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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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Cancedda R, Mastrogiacomo M. The Phoenix of stem cells: pluripotent cells in adult tissues and peripheral blood. Front Bioeng Biotechnol 2024; 12:1414156. [PMID: 39139297 PMCID: PMC11319133 DOI: 10.3389/fbioe.2024.1414156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 07/09/2024] [Indexed: 08/15/2024] Open
Abstract
Pluripotent stem cells are defined as cells that can generate cells of lineages from all three germ layers, ectoderm, mesoderm, and endoderm. On the contrary, unipotent and multipotent stem cells develop into one or more cell types respectively, but their differentiation is limited to the cells present in the tissue of origin or, at most, from the same germ layer. Multipotent and unipotent stem cells have been isolated from a variety of adult tissues, Instead, the presence in adult tissues of pluripotent stem cells is a very debated issue. In the early embryos, all cells are pluripotent. In mammalians, after birth, pluripotent cells are maintained in the bone-marrow and possibly in gonads. In fact, pluripotent cells were isolated from marrow aspirates and cord blood and from cultured bone-marrow stromal cells (MSCs). Only in few cases, pluripotent cells were isolated from other tissues. In addition to have the potential to differentiate toward lineages derived from all three germ layers, the isolated pluripotent cells shared other properties, including the expression of cell surface stage specific embryonic antigen (SSEA) and of transcription factors active in the early embryos, but they were variously described and named. However, it is likely that they are part of the same cell population and that observed diversities were the results of different isolation and expansion strategies. Adult pluripotent stem cells are quiescent and self-renew at very low rate. They are maintained in that state under the influence of the "niche" inside which they are located. Any tissue damage causes the release in the blood of inflammatory cytokines and molecules that activate the stem cells and their mobilization and homing in the injured tissue. The inflammatory response could also determine the dedifferentiation of mature cells and their reversion to a progenitor stage and at the same time stimulate the progenitors to proliferate and differentiate to replace the damaged cells. In this review we rate articles reporting isolation and characterization of tissue resident pluripotent cells. In the attempt to reconcile observations made by different authors, we propose a unifying picture that could represent a starting point for future experiments.
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Affiliation(s)
- Ranieri Cancedda
- Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genova, Italy
| | - Maddalena Mastrogiacomo
- Dipartimento di Medicina Interna e Specialità Mediche (DIMI), Università Degli Studi di Genova, IRCCS Ospedale Policlinico San Martino, Genova, Italy
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Taherian M, Bayati P, Mojtabavi N. Stem cell-based therapy for fibrotic diseases: mechanisms and pathways. Stem Cell Res Ther 2024; 15:170. [PMID: 38886859 PMCID: PMC11184790 DOI: 10.1186/s13287-024-03782-5] [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: 01/29/2024] [Accepted: 06/04/2024] [Indexed: 06/20/2024] Open
Abstract
Fibrosis is a pathological process, that could result in permanent scarring and impairment of the physiological function of the affected organ; this condition which is categorized under the term organ failure could affect various organs in different situations. The involvement of the major organs, such as the lungs, liver, kidney, heart, and skin, is associated with a high rate of morbidity and mortality across the world. Fibrotic disorders encompass a broad range of complications and could be traced to various illnesses and impairments; these could range from simple skin scars with beauty issues to severe rheumatologic or inflammatory disorders such as systemic sclerosis as well as idiopathic pulmonary fibrosis. Besides, the overactivation of immune responses during any inflammatory condition causing tissue damage could contribute to the pathogenic fibrotic events accompanying the healing response; for instance, the inflammation resulting from tissue engraftment could cause the formation of fibrotic scars in the grafted tissue, even in cases where the immune system deals with hard to clear infections, fibrotic scars could follow and cause severe adverse effects. A good example of such a complication is post-Covid19 lung fibrosis which could impair the life of the affected individuals with extensive lung involvement. However, effective therapies that halt or slow down the progression of fibrosis are missing in the current clinical settings. Considering the immunomodulatory and regenerative potential of distinct stem cell types, their application as an anti-fibrotic agent, capable of attenuating tissue fibrosis has been investigated by many researchers. Although the majority of the studies addressing the anti-fibrotic effects of stem cells indicated their potent capabilities, the underlying mechanisms, and pathways by which these cells could impact fibrotic processes remain poorly understood. Here, we first, review the properties of various stem cell types utilized so far as anti-fibrotic treatments and discuss the challenges and limitations associated with their applications in clinical settings; then, we will summarize the general and organ-specific mechanisms and pathways contributing to tissue fibrosis; finally, we will describe the mechanisms and pathways considered to be employed by distinct stem cell types for exerting anti-fibrotic events.
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Affiliation(s)
- Marjan Taherian
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Paria Bayati
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Nazanin Mojtabavi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.
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Song Y, Lu Z, Shu W, Xiang Z, Wang Z, Wei X, Xu X. Arouse potential stemness: Intrinsic and acquired stem cell therapeutic strategies for advanced liver diseases. CELL INSIGHT 2023; 2:100115. [PMID: 37719773 PMCID: PMC10502372 DOI: 10.1016/j.cellin.2023.100115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Revised: 08/10/2023] [Accepted: 08/10/2023] [Indexed: 09/19/2023]
Abstract
Liver diseases are a major health issue, and prolonged liver injury always progresses. Advanced liver disorders impair liver regeneration. Millions of patients die yearly worldwide, even with the available treatments of liver transplantation and artificial liver support system. With its abundant cell resources and significant differentiative potential, stem cell therapy is a viable treatment for various disorders and offers hope to patients waiting for orthotopic liver transplantation. Considering such plight, stem cell therapeutic strategies deliver hope to the patients. Moreover, we conclude intrinsic and acquired perspectives based on stem cell sources. The properties and therapeutic uses of these stem cells' specific types or sources were then reviewed. Owing to the recent investigations of the above cells, a safe and effective therapy will emerge for advanced liver diseases soon.
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Affiliation(s)
- Yisu Song
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People’s Hospital Zhejiang University School of Medicine Hangzhou, Zhejiang, 310006, China
- Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
| | - Zhengyang Lu
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People’s Hospital Zhejiang University School of Medicine Hangzhou, Zhejiang, 310006, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
- Zhejiang Chinese Medical University, Hangzhou, 310053, PR China
| | - Wenzhi Shu
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People’s Hospital Zhejiang University School of Medicine Hangzhou, Zhejiang, 310006, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
| | - Ze Xiang
- Zhejiang University School of Medicine, Hangzhou, China
| | - Zhengxin Wang
- Department of General Surgery, Huashan Hospital, Fudan University Shanghai, 200040, China
| | - Xuyong Wei
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People’s Hospital Zhejiang University School of Medicine Hangzhou, Zhejiang, 310006, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
| | - Xiao Xu
- Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
- Institute of Organ Transplantation, Zhejiang University, Hangzhou, 310003, China
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Yang X, Li Q, Liu W, Zong C, Wei L, Shi Y, Han Z. Mesenchymal stromal cells in hepatic fibrosis/cirrhosis: from pathogenesis to treatment. Cell Mol Immunol 2023; 20:583-599. [PMID: 36823236 PMCID: PMC10229624 DOI: 10.1038/s41423-023-00983-5] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 01/29/2023] [Indexed: 02/25/2023] Open
Abstract
Hepatic fibrosis/cirrhosis is a significant health burden worldwide, resulting in liver failure or hepatocellular carcinoma (HCC) and accounting for many deaths each year. The pathogenesis of hepatic fibrosis/cirrhosis is very complex, which makes treatment challenging. Endogenous mesenchymal stromal cells (MSCs) have been shown to play pivotal roles in the pathogenesis of hepatic fibrosis. Paradoxically, exogenous MSCs have also been used in clinical trials for liver cirrhosis, and their effectiveness has been observed in most completed clinical trials. There are still many issues to be resolved to promote the use of MSCs in the clinic in the future. In this review, we will examine the controversial role of MSCs in the pathogenesis and treatment of hepatic fibrosis/cirrhosis. We also investigated the clinical trials involving MSCs in liver cirrhosis, summarized the parameters that need to be standardized, and discussed how to promote the use of MSCs from a clinical perspective.
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Affiliation(s)
- Xue Yang
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Key Laboratory of Stem Cells and Medical Biomaterials of Jiangsu Province, Medical College of Soochow University, Soochow University, Suzhou, 215000, China
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy
| | - Qing Li
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Wenting Liu
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China
| | - Chen Zong
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China
| | - Lixin Wei
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China
| | - Yufang Shi
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Key Laboratory of Stem Cells and Medical Biomaterials of Jiangsu Province, Medical College of Soochow University, Soochow University, Suzhou, 215000, China.
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy.
| | - Zhipeng Han
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China.
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China.
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Zheng SP, Deng AJ, Zhou JJ, Yuan LZ, Shi X, Wang F. Endoscopic ultrasound-guided intraportal injection of autologous bone marrow in patients with decompensated liver cirrhosis: A case series. World J Gastrointest Surg 2023; 15:655-663. [PMID: 37206071 PMCID: PMC10190720 DOI: 10.4240/wjgs.v15.i4.655] [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: 10/17/2022] [Revised: 01/31/2023] [Accepted: 03/21/2023] [Indexed: 04/22/2023] Open
Abstract
BACKGROUND Recently, stem cell therapy has been extensively studied as a promising treatment for decompensated liver cirrhosis (DLC). Technological advances in endoscopic ultrasonography (EUS) have facilitated EUS-guided portal vein (PV) access, through which stem cells can be precisely infused.
AIM To investigate the feasibility and safety of fresh autologous bone marrow injection into the PV under EUS guidance in patients with DLC.
METHODS Five patients with DLC were enrolled in this study after they provided written informed consent. EUS-guided intraportal bone marrow injection with a 22G FNA needle was performed using a transgastric, transhepatic approach. Several parameters were assessed before and after the procedure for a follow-up period of 12 mo.
RESULTS Four males and one female with a mean age of 51 years old participated in this study. All patients had hepatitis B virus-related DLC. EUS-guided intraportal bone marrow injection was performed in all patients successfully without any complications such as hemorrhage. The clinical outcomes of the patients revealed improvements in clinical symptoms, serum albumin, ascites, and Child-Pugh scores throughout the 12-mo follow-up.
CONCLUSION The use of EUS-guided fine needle injection for intraportal delivery of bone marrow was feasible and safe and appeared effective in patients with DLC. This treatment may thus be a safe, effective, non-radioactive, and minimally invasive treatment for DLC.
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Affiliation(s)
- Shao-Peng Zheng
- Department of Gastroenterology, Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
- Hunan Key Laboratory of Non-resolving Inflammation and Cancer, Central South University, Changsha 410000, Hunan Province, China
| | - Ao-Jian Deng
- Department of Gastroenterology, Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
- Hunan Key Laboratory of Non-resolving Inflammation and Cancer, Central South University, Changsha 410000, Hunan Province, China
| | - Jing-Jing Zhou
- Department of Gastroenterology, Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
| | - Ling-Zhi Yuan
- Department of Gastroenterology, Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
- Hunan Key Laboratory of Non-resolving Inflammation and Cancer, Central South University, Changsha 410000, Hunan Province, China
| | - Xiao Shi
- Department of Gastroenterology, Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
| | - Fen Wang
- Department of Gastroenterology, Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
- Hunan Key Laboratory of Non-resolving Inflammation and Cancer, Central South University, Changsha 410000, Hunan Province, China
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Shao B, Qin YF, Ren SH, Peng QF, Qin H, Wang ZB, Wang HD, Li GM, Zhu YL, Sun CL, Zhang JY, Li X, Wang H. Structural and Temporal Dynamics of Mesenchymal Stem Cells in Liver Diseases From 2001 to 2021: A Bibliometric Analysis. Front Immunol 2022; 13:859972. [PMID: 35663940 PMCID: PMC9160197 DOI: 10.3389/fimmu.2022.859972] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 04/20/2022] [Indexed: 12/14/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) have important research value and broad application prospects in liver diseases. This study aims to comprehensively review the cooperation and influence of countries, institutions, authors, and journals in the field of MSCs in liver diseases from the perspective of bibliometrics, evaluate the clustering evolution of knowledge structure, and discover hot trends and emerging topics. Methods The articles and reviews related to MSCs in liver diseases were retrieved from the Web of Science Core Collection using Topic Search. A bibliometric study was performed using CiteSpace and VOSviewer. Results A total of 3404 articles and reviews were included over the period 2001-2021. The number of articles regarding MSCs in liver diseases showed an increasing trend. These publications mainly come from 3251 institutions in 113 countries led by China and the USA. Li L published the most papers among the publications, while Pittenger MF had the most co-citations. Analysis of the most productive journals shows that most are specialized in medical research, experimental medicine and cell biology, and cell & tissue engineering. The macroscopical sketch and micro-representation of the whole knowledge field are realized through co-citation analysis. Liver scaffold, MSC therapy, extracellular vesicle, and others are current and developing areas of the study. The keywords "machine perfusion", "liver transplantation", and "microRNAs" also may be the focus of new trends and future research. Conclusions In this study, bibliometrics and visual methods were used to review the research of MSCs in liver diseases comprehensively. This paper will help scholars better understand the dynamic evolution of the application of MSCs in liver diseases and point out the direction for future research.
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Affiliation(s)
- Bo Shao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Ya-Fei Qin
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Shao-Hua Ren
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Qiu-Feng Peng
- Department of Respiratory and Critical Care Medicine, Tianjin Fourth Central Hospital, Tianjin, China
| | - Hong Qin
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Zhao-Bo Wang
- School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Hong-da Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Guang-Ming Li
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Yang-Lin Zhu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Cheng-Lu Sun
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Jing-Yi Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Xiang Li
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Hao Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
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Fagoonee S, Shukla SP, Dhasmana A, Birbrair A, Haque S, Pellicano R. Routes of Stem Cell Administration. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022:63-82. [PMID: 35389198 DOI: 10.1007/5584_2022_710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Stem cells are very promising for the treatment of a plethora of human diseases. Numerous clinical studies have been conducted to assess the safety and efficacy of various stem cell types. Factors that ensure successful therapeutic outcomes in patients are cell-based parameters such as source, viability, and number, as well as frequency and timing of intervention and disease stage. Stem cell administration routes should be appropriately chosen as these can affect homing and engraftment of the cells and hence reduce therapeutic effects, or compromise safety, resulting in serious adverse events. In this chapter, we will describe the use of stem cells in organ repair and regeneration, in particular, the liver and the available routes of cell delivery in the clinic for end-stage liver diseases. Factors affecting homing and engraftment of stem cells for each administration route will be discussed.
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Affiliation(s)
- Sharmila Fagoonee
- Institute of Biostructure and Bioimaging, National Research Council (CNR), Molecular Biotechnology Center, Turin, Italy.
| | - Shiv Poojan Shukla
- Department of Dermatology & Cutaneous Biology, Sydney Kimmel Cancer Center Thomas Jefferson University, Philadelphia, PA, USA
| | - Anupam Dhasmana
- Department of Immunology and Microbiology and South Texas Center of Excellence in Cancer Research, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX, USA
- Department of Biosciences and Cancer Research Institute, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Dehradun, India
| | - Alexander Birbrair
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
- Department of Radiology, Columbia University Medical Center, New York, NY, USA
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia
- Bursa Uludağ University Faculty of Medicine, Nilüfer, Bursa, Turkey
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Autologous bone marrow mononuclear cell infusion for liver cirrhosis after the Kasai operation in children with biliary atresia. Stem Cell Res Ther 2022; 13:108. [PMID: 35287722 PMCID: PMC8919575 DOI: 10.1186/s13287-022-02762-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 02/01/2022] [Indexed: 02/06/2023] Open
Abstract
Aim To evaluate the safety and early outcomes of autologous bone marrow mononuclear cell (BMMNC) infusion for liver cirrhosis due to biliary atresia (BA) after Kasai operation.
Methods An open-label clinical trial was performed from January 2017 to December 2019. Nineteen children with liver cirrhosis due to BA after Kasai operation were included. Bone marrow was harvested through anterior iliac crest puncture under general anesthesia. Mononuclear cells (MNCs) were isolated by Ficoll gradient centrifugation and then infused into the hepatic artery. The same procedure was repeated 6 months later. Serum bilirubin, albumin, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and prothrombin time were monitored at baseline, 3 months, 6 months, and 12 months after the first transplantation. Esophagoscopies and liver biopsies were performed in patients whose parents provided consent. Mixed-effect analysis was used to evaluate the changes in Pediatric End-Stage Liver Disease (PELD) scores.
Results The average MNC and CD34+ cell counts per kg body weight were 50.1 ± 58.5 × 106/kg and 3.5 ± 2.8 × 106 for the first transplantation and 57.1 ± 42.0 × 106/kg and 3.7 ± 2.7 × 106 for the second transplantation. No severe adverse events associated with the cell therapy were observed in the patients. One patient died 5 months after the first infusion at a provincial hospital due to the rupture of esophageal varices, while 18 patients survived. Liver function was maintained or improved after infusion, as assessed by biochemical tests. The severity of the disease reduced markedly, with a significant reduction in PELD scores.
Conclusion Autologous BMMNC administration for liver cirrhosis due to BA is safe and may maintain or improve liver function. Trial registration ClinicalTrials.gov identifier: NCT03468699. Name of the registry: Vinmec Research Institute of Stem Cell and Gene Technology. https://clinicaltrials.gov/ct2/show/NCT03468699?cond=biliary+atresia&cntry=VN&draw=2&rank=2. Registered on March 16, 2018. The trial results will also be published according to the CONSORT statement at conferences and reported in peer-reviewed journals.
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Gharibeh N, Aghebati-Maleki L, Madani J, Pourakbari R, Yousefi M, Ahmadian Heris J. Cell-based therapy in thin endometrium and Asherman syndrome. Stem Cell Res Ther 2022; 13:33. [PMID: 35090547 PMCID: PMC8796444 DOI: 10.1186/s13287-021-02698-8] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 12/24/2021] [Indexed: 12/17/2022] Open
Abstract
Numerous treatment strategies have so far been proposed for treating refractory thin endometrium either without or with the Asherman syndrome. Inconsistency in the improvement of endometrial thickness is a common limitation of such therapies including tamoxifen citrate as an ovulation induction agent, acupuncture, long-term pentoxifylline and tocopherol or tocopherol only, low-dose human chorionic gonadotropin during endometrial preparation, aspirin, luteal gonadotropin-releasing hormone agonist supplementation, and extended estrogen therapy. Recently, cell therapy has been proposed as an ideal alternative for endometrium regeneration, including the employment of stem cells, platelet-rich plasma, and growth factors as therapeutic agents. The mechanisms of action of cell therapy include the cytokine induction, growth factor production, natural killer cell activity reduction, Th17 and Th1 decrease, and Treg cell and Th2 increase. Since cell therapy is personalized, dynamic, interactive, and specific and could be an effective strategy. Despite its promising nature, further research is required for improving the procedure and the safety of this strategy. These methods and their results are discussed in this article.
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Affiliation(s)
- Nastaran Gharibeh
- Student's Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Javad Madani
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ramin Pourakbari
- Student's Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Javad Ahmadian Heris
- Department of Allergy and Clinical Immunology, Pediatric Hospital, Tabriz University of Medical Sciences, Tabriz, Iran.
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Wang DH, Wu XM, Chen JS, Cai ZG, An JH, Zhang MY, Li Y, Li FP, Hou R, Liu YL. Isolation and characterization mesenchymal stem cells from red panda ( Ailurus fulgens styani) endometrium. CONSERVATION PHYSIOLOGY 2022; 10:coac004. [PMID: 35211318 PMCID: PMC8862722 DOI: 10.1093/conphys/coac004] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 08/30/2021] [Accepted: 02/07/2022] [Indexed: 06/14/2023]
Abstract
Endometrial mesenchymal stem cells (eMSCs) are undifferentiated endometrial cells with self-renewal, multidirectional differentiation and high proliferation potential. Nowadays, eMSCs have been found in a few species, but it has never been reported in endangered wild animals, especially the red panda. In this study, we successfully isolated and characterized the eMSCs derived from red panda. Red panda eMSCs were fibroblast-like, had a strong proliferative potential and a stable chromosome number. Pluripotency genes including Klf4, Sox2 and Thy1 were highly expressed in eMSCs. Besides, cultured eMSCs were positive for MSC markers CD44, CD49f and CD105 and negative for endothelial cell marker CD31 and haematopoietic cell marker CD34. Moreover, no reference RNA-seq was used to analyse the eMSCs transcriptional expression profile and key pathways. Compared with skin fibroblast cell group, 9104 differentially expressed genes (DEGs) were identified, among which are 5034 genes upregulated, 4070 genes downregulated and the top 20 enrichment pathways of DEGs in Gene Ontology (GO) and the Kyoto Encyclopedia of Genes Genomes (KEGG) mainly associated with G-protein coupled receptor signalling pathway, carbohydrate derivative binding, nucleoside binding, ribosome biogenesis, cell cycle, DNA replication, Ras signalling pathway and purine metabolism. Among the DEGs, some representative genes about promoting MSCs differentiation and proliferation were upregulated and promoting fibroblasts proliferation were downregulated in eMSCs group. Red panda eMSCs also had multiple differentiation ability and could differentiate into adipocytes, chondrocytes and hepatocytes. In conclusion, we, for the first time, isolated and characterized the red panda eMSCs with ability of multiplication and multilineage differentiation in vitro. The new multipotential stem cell could be beneficial not only for the germ plasm resources conservation of red panda, but also for basic or pre-clinical studies in the future.
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Affiliation(s)
- Dong-Hui Wang
- Chengdu Research Base of Giant Panda Breeding, 1375 Panda Road, Northern Suburb, Chengdu, 610081, Sichuan Province, China
- Sichuan Key Laboratory of Conservation Biology for Endangered Wildlife, 1375 Panda Road, Northern Suburb, Chengdu, 610081, Sichuan Province, China
- Sichuan Academy of Giant Panda, 1375 Panda Road, Northern Suburb, Chengdu, 610081, Sichuan Province, China
| | - Xue-Mei Wu
- Sichuan Key Laboratory of Conservation Biology for Endangered Wildlife, 1375 Panda Road, Northern Suburb, Chengdu, 610081, Sichuan Province, China
| | - Jia-Song Chen
- Chengdu Research Base of Giant Panda Breeding, 1375 Panda Road, Northern Suburb, Chengdu, 610081, Sichuan Province, China
- Sichuan Key Laboratory of Conservation Biology for Endangered Wildlife, 1375 Panda Road, Northern Suburb, Chengdu, 610081, Sichuan Province, China
- Sichuan Academy of Giant Panda, 1375 Panda Road, Northern Suburb, Chengdu, 610081, Sichuan Province, China
| | - Zhi-Gang Cai
- Chengdu Research Base of Giant Panda Breeding, 1375 Panda Road, Northern Suburb, Chengdu, 610081, Sichuan Province, China
- Sichuan Key Laboratory of Conservation Biology for Endangered Wildlife, 1375 Panda Road, Northern Suburb, Chengdu, 610081, Sichuan Province, China
- Sichuan Academy of Giant Panda, 1375 Panda Road, Northern Suburb, Chengdu, 610081, Sichuan Province, China
| | - Jun-Hui An
- Chengdu Research Base of Giant Panda Breeding, 1375 Panda Road, Northern Suburb, Chengdu, 610081, Sichuan Province, China
- Sichuan Key Laboratory of Conservation Biology for Endangered Wildlife, 1375 Panda Road, Northern Suburb, Chengdu, 610081, Sichuan Province, China
- Sichuan Academy of Giant Panda, 1375 Panda Road, Northern Suburb, Chengdu, 610081, Sichuan Province, China
| | - Ming-Yue Zhang
- Chengdu Research Base of Giant Panda Breeding, 1375 Panda Road, Northern Suburb, Chengdu, 610081, Sichuan Province, China
- Sichuan Key Laboratory of Conservation Biology for Endangered Wildlife, 1375 Panda Road, Northern Suburb, Chengdu, 610081, Sichuan Province, China
- Sichuan Academy of Giant Panda, 1375 Panda Road, Northern Suburb, Chengdu, 610081, Sichuan Province, China
| | - Yuan Li
- Sichuan Key Laboratory of Conservation Biology for Endangered Wildlife, 1375 Panda Road, Northern Suburb, Chengdu, 610081, Sichuan Province, China
| | - Fei-Ping Li
- Chengdu Research Base of Giant Panda Breeding, 1375 Panda Road, Northern Suburb, Chengdu, 610081, Sichuan Province, China
- Sichuan Key Laboratory of Conservation Biology for Endangered Wildlife, 1375 Panda Road, Northern Suburb, Chengdu, 610081, Sichuan Province, China
- Sichuan Academy of Giant Panda, 1375 Panda Road, Northern Suburb, Chengdu, 610081, Sichuan Province, China
| | - Rong Hou
- Chengdu Research Base of Giant Panda Breeding, 1375 Panda Road, Northern Suburb, Chengdu, 610081, Sichuan Province, China
- Sichuan Key Laboratory of Conservation Biology for Endangered Wildlife, 1375 Panda Road, Northern Suburb, Chengdu, 610081, Sichuan Province, China
- Sichuan Academy of Giant Panda, 1375 Panda Road, Northern Suburb, Chengdu, 610081, Sichuan Province, China
| | - Yu-Liang Liu
- Chengdu Research Base of Giant Panda Breeding, 1375 Panda Road, Northern Suburb, Chengdu, 610081, Sichuan Province, China
- Sichuan Key Laboratory of Conservation Biology for Endangered Wildlife, 1375 Panda Road, Northern Suburb, Chengdu, 610081, Sichuan Province, China
- Sichuan Academy of Giant Panda, 1375 Panda Road, Northern Suburb, Chengdu, 610081, Sichuan Province, China
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12
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Role of the Microenvironment in Mesenchymal Stem Cell-Based Strategies for Treating Human Liver Diseases. Stem Cells Int 2021; 2021:5513309. [PMID: 34824587 PMCID: PMC8610645 DOI: 10.1155/2021/5513309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 10/23/2021] [Accepted: 10/30/2021] [Indexed: 11/17/2022] Open
Abstract
Liver disease is a severe health problem that endangers human health worldwide. Mesenchymal stem cell (MSC) therapy is a novel treatment for patients with different liver diseases due to its vast expansion potential and distinctive immunomodulatory properties. Despite several preclinical trials having confirmed the considerable efficacy of MSC therapy in liver diseases, the questionable safety and efficacy still limit its application. As a precursor cell, MSCs can adjust their characteristics in response to the surrounding microenvironment. The microenvironment provides physical and chemical factors essential for stem cell survival, proliferation, and differentiation. However, the mechanisms are still not completely understood. We, therefore, summarized the mechanisms underlying the MSC immune response, especially the interaction between MSCs and the liver microenvironment, discussing how to achieve better therapeutic effects.
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Gil-Recio C, Montori S, Al Demour S, Ababneh MA, Ferrés-Padró E, Marti C, Ferrés-Amat E, Barajas M, Al Madhoun A, Atari M. Chemically Defined Conditions Mediate an Efficient Induction of Dental Pulp Pluripotent-Like Stem Cells into Hepatocyte-Like Cells. Stem Cells Int 2021; 2021:5212852. [PMID: 34795766 PMCID: PMC8593589 DOI: 10.1155/2021/5212852] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 10/15/2021] [Accepted: 10/18/2021] [Indexed: 01/01/2023] Open
Abstract
Liver diseases are major causes of morbidity and mortality. Dental pulp pluripotent-like stem cells (DPPSCs) are of a considerable promise in tissue engineering and regenerative medicine as a new source of tissue-specific cells; therefore, this study is aimed at demonstrating their ability to generate functional hepatocyte-like cells in vitro. Cells were differentiated on a collagen scaffold in serum-free media supplemented with growth factors and cytokines to recapitulate liver development. At day 5, the differentiated DPPSC cells expressed the endodermal markers FOXA1 and FOXA2. Then, the cells were derived into the hepatic lineage generating hepatocyte-like cells. In addition to the associated morphological changes, the cells expressed the hepatic genes HNF6 and AFP. The terminally differentiated hepatocyte-like cells expressed the liver functional proteins albumin and CYP3A4. In this study, we report an efficient serum-free protocol to differentiate DPPSCs into functional hepatocyte-like cells. Our approach promotes the use of DPPSCs as a new source of adult stem cells for prospective use in liver regenerative medicine.
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Affiliation(s)
- Carlos Gil-Recio
- Regenerative Medicine Research Institute, UIC Barcelona, Barcelona, Spain
| | - Sheyla Montori
- Regenerative Medicine Research Institute, UIC Barcelona, Barcelona, Spain
| | - Saddam Al Demour
- Department of Special Surgery/Division of Urology, The University of Jordan, School of Medicine, Amman, Jordan
| | - Mera A. Ababneh
- Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Amman, Jordan
| | - Eduard Ferrés-Padró
- Oral and Maxillofacial Surgery Department, Fundació Hospital de Nens de Barcelona, Barcelona, Spain
| | - Carles Marti
- Oral and Maxillofacial Surgery Department, Hospital Clinico de Barcelona, Barcelona, Spain
| | - Elvira Ferrés-Amat
- Pediatric Dentistry Service, Oral and Maxillofacial Surgery Service, Hospital de Nens de Barcelona, Barcelona, Spain
| | - Miguel Barajas
- Biochemistry and Molecular Biology Department, Universidad Pública de Navarra, Pamplona, Spain
| | - Ashraf Al Madhoun
- Department of Genetics and Bioinformatics, Functional Genomic Unit, Dasman Diabetes Institute, Kuwait
| | - Maher Atari
- Regenerative Medicine Research Institute, UIC Barcelona, Barcelona, Spain
- Biointelligent Technology Systems SL, Diputaccion 316, 3D, 08009 Barcelona, Spain
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14
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Zhao X, Li D, Zhang L, Niu Y, Wang W, Niu B. Mesenchymal stem cell therapies for Alzheimer's disease: preclinical studies. Metab Brain Dis 2021; 36:1687-1695. [PMID: 34213730 DOI: 10.1007/s11011-021-00777-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 06/06/2021] [Indexed: 12/17/2022]
Abstract
Alzheimer's disease (AD) is a chronic, progressive, and fatal neurodegenerative disorder that is characterized by memory failure, cognitive impairment, as well as behavioral and psychological manifestations. Drugs can only moderately manage, but not alleviate, clinical symptoms. Results, based on animal models, have demonstrated that cell therapy is a promising strategy for treating neurodegenerative disorders. The homing effect of mesenchymal stem cells (MSCs) replaces damaged cells, while some scholars believe that the paracrine effects play a crucial role in treating diseases. In fact, these cells have rich sources, exhibit high proliferation rates, low tumorigenicity, and immunogenicity, and have no ethical concerns. Consequently, MSCs have been used across various disease aspects, such as regulating immunity, nourishing nerves, and promoting regeneration. Deterioration of public health status have exposed both Alzheimer's patients and researchers to various difficulties during epidemics. In this review, we discuss the advances and challenges in the application of mesenchymal stem cell therapy for treatment of Alzheimer's disease.
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Affiliation(s)
- Xiaorong Zhao
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Dandan Li
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Li Zhang
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Yuhu Niu
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Wenzhuo Wang
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Bo Niu
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Shanxi Medical University, Taiyuan, 030001, Shanxi, China.
- Department of Biotechnology, Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China.
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15
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Progress in Mesenchymal Stem Cell Therapy for Ischemic Stroke. Stem Cells Int 2021; 2021:9923566. [PMID: 34221026 PMCID: PMC8219421 DOI: 10.1155/2021/9923566] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/27/2021] [Accepted: 06/03/2021] [Indexed: 12/12/2022] Open
Abstract
Ischemic stroke (IS) is a serious cerebrovascular disease with high morbidity and disability worldwide. Despite the great efforts that have been made, the prognosis of patients with IS remains unsatisfactory. Notably, recent studies indicated that mesenchymal stem cell (MSCs) therapy is becoming a novel research hotspot with large potential in treating multiple human diseases including IS. The current article is aimed at reviewing the progress of MSC treatment on IS. The mechanism of MSCs in the treatment of IS involved with immune regulation, neuroprotection, angiogenesis, and neural circuit reconstruction. In addition, nutritional cytokines, mitochondria, and extracellular vesicles (EVs) may be the main mediators of the therapeutic effect of MSCs. Transplantation of MSCs-derived EVs (MSCs-EVs) affords a better neuroprotective against IS when compared with transplantation of MSCs alone. MSC therapy can prolong the treatment time window of ischemic stroke, and early administration within 7 days after stroke may be the best treatment opportunity. The deliver routine consists of intraventricular, intravascular, intranasal, and intraperitoneal. Furthermore, several methods such as hypoxic preconditioning and gene technology could increase the homing and survival ability of MSCs after transplantation. In addition, MSCs combined with some drugs or physical therapy measures also show better neurological improvement. These data supported the notion that MSC therapy might be a promising therapeutic strategy for IS. And the application of new technology will promote MSC therapy of IS.
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16
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Kang SH, Kim MY, Eom YW, Baik SK. Mesenchymal Stem Cells for the Treatment of Liver Disease: Present and Perspectives. Gut Liver 2021; 14:306-315. [PMID: 31581387 PMCID: PMC7234888 DOI: 10.5009/gnl18412] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2018] [Revised: 12/14/2018] [Accepted: 12/23/2018] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cell transplantation is an emerging therapy for treating chronic liver diseases. The potential of this treatment has been evaluated in preclinical and clinical studies. Although the mechanisms of mesenchymal stem cell transplantation are still not completely understood, accumulating evidence has revealed that their immunomodulation, differentiation, and antifibrotic properties play a crucial role in liver regeneration. The safety and therapeutic effects of mesenchymal stem cells in patients with chronic liver disease have been observed in many clinical studies. However, only modest improvements have been seen, partly because of the limited feasibility of transplanted cells at present. Here, we discuss several strategies targeted at improving viable cell engraftment and the potential challenges in the use of extracellular vesicle-based therapies for liver disease in the future.
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Affiliation(s)
- Seong Hee Kang
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.,Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Institute of Evidence Based Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Moon Young Kim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.,Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Young Woo Eom
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.,Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Soon Koo Baik
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.,Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Institute of Evidence Based Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
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17
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Reichert D, Adolph L, Köhler JP, Buschmann T, Luedde T, Häussinger D, Kordes C. Improved Recovery from Liver Fibrosis by Crenolanib. Cells 2021; 10:804. [PMID: 33916518 PMCID: PMC8067177 DOI: 10.3390/cells10040804] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/30/2021] [Accepted: 04/01/2021] [Indexed: 01/03/2023] Open
Abstract
Chronic liver diseases are associated with excessive deposition of extracellular matrix proteins. This so-called fibrosis can progress to cirrhosis and impair vital functions of the liver. We examined whether the receptor tyrosine kinase (RTK) class III inhibitor Crenolanib affects the behavior of hepatic stellate cells (HSC) involved in fibrogenesis. Rats were treated with thioacetamide (TAA) for 18 weeks to trigger fibrosis. After TAA treatment, the animals received Crenolanib for two weeks, which significantly improved recovery from liver fibrosis. Because Crenolanib predominantly inhibits the RTK platelet-derived growth factor receptor-β, impaired HSC proliferation might be responsible for this beneficial effect. Interestingly, blocking of RTK signaling by Crenolanib not only hindered HSC proliferation but also triggered their specification into hepatic endoderm. Endodermal specification was mediated by p38 mitogen-activated kinase (p38 MAPK) and c-Jun-activated kinase (JNK) signaling; however, this process remained incomplete, and the HSC accumulated lipids. JNK activation was induced by stress response-associated inositol-requiring enzyme-1α (IRE1α) in response to Crenolanib treatment, whereas β-catenin-dependent WNT signaling was able to counteract this process. In conclusion, the Crenolanib-mediated inhibition of RTK impeded HSC proliferation and triggered stress responses, initiating developmental processes in HSC that might have contributed to improved recovery from liver fibrosis in TAA-treated rats.
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Affiliation(s)
| | | | | | | | | | | | - Claus Kordes
- Clinic of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University, Moorenstraße 5, 40225 Düsseldorf, Germany; (D.R.); (L.A.); (J.P.K.); (T.B.); (T.L.); (D.H.)
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18
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Pfefferlé M, Ingoglia G, Schaer CA, Yalamanoglu A, Buzzi R, Dubach IL, Tan G, López-Cano EY, Schulthess N, Hansen K, Humar R, Schaer DJ, Vallelian F. Hemolysis transforms liver macrophages into antiinflammatory erythrophagocytes. J Clin Invest 2021; 130:5576-5590. [PMID: 32663195 DOI: 10.1172/jci137282] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 07/07/2020] [Indexed: 12/15/2022] Open
Abstract
During hemolysis, macrophages in the liver phagocytose damaged erythrocytes to prevent the toxic effects of cell-free hemoglobin and heme. It remains unclear how this homeostatic process modulates phagocyte functions in inflammatory diseases. Using a genetic mouse model of spherocytosis and single-cell RNA sequencing, we found that erythrophagocytosis skewed liver macrophages into an antiinflammatory phenotype that we defined as MarcohiHmoxhiMHC class IIlo erythrophagocytes. This phenotype transformation profoundly mitigated disease expression in a model of an anti-CD40-induced hyperinflammatory syndrome with necrotic hepatitis and in a nonalcoholic steatohepatitis model, representing 2 macrophage-driven sterile inflammatory diseases. We reproduced the antiinflammatory erythrophagocyte transformation in vitro by heme exposure of mouse and human macrophages, yielding a distinctive transcriptional signature that segregated heme-polarized from M1- and M2-polarized cells. Mapping transposase-accessible chromatin in single cells by sequencing defined the transcription factor NFE2L2/NRF2 as a critical driver of erythrophagocytes, and Nfe2l2/Nrf2 deficiency restored heme-suppressed inflammation. Our findings point to a pathway that regulates macrophage functions to link erythrocyte homeostasis with innate immunity.
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Affiliation(s)
| | | | | | | | | | | | - Ge Tan
- Functional Genomics Center Zurich, ETH Zurich and University of Zurich, Zurich, Switzerland
| | - Emilio Y López-Cano
- Functional Genomics Center Zurich, ETH Zurich and University of Zurich, Zurich, Switzerland
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19
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He C, Yang Y, Zheng K, Chen Y, Liu S, Li Y, Han Q, Zhao RC, Wang L, Zhang F. Mesenchymal stem cell-based treatment in autoimmune liver diseases: underlying roles, advantages and challenges. Ther Adv Chronic Dis 2021; 12:2040622321993442. [PMID: 33633826 PMCID: PMC7887681 DOI: 10.1177/2040622321993442] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 01/18/2021] [Indexed: 12/20/2022] Open
Abstract
Autoimmune liver disease (AILD) is a series of chronic liver diseases with abnormal immune responses, including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). The treatment options for AILD remain limited, and the adverse side effects of the drugs that are typically used for treatment frequently lead to a low quality of life for AILD patients. Moreover, AILD patients may have a poor prognosis, especially those with an incomplete response to first-line treatment. Mesenchymal stem cells (MSCs) are pluripotent stem cells with low immunogenicity and can be conveniently harvested. MSC-based therapy is emerging as a promising approach for treating liver diseases based on their advantageous characteristics of immunomodulation, anti-fibrosis effects, and differentiation to hepatocytes, and accumulating evidence has revealed the positive effects of MSC therapy in AILD. In this review, we first summarize the mechanisms, safety, and efficacy of MSC treatment for AILD based on work in animal and clinical studies. We also discuss the challenges of MSC therapy in clinical applications. In summary, although promising data from preclinical studies are now available, MSC therapy is currently far for being applied in clinical practice, thus developing MSC therapy in AILD is still challenging and warrants further research.
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Affiliation(s)
- Chengmei He
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yanlei Yang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Kunyu Zheng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yiran Chen
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Suying Liu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yongzhe Li
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Qin Han
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Peking Union Medical College Hospital, Beijing, China
| | - Robert Chunhua Zhao
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Peking Union Medical College Hospital, Beijing, China
| | - Li Wang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Shuaifuyuan, Dongcheng District, Beijing 100730, China
| | - Fengchun Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Shuaifuyuan, Dongcheng District, Beijing 100730, China
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20
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Soret PA, Magusto J, Housset C, Gautheron J. In Vitro and In Vivo Models of Non-Alcoholic Fatty Liver Disease: A Critical Appraisal. J Clin Med 2020; 10:jcm10010036. [PMID: 33374435 PMCID: PMC7794936 DOI: 10.3390/jcm10010036] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/22/2020] [Accepted: 12/23/2020] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), including non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), represents the hepatic manifestation of obesity and metabolic syndrome. Due to the spread of the obesity epidemic, NAFLD is becoming the most common chronic liver disease and one of the principal indications for liver transplantation. However, no pharmacological treatment is currently approved to prevent the outbreak of NASH, which leads to fibrosis and cirrhosis. Preclinical research is required to improve our knowledge of NAFLD physiopathology and to identify new therapeutic targets. In the present review, we summarize advances in NAFLD preclinical models from cellular models, including new bioengineered platforms, to in vivo models, with a particular focus on genetic and dietary mouse models. We aim to discuss the advantages and limits of these different models.
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Affiliation(s)
- Pierre-Antoine Soret
- Centre de Recherche Saint-Antoine (CRSA), Sorbonne Université, Inserm, 75012 Paris, France; (P.-A.S.); (J.M.); (C.H.)
- Assistance Publique-Hôpitaux de Paris (AP-HP), Hepatology Department, Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, Saint-Antoine Hospital, 75012 Paris, France
| | - Julie Magusto
- Centre de Recherche Saint-Antoine (CRSA), Sorbonne Université, Inserm, 75012 Paris, France; (P.-A.S.); (J.M.); (C.H.)
- Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Université, Inserm, AP-HP, 75013 Paris, France
| | - Chantal Housset
- Centre de Recherche Saint-Antoine (CRSA), Sorbonne Université, Inserm, 75012 Paris, France; (P.-A.S.); (J.M.); (C.H.)
- Assistance Publique-Hôpitaux de Paris (AP-HP), Hepatology Department, Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, Saint-Antoine Hospital, 75012 Paris, France
- Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Université, Inserm, AP-HP, 75013 Paris, France
| | - Jérémie Gautheron
- Centre de Recherche Saint-Antoine (CRSA), Sorbonne Université, Inserm, 75012 Paris, France; (P.-A.S.); (J.M.); (C.H.)
- Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Université, Inserm, AP-HP, 75013 Paris, France
- Correspondence:
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Wu X, Zhang S, Lai J, Lu H, Sun Y, Guan W. Therapeutic Potential of Bama Pig Adipose-Derived Mesenchymal Stem Cells for the Treatment of Carbon Tetrachloride-Induced Liver Fibrosis. EXP CLIN TRANSPLANT 2020; 18:823-831. [PMID: 33349209 DOI: 10.6002/ect.2020.0108] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Liver fibrosis is inevitable in the healing process of liver injury. Liver fibrosis will develop into liver cirrhosis unless the damaging factors are removed. This study investigated the potential therapy of Bama pig adipose-derived mesenchymal stem cells in a carbon tetrachloride-induced liver fibrosis Institute of Cancer Research strain mice model. MATERIALS AND METHODS Adipose-derived mesenchymal stem cells were injected intravenously into the tails of mice of the Institute of Cancer Research strain that had been treated with carbon tetrachloride for 4 weeks. Survival rate, migration, and proliferation of adipose-derived mesenchymal stem cells in the liver were observed by histochemistry, fluorescent labeling, and serological detection. RESULTS At 1, 2, and 3 weeks after adipose-derived mesenchymal stem cell injection, liver fibrosis was significantly ameliorated. The injected adipose-derived mesenchymal stem cells had hepatic differentiation potential in vivo, and the survival rate of adipose-derived mesenchymal stem cells declined over time. CONCLUSIONS The findings in this study confirmed that adipose-derived mesenchymal stem cells derived from the Bama pig can be used in the treatment of liver fibrosis, and the grafted adipose-derived mesenchy-mal stem cells can migrate, survive, and differentiate into hepatic cells in vivo.
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Affiliation(s)
- Xinran Wu
- From the Sport and Exercise Sciences Centre, University of Malaya, Kuala Lumpur, Malaysia
| | - Shuang Zhang
- From the Scientific Experimental Research Center, Harbin Sport University, Nangang District, Harbin, Heilongjiang Province, China
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22
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Lim YL, Eom YW, Park SJ, Hong T, Kang SH, Baik SK, Park KS, Kim MY. Bone Marrow-Derived Mesenchymal Stem Cells Isolated from Patients with Cirrhosis and Healthy Volunteers Show Comparable Characteristics. Int J Stem Cells 2020; 13:394-403. [PMID: 32840228 PMCID: PMC7691862 DOI: 10.15283/ijsc20072] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 07/17/2020] [Accepted: 07/21/2020] [Indexed: 12/19/2022] Open
Abstract
Background and Objectives Autologous or allogeneic bone marrow-derived mesenchymal stem cells (BMSCs) have been applied in clinical trials to treat liver disease. However, only a few studies are comparing the characteristics of autologous MSCs from patients and allogeneic MSCs from normal subjects. Methods and Results We compared the characteristics of BMSCs (BCs and BPs, respectively) isolated from six healthy volunteers and six patients with cirrhosis. In passage 3 (P3), senescent population and expression of p53 and p21 were slightly higher in BPs, but the average population doubling time for P3–P5 in BPs was approximately 65.3±11.1 h, which is 18.4 h shorter than that in BCs (83.7±9.2 h). No difference was observed in the expression of CD73, CD90, or CD105 between BCs and BPs. Adipogenic differentiation slightly increased in BCs, but the expression levels of leptin, peroxisome proliferator-activated receptor γ, and CCAAT-enhancer-binding protein α did not vary between differentiated BCs and BPs. While ATP and reactive oxygen species levels were slightly lower in BPs, mitochondrial membrane potential, oxygen consumption rate, and expression of mitochondria-related genes such as cytochrome c oxidase 1 were not significantly different between BCs and BPs. Conclusions Taken together, there are marginal differences in the proliferation, differentiation, and mitochondrial activities of BCs and BPs, but both BMSCs from patients with cirrhosis and healthy volunteers show comparable characteristics.
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Affiliation(s)
- Yoo Li Lim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Young Woo Eom
- Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Su Jung Park
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Taeui Hong
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Seong Hee Kang
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.,Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Soon Koo Baik
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.,Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Kyu-Sang Park
- Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Moon Young Kim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.,Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
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23
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Neo S, Makiishi E, Fujimoto A, Hisasue M. Human placental hydrolysate promotes the long-term culture of hepatocyte-like cells derived from canine bone marrow. J Vet Med Sci 2020; 82:1821-1827. [PMID: 33132358 PMCID: PMC7804030 DOI: 10.1292/jvms.20-0320] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Long-term culture of canine artificial hepatocytes has not been established. We hypothesized that human placental hydrolysate (hPH) may support the long-term
culture of differentiated hepatocyte-like cells. Canine bone marrow cells were cultured using modified hepatocyte growth medium supplemented with hPH.
Quantitative reverse transcription polymerase chain reaction (RT-PCR) and immunocytochemical analysis for albumin, qualitative RT-PCR for cytochrome P450 1A1
(CYP1A1), hepatocyte growth factor (HGF), Cytokeratin 7 (CK7), CD90, CD44, and CD34, and functional analyses of CYP450 activity and low-density lipoprotein
(LDL) uptake were performed. Cultured hepatocyte-like cells were able to maintain hepatocyte characteristics, including morphology, albumin synthesis, CYP450
activity, and LDL uptake for 80 days. Thus, hPH may be a potential facilitator for the long-term culture of hepatocyte-like cells. Clinicopathologically, this
culture protocol of artificial hepatocytes will contribute to liver function evaluation.
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Affiliation(s)
- Sakurako Neo
- Laboratory of Clinical Diagnosis, Azabu University, Sagamihara, Kanagawa 252-5201, Japan
| | - Eri Makiishi
- Laboratory of Small Animal Medicine, Azabu University, Sagamihara, Kanagawa 252-5201, Japan
| | - Ayumi Fujimoto
- Laboratory of Small Animal Medicine, Azabu University, Sagamihara, Kanagawa 252-5201, Japan
| | - Masaharu Hisasue
- Laboratory of Small Animal Medicine, Azabu University, Sagamihara, Kanagawa 252-5201, Japan
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24
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Kulkeaw K, Tubsuwan A, Tongkrajang N, Whangviboonkij N. Generation of human liver organoids from pluripotent stem cell-derived hepatic endoderms. PeerJ 2020; 8:e9968. [PMID: 33133779 PMCID: PMC7580584 DOI: 10.7717/peerj.9968] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 08/26/2020] [Indexed: 12/18/2022] Open
Abstract
Background The use of a personalized liver organoid derived from human-induced pluripotent stem cells (HuiPSCs) is advancing the use of in vitro disease models for the design of specific, effective therapies for individuals. Collecting patient peripheral blood cells for HuiPSC generation is preferable because it is less invasive; however, the capability of blood cell-derived HuiPSCs for hepatic differentiation and liver organoid formation remains uncertain. Moreover, the currently available methods for liver organoid formation require a multistep process of cell differentiation or a combination of hepatic endodermal, endothelial and mesenchymal cells, which is a major hurdle for the application of personalized liver organoids in high-throughput testing of drug toxicity and safety. To demonstrate the capability of blood cell-derived HuiPSCs for liver organoid formation without support from endothelial and mesenchymal cells. Methods The peripheral blood-derived HuiPSCs first differentiated into hepatic endoderm (HE) in two-dimensional (2D) culture on Matrigel-coated plates under hypoxia for 10 days. The HE was then collected and cultured in 3D culture using 50% Matrigel under ambient oxygen. The maturation of hepatocytes was further induced by adding hepatocyte growth medium containing HGF and oncostatin M on top of the 3D culture and incubating the culture for an additional 12–17 days. The function of the liver organoids was assessed using expression analysis of hepatocyte-specific gene and proteins. Albumin (ALB) synthesis, glycogen and lipid storage, and metabolism of indocyanine were evaluated. The spatial distribution of albumin was examined using immunofluorescence and confocal microscopy. Results CD34+ hematopoietic cell-derived HuiPSCs were capable of differentiating into definitive endoderm expressing SOX17 and FOXA2, hepatic endoderm expressing FOXA2, hepatoblasts expressing AFP and hepatocytes expressing ALB. On day 25 of the 2D culture, cells expressed SOX17, FOXA2, AFP and ALB, indicating the presence of cellular heterogeneity. In contrast, the hepatic endoderm spontaneously formed a spherical, hollow structure in a 3D culture of 50% Matrigel, whereas hepatoblasts and hepatocytes could not form. Microscopic observation showed a single layer of polygonal-shaped cells arranged in a 3D structure. The hepatic endoderm-derived organoid synthesis ALB at a higher level than the 2D culture but did not express definitive endoderm-specific SOX17, indicating the greater maturity of the hepatocytes in the liver organoids. Confocal microscopic images and quantitative ELISA confirmed albumin synthesis in the cytoplasm of the liver organoid and its secretion. Overall, 3D culture of the hepatic endoderm is a relatively fast, simple, and less laborious way to generate liver organoids from HuiPSCs that is more physiologically relevant than 2D culture.
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Affiliation(s)
- Kasem Kulkeaw
- Department of Parasitology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Alisa Tubsuwan
- Stem Cell Research Group, Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand
| | - Nongnat Tongkrajang
- Department of Parasitology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Narisara Whangviboonkij
- Department of Parasitology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
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25
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Fan XL, Zhang Y, Li X, Fu QL. Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy. Cell Mol Life Sci 2020; 77:2771-2794. [PMID: 31965214 PMCID: PMC7223321 DOI: 10.1007/s00018-020-03454-6] [Citation(s) in RCA: 332] [Impact Index Per Article: 66.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 01/02/2020] [Accepted: 01/03/2020] [Indexed: 02/06/2023]
Abstract
Mesenchymal stem cells (MSCs) have been extensively investigated for the treatment of various diseases. The therapeutic potential of MSCs is attributed to complex cellular and molecular mechanisms of action including differentiation into multiple cell lineages and regulation of immune responses via immunomodulation. The plasticity of MSCs in immunomodulation allow these cells to exert different immune effects depending on different diseases. Understanding the biology of MSCs and their role in treatment is critical to determine their potential for various therapeutic applications and for the development of MSC-based regenerative medicine. This review summarizes the recent progress of particular mechanisms underlying the tissue regenerative properties and immunomodulatory effects of MSCs. We focused on discussing the functional roles of paracrine activities, direct cell-cell contact, mitochondrial transfer, and extracellular vesicles related to MSC-mediated effects on immune cell responses, cell survival, and regeneration. This will provide an overview of the current research on the rapid development of MSC-based therapies.
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Affiliation(s)
- Xing-Liang Fan
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan Road II, Guangzhou, 510080, People's Republic of China
| | - Yuelin Zhang
- Department of Emergency, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan Road II, Guangzhou, 510080, People's Republic of China
| | - Xin Li
- Department of Emergency, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan Road II, Guangzhou, 510080, People's Republic of China
| | - Qing-Ling Fu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan Road II, Guangzhou, 510080, People's Republic of China.
- Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China.
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26
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Zhuo JY, Lu D, Tan WY, Zheng SS, Shen YQ, Xu X. CK19-positive Hepatocellular Carcinoma is a Characteristic Subtype. J Cancer 2020; 11:5069-5077. [PMID: 32742454 PMCID: PMC7378918 DOI: 10.7150/jca.44697] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Accepted: 06/13/2020] [Indexed: 12/12/2022] Open
Abstract
The heterogeneity of hepatocellular carcinoma (HCC) commonly leads to therapeutic failure of HCC. Cytokeratin 19 (CK19) is well acknowledged as a biliary/progenitor cell marker and a marker of tumor stem cell. CK19-positive HCCs demonstrate aggressive behaviors and poor outcomes which including worse overall survival and early tumor recurrence after hepatectomy and liver transplantation. CK19-positive HCCs are resistant to chemotherapies as well as local treatment. This subset of HCC is thought to derive from liver progenitor cells and can be induced by extracellular stimulation such as hypoxia. Besides being a stemness marker, CK19 plays an important role in promoting malignant property of HCC. The regulatory network associated with CK19 expression has been summarized that extracellular stimulations which transmit into cytoplasm through signal transduction pathways (TGF-β, MAKP/JNK and MEK-ERK1/2), further induce important nuclear transcriptional factors (SALL4, AP1, SP1) to activate CK19 promoter. Novel noncoding RNAs are also involved in the regulation of CK19 expression. TGFβR1 becomes a therapeutic target for CK19-positive HCC. In conclusion, CK19 can be a potential biomarker for predicting poor prognosis after surgical and adjuvant therapies. CK19-pisitive HCCs exhibit distinctive molecular profiling, should be diagnosed and treated as a separate subtype of HCCs.
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Affiliation(s)
- Jian-Yong Zhuo
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang Province, China.,NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, 310003, Zhejiang Province, China
| | - Di Lu
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang Province, China.,NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, 310003, Zhejiang Province, China
| | - Win-Yen Tan
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang Province, China.,NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, 310003, Zhejiang Province, China
| | - Shu-Sen Zheng
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang Province, China.,NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, 310003, Zhejiang Province, China.,Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou, 310003, Zhejiang Province, China
| | - You-Qing Shen
- Center for Bionanoengineering and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, 310003, Zhejiang Province, China
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang Province, China.,NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, 310003, Zhejiang Province, China
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27
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Carluccio M, Ziberi S, Zuccarini M, Giuliani P, Caciagli F, Di Iorio P, Ciccarelli R. Adult mesenchymal stem cells: is there a role for purine receptors in their osteogenic differentiation? Purinergic Signal 2020; 16:263-287. [PMID: 32500422 DOI: 10.1007/s11302-020-09703-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 05/04/2020] [Indexed: 02/06/2023] Open
Abstract
The role played by mesenchymal stem cells (MSCs) in contributing to adult tissue homeostasis and damage repair thanks to their differentiation capabilities has raised a great interest, mainly in bone regenerative medicine. The growth/function of these undifferentiated cells of mesodermal origin, located in specialized structures (niches) of differentiated organs is influenced by substances present in this microenvironment. Among them, ancestral and ubiquitous molecules such as adenine-based purines, i.e., ATP and adenosine, may be included. Notably, extracellular purine concentrations greatly increase during tissue injury; thus, MSCs are exposed to effects mediated by these agents interacting with their own receptors when they act/migrate in vivo or are transplanted into a damaged tissue. Here, we reported that ATP modulates MSC osteogenic differentiation via different P2Y and P2X receptors, but data are often inconclusive/contradictory so that the ATP receptor importance for MSC physiology/differentiation into osteoblasts is yet undetermined. An exception is represented by P2X7 receptors, whose expression was shown at various differentiation stages of bone cells resulting essential for differentiation/survival of both osteoclasts and osteoblasts. As well, adenosine, usually derived from extracellular ATP metabolism, can promote osteogenesis, likely via A2B receptors, even though findings from human MSCs should be implemented and confirmed in preclinical models. Therefore, although many data have revealed possible effects caused by extracellular purines in bone healing/remodeling, further studies, hopefully performed in in vivo models, are necessary to identify defined roles for these compounds in favoring/increasing the pro-osteogenic properties of MSCs and thereby their usefulness in bone regenerative medicine.
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Affiliation(s)
- Marzia Carluccio
- Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Via dei Vestini 29, 66100, Chieti, Italy.,Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100, Chieti, Italy.,StemTeCh Group, Via L. Polacchi, 66100, Chieti, Italy
| | - Sihana Ziberi
- Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Via dei Vestini 29, 66100, Chieti, Italy.,Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100, Chieti, Italy.,StemTeCh Group, Via L. Polacchi, 66100, Chieti, Italy
| | - Mariachiara Zuccarini
- Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Via dei Vestini 29, 66100, Chieti, Italy.,Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100, Chieti, Italy
| | - Patricia Giuliani
- Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Via dei Vestini 29, 66100, Chieti, Italy.,Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100, Chieti, Italy
| | - Francesco Caciagli
- Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100, Chieti, Italy
| | - Patrizia Di Iorio
- Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Via dei Vestini 29, 66100, Chieti, Italy.,Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100, Chieti, Italy
| | - Renata Ciccarelli
- Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Via dei Vestini 29, 66100, Chieti, Italy. .,Center for Advanced Studies and Technologies (CAST), University of Chieti-Pescara, Via L. Polacchi, 66100, Chieti, Italy. .,StemTeCh Group, Via L. Polacchi, 66100, Chieti, Italy.
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28
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Zhao X, Zhu Y, Laslett AL, Chan HF. Hepatic Differentiation of Stem Cells in 2D and 3D Biomaterial Systems. Bioengineering (Basel) 2020; 7:E47. [PMID: 32466173 PMCID: PMC7356247 DOI: 10.3390/bioengineering7020047] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 05/18/2020] [Accepted: 05/22/2020] [Indexed: 02/06/2023] Open
Abstract
A critical shortage of donor livers for treating end-stage liver failure signifies the urgent need for alternative treatment options. Hepatocyte-like cells (HLC) derived from various stem cells represent a promising cell source for hepatocyte transplantation, liver tissue engineering, and development of a bioartificial liver assist device. At present, the protocols of hepatic differentiation of stem cells are optimized based on soluble chemical signals introduced in the culture medium and the HLC produced typically retain an immature phenotype. To promote further hepatic differentiation and maturation, biomaterials can be designed to recapitulate cell-extracellular matrix (ECM) interactions in both 2D and 3D configurations. In this review, we will summarize and compare various 2D and 3D biomaterial systems that have been applied to hepatic differentiation, and highlight their roles in presenting biochemical and physical cues to different stem cell sources.
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Affiliation(s)
- Xiaoyu Zhao
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China; (X.Z.); (Y.Z.)
- Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Yanlun Zhu
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China; (X.Z.); (Y.Z.)
- Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Andrew L. Laslett
- CSIRO Manufacturing, Clayton, Victoria 3168, Australia;
- Australian Regenerative Medicine Institute, Monash University, Victoria 3800, Australia
| | - Hon Fai Chan
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China; (X.Z.); (Y.Z.)
- Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China
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29
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Eom YW, Kang SH, Kim MY, Lee JI, Baik SK. Mesenchymal stem cells to treat liver diseases. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:563. [PMID: 32775364 PMCID: PMC7347787 DOI: 10.21037/atm.2020.02.163] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Mesenchymal stem cells (MSCs) are being developed for stem cell therapy and can be efficiently used in regenerative medicine. To date, more than 1,000 clinical trials have used MSCs; of these, more than 80 clinical trials have targeted liver disease. MSCs migrate to damaged liver tissues, differentiate into hepatocytes, reduce liver inflammatory responses, reduce liver fibrosis, and act as antioxidants. According to the reported literature, MSCs are safe, have no side effects, and improve liver function; however, their regenerative therapeutic effects are unsatisfactory. Here, we explain, in detail, the basic therapeutic effects and recent clinical advances of MSCs. Furthermore, we discuss future research directions for improving the regenerative therapeutic effects of MSCs.
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Affiliation(s)
- Young Woo Eom
- Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Seong Hee Kang
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Moon Young Kim
- Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Jong In Lee
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Soon Koo Baik
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
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30
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Tricot T, De Boeck J, Verfaillie C. Alternative Cell Sources for Liver Parenchyma Repopulation: Where Do We Stand? Cells 2020; 9:E566. [PMID: 32121068 PMCID: PMC7140465 DOI: 10.3390/cells9030566] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 02/20/2020] [Accepted: 02/22/2020] [Indexed: 12/28/2022] Open
Abstract
Acute and chronic liver failure is a highly prevalent medical condition with high morbidity and mortality. Currently, the therapy is orthotopic liver transplantation. However, in some instances, chiefly in the setting of metabolic diseases, transplantation of individual cells, specifically functional hepatocytes, can be an acceptable alternative. The gold standard for this therapy is the use of primary human hepatocytes, isolated from livers that are not suitable for whole organ transplantations. Unfortunately, primary human hepatocytes are scarcely available, which has led to the evaluation of alternative sources of functional hepatocytes. In this review, we will compare the ability of most of these candidate alternative cell sources to engraft and repopulate the liver of preclinical animal models with the repopulation ability found with primary human hepatocytes. We will discuss the current shortcomings of the different cell types, and some of the next steps that we believe need to be taken to create alternative hepatocyte progeny capable of regenerating the failing liver.
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31
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Huang KC, Chuang MH, Lin ZS, Lin YC, Chen CH, Chang CL, Huang PC, Syu WS, Chiou TW, Hong ZH, Tsai YC, Harn HJ, Lin PC, Lin SZ. Transplantation with GXHPC1 for Liver Cirrhosis: Phase 1 Trial. Cell Transplant 2019; 28:100S-111S. [PMID: 31722556 PMCID: PMC7016466 DOI: 10.1177/0963689719884885] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Currently, the only effective therapy for cirrhosis of the liver is liver transplantation. However, finding a compatible liver is difficult due to the low supply of healthy livers and the ever-increasing demand. However, stem-cell therapy may offer a solution for liver cirrhosis; for example, GXHPC1 therapy preparation contains adipose-derived mesenchymal stem cells (AD-MSCs) and was developed for the treatment of liver cirrhosis. In our previous report, animal studies suggested that treatment of a diseased liver via GXHPC1 transplantation can abrogate liver fibrosis and facilitate recovery of liver function. In our current human trial, patients with liver cirrhosis were included. Their adipose tissue was harvested from the subcutaneous fat of the abdominal wall during surgery. AD-MSCs were cultured and suspended at a concentration of 100 million cells in 1 ml of physiological saline (i.e., GXHPC1). This human study passed the Taiwan Food and Drug Administration IND inspection and received Phase I clinical trial permission. The trial was conducted with six patients with liver cirrhosis to demonstrate the safety and efficacy of administering GXHPC1. Intrahepatic injection of GXHPC1 did not cause any safety issues in the analysis of adverse drug reactions and suspected unexpected serious adverse reactions, and showed a tendency for improvement of liver function, METAVIR score, Child–Pugh score, MELD score, and quality of life for patients with liver cirrhosis.
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Affiliation(s)
- Ko-Chang Huang
- Department of Gastroenterological, China Medical University Beigan Hospital, Yunlin
| | - Ming-Hsi Chuang
- PhD Program of Technology Management, Chung Hua University, Hsinchu.,Department of Bioinformatics, Chung Hua University, Hsinchu
| | - Zung-Sheng Lin
- Department of General Surgery, China Medical University Beigan Hospital, Yunlin
| | - Yi-Chun Lin
- Department of Stem Cell Applied Technology, Gwo Xi Stem Cell Applied Technology, Hsinchu
| | | | | | - Pi-Chun Huang
- Department of Stem Cell Applied Technology, Gwo Xi Stem Cell Applied Technology, Hsinchu
| | - Wan-Sin Syu
- Department of Stem Cell Applied Technology, Gwo Xi Stem Cell Applied Technology, Hsinchu
| | - Tzyy-Wen Chiou
- Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien
| | - Zih-Han Hong
- Department of Stem Cell Applied Technology, Gwo Xi Stem Cell Applied Technology, Hsinchu
| | - Yu-Chen Tsai
- Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei
| | - Horng-Jyh Harn
- Bioinnovation Center, Tzu Chi foundation; Department of Pathology, Buddhist Tzu Chi General hospital, Tzu Chi University, Hualien
| | - Po-Cheng Lin
- Department of Stem Cell Applied Technology, Gwo Xi Stem Cell Applied Technology, Hsinchu
| | - Shinn-Zong Lin
- Bioinnovation Center, Tzu Chi foundation; Department of Neurosurgery, Buddhist Tzu Chi General hospital, Tzu Chi University, Hualien
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Han Y, Li X, Zhang Y, Han Y, Chang F, Ding J. Mesenchymal Stem Cells for Regenerative Medicine. Cells 2019; 8:E886. [PMID: 31412678 PMCID: PMC6721852 DOI: 10.3390/cells8080886] [Citation(s) in RCA: 716] [Impact Index Per Article: 119.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 08/05/2019] [Accepted: 08/06/2019] [Indexed: 02/06/2023] Open
Abstract
In recent decades, the biomedical applications of mesenchymal stem cells (MSCs) have attracted increasing attention. MSCs are easily extracted from the bone marrow, fat, and synovium, and differentiate into various cell lineages according to the requirements of specific biomedical applications. As MSCs do not express significant histocompatibility complexes and immune stimulating molecules, they are not detected by immune surveillance and do not lead to graft rejection after transplantation. These properties make them competent biomedical candidates, especially in tissue engineering. We present a brief overview of MSC extraction methods and subsequent potential for differentiation, and a comprehensive overview of their preclinical and clinical applications in regenerative medicine, and discuss future challenges.
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Affiliation(s)
- Yu Han
- Department of Orthopedics, The Second Hospital of Jilin University, 218 Ziqiang Street, Changchun 130041, China
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, China
| | - Xuezhou Li
- Department of Orthopedics, The Second Hospital of Jilin University, 218 Ziqiang Street, Changchun 130041, China
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, China
| | - Yanbo Zhang
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, 126 Xiantai Street, Changchun 130033, China.
| | - Yuping Han
- Department of Urology, China-Japan Union Hospital of Jilin University, 126 Xiantai Street, Changchun 130033, China.
| | - Fei Chang
- Department of Orthopedics, The Second Hospital of Jilin University, 218 Ziqiang Street, Changchun 130041, China.
| | - Jianxun Ding
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, China
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33
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Di Nicola V. Omentum a powerful biological source in regenerative surgery. Regen Ther 2019; 11:182-191. [PMID: 31453273 PMCID: PMC6700267 DOI: 10.1016/j.reth.2019.07.008] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Accepted: 07/24/2019] [Indexed: 02/06/2023] Open
Abstract
The Omentum is a large flat adipose tissue layer nestling on the surface of the intra-peritoneal organs. Besides fat storage, omentum has key biological functions in immune-regulation and tissue regeneration. Omentum biological properties include neovascularization, haemostasis, tissue healing and regeneration and as an in vivo incubator for cells and tissue cultivation. Some of these properties have long been noted in surgical practice and used empirically in several procedures. In this review article, the author tries to highlight the omentum biological properties and their application in regenerative surgery procedures. Further, he has started a process of standardisation of basic biological principles to pave the way for future surgical practice.
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Panta W, Imsoonthornruksa S, Yoisungnern T, Suksaweang S, Ketudat-Cairns M, Parnpai R. Enhanced Hepatogenic Differentiation of Human Wharton's Jelly-Derived Mesenchymal Stem Cells by Using Three-Step Protocol. Int J Mol Sci 2019; 20:ijms20123016. [PMID: 31226809 PMCID: PMC6627410 DOI: 10.3390/ijms20123016] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 06/11/2019] [Accepted: 06/17/2019] [Indexed: 02/06/2023] Open
Abstract
Currently, human Wharton’s jelly-derived mesenchymal stem cells (hWJ-MSCs) are an attractive source of stem cells for cell-based therapy, owing to their ability to undergo self-renewal and differentiate into all mesodermal, some neuroectodermal, and endodermal progenies, including hepatocytes. Herein, this study aimed to investigate the effects of sodium butyrate (NaBu), an epigenetic regulator that directly inhibits histone deacetylase, on hepatic endodermal lineage differentiation of hWJ-MSCs. NaBu, at 1 mM, optimally promoted endodermal differentiation of hWJ-MSCs, along with epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) supplementation. CXCR4, HNF3β, SOX17 (endodermal), and GATA6 (mesendodermal) mRNAs were also up-regulated (p < 0.001). Immunocytochemistry and a Western blot analysis of SOX17 and HNF3β confirmed that the 1 mM NaBu along with EGF and bFGF supplementation condition was appropriately pre-treated with hWJ-MSCs before hepatogenic differentiation. Furthermore, the hepatic differentiation medium with NaBu pre-treatment up-regulated hepatoblast (AFP and HNF3β) and hepatic (CK18 and ALB) markers, and increased the proportion of mature hepatocyte functions, including G6P, C/EBPα, and CYP2B6 mRNAs, glycogen storage and urea secretion. The hepatic differentiation medium with NaBu in the pre-treatment step can induce hWJ-MSC differentiation toward endodermal, hepatoblastic, and hepatic lineages. Therefore, the hepatic differentiation medium with NaBu pre-treatment for differentiating hWJ-MSCs could represent an alternative protocol for cell-based therapy and drug screening in clinical applications.
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Affiliation(s)
- Wachira Panta
- Embryo Technology and Stem Cell Research Center, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand.
| | - Sumeth Imsoonthornruksa
- Embryo Technology and Stem Cell Research Center, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand.
| | - Ton Yoisungnern
- Embryo Technology and Stem Cell Research Center, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand.
| | - Sanong Suksaweang
- School of Pathology and Laboratory Medicine, Institute of Medicine, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand.
| | - Mariena Ketudat-Cairns
- Embryo Technology and Stem Cell Research Center, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand.
| | - Rangsun Parnpai
- Embryo Technology and Stem Cell Research Center, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand.
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Ye Z, Lu W, Liang L, Tang M, Wang Y, Li Z, Zeng H, Wang A, Lin M, Huang L, Wang H, Hu H. Mesenchymal stem cells overexpressing hepatocyte nuclear factor-4 alpha alleviate liver injury by modulating anti-inflammatory functions in mice. Stem Cell Res Ther 2019; 10:149. [PMID: 31133062 PMCID: PMC6537220 DOI: 10.1186/s13287-019-1260-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 05/03/2019] [Accepted: 05/10/2019] [Indexed: 01/20/2023] Open
Abstract
Background Mesenchymal stem cells (MSCs) can migrate to tissue injury sites where they can induce multipotential differentiation and anti-inflammation effects to treat tissue injury. When traditional therapeutic methods do not work, MSCs are considered to be one of the best candidates for cell therapy. MSCs have been used for treating several injury- and inflammation-associated diseases, including liver cirrhosis. However, the therapeutic effect of MSCs is limited. In some cases, the anti-inflammatory function of naïve MSCs is not enough to rescue tissue injury. Methods Carbon tetrachloride (CCl4) was used to establish a mouse liver cirrhosis model. Enhanced green fluorescence protein (EGFP) and hepatocyte nuclear factor-4α (HNF-4α) overexpression adenoviruses were used to modify MSCs. Three weeks after liver injury induction, mice were injected with bone marrow MSCs via their tail vein. The mice were then sacrificed 3 weeks after MSC injection. Liver injury was evaluated by measuring glutamic-pyruvic transaminase (ALT) and glutamic oxalacetic transaminase (AST) levels. Histological and molecular evaluations were performed to study the mechanisms. Results We found that HNF-4α-overexpressing MSCs had a better treatment effect than unmodified MSCs on liver cirrhosis. In the CCl4-induced mouse liver injury model, we found that HNF-4α-MSCs reduced inflammation in the liver and alleviated liver injury. In addition, we found that HNF-4α promoted the anti-inflammatory effect of MSCs by enhancing nitric oxide synthase (iNOS) expression, which was dependent on the nuclear factor kappa B (NF-κB) signalling pathway. Conclusions MSCs overexpressing HNF-4α exerted good therapeutic effects against mouse liver cirrhosis due to an enhanced anti-inflammatory effect. Gene modification is likely a promising method for improving the effects of cell therapy. Electronic supplementary material The online version of this article (10.1186/s13287-019-1260-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Zhenxiong Ye
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, 450 Teng Yue Road, Shanghai, 200090, China
| | - Wenfeng Lu
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, 450 Teng Yue Road, Shanghai, 200090, China.,Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Lei Liang
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, 450 Teng Yue Road, Shanghai, 200090, China.,Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Min Tang
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, 450 Teng Yue Road, Shanghai, 200090, China
| | - Yunfeng Wang
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, 450 Teng Yue Road, Shanghai, 200090, China
| | - Zhen Li
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, 450 Teng Yue Road, Shanghai, 200090, China
| | - Heping Zeng
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, 450 Teng Yue Road, Shanghai, 200090, China
| | - Aili Wang
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, 450 Teng Yue Road, Shanghai, 200090, China
| | - Moubin Lin
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, 450 Teng Yue Road, Shanghai, 200090, China
| | - Lei Huang
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, 450 Teng Yue Road, Shanghai, 200090, China
| | - Hui Wang
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, 450 Teng Yue Road, Shanghai, 200090, China
| | - Hai Hu
- Center of Gallbladder Disease, Shanghai East Hospital, Tongji University School of Medicine, 150 Ji Mo Road, Shanghai, 201200, China.
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Godoy P, Schmidt-Heck W, Hellwig B, Nell P, Feuerborn D, Rahnenführer J, Kattler K, Walter J, Blüthgen N, Hengstler JG. Assessment of stem cell differentiation based on genome-wide expression profiles. Philos Trans R Soc Lond B Biol Sci 2019; 373:rstb.2017.0221. [PMID: 29786556 DOI: 10.1098/rstb.2017.0221] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/03/2018] [Indexed: 12/24/2022] Open
Abstract
In recent years, protocols have been established to differentiate stem and precursor cells into more mature cell types. However, progress in this field has been hampered by difficulties to assess the differentiation status of stem cell-derived cells in an unbiased manner. Here, we present an analysis pipeline based on published data and methods to quantify the degree of differentiation and to identify transcriptional control factors explaining differences from the intended target cells or tissues. The pipeline requires RNA-Seq or gene array data of the stem cell starting population, derived 'mature' cells and primary target cells or tissue. It consists of a principal component analysis to represent global expression changes and to identify possible problems of the dataset that require special attention, such as: batch effects; clustering techniques to identify gene groups with similar features; over-representation analysis to characterize biological motifs and transcriptional control factors of the identified gene clusters; and metagenes as well as gene regulatory networks for quantitative cell-type assessment and identification of influential transcription factors. Possibilities and limitations of the analysis pipeline are illustrated using the example of human embryonic stem cell and human induced pluripotent cells to generate 'hepatocyte-like cells'. The pipeline quantifies the degree of incomplete differentiation as well as remaining stemness and identifies unwanted features, such as colon- and fibroblast-associated gene clusters that are absent in real hepatocytes but typically induced by currently available differentiation protocols. Finally, transcription factors responsible for incomplete and unwanted differentiation are identified. The proposed method is widely applicable and allows an unbiased and quantitative assessment of stem cell-derived cells.This article is part of the theme issue 'Designer human tissue: coming to a lab near you'.
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Affiliation(s)
- Patricio Godoy
- IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
| | - Wolfgang Schmidt-Heck
- Leibniz Institute for Natural Product Research and Infection Biology eV-Hans-Knöll Institute, Jena, Germany
| | - Birte Hellwig
- Department of Statistics, TU Dortmund University, Dortmund, Germany
| | - Patrick Nell
- IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
| | - David Feuerborn
- IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
| | | | - Kathrin Kattler
- Department of Genetics, University of Saarland, Saarbrücken 66123, Germany
| | - Jörn Walter
- Institute of Pathology, Charité Universitätsmedizin, 10117 Berlin, Germany
| | - Nils Blüthgen
- Institute of Pathology, Charité Universitätsmedizin, 10117 Berlin, Germany.,Integrative Research Institute for the Life Sciences, Institute for Theoretical Biology, Humboldt Universität, 10115 Berlin, Germany
| | - Jan G Hengstler
- IfADo-Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
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Natale A, Vanmol K, Arslan A, Van Vlierberghe S, Dubruel P, Van Erps J, Thienpont H, Buzgo M, Boeckmans J, De Kock J, Vanhaecke T, Rogiers V, Rodrigues RM. Technological advancements for the development of stem cell-based models for hepatotoxicity testing. Arch Toxicol 2019; 93:1789-1805. [PMID: 31037322 DOI: 10.1007/s00204-019-02465-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 04/18/2019] [Indexed: 02/07/2023]
Abstract
Stem cells are characterized by their self-renewal capacity and their ability to differentiate into multiple cell types of the human body. Using directed differentiation strategies, stem cells can now be converted into hepatocyte-like cells (HLCs) and therefore, represent a unique cell source for toxicological applications in vitro. However, the acquired hepatic functionality of stem cell-derived HLCs is still significantly inferior to primary human hepatocytes. One of the main reasons for this is that most in vitro models use traditional two-dimensional (2D) setups where the flat substrata cannot properly mimic the physiology of the human liver. Therefore, 2D-setups are progressively being replaced by more advanced culture systems, which attempt to replicate the natural liver microenvironment, in which stem cells can better differentiate towards HLCs. This review highlights the most recent cell culture systems, including scaffold-free and scaffold-based three-dimensional (3D) technologies and microfluidics that can be employed for culture and hepatic differentiation of stem cells intended for hepatotoxicity testing. These methodologies have shown to improve in vitro liver cell functionality according to the in vivo liver physiology and allow to establish stem cell-based hepatic in vitro platforms for the accurate evaluation of xenobiotics.
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Affiliation(s)
- Alessandra Natale
- Department of In Vitro Toxicology and Dermato-Cosmetology (IVTD), Vrije Universiteit Brussel, Brussels, Belgium
| | - Koen Vanmol
- Brussels Photonics (B-PHOT), Vrije Universiteit Brussel and Flanders Make, Brussels, Belgium
| | - Aysu Arslan
- Polymer Chemistry and Biomaterials Group (PBM), Centre of Macromolecular Chemistry, Ghent University, Ghent, Belgium
| | - Sandra Van Vlierberghe
- Brussels Photonics (B-PHOT), Vrije Universiteit Brussel and Flanders Make, Brussels, Belgium
- Polymer Chemistry and Biomaterials Group (PBM), Centre of Macromolecular Chemistry, Ghent University, Ghent, Belgium
| | - Peter Dubruel
- Polymer Chemistry and Biomaterials Group (PBM), Centre of Macromolecular Chemistry, Ghent University, Ghent, Belgium
| | - Jürgen Van Erps
- Brussels Photonics (B-PHOT), Vrije Universiteit Brussel and Flanders Make, Brussels, Belgium
| | - Hugo Thienpont
- Brussels Photonics (B-PHOT), Vrije Universiteit Brussel and Flanders Make, Brussels, Belgium
| | | | - Joost Boeckmans
- Department of In Vitro Toxicology and Dermato-Cosmetology (IVTD), Vrije Universiteit Brussel, Brussels, Belgium
| | - Joery De Kock
- Department of In Vitro Toxicology and Dermato-Cosmetology (IVTD), Vrije Universiteit Brussel, Brussels, Belgium
| | - Tamara Vanhaecke
- Department of In Vitro Toxicology and Dermato-Cosmetology (IVTD), Vrije Universiteit Brussel, Brussels, Belgium
| | - Vera Rogiers
- Department of In Vitro Toxicology and Dermato-Cosmetology (IVTD), Vrije Universiteit Brussel, Brussels, Belgium
| | - Robim M Rodrigues
- Department of In Vitro Toxicology and Dermato-Cosmetology (IVTD), Vrije Universiteit Brussel, Brussels, Belgium.
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Comparative analysis of mesenchymal stem cells derived from amniotic membrane, umbilical cord, and chorionic plate under serum-free condition. Stem Cell Res Ther 2019; 10:19. [PMID: 30635045 PMCID: PMC6330472 DOI: 10.1186/s13287-018-1104-x] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 11/15/2018] [Accepted: 12/09/2018] [Indexed: 02/07/2023] Open
Abstract
Background Mesenchymal stem cells (MSCs) have emerged as a promising regenerative tool, owing mainly to their multi-differentiation potential and immunosuppressive capacity. When compared with MSCs classically derived from the adult bone marrow (BM), MSCs of neonatal origins exhibit superior proliferation ability, lower immunogenicity, and possible lower incorporated mutation; hence, they are considered as an alternative source for clinical use. Several researches have focused on the biological differences among some neonatal MSCs cultured in serum-containing medium (SCM). However, since it has been reported that MSCs possess different biological characteristics when cultured in serum-free medium (SFM), these comparative studies in SCM cannot exactly represent the results under the serum-free Good Manufacturing Practice (GMP) standard. Methods Here, MSCs were isolated from three neonatal tissues, namely amniotic membrane (AM), umbilical cord (UC), and chorionic plate (CP), from the same donor, and their morphologies, immunophenotypes, trilineage differentiation potentials, global gene expression patterns, and proliferation abilities were systematically compared under chemical-defined SFM. Results Our study demonstrated that these three neonatal MSCs exhibited a similar morphology and immunophenotypic pattern but various mesodermal differentiation potentials under SFM: amniotic membrane-derived MSCs showed a higher rate for osteogenic differentiation; chorionic plate-derived MSCs presented better adipogenic induction efficiency; and all these three neonatal MSCs exhibited similar chondrogenic potential. Moreover, by the analysis of global gene expression patterns, we speculated a possible higher proliferation ability of CP-MSCs in SFM, and we subsequently validated this conjecture. Conclusions Collectively, these results suggest that MSCs of different neonatal origins possess different biological features in SFM and thus may represent an optimal choice for different clinical applications. Electronic supplementary material The online version of this article (10.1186/s13287-018-1104-x) contains supplementary material, which is available to authorized users.
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Autophagy promotes hepatic differentiation of hepatic progenitor cells by regulating the Wnt/β-catenin signaling pathway. J Mol Histol 2019; 50:75-90. [PMID: 30604254 PMCID: PMC6323068 DOI: 10.1007/s10735-018-9808-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 12/07/2018] [Indexed: 12/11/2022]
Abstract
Hepatic progenitor cells (HPCs) can be activated when the liver suffers persistent and severe damage and can differentiate into hepatocytes to maintain liver regeneration and homeostasis. However, the molecular mechanism underlying the hepatic differentiation of HPCs is unclear. Therefore, in this study, we aimed to investigate the roles of autophagy and the Wnt/β-catenin signaling pathway during hepatic differentiation of HPCs in vivo and in vitro. First, immunohistochemistry, immunofluorescence and electron microscopy showed that Atg5 and β-catenin were highly expressed in human fibrotic liver and mouse liver injury induced by feeding a 50% choline-deficient diet plus 0.15% ethionine solution in drinking water (CDE diet) for 21 days; in addition, these factors were expressed in CK19-positive HPCs. Second, Western blotting and immunofluorescence confirmed that CK19-positive HPCs incubated in differentiation medium for 7 days can differentiate into hepatocytes and that differentiated HPCs were able to take up ICG and secrete albumin and urea. Further investigation via Western blotting, immunofluorescence and electron microscopy revealed autophagy and the Wnt/β-catenin pathway to be activated during hepatic differentiation of HPCs. Next, we found that inhibiting autophagy by downregulating Atg5 gene expression impaired hepatic differentiation of HPCs and inhibited activation of the Wnt/β-catenin pathway, which was rescued by overexpression of the β-catenin gene. Moreover, downregulating β-catenin gene expression without inhibiting autophagy still impeded the differentiation of HPCs. Finally, coimmunoprecipitation demonstrated that P62 forms a complex with phosphorylated glycogen synthase kinase 3 beta (pGSK3β). Third, in mouse CDE-induced liver injury, immunohistochemistry and immunofluorescence confirmed that downregulating Atg5 gene expression inhibited autophagy, thus impeding hepatic differentiation of HPCs and inhibiting activation of the Wnt/β-catenin pathway. As observed in vitro, overexpression of β-catenin rescued this phenomenon caused by autophagy inhibition, though decreasing β-catenin levels without autophagy inhibition still impeded HPC differentiation. We also found that HPCs differentiated into hepatocytes in human fibrotic liver tissue. Collectively, these results demonstrate that autophagy promotes HPC differentiation by regulating Wnt/β-catenin signaling. Our results are the first to identify a role for autophagy in promoting the hepatic differentiation of HPCs.
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Solis MA, Moreno Velásquez I, Correa R, Huang LLH. Stem cells as a potential therapy for diabetes mellitus: a call-to-action in Latin America. Diabetol Metab Syndr 2019; 11:20. [PMID: 30820250 PMCID: PMC6380040 DOI: 10.1186/s13098-019-0415-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 02/13/2019] [Indexed: 02/06/2023] Open
Abstract
Latin America is a fast-growing region that currently faces unique challenges in the treatment of all forms of diabetes mellitus. The burden of this disease will be even greater in the coming years due, in part, to the large proportion of young adults living in urban areas and engaging in unhealthy lifestyles. Unfortunately, the national health systems in Latin-American countries are unprepared and urgently need to reorganize their health care services to achieve diabetic therapeutic goals. Stem cell research is attracting increasing attention as a promising and fast-growing field in Latin America. As future healthcare systems will include the development of regenerative medicine through stem cell research, Latin America is urged to issue a call-to-action on stem cell research. Increased efforts are required in studies focused on stem cells for the treatment of diabetes. In this review, we aim to inform physicians, researchers, patients and funding sources about the advances in stem cell research for possible future applications in diabetes mellitus. Emerging studies are demonstrating the potential of stem cells for β cell differentiation and pancreatic regeneration. The major economic burden implicated in patients with diabetes complications suggests that stem cell research may relieve diabetic complications. Closer attention should be paid to stem cell research in the future as an alternative treatment for diabetes mellitus.
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Affiliation(s)
| | | | - Ricardo Correa
- Department of Medicine, Warren Alpert School of Medicine, Brown University, Rhode Island, USA
- Department of Medicine, University of Arizona College of Medicine, Phoenix, AZ USA
| | - Lynn L. H. Huang
- Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, Tainan, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Research Center of Excellence in Regenerative Medicine, National Cheng Kung University, Tainan, Taiwan
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Ohkoshi S, Hirono H, Nakahara T, Ishikawa H. Dental pulp cell bank as a possible future source of individual hepatocytes. World J Hepatol 2018; 10:702-707. [PMID: 30386463 PMCID: PMC6206155 DOI: 10.4254/wjh.v10.i10.702] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 05/30/2018] [Accepted: 07/10/2018] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) as a source for regenerative medicine are now the subject of much clinical attention. There are high expectations due to their safety, low tumorigenic risk, and low ethical concerns. MSC therapy has been approved for acute graft-versus host diseases since 2015. Tooth-derived MSCs are known to have a great potential in their proliferation and differentiation capacities, even when compared with bone-marrow-derived MSCs. In particular, stem cells from human exfoliated deciduous teeth (SHEDs) are the best candidates for personal cell banking (dental pulp cell bank), because they can be obtained less invasively in the natural process of individual growth. SHEDs are known to differentiate into hepatocytes. There have been several studies showing the effectiveness of SHEDs on the treatment of liver failure in animal models. They may exert their effects either by repopulation of cells in injured liver or by paracrine mechanisms due to their immune-regulatory functions. Moreover, it may be possible to use each individuals' dental pulp cells as a future source of tailor-made differentiated hepatocytes in the context of a bioartificial liver or liver-on-a-chip to screen for drug toxicity.
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Affiliation(s)
- Shogo Ohkoshi
- Department of Internal Medicine, School of Life Dentistry at Niigata, the Nippon Dental University, Niigata 951-8580, Japan.
| | - Haruka Hirono
- Department of Internal Medicine, School of Life Dentistry at Niigata, the Nippon Dental University, Niigata 951-8580, Japan
| | - Taka Nakahara
- Department of Developmental and Regenerative Dentistry, School of Life Dentistry at Tokyo, the Nippon Dental University, Chiyoda-ku 102-8159, Japan
| | - Hiroshi Ishikawa
- Laboratory of Clinical Regenerative Medicine, Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, Laboratory of Advanced Research D #326, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
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Current Status of Canine Umbilical Cord Blood-Derived Mesenchymal Stem Cells in Veterinary Medicine. Stem Cells Int 2018; 2018:8329174. [PMID: 30123294 PMCID: PMC6079340 DOI: 10.1155/2018/8329174] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Accepted: 06/19/2018] [Indexed: 12/26/2022] Open
Abstract
Stem cell therapy has prompted the expansion of veterinary medicine both experimentally and clinically, with the potential to contribute to contemporary treatment strategies for various diseases and conditions for which limited or no therapeutic options are presently available. Although the application of various types of stem cells, such as bone marrow-derived mesenchymal stem cells (BM-MSCs), adipose tissue-derived mesenchymal stem cells (AT-MSCs), and umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs), has promising potential to improve the health of different species, it is crucial that the benefits and drawbacks are completely evaluated before use. Umbilical cord blood (UCB) is a rich source of stem cells; nonetheless, isolation of mesenchymal stem cells (MSCs) from UCB presents technical challenges. Although MSCs have been isolated from UCB of diverse species such as human, equine, sheep, goat, and canine, there are inherent limitations of using UCB from these species for the expansion of MSCs. In this review, we investigated canine UCB (cUCB) and compared it with UCB from other species by reviewing recent articles published from February 2003 to June 2017 to gain an understanding of the limitations of cUCB in the acquisition of MSCs and to determine other suitable sources for the isolation of MSCs from canine. Our review indicates that cUCB is not an ideal source of MSCs because of insufficient volume and ethical issues. However, canine reproductive organs discarded during neutering may help broaden our understanding of effective isolation of MSCs. We recommend exploring canine reproductive and adipose tissue rather than UCB to fulfill the current need in veterinary medicine for the well-designed and ethically approved source of MSCs.
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Lee JC. Microarray analysis after adipose derived mesenchymal stem cells injection in monosodium iodoacetate-induced osteoarthritis rats. Genes Genomics 2018; 40:25-37. [PMID: 29892899 DOI: 10.1007/s13258-017-0607-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Accepted: 08/23/2017] [Indexed: 02/08/2023]
Abstract
Osteoarthritis (OA) is a degenerative joint disease characterized by abrasion, and ultimately, destruction of the articular cartilage and trabecular bone loss. OA is still considered a devastating disease, which requires an aggressive therapeutic approach. Despite the therapeutic potential of human adipose-derived mesenchymal stem cells (AD-MSCs), the molecular parameters needed to define the "stemness" remain largely unknown. Using high-density oligonucleotide microarrays, the differential gene expression profiles between a fraction of human adipose-derived (AD) mononuclear cells and its MSC subpopulation were obtained. Of particular interest was a subset of 58 genes preferentially expressed at sevenfold or higher in the group treated with human AD-MSCs. This subset contained numerous genes involved in the inflammatory response, immune response, lipid metabolism, cell death, cell proliferation, and DNA repair. Additionally, four protein networks were constructed. The interaction network consisted of 46 proteins encoded by up-regulated genes. However, the interaction network also consisted of 38 proteins encoded by down-regulated genes. My results provide a basis for a more reproducible and reliable quality control using genotypic analysis for the definition of human AD-MSCs. Therefore, these results will provide a basis for studies on molecular mechanisms controlling the core properties of human MSCs.
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Affiliation(s)
- Jae Chul Lee
- Department of Plastic and Reconstructive Surgery, Seoul National University Bundang Hospital, 82, Gumi-ro 173 Beon-Gil, Bundang-Gu, Seongnam-si, Gyeonggi-do, 463707, Republic of Korea.
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Immune regulatory cell infusion for graft-versus-host disease prevention and therapy. Blood 2018; 131:2651-2660. [PMID: 29728401 DOI: 10.1182/blood-2017-11-785865] [Citation(s) in RCA: 121] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 12/08/2017] [Indexed: 12/13/2022] Open
Abstract
Current approaches to prevent and treat graft-versus-host disease (GVHD) after stem cell transplantation rely principally on pharmacological immune suppression. Such approaches are limited by drug toxicity, nonspecific immune suppression, and a requirement for long-term therapy. Our increased understanding of the regulatory cells and molecular pathways involved in limiting pathogenic immune responses opens the opportunity for the use of these cell subsets to prevent and/or GVHD. The theoretical advantages of this approach is permanency of effect, potential for facilitating tissue repair, and induction of tolerance that obviates a need for ongoing drug therapy. To date, a number of potential cell subsets have been identified, including FoxP3+ regulatory T (Treg) and FoxP3negIL-10+ (FoxP3-negative) regulatory T (Tr1), natural killer (NK) and natural killer T (NKT) cells, innate lymphoid cells, and various myeloid suppressor populations of hematopoietic (eg, myeloid derived suppressor cells) and stromal origin (eg, mesenchymal stem cells). Despite initial technical challenges relating to large-scale selection and expansion, these regulatory lineages are now undergoing early phase clinical testing. To date, Treg therapies have shown promising results in preventing clinical GVHD when infused early after transplant. Results from ongoing studies over the next 5 years will delineate the most appropriate cell lineage, source (donor, host, third party), timing, and potential exogenous cytokine support needed to achieve the goal of clinical transplant tolerance.
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Salem NA, El-Shamarka M, Khadrawy Y, El-Shebiney S. New prospects of mesenchymal stem cells for ameliorating temporal lobe epilepsy. Inflammopharmacology 2018; 26:963-972. [PMID: 29470694 DOI: 10.1007/s10787-018-0456-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Accepted: 02/09/2018] [Indexed: 12/29/2022]
Abstract
Temporal lobe epilepsy (TLE) is present in 30% of epileptic patients and does not respond to conventional treatments. Bone marrow derived mesenchymal stem cells (BMSCs) induce endogenous neural stem cells, inhibit neurodegeneration, and promote brain self-repair mechanisms. The present study addresses the feasibility of BMSCs transplantation against pilocarpine-induced TLE experimentally. BMSCs were injected either intravenously (IV) or in hippocampus bilaterally (IC). Increased cell count of BMSCs was achieved via IC route. BMSCs treatment ameliorated the pilocarpine-induced neurochemical and histological changes, retained amino acid neurotransmitters to the normal level, downregulated the immunoreactivity to insulin growth factor-1 receptor, synaptophysin, and caspase-3 and reduced oxidative insult and inflammatory markers detected in epileptic model. It is worth noting that BMSCs IC-administered showed more pronounced effects than those administered via IV route. BMSCs transplantation presents a promise for TLE treatment that has to be elucidated clinically.
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Affiliation(s)
- Neveen A Salem
- Biochemistry Department, Faculty of Science, Al Faisalia, King Abdulaziz University, Jeddah, Saudi Arabia. .,Medical Research Division, Narcotics, Ergogenic Aids and Poisons Department, National Research Centre, El-Bohouth Street, Dokki, Giza, 12622, Egypt.
| | - Marwa El-Shamarka
- Medical Research Division, Narcotics, Ergogenic Aids and Poisons Department, National Research Centre, El-Bohouth Street, Dokki, Giza, 12622, Egypt
| | - Yasser Khadrawy
- Medical Research Division, Physiology Department, NRC, Cairo, Egypt
| | - Shaimaa El-Shebiney
- Medical Research Division, Narcotics, Ergogenic Aids and Poisons Department, National Research Centre, El-Bohouth Street, Dokki, Giza, 12622, Egypt
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Current Perspectives Regarding Stem Cell-Based Therapy for Liver Cirrhosis. Can J Gastroenterol Hepatol 2018; 2018:4197857. [PMID: 29670867 PMCID: PMC5833156 DOI: 10.1155/2018/4197857] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 01/16/2018] [Indexed: 12/12/2022] Open
Abstract
Liver cirrhosis is a major cause of mortality and a common end of various progressive liver diseases. Since the effective treatment is currently limited to liver transplantation, stem cell-based therapy as an alternative has attracted interest due to promising results from preclinical and clinical studies. However, there is still much to be understood regarding the precise mechanisms of action. A number of stem cells from different origins have been employed for hepatic regeneration with different degrees of success. The present review presents a synopsis of stem cell research for the treatment of patients with liver cirrhosis according to the stem cell type. Clinical trials to date are summarized briefly. Finally, issues to be resolved and future perspectives are discussed with regard to clinical applications.
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Reversal of Experimental Liver Damage after Transplantation of Stem-Derived Cells Detected by FTIR Spectroscopy. Stem Cells Int 2017; 2017:4585169. [PMID: 29445403 PMCID: PMC5763141 DOI: 10.1155/2017/4585169] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 08/23/2017] [Accepted: 09/10/2017] [Indexed: 01/09/2023] Open
Abstract
The transplantation of autologous BM-MSCs holds great potential for treating end-stage liver diseases. The aim of this study was to compare the efficiency of transplanted rBM-MSCs and rBM-MSC-derived differentiated stem cells (rBM-MSC-DSCs) for suppression of dimethylnitrosamine-injured liver damage in rat model. Synchrotron radiation Fourier-transform infrared (SR-FTIR) microspectroscopy was applied to investigate changes in the macromolecular composition. Transplantation of rBM-MSC-DSCs into liver-injured rats restored their serum albumin level and significantly suppressed transaminase activity as well as the morphological manifestations of liver disease. The regenerative effects of rBM-MSC-DSCs were corroborated unequivocally by the phenotypic difference analysis between liver tissues revealed by infrared spectroscopy. Spectroscopic changes in the spectral region from 1190–970 cm−1 (bands with absorbance maxima at 1150 cm−1, 1081 cm−1, and 1026 cm−1) indicated decreased levels of carbohydrates, in rBM-MSC-DSC-transplanted livers, compared with untreated and rBM-MSC--transplanted animals. Principal component analysis (PCA) of spectra acquired from liver tissue could readily discriminate rBM-MSC-DSC-transplanted animals from the untreated and rBM-MSC-transplanted animals. We conclude that the transplantation of rBM-MSC-DSCs effectively treats liver disease in rats and SR-FTIR microspectroscopy provides important insights into the fundamental biochemical alterations induced by the stem-derived cell transplantation, including an objective “signature” of the regenerative effects of stem cell therapy upon liver injury.
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Wu Q, Tang J, Li Y, Li L, Wang Y, Bao J, Bu H. Hepatic differentiation of mouse bone marrow‑derived mesenchymal stem cells using a novel 3D culture system. Mol Med Rep 2017; 16:9473-9479. [PMID: 29152658 PMCID: PMC5780005 DOI: 10.3892/mmr.2017.7818] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Accepted: 05/16/2017] [Indexed: 02/05/2023] Open
Abstract
The development of novel culture systems that mimic the in vivo microenvironment may be beneficial for inducing the differentiation of stem cells and promoting liver function. In the present study, spheroid cultures and decellularized liver scaffolds (DLSs) were utilized to obtain differentiated hepatocyte-like cells. Mouse bone marrow (BM)-derived mesenchymal stem cells (MSCs) self-aggregated into spheroids under low-attachment conditions and implanted into the DLSs via a negative pressure suction device. The Albp-ZsGreen adenoviral vector was utilized for real-time monitoring of hepatocyte-like cell differentiation. To detect the differentiation stages of the MSCs, immunostaining of hepatocyte markers and functional analysis was performed. Compared with traditional 2D monolayer induction, mouse BM-MSCs spheroids and DLSs in 3D culture generated greater yields of mature, differentiated hepatocytes. In conclusion, this 3D culture system may provide a strategy for generating hepatocyte-like cells for portable liver micro-organs, and aid clinical hepatocyte transplantation and liver tissue engineering.
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Affiliation(s)
- Qiong Wu
- Laboratory of Pathology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Jing Tang
- Laboratory of Pathology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yi Li
- Laboratory of Pathology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Li Li
- Laboratory of Pathology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yujia Wang
- Laboratory of Pathology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Ji Bao
- Laboratory of Pathology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Hong Bu
- Laboratory of Pathology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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Fu LL, Pang BY, Zhu Y, Wang L, Leng AJ, Chen HL. Yi Guan Jian decoction may enhance hepatic differentiation of bone marrow‑derived mesenchymal stem cells via SDF‑1 in vitro. Mol Med Rep 2017; 16:2511-2521. [PMID: 28677743 PMCID: PMC5548069 DOI: 10.3892/mmr.2017.6888] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 12/12/2016] [Indexed: 01/25/2023] Open
Abstract
A previous study reported that Yi Guan Jian (YGJ) may increase the proliferation and differentiation of hepatic oval cells in a rat liver cirrhosis model. The aim of the present study was to investigate the effect and mechanism of action of YGJ on inducing hepatic differentiation in bone marrow-derived mesenchymal stem cells (BM-MSCs) via stromal-cell derived factor-1 (SDF-1). Murine BM-MSCs were isolated with whole bone marrow adherence, then identified by immunocytochemical staining and flow cytometry. Passage 2 cells were divided into 8 groups and their differentiation was induced by cell factors added to the medium, including hepatocyte growth factor (HGF), SDF-1 and YGJ. Each of the cell factors was used alone and any two or three of them were combined to establish different cell microenvironments in the different treatment groups. Albumin (ALB) was selected as a hepatocellular marker and cytokeratin-18 (CK-18) as a cholangiocellular marker. The protein and mRNA expression levels of ALB and CK-18 were used to determine the differentiation of BM-MSCs using immunocytochemical staining, western blotting and reverse transcription-quantitative polymerase chain reaction on days 7, 14, 21 and 28 during induction. The relative expression levels of ALB and CK-18 resulted in time-dependent increases in the groups supplemented only with HGF, SDF-1 or YGJ. Combination treatment of any two HGF, SDF-1 and YGJ led to a higher expression of ALB and CK-18 compared with only one cell factor treatment. Additionally, when all three were used in a combined treatment the expression levels of ALB and CK-18 occurred at an earlier time and was higher overall. Therefore, the present study suggested that YGJ had an effect on inducing hepatic differentiation in BM-MSCs via SDF-1 and may act in a synergistic manner with HGF and SDF-1.
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Affiliation(s)
- Lin-Lin Fu
- Department of Infectious Disease, The First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Bing-Yao Pang
- Department of Infectious Disease, The First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Ying Zhu
- Department of Infectious Disease, The First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Ling Wang
- Department of Digestive Disease, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Ai-Jing Leng
- Department of Chinese Medicine, The First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning 116011, P.R. China
| | - Hai-Long Chen
- Department of General Surgery, The First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning 116011, P.R. China
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Sang J, Wang S, Zhang J, Ding W, Luo J. [Effect of porcine small intestinal submucosa extracellular matrix in promoting vitality and functional gene expression of hepatocyte]. ZHONGGUO XIU FU CHONG JIAN WAI KE ZA ZHI = ZHONGGUO XIUFU CHONGJIAN WAIKE ZAZHI = CHINESE JOURNAL OF REPARATIVE AND RECONSTRUCTIVE SURGERY 2017; 31:607-613. [PMID: 29798552 DOI: 10.7507/1002-1892.201702072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Objective To investigate the effect of porcine small intestinal submucosa extracellular matrix (PSISM) on the vitality and gene regulation of hepatocyte so as to lay the experimental foundation for the application of PSISM in liver tissue engineering. Methods The experiment was divided into two parts: ① BRL cells were cultured with 50, 100, and 200 μg/mL PSISM-medium which were prepared by adding PSISM into the H-DMEM-medium containing 10%FBS in groups A1, B1, and C1, and simple H-DMEM-medium served as a control (group D1); ② BRL cells were seeded on 1%, 2%, and 3% PSISM hydrogel which were prepared by dissolving PSISM in sterile PBS solution containing 0.1 mol/L NaOH in groups A2, B2, and C2, and collagen type I gel served as a control (group D2). At 1, 3, and 5 days after culture, the morphology and survival of liver cells were detected by the Live/Dead fluorescent staining. The cell vitality was tested by cell counting kit-8 (CCK-8) assay. And the relative expressions of albumin (ALB), cytokeratin 18 (CK18), and alpha-fetoprotein (AFP) in hepatocytes were determined by real-time fluorescent quantitative PCR (RT-qPCR). Results The Live/Dead fluorescent staining showed the cells survived well in all groups. CCK-8 results displayed that the absorbance ( A) value of group C1 was significantly higher than that of group D1 at 5 days after culture with PSISM-medium, and there was no significant difference between groups at other time points ( P>0.05). After cultured with PSISM hydrogels, the A values of groups A2, B2, and C2 were significantly higher than those of group D2 at 3 and 5 days ( P<0.05), the A value of group A2 was significantly higher than that of groups B2 and C2 at 5 days ( P<0.05), but there was no significant difference between groups at other time points ( P>0.05). RT-qPCR showed that the relative expressions of ALB and CK18 mRNA significantly increased and the relative expression of AFP mRNA significantly decreased in groups A1, B1, and C1 when compared with group D1 ( P<0.05). The relative expression of CK18 mRNA in group C1 was significantly lower than that in groups A1 and B1 ( P<0.05). The relative expressions of ALB and CK18 mRNA were significantly higher and the relative expression of AFP mRNA was significantly lower in groups A2, B2, and C2 than group D2 ( P<0.05); the relative expression of CK18 mRNA in group A2 was significantly higher than that in group B2 ( P<0.05), and the relative expression of AFP mRNA in group A2 was significantly lower than that in group C2 ( P<0.05), but no significant difference was found between other groups ( P>0.05). Conclusion PSISM has good compatibility with hepatocyte and can promote the vitality and functional gene expression of hepatocyte. PSISM is expected to be used as culture medium supplement or cell carrier for liver tissue engineering.
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Affiliation(s)
- Jiangwei Sang
- Division of Stem Cell and Tissue Engineering, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu Sichuan, 610041, P.R.China
| | - Suya Wang
- Division of Stem Cell and Tissue Engineering, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu Sichuan, 610041, P.R.China
| | - Jie Zhang
- Division of Stem Cell and Tissue Engineering, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu Sichuan, 610041, P.R.China
| | - Wei Ding
- Division of Stem Cell and Tissue Engineering, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu Sichuan, 610041, P.R.China
| | - Jingcong Luo
- Division of Stem Cell and Tissue Engineering, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu Sichuan, 610041,
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