)
| | - Byung Hyune Choi
- Department of Biomedical Sciences, Inha University College of Medicine, Incheon, South Korea
- * E-mail: (BHC); (KHK)
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29
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Luo L, Lai C, Feng T, Yao Y, Xue H, Xiang G, Luo L, Huang X. Umbilical cord blood-derived mesenchymal stem cells transplantation decreases incidence of liver cancer in end-stage liver disease patients: a retrospective analysis over 5 years. Am J Transl Res 2022; 14:5848-5858. [PMID: 36105061 PMCID: PMC9452340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 07/21/2022] [Indexed: 06/15/2023]
Abstract
OBJECTIVE To investigate effects of umbilical cord blood-derived mesenchymal stem cells (UC-MSCs) transplantation on the risks of liver cancers in end-stage liver disease (ESLD) patients. METHODS Data of 45 ESLD patients received UC-MSCs transplantation (UC-MSCs group) and 50 ESLD patients received non-UC-MSCs transplantation (non-UC-MSCs group) were retrospectively analyzed, and they were followed up for 5 years. RESULTS The incidence of liver cancer was much lower in UC-MSCs group than that in the non-UC-MSCs group (12% vs 2.2%, P=0.008). The survival rate of patients was significantly higher in the UC-MSCs group than that in the non-UC-MSCs group during the five years follow-up (P=0.043). The inflammation and fibrosis scores were lower in the UC-MSCs group than those in the non-UC-MSCs group (P<0.036). Compared with the non-UC-MSCs group, the UC-MSCs group showed largely improved liver cirrhosis degree and lower Child-Pugh scores (P<0.05). CONCLUSIONS UC-MSCs transplantation is able to decrease the risks of liver cancers in ESLD patients, which might work by inhibiting inflammation.
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Affiliation(s)
- Le Luo
- Department of Hepatobiliary and Pancreatic Surgery Center & Cell Transplantation Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China Chengdu 610072, Sichuan Province, China
| | - Chunyou Lai
- Department of Hepatobiliary and Pancreatic Surgery Center & Cell Transplantation Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China Chengdu 610072, Sichuan Province, China
| | - Tianhang Feng
- Department of Hepatobiliary and Pancreatic Surgery Center & Cell Transplantation Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China Chengdu 610072, Sichuan Province, China
| | - Yutong Yao
- Department of Hepatobiliary and Pancreatic Surgery Center & Cell Transplantation Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China Chengdu 610072, Sichuan Province, China
| | - Hua Xue
- Department of Hepatobiliary and Pancreatic Surgery Center & Cell Transplantation Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China Chengdu 610072, Sichuan Province, China
| | - Guangming Xiang
- Department of Hepatobiliary and Pancreatic Surgery Center & Cell Transplantation Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China Chengdu 610072, Sichuan Province, China
| | - Lanyun Luo
- Department of Hepatobiliary and Pancreatic Surgery Center & Cell Transplantation Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China Chengdu 610072, Sichuan Province, China
| | - Xiaolun Huang
- Department of Hepatobiliary and Pancreatic Surgery Center & Cell Transplantation Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China Chengdu 610072, Sichuan Province, China
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Liu C, Xiao K, Xie L. Advances in mesenchymal stromal cell therapy for acute lung injury/acute respiratory distress syndrome. Front Cell Dev Biol 2022; 10:951764. [PMID: 36036014 PMCID: PMC9399751 DOI: 10.3389/fcell.2022.951764] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 07/19/2022] [Indexed: 11/29/2022] Open
Abstract
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) develops rapidly and has high mortality. ALI/ARDS is mainly manifested as acute or progressive hypoxic respiratory failure. At present, there is no effective clinical intervention for the treatment of ALI/ARDS. Mesenchymal stromal cells (MSCs) show promise for ALI/ARDS treatment due to their biological characteristics, easy cultivation, low immunogenicity, and abundant sources. The therapeutic mechanisms of MSCs in diseases are related to their homing capability, multidirectional differentiation, anti-inflammatory effect, paracrine signaling, macrophage polarization, the polarization of the MSCs themselves, and MSCs-derived exosomes. In this review, we discuss the pathogenesis of ALI/ARDS along with the biological characteristics and mechanisms of MSCs in the treatment of ALI/ARDS.
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Affiliation(s)
- Chang Liu
- School of Medicine, Nankai University, Tianjin, China
- Center of Pulmonary and Critical Care Medicine, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Medical School of Chinese People’s Liberation Army (PLA), Beijing, China
| | - Kun Xiao
- Center of Pulmonary and Critical Care Medicine, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Medical School of Chinese People’s Liberation Army (PLA), Beijing, China
- *Correspondence: Kun Xiao, ; Lixin Xie,
| | - Lixin Xie
- School of Medicine, Nankai University, Tianjin, China
- Center of Pulmonary and Critical Care Medicine, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Medical School of Chinese People’s Liberation Army (PLA), Beijing, China
- *Correspondence: Kun Xiao, ; Lixin Xie,
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Wang Z, Zhong C, Li H. Histone demethylase KDM5B catalyzed H3K4me3 demethylation to promote differentiation of bone marrow mesenchymal stem cells into cardiomyocytes. Mol Biol Rep 2022; 49:7239-7249. [PMID: 35788877 PMCID: PMC9304058 DOI: 10.1007/s11033-022-07428-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Accepted: 03/24/2022] [Indexed: 11/24/2022]
Abstract
Background Studies have shown that histone H3 methylation is involved in regulating the differentiation of Bone Marrow Mesenchymal Stem Cells (BMSCs). KDM5B can specifically reduce the level of histone 3 lysine 4 trimethylation (H3K4me3), thereby activating the expression of related genes and participating in biological processes such as cell differentiation, embryonic development and tumor formation. Whether KDM5B is involved in the regulation of BMSCs differentiation into cardiomyocytes through the above manner has not been reported. Objective To investigate the effect of KDM5B on the induction and differentiation of swine BMSCs into myocardial cells in vitro. Methods Swine bone marrow BMSCs were isolated and cultured, and the overexpression, interference expression and blank vector of KMD5B were constructed and transfected by lentivirus. BMSCs was induced to differentiate into cardiomyocytes by 5-azacytidine (5-AZA) in vitro, and the differentiation efficiency was compared by immunofluorescence, RT-PCR, Western Blot and whole-cell patch clamp detection. Result Compared with the control group, the expression levels of histone H3K4me3 and pluripotency gene Nanog in KDM5B overexpression group were significantly decreased, while the expression level of key myocardial gene HCN4 and myocardial marker gene α-Actin and cTNT were significantly increased, and the Na+ current density on the surface of differentiated myocardial cell membrane was significantly increased. Meanwhile, the corresponding results of the KDM5B silent expression group were just opposite. Conclusions It indicated that enhanced KDM5B expression could promote the differentiation of BMSCs into cardiomyocytes and improve the differentiation efficiency by controlling H3K4 methylation levels.
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Affiliation(s)
- Zhen Wang
- Medical College of Yangzhou University, Yangzhou, 225001, Jiangsu, China.,Friendliness Hospital Yangzhou, Jiangsu, 225009, China
| | - Chenlu Zhong
- Medical College of Yangzhou University, Yangzhou, 225001, Jiangsu, China.,Department of Cardiology, Northern Jiangsu People's Hospital, Yangzhou, 225001, Jiangsu, China
| | - Hongxiao Li
- Medical College of Yangzhou University, Yangzhou, 225001, Jiangsu, China. .,Department of Cardiology, Northern Jiangsu People's Hospital, Yangzhou, 225001, Jiangsu, China.
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Jahnavi S, Garg V, Vasandan AB, SundarRaj S, Kumar A, Prasanna S J. Lineage reprogramming of human adipose mesenchymal stem cells to immune modulatory i-Heps. Int J Biochem Cell Biol 2022; 149:106256. [PMID: 35772664 DOI: 10.1016/j.biocel.2022.106256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 06/14/2022] [Accepted: 06/24/2022] [Indexed: 11/19/2022]
Abstract
Pluripotent stem cell derived-hepatocytes depict fetal -hepatocyte characteristics/maturity and are immunogenic limiting their applications. Attempts have been made to derive hepatocytes from mesenchymal stem cells using developmental cocktails, epigenetic modulators and small molecules. However, achieving a stable terminally differentiated functional state had been a challenge. Inefficient hepatic differentiation could be due to lineage restrictions set during development. Hence a novel lineage reprogramming approach has been utilized to confer competence to adipose-mesenchymal stem cells (ADMSCs) to efficiently respond to hepatogenic cues and achieve a stable functional hepatic state. Lineage reprogramming involved co-transduction of ADMSCs with hepatic endoderm pioneer Transcription factor (TF)-FOXA2, HHEX-a homeobox gene and HNF4α-master TF indispensable for hepatic state maintenance. Lineage priming was evidenced by endogenous HFN4α promoter demethylation and robust responsiveness to minimal hepatic maturation cues. Induced hepatocytes (i-Heps) exhibited mesenchymal-to-epithelial transition and terminal hepatic signatures. Functional characterisation of i-Heps for hepatic drug detoxification systems, xenobiotic uptake/clearance, metabolic status and hepatotropic virus entry validated acquisition of stable hepatic state and junctional maturity Exhaustive analysis of MSC memory in i-Heps indicated loss of MSC-immunophenotype and terminal differentiation to osteogenic/adipogenic lineages. Importantly, i-Heps suppressed phytohemagglutinin-induced T-cell blasts, inhibited allogenic mixed-lymphocyte reactions (MLRs) and secreted immunomodulatory- indoleamine 2,3-dioxygenase in T-cell blast co-cultures akin to native ADMSCs. In a nutshell, the present study identifies a novel cocktail of TFs that reprogram ADMSCs to stable hepatic state. i-Heps exhibit adult hepatocyte functional maturity with robust immune-modulatory abilities rendering suitability for rigorous drug testing, hepatocyte-pathogen interaction studies and transplantation in allogenic settings.
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Affiliation(s)
- Sowmya Jahnavi
- Manipal Institute of Regenerative Medicine, MAHE, Bangalore, India
| | - Vaishali Garg
- Manipal Institute of Regenerative Medicine, MAHE, Bangalore, India
| | | | - Swathi SundarRaj
- Principal Scientist, Stempeutics Research Pvt. Ltd, Bangalore, India
| | - Anujith Kumar
- Manipal Institute of Regenerative Medicine, MAHE, Bangalore, India
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Masoudi MR, Rafati A. Immunogenicity against hepatitis C virus with mesenchymal stem cells of inbreed BALB/c mice sub cloned with HCVcp protein gene. Transpl Immunol 2022; 74:101651. [PMID: 35764239 DOI: 10.1016/j.trim.2022.101651] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 06/09/2022] [Accepted: 06/22/2022] [Indexed: 10/17/2022]
Abstract
BACKGROUND AND AIM Hepatitis C is one of the leading causes of liver disease in the world and despite extensive research, there is still no vaccine against it. Researchers have identified cell-based therapies as an alternative strategy in advanced liver disorders. The aim of this study was to transfer the hepatitis C virus core protein (HCVcp) gene into mesenchymal stem cells and to evaluate its immunogenicity after injection into mice. MATERIALS AND METHODS The present study had two experimental and animal stages. In the first step, by designing a vector containing the HCVcp gene and transferring it into the mesenchymal stem cell, gene expression and protein production by the mesenchymal stem cell manipulated by PCR and SDS-PAGE were confirmed. In the second stage, by injecting manipulated mesenchymal stem cells into mice, the level of humoral immune stimulation and splenocytes proliferation was assessed by the ELISA commercial kit. RESULTS According to molecular studies, the expression of HCVcp was confirmed by mesenchymal stem cells. Also, splenocytes proliferation rate (0.316 ± 0.029) and antibody titer (284 ± 47) in mice treated with manipulated mesenchymal stem cells were significantly increased compared to the control group. CONCLUSION The results of the present study showed that the use of genetically engineered mesenchymal stem cells while maintaining the immunomodulatory properties of these cells can stimulate specific immune system responses against hepatitis C central protein.
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Affiliation(s)
- Mahmood Reza Masoudi
- Department of Internal Medicine, Sirjan School of Medical Sciences, Sirjan, Iran
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Zhang L, Ma XJN, Fei YY, Han HT, Xu J, Cheng L, Li X. Stem cell therapy in liver regeneration: Focus on mesenchymal stem cells and induced pluripotent stem cells. Pharmacol Ther 2022; 232:108004. [PMID: 34597754 DOI: 10.1016/j.pharmthera.2021.108004] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 08/11/2021] [Accepted: 09/23/2021] [Indexed: 02/07/2023]
Abstract
The liver has the ability to repair itself after injury; however, a variety of pathological changes in the liver can affect its ability to regenerate, and this could lead to liver failure. Mesenchymal stem cells (MSCs) are considered a good source of cells for regenerative medicine, as they regulate liver regeneration through different mechanisms, and their efficacy has been demonstrated by many animal experiments and clinical studies. Induced pluripotent stem cells, another good source of MSCs, have also made great progress in the establishment of organoids, such as liver disease models, and in drug screening. Owing to the recent developments in MSCs and induced pluripotent stem cells, combined with emerging technologies including graphene, nano-biomaterials, and gene editing, precision medicine and individualized clinical treatment may be realized in the near future.
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Affiliation(s)
- Lu Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China; The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Xiao-Jing-Nan Ma
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Yuan-Yuan Fei
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China
| | - Heng-Tong Han
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Jun Xu
- The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China
| | - Lu Cheng
- Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China
| | - Xun Li
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, PR China; Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, Lanzhou 730000, PR China; Hepatopancreatobiliary Surgery Institute of Gansu Province, Lanzhou 730000, PR China; The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, PR China.
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Tang S, Bai L, Duan Z, Zheng S. Stem Cells Treatment for Wilson Disease. Curr Stem Cell Res Ther 2022; 17:712-719. [PMID: 34615454 DOI: 10.2174/1574888x16666211006111556] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 07/21/2021] [Accepted: 07/27/2021] [Indexed: 11/22/2022]
Abstract
Wilson Disease (WD) is a copper excretion disorder, mainly caused by mutations in the ATP7B gene. Pharmacological therapies and liver transplantation are currently the main treatment methods for WD, but they face problems such as drug treatment compliance, adverse reactions, and shortage of liver donors. Stem cell therapy of WD may correct abnormal copper metabolism permanently, which is the focus of current research. In this review, we summarized the latest research on stem cells treatment for WD, as well as current challenges and future expectations.
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Affiliation(s)
- Shan Tang
- The First Unit, Department of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Li Bai
- The Fourth Unit, Department of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Liver Failure and Artificial Liver Treatment Research, China
| | - Zhongping Duan
- The Fourth Unit, Department of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Sujun Zheng
- The First Unit, Department of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
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36
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Synthesis, photophysical characterization, relaxometric studies and molecular docking studies of gadolinium-free contrast agents for dual modal imaging. RESULTS IN CHEMISTRY 2022. [DOI: 10.1016/j.rechem.2022.100307] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
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Nazarie (Ignat) SR, Gharbia S, Hermenean A, Dinescu S, Costache M. Regenerative Potential of Mesenchymal Stem Cells' (MSCs) Secretome for Liver Fibrosis Therapies. Int J Mol Sci 2021; 22:ijms222413292. [PMID: 34948088 PMCID: PMC8705326 DOI: 10.3390/ijms222413292] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/07/2021] [Accepted: 12/08/2021] [Indexed: 12/11/2022] Open
Abstract
Chronic liver injuries lead to liver fibrosis and then to end-stage liver cirrhosis. Liver transplantation is often needed as a course of treatment for patients in critical conditions, but limitations associated with transplantation prompted the continuous search for alternative therapeutic strategies. Cell therapy with stem cells has emerged as an attractive option in order to stimulate tissue regeneration and liver repair. Transplanted mesenchymal stem cells (MSCs) could trans-differentiate into hepatocyte-like cells and, moreover, show anti-fibrotic and immunomodulatory effects. However, cell transplantation may lead to some uncontrolled side effects, risks associated with tumorigenesis, and cell rejection. MSCs' secretome includes a large number of soluble factors and extracellular vesicles (EVs), through which they exert their therapeutic role. This could represent a cell-free strategy, which is safer and more effective than MSC transplantation. In this review, we focus on cell therapies based on MSCs and how the MSCs' secretome impacts the mechanisms associated with liver diseases. Moreover, we discuss the important therapeutic role of EVs and how their properties could be further used in liver regeneration.
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Affiliation(s)
- Simona-Rebeca Nazarie (Ignat)
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050663 Bucharest, Romania; (S.-R.N.); (S.G.); (A.H.); (M.C.)
| | - Sami Gharbia
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050663 Bucharest, Romania; (S.-R.N.); (S.G.); (A.H.); (M.C.)
- “Aurel Ardelean” Institute of Life Sciences, “Vasile Goldiș” Western University of Arad, 310025 Arad, Romania
| | - Anca Hermenean
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050663 Bucharest, Romania; (S.-R.N.); (S.G.); (A.H.); (M.C.)
- “Aurel Ardelean” Institute of Life Sciences, “Vasile Goldiș” Western University of Arad, 310025 Arad, Romania
| | - Sorina Dinescu
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050663 Bucharest, Romania; (S.-R.N.); (S.G.); (A.H.); (M.C.)
- The Research Institute of the University of Bucharest (ICUB), University of Bucharest, 050663 Bucharest, Romania
- Correspondence:
| | - Marieta Costache
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050663 Bucharest, Romania; (S.-R.N.); (S.G.); (A.H.); (M.C.)
- The Research Institute of the University of Bucharest (ICUB), University of Bucharest, 050663 Bucharest, Romania
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Cell-Based Regeneration and Treatment of Liver Diseases. Int J Mol Sci 2021; 22:ijms221910276. [PMID: 34638617 PMCID: PMC8508969 DOI: 10.3390/ijms221910276] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 09/13/2021] [Accepted: 09/23/2021] [Indexed: 12/11/2022] Open
Abstract
The liver, in combination with a functional biliary system, is responsible for maintaining a great number of vital body functions. However, acute and chronic liver diseases may lead to irreversible liver damage and, ultimately, liver failure. At the moment, the best curative option for patients suffering from end-stage liver disease is liver transplantation. However, the number of donor livers required by far surpasses the supply, leading to a significant organ shortage. Cellular therapies play an increasing role in the restoration of organ function and can be integrated into organ transplantation protocols. Different types and sources of stem cells are considered for this purpose, but highly specific immune cells are also the focus of attention when developing individualized therapies. In-depth knowledge of the underlying mechanisms governing cell differentiation and engraftment is crucial for clinical implementation. Additionally, novel technologies such as ex vivo machine perfusion and recent developments in tissue engineering may hold promising potential for the implementation of cell-based therapies to restore proper organ function.
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Zhang N, Zhao L, Liu D, Hu C, Wang Y, He T, Bi Y, He Y. Characterization of Urine-Derived Stem Cells from Patients with End-Stage Liver Diseases and Application to Induced Acute and Chronic Liver Injury of Nude Mice Model. Stem Cells Dev 2021; 30:1126-1138. [PMID: 34549601 DOI: 10.1089/scd.2021.0137] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Urine-derived stem cells (USCs) are adult stem cells isolated from urine with strong proliferative ability and differentiation potentials. Cell transplantation of USCs could partly repair liver injury. It has been reported that the proliferative ability of bone mesenchymal stem cells in patients with chronic liver failure is significantly lower than in patients without liver disease. The aim of this study was therefore to evaluate the biological characteristics of USCs from end-stage liver disease patients (LD-USCs, USCs from patients with liver disease) compared with those from normal healthy individuals (N-USCs, USCs from normal individuals), with a view to determining whether autologous USCs can be applied to the treatment of liver disease. In this study USCs were isolated from urine samples of male patients with end-stage liver disease. Adherent USCs exhibit a spindle- or rice grain-like morphology, and express CD24, CD29, CD73, CD90, and CD146 surface markers, but not CD31, CD34, CD45, and CD105. We observed no differences in cell morphology or cell surface marker profile between LD-USCs and N-USCs. LD-USCs exhibited similar proliferative, colony-forming, apoptotic, and migratory abilities to N-USCs. Both USCs demonstrated similar capacities for osteogenic, adipogenic, and chondrogenic differentiation. When USCs were transplanted into CCl4 treatment-induced acute and chronic liver fibrosis mouse models, we observed a decrease in liver index, recovery of alanine aminotransferase and aspartate aminotransferase levels, alleviation of liver tissue injury, and dramatic improvement of liver tissue structure. USC transplantation can effectively recover liver function and improve liver tissue damage in acute or chronic liver injury mouse models. According to the results, we concluded that the biological characteristics of LD-USCs are not affected by basic liver disease. This study provides further evidence of the stem cell characteristics and liver repair function of LD-USCs, which may serve as a theoretical and experimental foundation for autologous USC transplantation technology in the treatment of liver failure and end-stage liver diseases.
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Affiliation(s)
- Nannan Zhang
- Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Li Zhao
- Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Daijiang Liu
- Department of Gastroenterology, Chongqing Emergency Medical Center, Chongqing, China
| | - Chaoqun Hu
- Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Yi Wang
- Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Tongchuan He
- Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois, USA
| | - Yang Bi
- Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Yun He
- Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China
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Lo Nigro A, Gallo A, Bulati M, Vitale G, Paini DS, Pampalone M, Galvagno D, Conaldi PG, Miceli V. Amnion-Derived Mesenchymal Stromal/Stem Cell Paracrine Signals Potentiate Human Liver Organoid Differentiation: Translational Implications for Liver Regeneration. Front Med (Lausanne) 2021; 8:746298. [PMID: 34631757 PMCID: PMC8494784 DOI: 10.3389/fmed.2021.746298] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 08/30/2021] [Indexed: 02/05/2023] Open
Abstract
The prevalence of end-stage liver diseases has reached very high levels globally. The election treatment for affected patients is orthotopic liver transplantation, which is a very complex procedure, and due to the limited number of suitable organ donors, considerable research is being done on alternative therapeutic options. For instance, the use of cell therapy, such as the transplantation of hepatocytes to promote liver repair/regeneration, has been explored, but standardized protocols to produce suitable human hepatocytes are still limited. On the other hand, liver progenitor and multipotent stem cells offer potential cell sources that could be used clinically. Different studies have reported regarding the therapeutic effects of transplanted mesenchymal stromal/stem cells (MSCs) on end-stage liver diseases. Moreover, it has been shown that delivery of MSC-derived conditioned medium (MSC-CM) can reduce cell death and enhance liver proliferation in fulminant hepatic failure. Therefore, it is believed that MSC-CM contains many factors that probably support liver regeneration. In our work, we used an in vitro model of human liver organoids to study if the paracrine components secreted by human amnion-derived MSCs (hAMSCs) affected liver stem/progenitor cell differentiation. In particular, we differentiated liver organoids derived from bipotent EpCAM+ human liver cells and tested the effects of hAMSC secretome, derived from both two-dimensional (2D) and three-dimensional (3D) hAMSC cultures, on that model. Our analysis showed that conditioned medium (CM) produced by 3D hAMSCs was able to induce an over-expression of mature hepatocyte markers, such as ALB, NTCP, and CYP3A4, compared with both 2D hAMSC cultures and the conventional differentiation medium (DM). These data were confirmed by the over-production of ALB protein and over-activity of CYP3A4 observed in organoids grown in 3D hAMSC-CM. Liver repair dysfunction plays a role in the development of liver diseases, and effective repair likely requires the normal functioning of liver stem/progenitor cells. Herein, we showed that hAMSC-CM produced mainly by 3D cultures had the potential to increase hepatic stem/progenitor cell differentiation, demonstrating that soluble factors secreted by those cells are potentially responsible for the reaction. This work shows a potential approach to improve liver repair/regeneration also in a transplantation setting.
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Affiliation(s)
| | - Alessia Gallo
- Research Department, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS ISMETT), Palermo, Italy
| | - Matteo Bulati
- Research Department, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS ISMETT), Palermo, Italy
| | | | | | - Mariangela Pampalone
- Ri.MED Foundation, Palermo, Italy
- Research Department, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS ISMETT), Palermo, Italy
| | | | - Pier Giulio Conaldi
- Research Department, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS ISMETT), Palermo, Italy
| | - Vitale Miceli
- Research Department, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS ISMETT), Palermo, Italy
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Tumor-associated mesenchymal stem cells promote hepatocellular carcinoma metastasis via a DNM3OS/KDM6B/TIAM1 axis. Cancer Lett 2021; 503:19-31. [PMID: 33472090 DOI: 10.1016/j.canlet.2021.01.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 12/12/2020] [Accepted: 01/13/2021] [Indexed: 02/06/2023]
Abstract
Tumor-associated mesenchymal stem cells (MSCs) play a critical role in the growth and metastasis of hepatocellular carcinoma (HCC). However, the mechanism underlying the crosstalk between MSCs and HCC cells is not completely understood. Here, HCC cells were treated with or without conditioned medium of MSCs (CM-MSC), and examined for differential expression of long non-coding RNAs (lncRNAs). Knockdown and overexpression experiments were conducted to explore the function of the lncRNA DNM3OS in MSC-induced HCC growth and metastasis. CM-MSC treatment led to a concentration-dependent induction of DNM3OS in HCC cells. DNM3OS was significantly upregulated in HCC compared to adjacent liver tissues. High DNM3OS expression was associated with TNM stage, vascular invasion, and poor prognosis of HCC patients. Silencing of DNM3OS inhibited HCC cell proliferation and invasion in vitro and tumorigenesis and metastasis in vivo. Overexpression of DNM3OS enhanced HCC cell proliferation, invasion, and metastasis. Biochemically, DNM3OS was mainly localized in the nucleus and physically interacted with KDM6B. The association of DNM3OS with KDM6B induced the expression of TIAM1 through reduction of H3K27me3 at the TIAM1 promoter. TIAM1 overexpression restored the proliferation and invasion of DNM3OS-depleted HCC cells. Our data delineate a mechanism by which MSCs accelerate HCC growth and metastasis through a DNM3OS/KDM6B/TIAM1 axis.
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Suhito IR, Koo KM, Kim TH. Recent Advances in Electrochemical Sensors for the Detection of Biomolecules and Whole Cells. Biomedicines 2020; 9:15. [PMID: 33375330 PMCID: PMC7824644 DOI: 10.3390/biomedicines9010015] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 12/22/2020] [Accepted: 12/23/2020] [Indexed: 02/06/2023] Open
Abstract
Electrochemical sensors are considered an auspicious tool to detect biomolecules (e.g., DNA, proteins, and lipids), which are valuable sources for the early diagnosis of diseases and disorders. Advances in electrochemical sensing platforms have enabled the development of a new type of biosensor, enabling label-free, non-destructive detection of viability, function, and the genetic signature of whole cells. Numerous studies have attempted to enhance both the sensitivity and selectivity of electrochemical sensors, which are the most critical parameters for assessing sensor performance. Various nanomaterials, including metal nanoparticles, carbon nanotubes, graphene and its derivatives, and metal oxide nanoparticles, have been used to improve the electrical conductivity and electrocatalytic properties of working electrodes, increasing sensor sensitivity. Further modifications have been implemented to advance sensor platform selectivity and biocompatibility using biomaterials such as antibodies, aptamers, extracellular matrix (ECM) proteins, and peptide composites. This paper summarizes recent electrochemical sensors designed to detect target biomolecules and animal cells (cancer cells and stem cells). We hope that this review will inspire researchers to increase their efforts to accelerate biosensor progress-enabling a prosperous future in regenerative medicine and the biomedical industry.
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Affiliation(s)
- Intan Rosalina Suhito
- School of Integrative Engineering, Chung-Ang University, Seoul 06974, Korea; (I.R.S.); (K.-M.K.)
| | - Kyeong-Mo Koo
- School of Integrative Engineering, Chung-Ang University, Seoul 06974, Korea; (I.R.S.); (K.-M.K.)
| | - Tae-Hyung Kim
- School of Integrative Engineering, Chung-Ang University, Seoul 06974, Korea; (I.R.S.); (K.-M.K.)
- Integrative Research Center for Two-Dimensional Functional Materials, Institute of Interdisciplinary Convergence Research, Chung Ang University, Seoul 06974, Korea
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Lee SW, Jung DJ, Jeong GS. Gaining New Biological and Therapeutic Applications into the Liver with 3D In Vitro Liver Models. Tissue Eng Regen Med 2020; 17:731-745. [PMID: 32207030 PMCID: PMC7710770 DOI: 10.1007/s13770-020-00245-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 02/17/2020] [Accepted: 02/18/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Three-dimensional (3D) cell cultures with architectural and biomechanical properties similar to those of natural tissue have been the focus for generating liver tissue. Microarchitectural organization is believed to be crucial to hepatic function, and 3D cell culture technologies have enabled the construction of tissue-like microenvironments, thereby leading to remarkable progress in vitro models of human tissue and organs. Recently, to recapitulate the 3D architecture of tissues, spheroids and organoids have become widely accepted as new practical tools for 3D organ modeling. Moreover, the combination of bioengineering approach offers the promise to more accurately model the tissue microenvironment of human organs. Indeed, the employment of sophisticated bioengineered liver models show long-term viability and functional enhancements in biochemical parameters and disease-orient outcome. RESULTS Various 3D in vitro liver models have been proposed as a new generation of liver medicine. Likewise, new biomedical engineering approaches and platforms are available to more accurately replicate the in vivo 3D microarchitectures and functions of living organs. This review aims to highlight the recent 3D in vitro liver model systems, including micropatterning, spheroids, and organoids that are either scaffold-based or scaffold-free systems. Finally, we discuss a number of challenges that will need to be addressed moving forward in the field of liver tissue engineering for biomedical applications. CONCLUSION The ongoing development of biomedical engineering holds great promise for generating a 3D biomimetic liver model that recapitulates the physiological and pathological properties of the liver and has biomedical applications.
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Affiliation(s)
- Sang Woo Lee
- Biomedical Engineering Research Center, Asan Institute for Life Sciences, Asan Medical Center, 88 Olympic-Ro 43 Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Da Jung Jung
- Biomedical Engineering Research Center, Asan Institute for Life Sciences, Asan Medical Center, 88 Olympic-Ro 43 Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Gi Seok Jeong
- Biomedical Engineering Research Center, Asan Institute for Life Sciences, Asan Medical Center, 88 Olympic-Ro 43 Gil, Songpa-Gu, Seoul, 05505, Republic of Korea.
- Department of Convergence Medicine, University of Ulsan College of Medicine, 88 Olympic-Ro 43 Gil, Songpa-Gu, Seoul, 05505, Republic of Korea.
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Zhou GP, Sun LY, Zhu ZJ. The concept of "domino" in liver and hepatocyte transplantation. Therap Adv Gastroenterol 2020; 13:1756284820968755. [PMID: 33149765 PMCID: PMC7586492 DOI: 10.1177/1756284820968755] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 10/01/2020] [Indexed: 02/04/2023] Open
Abstract
Although orthotopic liver transplantation remains the only proven treatment for end-stage liver disease and inherited metabolic liver disease, its application has been limited by the scarcity of donor organs available for transplantation. Among feasible approaches developed to expand the donor organ pool, domino liver transplantation is a strategy in which explanted genetically defective livers of liver transplant recipients are used as grafts in other patients. Another promising therapeutic strategy is hepatocyte transplantation, an alternative to liver transplantation for certain groups of patients. However, the availability of primary hepatocytes is also hindered by the shortage of donor liver tissues. Against this background, domino hepatocyte transplantation, a strategy that utilizes the hepatocytes derived from the explanted livers of liver transplant recipients with noncirrhotic inherited metabolic liver diseases as the source of primary hepatocytes, may help increase the supply of liver cells available for transplantation. In this review, we focus on the status quo of domino liver transplantation and domino hepatocyte transplantation. We also describe recent innovative transplant strategies based on domino transplantation.
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Affiliation(s)
- Guang-Peng Zhou
- Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China,Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing, China
| | - Li-Ying Sun
- Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China,Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing, China,Intensive Care Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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Kao YH, Lin YC, Lee PH, Lin CW, Chen PH, Tai TS, Chang YC, Chou MH, Chang CY, Sun CK. Infusion of Human Mesenchymal Stem Cells Improves Regenerative Niche in Thioacetamide-Injured Mouse Liver. Tissue Eng Regen Med 2020; 17:671-682. [PMID: 32880852 DOI: 10.1007/s13770-020-00274-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 05/13/2020] [Accepted: 05/14/2020] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND This study investigated whether xenotransplantation of human Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) reduces thioacetamide (TAA)-induced mouse liver fibrosis and the underlying molecular mechanism. METHODS Recipient NOD/SCID mice were injected intraperitoneally with TAA twice weekly for 6 weeks before initial administration of WJ-MSCs. Expression of regenerative and pro-fibrogenic markers in mouse fibrotic livers were monitored post cytotherapy. A hepatic stallate cell line HSC-T6 and isolated WJ-MSCs were used for in vitro adhesion, migration and mechanistic studies. RESULTS WJ-MSCs were isolated from human umbilical cords by an explant method and characterized by flow cytometry. A single infusion of WJ-MSCs to TAA-treated mice significantly reduced collagen deposition and ameliorated liver fibrosis after 2-week therapy. In addition to enhanced expression of hepatic regenerative factor, hepatocyte growth factor, and PCNA proliferative marker, WJ-MSC therapy significantly blunted pro-fibrogenic signals, including Smad2, RhoA, ERK. Intriguingly, reduction of plasma fibronectin (pFN) in fibrotic livers was noted in MSC-treated mice. In vitro studies further demonstrated that suspending MSCs triggered pFN degradation, soluble pFN conversely retarded adhesion of suspending MSCs onto type I collagen-coated surface, whereas pFN coating enhanced WJ-MSC migration across mimicked wound bed. Moreover, pretreatment with soluble pFN and conditioned medium from MSCs with pFN strikingly attenuated the response of HSC-T6 cells to TGF-β1-stimulation in Smad2 phosphorylation and RhoA upregulation. CONCLUSION These findings suggest that cytotherapy using WJ-MSCs may modulate hepatic pFN deposition for a better regenerative niche in the fibrotic livers and may constitute a useful anti-fibrogenic intervention in chronic liver diseases.
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Affiliation(s)
- Ying-Hsien Kao
- Department of Medical Research, E-Da Hospital, No. 1, Yida Rd., Yanchau District, Kaohsiung, 82445, Taiwan
| | - Yu-Chun Lin
- Department of Surgery, E-Da Hospital, Kaohsiung, Taiwan
| | - Po-Huang Lee
- Department of Surgery, E-Da Hospital, Kaohsiung, Taiwan.,Committee for Integration and Promotion of Advanced Medicine and Biotechnology, E-Da Healthcare Group, Kaohsiung, Taiwan
| | - Chia-Wei Lin
- Department of Ophthalmology, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Po-Han Chen
- Department of Medical Research, E-Da Hospital, No. 1, Yida Rd., Yanchau District, Kaohsiung, 82445, Taiwan
| | - Tzong-Shyuan Tai
- Department of Medical Research, E-Da Hospital, No. 1, Yida Rd., Yanchau District, Kaohsiung, 82445, Taiwan
| | - Yo-Chen Chang
- Department of Ophthalmology, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Huei Chou
- Graduate Institute of Clinical Medical Sciences, Chang Gung University College Medicine, Kaohsiung, Taiwan.,Center for General Education, Cheng-Shiu University, Kaohsiung, Taiwan
| | - Chih-Yang Chang
- Department of Gynecology and Obstetrics, E-Da Hospital, I-Shou University, No. 1, Yida Rd., Yanchau District, Kaohsiung, 82445, Taiwan.
| | - Cheuk-Kwan Sun
- Department of Medical Research, E-Da Hospital, No. 1, Yida Rd., Yanchau District, Kaohsiung, 82445, Taiwan. .,The School of Medicine for International Students, I-Shou University, Kaohsiung, Taiwan.
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Choi B, Park W, Park SB, Rhim WK, Han DK. Recent trends in cell membrane-cloaked nanoparticles for therapeutic applications. Methods 2019; 177:2-14. [PMID: 31874237 DOI: 10.1016/j.ymeth.2019.12.004] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 12/17/2019] [Accepted: 12/17/2019] [Indexed: 12/22/2022] Open
Abstract
Synthetic nanoparticles are extensively utilized in various biomedical engineering fields because of their unique physicochemical properties. However, their exogenous characteristics result in synthetic nanosystem invaders that easily induce the passive immune clearance mechanism, thereby increasing the retention effect caused by reticuloendothelial system (RES), resulting in low therapeutic efficacy and toxic effects. Recently, a cell membrane cloaking has been emerging technique as a novel interfacing approach from the biological/immunological perspective. This has been considered as useful technique for improving the performance of synthetic nanocarriers in vivo. By cell membrane cloaking, nanoparticles acquire the biological functions of natural cell membranes due to the presence of membrane-anchored proteins, antigens, and immunological moieties as well as physicochemical property of natural cell membrane. Due to cell membrane cloaking, the derived biological properties and functions of nanoparticles such as their immunosuppressive capability, long circulation time, and disease targeting ability have enhanced their future potential in biomedicine. Here, we review the cell membrane-cloaked nanosystems, highlight their novelty, introduce the preparation and characterization methods with relevant biomedical applications, and describe the prospects for using this novel biomimetic system that was developed from a combination of cell membranes and synthetic nanomaterials.
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Affiliation(s)
- Bogyu Choi
- Department of Biomedical Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam, Gyeonggi 13488, Republic of Korea
| | - Wooram Park
- Department of Biomedical Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam, Gyeonggi 13488, Republic of Korea
| | - Sung-Bin Park
- Department of Biomedical Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam, Gyeonggi 13488, Republic of Korea
| | - Won-Kyu Rhim
- Department of Biomedical Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam, Gyeonggi 13488, Republic of Korea.
| | - Dong Keun Han
- Department of Biomedical Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam, Gyeonggi 13488, Republic of Korea.
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Tsujimura M, Kusamori K, Nishikawa M. Rapid Regulation of Human Mesenchymal Stem Cell Proliferation Using Inducible Caspase-9 Suicide Gene for Safe Cell-Based Therapy. Int J Mol Sci 2019; 20:ijms20225759. [PMID: 31744061 PMCID: PMC6887989 DOI: 10.3390/ijms20225759] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 11/01/2019] [Accepted: 11/14/2019] [Indexed: 12/18/2022] Open
Abstract
The regulation of transplanted cell proliferation and function is important to achieve safe cell-based therapies. We previously reported that the proliferation and function of transplanted cells, which expressed the herpes simplex virus thymidine kinase (HSVtk) suicide gene, could be controlled by ganciclovir (GCV) administration. However, there are some concerns regarding the use of GCV. It is reported that the inducible caspase-9 (iC9) gene, a human caspase-9-derived genetically engineered suicide gene, rapidly induces cell apoptosis in the presence of apoptosis inducers, such as AP20187. In this study, we used a combination of the iC9 gene and AP20187 to achieve rapid regulation of transplanted cell proliferation. Cells from the human mesenchymal stem cell line UE7T-13 were transfected with the iC9 gene to obtain UE7T-13/iC9 cells. AP20187 significantly reduced the number of UE7T-13/iC9 cells within 24 h in a concentration-dependent manner. This reduction was much faster than the reduction of HSVtk-expressing UE7T-13 cells induced by GCV addition. Subcutaneous AP20187 administration rapidly reduced the luminescence signal from NanoLuc luciferase (Nluc)-expressing UE7T-13/iC9 cells transplanted into mice. These results indicate that the combined use of the iC9 gene and AP20187 is effective in rapidly regulating transplanted cell proliferation.
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Affiliation(s)
| | - Kosuke Kusamori
- Correspondence: ; Tel.: +81-4-7124-1501; Fax: +81-4-7121-4450
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Abughanam G, Elkashty OA, Liu Y, Bakkar MO, Tran SD. Mesenchymal Stem Cells Extract (MSCsE)-Based Therapy Alleviates Xerostomia and Keratoconjunctivitis Sicca in Sjogren's Syndrome-Like Disease. Int J Mol Sci 2019; 20:ijms20194750. [PMID: 31557796 PMCID: PMC6801785 DOI: 10.3390/ijms20194750] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 09/19/2019] [Accepted: 09/20/2019] [Indexed: 12/16/2022] Open
Abstract
Sjogren’s syndrome (SS) is an autoimmune disease that manifests primarily in salivary and lacrimal glands leading to dry mouth and eyes. Unfortunately, there is no cure for SS due to its complex etiopathogenesis. Mesenchymal stem cells (MSCs) were successfully tested for SS, but some risks and limitations remained for their clinical use. This study combined cell- and biologic-based therapies by utilizing the MSCs extract (MSCsE) to treat SS-like disease in NOD mice. We found that MSCsE and MSCs therapies were successful and comparable in preserving salivary and lacrimal glands function in NOD mice when compared to control group. Cells positive for AQP5, AQP4, α-SMA, CK5, and c-Kit were preserved. Gene expression of AQP5, EGF, FGF2, BMP7, LYZ1 and IL-10 were upregulated, and downregulated for TNF-α, TGF-β1, MMP2, CASP3, and IL-1β. The proliferation rate of the glands and serum levels of EGF were also higher. Cornea integrity and epithelial thickness were maintained due to tear flow rate preservation. Peripheral tolerance was re-established, as indicated by lower lymphocytic infiltration and anti-SS-A antibodies, less BAFF secretion, higher serum IL-10 levels and FoxP3+ Treg cells, and selective inhibition of B220+ B cells. These promising results opened new venues for a safer and more convenient combined biologic- and cell-based therapy.
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Affiliation(s)
- Ghada Abughanam
- McGill Craniofacial Tissue Engineering and Stem Cells Laboratory, Faculty of Dentistry, McGill University, Montreal, QC H3A 0C7, Canada.
| | - Osama A Elkashty
- McGill Craniofacial Tissue Engineering and Stem Cells Laboratory, Faculty of Dentistry, McGill University, Montreal, QC H3A 0C7, Canada.
| | - Younan Liu
- McGill Craniofacial Tissue Engineering and Stem Cells Laboratory, Faculty of Dentistry, McGill University, Montreal, QC H3A 0C7, Canada.
| | - Mohammed O Bakkar
- McGill Craniofacial Tissue Engineering and Stem Cells Laboratory, Faculty of Dentistry, McGill University, Montreal, QC H3A 0C7, Canada.
| | - Simon D Tran
- McGill Craniofacial Tissue Engineering and Stem Cells Laboratory, Faculty of Dentistry, McGill University, Montreal, QC H3A 0C7, Canada.
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