1
|
Thanh LN, Nguyen HP, Kieu TPT, Duy MN, Ha HTT, Thi HB, Nguyen TQ, Pham HD, Tran TD. Modified Kasai operation combined with autologous bone marrow mononuclear cell infusion for biliary atresia. BMC Surg 2024; 24:368. [PMID: 39568009 PMCID: PMC11577823 DOI: 10.1186/s12893-024-02669-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 11/12/2024] [Indexed: 11/22/2024] Open
Abstract
AIM To evaluate the safety and outcomes of modified Kasai operation combined with autologous bone marrow mononuclear cell (BMMNC) infusion for biliary atresia (BA). METHODS A matched control study was conducted between January 2015 and December 2021. Ten consecutive children with biliary atresia (BA) who underwent the modified Kasai operation combined with autologous BMMNC infusion (cell therapy group) and ten children who had only the modified Kasai operation (control group) were included in the study. The Kasai operation was performed with two modifications: partial exteriorization of the liver, and encirclement with lateral retraction of two hepatic pedicles to facilitate the removal of fibrotic tissue. Bone marrow was harvested through anterior iliac crest under general anesthesia then a modified Kasai operation was performed. After processing, bone marrow mononuclear cells were infused through the umbilical vein at the end of the operation. Serum bilirubin, albumin, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and prothrombin time were monitored at baseline, six months, twelve months, and the last follow-up (4.5 years) after the operation. In addition, esophagoscopy and liver biopsies were performed on patients whose parents agreed. Mixed-effects analysis was used to evaluate the changes in Pediatric End-Stage Liver Disease (PELD) scores. RESULTS There were no intraoperative or postoperative complications related to the operation or cell infusion. The average infused BMMNC and CD34 + cell counts per kg bodyweight were 85.5 ± 56.0 × 106/kg and 10.0 ± 3.6 × 106 for the injection, respectively. Following the intervention, all ten patients in the cell therapy group survived, with a mean follow-up duration of 4.5 ± 0.9 years. Meanwhile, three patients in the control group died due to end-stage liver failure, with a mean follow-up time of 4.3 ± 0.9 years. Liver function of the cell therapy group was maintained or improved after the operation and cell infusion, as assessed by biochemical tests. The disease severity reduced markedly in the CT group compared to the control group, with a significant reduction in PELD scores (p < 0.05). CONCLUSION Autologous BMMNC administration combined with Kasai operation for BA is safe and may maintain or improve liver function in the studied patients. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT05517317 on August 26th, 2022.
Collapse
Affiliation(s)
- Liem Nguyen Thanh
- Research Institute of Stem Cell and Gene Technology, Colleague of Health Sciences, VinUniversity, Hanoi, Vietnam.
- Vinmec Times City International Hospital, Vinmec Healthcare System, 458 Minh Khai Street, Hanoi, Vietnam.
| | - Hoang-Phuong Nguyen
- Research Institute of Stem Cell and Gene Technology, Colleague of Health Sciences, VinUniversity, Hanoi, Vietnam
- School of Preventive Medicine and Public Health, Hanoi Medical University, Hanoi, Vietnam
| | - Trang Phan Thi Kieu
- Research Institute of Stem Cell and Gene Technology, Colleague of Health Sciences, VinUniversity, Hanoi, Vietnam
| | - Minh Ngo Duy
- Vinmec Times City International Hospital, Vinmec Healthcare System, 458 Minh Khai Street, Hanoi, Vietnam
| | - Hien Thi Thu Ha
- Vinmec Times City International Hospital, Vinmec Healthcare System, 458 Minh Khai Street, Hanoi, Vietnam
| | - Hang Bui Thi
- Vinmec Times City International Hospital, Vinmec Healthcare System, 458 Minh Khai Street, Hanoi, Vietnam
| | - Thanh Quang Nguyen
- Vietnam National Children Hospital, Hanoi, Vietnam
- Colleague of Health Sciences, VinUniversity, Hanoi, Vietnam
| | | | - Tam Duc Tran
- Vietnam National Children Hospital, Hanoi, Vietnam
| |
Collapse
|
2
|
Jia Y, Wang A, Zhao B, Wang C, Su R, Zhang B, Fan Z, Zeng Q, He L, Pei X, Yue W. An optimized method for obtaining clinical-grade specific cell subpopulations from human umbilical cord-derived mesenchymal stem cells. Cell Prolif 2022; 55:e13300. [PMID: 35768999 PMCID: PMC9528761 DOI: 10.1111/cpr.13300] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 05/25/2022] [Accepted: 06/13/2022] [Indexed: 11/30/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are heterogeneous populations with broad application prospects in cell therapy, and using specific subpopulations of MSCs can enhance their particular capability under certain conditions and achieve better therapeutic effects. However, no studies have reported how to obtain high‐quality specific MSC subpopulations in vitro culture. Here, for the first time, we established a general operation process for obtaining high‐quality clinical‐grade cell subpopulations from human umbilical cord MSCs (hUC‐MSCs) based on particular markers. We used the MSC‐CD106+ subpopulations, whose biological function has been well documented, as an example to explore and optimize the crucial links of primary preparation, pre‐treatment, antibody incubation, flow sorting, quality and function test. After comprehensively evaluating the quality and function of the acquired MSC‐CD106+ subpopulations, including in vitro cell viability, apoptosis, proliferation, marker stability, adhesion ability, migration ability, tubule formation ability, immunomodulatory function and in vivo wound healing ability and proangiogenic activity, we defined an important pre‐treatment scheme which might effectively improve the therapeutic efficiency of MSC‐CD106+ subpopulations in two critical clinical application scenarios—direct injection after cell sorting and post‐culture injection into bodies. Based on the above, we tried to establish a general five‐step operation procedure for acquiring high‐quality clinical‐grade MSC subpopulations based on specific markers, which cannot only improve their enrichment efficiency and the reliability of preclinical studies, but also provide valuable methodological guidance for the rapid clinical transformation of specific MSC subpopulations.
Collapse
Affiliation(s)
- Yali Jia
- Stem Cell and Regenerative Medicine Lab, Beijing Institute of Radiation Medicine, Beijing, China.,South China Institute of Biomedicine, Guangzhou, China
| | - Ailin Wang
- Stem Cell and Regenerative Medicine Lab, Beijing Institute of Radiation Medicine, Beijing, China.,Institute of Health Service and Transfusion Medicine, Beijing, China
| | - Bichun Zhao
- Stem Cell and Regenerative Medicine Lab, Beijing Institute of Radiation Medicine, Beijing, China
| | - Chao Wang
- Stem Cell and Regenerative Medicine Lab, Beijing Institute of Radiation Medicine, Beijing, China
| | - Ruyu Su
- South China Institute of Biomedicine, Guangzhou, China
| | - Biao Zhang
- Stem Cell and Regenerative Medicine Lab, Beijing Institute of Radiation Medicine, Beijing, China
| | - Zeng Fan
- South China Institute of Biomedicine, Guangzhou, China.,Institute of Health Service and Transfusion Medicine, Beijing, China
| | - Quan Zeng
- Stem Cell and Regenerative Medicine Lab, Beijing Institute of Radiation Medicine, Beijing, China.,South China Institute of Biomedicine, Guangzhou, China
| | - Lijuan He
- South China Institute of Biomedicine, Guangzhou, China.,Institute of Health Service and Transfusion Medicine, Beijing, China
| | - Xuetao Pei
- Stem Cell and Regenerative Medicine Lab, Beijing Institute of Radiation Medicine, Beijing, China.,South China Institute of Biomedicine, Guangzhou, China.,Institute of Health Service and Transfusion Medicine, Beijing, China
| | - Wen Yue
- Stem Cell and Regenerative Medicine Lab, Beijing Institute of Radiation Medicine, Beijing, China.,South China Institute of Biomedicine, Guangzhou, China
| |
Collapse
|
3
|
Hayashi K, Fang X, Ueda H, Miwa A, Naka T, Tsuchiya H. Bone Regeneration Using Autologous Adipose-Derived Stem Cell Spheroid Complex. J BIOMATER TISS ENG 2022. [DOI: 10.1166/jbt.2022.3014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Bone defects require reconstruction using various biomaterials or non-biological materials. Stem cell spheroids can be used for scaffold-free approaches for osteogenesis. We set up a culture method for creating an optimal osteogenic adipose-derived stem cell (ADSC) spheroid complex
by measuring the expression of protein in a sequential series of culture media. After culturing ADSC spheroids for 24 hours in DMEM, the spheroids were cultured in ascorbic acid-containing medium for five days followed by osteoblast differentiation medium. One day after exchanging to osteoblast
differentiation medium, spheroids were collected and cultured for four days to obtain a spheroid complex. Each culture period was determined by analyzing the expression of collagen type I, alkaline phosphatase and integrin α5 to maximize the activity of ADSC spheroids. The expression
of collagen type I increased significantly in ascorbic acid-containing medium (p < 0.05) compared with control medium on day five, suggesting that culturing spheroids in ascorbic acid increases collagen synthesis. RNA was extracted from ADSC spheroids after 1, 3, 5, and 7 days in
each medium and RT-PCR was performed to measure integrin α5 expression. The expression was transiently high on the first day of osteoblast differentiation culture and then gradually decreased. Osteoblast differentiation medium enhanced cell adhesion in spheroids. An in vivo
study confirmed the osteogenic potential of the ADSC spheroid complex created by the established protocol. The ADSC spheroid complex stimulated bone regeneration and will be applied to the treatment of large bone defects.
Collapse
Affiliation(s)
- Katsuhiro Hayashi
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, 920-8641, Japan
| | - Xang Fang
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, 920-8641, Japan
| | - Hiroshi Ueda
- Shibuya Corporation, Ko-58 Mameda-Honmachi, Kanazawa, Ishikawa, 920-8681, Japan
| | - Akihiro Miwa
- Shibuya Corporation, Ko-58 Mameda-Honmachi, Kanazawa, Ishikawa, 920-8681, Japan
| | - Toshiaki Naka
- Shibuya Corporation, Ko-58 Mameda-Honmachi, Kanazawa, Ishikawa, 920-8681, Japan
| | - Hiroyuki Tsuchiya
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, 920-8641, Japan
| |
Collapse
|
4
|
The assessment of mesenchymal stem cells therapy in acute on chronic liver failure and chronic liver disease: a systematic review and meta-analysis of randomized controlled clinical trials. Stem Cell Res Ther 2022; 13:204. [PMID: 35578365 PMCID: PMC9109309 DOI: 10.1186/s13287-022-02882-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 05/04/2022] [Indexed: 11/29/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) therapy is showing potential therapeutic effects on liver function improvement in patients with chronic liver disease; however, the consensus on efficacy and safety of MSCs has not been reached. Methods We performed this systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of MSCs therapy for patients with chronic liver disease. A detailed search of the Cochrane Library, MEDLINE, Web of Science, and EMBASE databases was conducted to find studies published prior to September 15, 2021. The outcome measures were survival rate, model of end-stage liver disease (MELD) score, albumin, total bilirubin, coagulation function, and aminotransferase. Results A literature search resulted in 892 citations. Of these, 12 studies met the inclusion criteria. It was found that compared with conventional treatment, MSCs therapy was associated with improved liver function including the MELD score, albumin levels, and coagulation function. However, it had no obvious beneficial effects on survival rate and aminotransferase levels. Subgroup analyses indicated that MSCs therapy had therapeutic effects on patients with both acute on chronic liver failure (ACLF) and cirrhosis. BM-MSCs and UC-MSCs treatment had similar efficacy to improve liver function. The effectiveness varied slightly between the peripheral intravenous injection and hepatic arterial injection. Five studies reported that the only adverse event of the MSCs therapy was fever, and no serious adverse events and side effects were reported. Analysis on clinical symptoms showed that encephalopathy and gastrointestinal hemorrhage events were reduced after MSCs therapy. Conclusions In conclusion, this study suggested that MSCs therapy could be a potential therapeutic alternative for patients with chronic liver disease in clinical practice. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02882-4.
Collapse
|
5
|
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.
Collapse
|
6
|
Terai S, Tsuchiya A, Watanabe Y, Takeuchi S. Transition of clinical and basic studies on liver cirrhosis treatment using cells to seek the best treatment. Inflamm Regen 2021; 41:27. [PMID: 34530931 PMCID: PMC8444392 DOI: 10.1186/s41232-021-00178-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 09/06/2021] [Indexed: 02/08/2023] Open
Abstract
The liver is a highly regenerative organ; however, its regeneration potential is reduced by chronic inflammation with fibrosis accumulation, leading to cirrhosis. With an aim to tackle liver cirrhosis, a life-threatening disease, trials of autologous bone marrow cell infusion (ABMi) therapy started in 2003. Clinical studies revealed that ABMi attenuated liver fibrosis and improved liver function in some patients; however, this therapy has some limitations such as the need of general anesthesia. Following ABMi therapy, studies have focused on specific cells such as mesenchymal stromal cells (MSCs) from a variety of tissues such as bone marrow, adipose tissue, and umbilical cord tissues. Particularly, studies have focused on gaining mechanistic insights into MSC distribution and effects on immune cells, especially macrophages. Several basic studies have reported the use of MSCs for liver cirrhosis models, while a number of clinical studies have used autologous and allogeneic MSCs; however, there are only a few reports on the obvious substantial effect of MSCs in clinical studies. Since then, studies have analyzed and identified the important signals or components in MSCs that regulate immune cells, such as macrophages, under cirrhotic conditions and have revealed that MSC-derived exosomes are key regulators. Researchers are still seeking the best approach and filling the gap between basic and clinical studies to treat liver cirrhosis. This paper highlights the timeline of basic and clinical studies analyzing ABMi and MSC therapies for cirrhosis and the scope for future studies and therapy.
Collapse
Affiliation(s)
- Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.
| | - Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Yusuke Watanabe
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Suguru Takeuchi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| |
Collapse
|
7
|
Yoshida Y, Matsubara H, Fang X, Hayashi K, Nomura I, Ugaji S, Hamada T, Tsuchiya H. Adipose-derived stem cell sheets accelerate bone healing in rat femoral defects. PLoS One 2019; 14:e0214488. [PMID: 30921414 PMCID: PMC6438603 DOI: 10.1371/journal.pone.0214488] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Accepted: 03/13/2019] [Indexed: 12/15/2022] Open
Abstract
In the present study, we investigated whether both adipose-derived stem cell (ADSC) and osteogenic-induced ADSC sheets could promote bone healing in a rat distal femoral metaphysis bone defect model. A through-hole defect of 1 mm diameter was drilled into each distal femur of 12 week old rats. Forty-five rats were randomly assigned to three groups: (1) control group; (2) ADSC sheet group; or (3) osteogenic-induced ADSC sheet group. We evaluated each group by analysis of computerized tomography scans every week after the surgery, histological analysis, and DiI labeling (a method of membrane staining for post implant cell tracing). Radiological and histological evaluations showed that a part of the hole persisted in the control group at four weeks after surgery, whereas the hole was restored almost completely by new bone formation in both sheet groups. The mean value of bone density (in Houndsfield units) for the bone defect area was significantly higher in both sheet groups than that in the control group (p = 0.05) at four weeks postoperative. A large number of osteocalcin positive osteoblasts were observed at the area of bone defect, especially in the osteogenic-induced ADCS sheet group. DiI labeling in the newly formed bone showed that each sheet had differentiated into bone tissue at four weeks after surgery. The ADSC and the osteogenic-induced ADSC sheets promoted significantly quicker bone healing in the bone defect. Moreover, the osteogenic-induced ADSC sheet may be more advantageous for bone healing than the ADSC sheet because of the higher number of osteocalcin positive osteoblasts via the transplantation.
Collapse
Affiliation(s)
- Yasuhisa Yoshida
- Department of Orthopaedic Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
| | - Hidenori Matsubara
- Department of Orthopaedic Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
| | - Xiang Fang
- Department of Orthopaedic Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
| | - Katsuhiro Hayashi
- Department of Orthopaedic Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
| | - Issei Nomura
- Department of Orthopaedic Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
| | - Shuhei Ugaji
- Department of Orthopaedic Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
| | - Tomo Hamada
- Department of Orthopaedic Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
| | - Hiroyuki Tsuchiya
- Department of Orthopaedic Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
| |
Collapse
|
8
|
Differentiation potential of the cells in the macula flava of the human vocal fold mucosa. Acta Histochem 2019; 121:164-170. [PMID: 30558911 DOI: 10.1016/j.acthis.2018.12.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 12/10/2018] [Accepted: 12/10/2018] [Indexed: 02/07/2023]
Abstract
The latest research suggests cells in the maculae flavae located at both ends of the lamina propria of the human vocal fold mucosa have stemness. This study investigated the differentiation potential of the cells in the maculae flavae of the human vocal fold mucosa. Four normal human adult vocal folds from surgical specimens were used. After extraction of the anterior maculae flavae located at the anterior end of the lamina propria of the human vocal fold mucosa under microscope, the maculae flavae were minced, cultured and proliferated in mesenchymal stem cell growth medium and morphological features were assessed. Cell surface markers were detected using flow cytometry. Cell differentiation into adipogenic, chondrogenic and osteogenic lineages was performed. Cell's differentiation potential was assessed using a human pluripotent stem cell functional identification kit and immunohistochemistry. Subcultured cells formed a colony-forming unit. Subcultured cells expressed CD90, CD105 and CD73 and lacked expression of CD45, CD34, CD11b, CD19 and HLA-DR. They differentiated into adipogenic, chondrogenic and osteogenic lineages. Consequently, the cell features in the maculae flavae meet the minimal criteria defining mesenchymal stromal cells. In addition, subcultured cells differentiated into ectoderm, mesoderm and endoderm and expressed stage-specific embryonic antigen 3 (SSEA-3). The results of this study are consistent with the hypothesis that the cells in the maculae flavae in the lamina propria of the human vocal fold mucosa are putative stem cells.
Collapse
|
9
|
Analysis of Treatment of 3 Patients with Acute-on-Chronic Liver Failure. Case Rep Med 2019; 2018:7421502. [PMID: 30595700 PMCID: PMC6282116 DOI: 10.1155/2018/7421502] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 09/30/2018] [Accepted: 10/17/2018] [Indexed: 11/22/2022] Open
Abstract
Acute-on-chronic liver failure (ACLF) is an acute liver decompensation that occurs within 4 weeks on the basis of chronic liver disease. At present, the treatments of ACLF include general supportive treatment, etiological treatment, prevention and treatment of complications, artificial liver treatment, and liver transplantation. Many studies suggest that stem cell therapy may become a new treatment for patients with ACLF. Our department has also tried the application of this treatment. Now, there are three cases of stem cell therapy for patients with ACLF by our department which will be briefly reported.
Collapse
|
10
|
Xue R, Meng Q, Dong J, Li J, Yao Q, Zhu Y, Yu H. Clinical performance of stem cell therapy in patients with acute-on-chronic liver failure: a systematic review and meta-analysis. J Transl Med 2018; 16:126. [PMID: 29747694 PMCID: PMC5946490 DOI: 10.1186/s12967-018-1464-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Accepted: 03/27/2018] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Stem cell therapy has been applied in the treatment of acute-on-chronic liver failure (ACLF). However, its clinical efficiency is still debatable. The aim of this systematic review and meta-analysis is to evaluate the clinical efficiency of stem cell therapy in the treatment of ACLF. METHODS The Cochrane Library, OVID, EMBASE, and PUBMED were searched to December 2017. Both randomized and non-randomized studies, assessing stem cell therapy in patients with ACLF, were included. The outcome measures were total bilirubin (TBIL), alanine transaminase (ALT), international normalized ratio (INR), albumin (ALB), and the model for end-stage liver disease (MELD) score. The quality of evidence was assessed by GRADEpro. RESULTS Four randomized controlled trials and six non-randomized controlled trials were included. The TBIL levels significantly decreased at 1-, 3-, 12-month after the stem cell therapy (p = 0.0008; p = 0.04; p = 0.007). The ALT levels decreased significantly compared with the control group in the short-term (p < 0.00001). There was no obvious change in the INR level compared with the control groups (p = 0.64). The ALB levels increased markedly as compared with the control groups (p < 0.0001). The significant difference can be found in MELD score between stem cell therapy and control groups (p = 0.008). Further subgroup analysis for 3-month clinical performance according to the stem cell types have also been performed. CONCLUSION This study suggests that the clinical outcomes of stem cell therapy were satisfied in patients with ACLF in the short-term. MSCs may be better than BM-MNCs in the stem cells transplantation of ACLF. However, more attention should focus on clinical trials in large-volume centers.
Collapse
Affiliation(s)
- Ran Xue
- Department of Critical Care Medicine of Liver Disease, Beijing You-An Hospital, Capital Medical University, No. 8, Xi tou tiao, You an men wai Street, Feng tai District, Beijing, 100069 People’s Republic of China
| | - Qinghua Meng
- Department of Critical Care Medicine of Liver Disease, Beijing You-An Hospital, Capital Medical University, No. 8, Xi tou tiao, You an men wai Street, Feng tai District, Beijing, 100069 People’s Republic of China
| | - Jinling Dong
- Department of Critical Care Medicine of Liver Disease, Beijing You-An Hospital, Capital Medical University, No. 8, Xi tou tiao, You an men wai Street, Feng tai District, Beijing, 100069 People’s Republic of China
| | - Juan Li
- Department of Critical Care Medicine of Liver Disease, Beijing You-An Hospital, Capital Medical University, No. 8, Xi tou tiao, You an men wai Street, Feng tai District, Beijing, 100069 People’s Republic of China
| | - Qinwei Yao
- Department of Critical Care Medicine of Liver Disease, Beijing You-An Hospital, Capital Medical University, No. 8, Xi tou tiao, You an men wai Street, Feng tai District, Beijing, 100069 People’s Republic of China
| | - Yueke Zhu
- Department of Critical Care Medicine of Liver Disease, Beijing You-An Hospital, Capital Medical University, No. 8, Xi tou tiao, You an men wai Street, Feng tai District, Beijing, 100069 People’s Republic of China
| | - Hongwei Yu
- Department of Critical Care Medicine of Liver Disease, Beijing You-An Hospital, Capital Medical University, No. 8, Xi tou tiao, You an men wai Street, Feng tai District, Beijing, 100069 People’s Republic of China
| |
Collapse
|
11
|
Mesenchymal Stem Cell Transplantation for Liver Cell Failure: A New Direction and Option. Gastroenterol Res Pract 2018; 2018:9231710. [PMID: 29686702 PMCID: PMC5857323 DOI: 10.1155/2018/9231710] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 11/17/2017] [Accepted: 11/22/2017] [Indexed: 12/17/2022] Open
Abstract
Background and Aims Mesenchymal stem cell transplantation (MSCT) became available with liver failure (LF), while the advantages of MSCs remain controversial. We aimed to assess clinical advantages of MSCT in patients with LF. Methods Clinical researches reporting MSCT in LF patients were searched and included. Results Nine articles (n = 476) related with LF patients were enrolled. After MSCT, alanine aminotransferase (ALT) baseline decreased largely at half a month (P < 0.05); total bilirubin (TBIL) baseline declined to a certain stable level of 78.57 μmol/L at 2 and 3 months (P < 0.05). Notably, the decreased value (D value) of Model for End-Stage Liver Disease score (MELD) of acute-on-chronic liver failure (ACLF) group was higher than that of chronic liver failure (CLF) group (14.93 ± 1.24 versus 4.6 ± 5.66, P < 0.05). Moreover, MELD baseline of ≥20 group was a higher D value of MELD than MELD baseline of <20 group with a significant statistical difference after MSCT (P = 0.003). Conclusion The early assessment of the efficacy of MSCT could be based on variations of ALT at half a month and TBIL at 2 and 3 months. And it had beneficial effects for patients with LF, especially in ACLF based on the D value of MELD.
Collapse
|
12
|
Kim D, Cho GS, Han C, Park DH, Park HK, Woo DH, Kim JH. Current Understanding of Stem Cell and Secretome Therapies in Liver Diseases. Tissue Eng Regen Med 2017; 14:653-665. [PMID: 30603518 PMCID: PMC6171672 DOI: 10.1007/s13770-017-0093-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2017] [Revised: 10/23/2017] [Accepted: 10/29/2017] [Indexed: 12/14/2022] Open
Abstract
Liver failure is one of the main risks of death worldwide, and it originates from repetitive injuries and inflammations of liver tissues, which finally leads to the liver cirrhosis or cancer. Currently, liver transplantation is the only effective treatment for the liver diseases although it has a limitation due to donor scarcity. Alternatively, cell therapy to regenerate and reconstruct the damaged liver has been suggested to overcome the current limitation of liver disease cures. Several transplantable cell types could be utilized for recovering liver functions in injured liver, including bone marrow cells, mesenchymal stem cells, hematopoietic stem cells, macrophages, and stem cell-derived hepatocytes. Furthermore, paracrine effects of transplanted cells have been suggested as a new paradigm for liver disease cures, and this application would be a new strategy to cure liver failures. Therefore, here we reviewed the current status and challenges of therapy using stem cells for liver disease treatments.
Collapse
Affiliation(s)
- Dongkyu Kim
- Laboratory of Stem Cells, NEXEL Co., Ltd., 9th Floor, 21 Wangsan-ro, Dongdaemun-gu, Seoul, 02580 Korea
| | - Gun-Sik Cho
- Laboratory of Stem Cells, NEXEL Co., Ltd., 9th Floor, 21 Wangsan-ro, Dongdaemun-gu, Seoul, 02580 Korea
| | - Choongseong Han
- Laboratory of Stem Cells, NEXEL Co., Ltd., 9th Floor, 21 Wangsan-ro, Dongdaemun-gu, Seoul, 02580 Korea
- Department of Oral Medicine and Oral Diagnosis, School of Dentistry and Dental Research Institute, Seoul National University, #101 Daehak-ro, Jongro-gu, Seoul, 03080 Korea
| | - Dong-Hyuk Park
- Department of Neurosurgery, Korea University Medical Center, Anam Hospital, Korea University College of Medicine, 73 Inchonro, Sungbuk-gu, Seoul, 02841 Korea
| | - Hee-Kyung Park
- Department of Oral Medicine and Oral Diagnosis, School of Dentistry and Dental Research Institute, Seoul National University, #101 Daehak-ro, Jongro-gu, Seoul, 03080 Korea
| | - Dong-Hun Woo
- Laboratory of Stem Cells, NEXEL Co., Ltd., 9th Floor, 21 Wangsan-ro, Dongdaemun-gu, Seoul, 02580 Korea
| | - Jong-Hoon Kim
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Science Campus, Korea University, 145 Anam-ro, Seongbu-gu, Seoul, 02841 Korea
| |
Collapse
|
13
|
Catani L, Sollazzo D, Bianchi E, Ciciarello M, Antoniani C, Foscoli L, Caraceni P, Giannone FA, Baldassarre M, Giordano R, Montemurro T, Montelatici E, D'Errico A, Andreone P, Giudice V, Curti A, Manfredini R, Lemoli RM. Molecular and functional characterization of CD133 + stem/progenitor cells infused in patients with end-stage liver disease reveals their interplay with stromal liver cells. Cytotherapy 2017; 19:1447-1461. [PMID: 28917627 DOI: 10.1016/j.jcyt.2017.08.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Revised: 08/01/2017] [Accepted: 08/03/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND AIMS Growing evidence supports the therapeutic potential of bone marrow (BM)-derived stem/progenitor cells for end-stage liver disease (ESLD). We recently demonstrated that CD133+ stem/progenitor cell (SPC) reinfusion in patients with ESLD is feasible and safe and improve, albeit transiently, liver function. However, the mechanism(s) through which BM-derived SPCs may improve liver function are not fully elucidated. METHODS Here, we characterized the circulating SPCs compartment of patients with ESLD undergoing CD133+ cell therapy. Next, we set up an in vitro model mimicking SPCs/liver microenvironment interaction by culturing granulocyte colony-stimulating factor (G-CSF)-mobilized CD133+and LX-2 hepatic stellate cells. RESULTS We found that patients with ESLD show normal basal levels of circulating hematopoietic and endothelial progenitors with impaired clonogenic ability. After G-CSF treatment, patients with ESLD were capable to mobilize significant numbers of functional multipotent SPCs, and interestingly, this was associated with increased levels of selected cytokines potentially facilitating SPC function. Co-culture experiments showed, at the molecular and functional levels, the bi-directional cross-talk between CD133+ SPCs and human hepatic stellate cells LX-2. Human hepatic stellate cells LX-2 showed reduced activation and fibrotic potential. In turn, hepatic stellate cells enhanced the proliferation and survival of CD133+ SPCs as well as their endothelial and hematopoietic function while promoting an anti-inflammatory profile. DISCUSSION We demonstrated that the interaction between CD133+ SPCs from patients with ESLD and hepatic stellate cells induces significant functional changes in both cellular types that may be instrumental for the improvement of liver function in cirrhotic patients undergoing cell therapy.
Collapse
Affiliation(s)
- Lucia Catani
- Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli," University of Bologna, Bologna, Italy.
| | - Daria Sollazzo
- Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli," University of Bologna, Bologna, Italy
| | - Elisa Bianchi
- Centre for Regenerative Medicine "Stefano Ferrari," Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Marilena Ciciarello
- Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli," University of Bologna, Bologna, Italy
| | - Chiara Antoniani
- Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli," University of Bologna, Bologna, Italy
| | - Licia Foscoli
- Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli," University of Bologna, Bologna, Italy
| | - Paolo Caraceni
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy; Center for Applied Biomedical Research (C.R.B.A.), Azienda Ospedaliero/Universitaria di Bologna, Bologna, Italy
| | | | - Maurizio Baldassarre
- Center for Applied Biomedical Research (C.R.B.A.), Azienda Ospedaliero/Universitaria di Bologna, Bologna, Italy
| | - Rosaria Giordano
- Cell Factory, Unit of Cellular Therapy and Cryobiology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Tiziana Montemurro
- Cell Factory, Unit of Cellular Therapy and Cryobiology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Elisa Montelatici
- Cell Factory, Unit of Cellular Therapy and Cryobiology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Antonia D'Errico
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Pietro Andreone
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Valeria Giudice
- Immunohematology Service and Blood Bank-Azienda Ospedaliero/Universitaria di Bologna, Bologna, Italy
| | - Antonio Curti
- Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli," University of Bologna, Bologna, Italy
| | - Rossella Manfredini
- Centre for Regenerative Medicine "Stefano Ferrari," Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Roberto Massimo Lemoli
- Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy
| |
Collapse
|
14
|
Matsuda T, Takami T, Sasaki R, Nishimura T, Aibe Y, Paredes BD, Quintanilha LF, Matsumoto T, Ishikawa T, Yamamoto N, Tani K, Terai S, Taura Y, Sakaida I. A canine liver fibrosis model to develop a therapy for liver cirrhosis using cultured bone marrow-derived cells. Hepatol Commun 2017; 1:691-703. [PMID: 29404486 PMCID: PMC5721436 DOI: 10.1002/hep4.1071] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Revised: 06/12/2017] [Accepted: 06/12/2017] [Indexed: 11/12/2022] Open
Abstract
We have been developing a therapy for liver cirrhosis using cultured autologous bone marrow-derived mesenchymal stem cells (BMSCs). Before human clinical trials can be considered, the safety and efficacy of BMSC infusion in medium to large animals must be confirmed; thus, we developed a canine liver fibrosis model. A small amount of bone marrow fluid was aspirated from the canine humerus to assess the characteristics of BMSCs. We implanted a venous catheter in the stomach and a subcutaneous infusion port in the back of the neck of each canine. Repeated injection of CCl4 through the catheter was performed to induce liver cirrhosis. After 10 weeks of CCl4 injection, eight canines were equally divided into two groups: no cell infusion (control group) and autologous BMSC infusion through the peripheral vein (BMSC group). A variety of assays were carried out before and 4 weeks after the infusion. The area of liver fibrosis stained with sirius red was significantly reduced in the BMSC group 4 weeks after BMSC infusion, consistent with a significantly shortened half-life of indocyanine green and improved liver function. Conclusion: We established a useful canine liver fibrosis model and confirmed that cultured autologous BMSC infusion improved liver fibrosis without adverse effects. (Hepatology Communications 2017;1:691-703).
Collapse
Affiliation(s)
- Takashi Matsuda
- Department of Gastroenterology & Hepatology Yamaguchi University Graduate School of Medicine Yamaguchi Japan
| | - Taro Takami
- Department of Gastroenterology & Hepatology Yamaguchi University Graduate School of Medicine Yamaguchi Japan
| | - Ryo Sasaki
- Department of Gastroenterology & Hepatology Yamaguchi University Graduate School of Medicine Yamaguchi Japan
| | - Tatsuro Nishimura
- Department of Gastroenterology & Hepatology Yamaguchi University Graduate School of Medicine Yamaguchi Japan
| | - Yuki Aibe
- Department of Gastroenterology & Hepatology Yamaguchi University Graduate School of Medicine Yamaguchi Japan
| | - Bruno Diaz Paredes
- Department of Gastroenterology & Hepatology Yamaguchi University Graduate School of Medicine Yamaguchi Japan
| | - Luiz Fernando Quintanilha
- Department of Gastroenterology & Hepatology Yamaguchi University Graduate School of Medicine Yamaguchi Japan
| | - Toshihiko Matsumoto
- Department of Oncology and Laboratory Medicine Yamaguchi University Graduate School of Medicine Yamaguchi Japan
| | - Tsuyoshi Ishikawa
- Department of Gastroenterology & Hepatology Yamaguchi University Graduate School of Medicine Yamaguchi Japan
| | - Naoki Yamamoto
- Yamaguchi University Health Administration Center Yamaguchi University Yamaguchi Japan
| | - Kenji Tani
- Department of Veterinary Surgery Joint Faculty of Veterinary Medicine, Yamaguchi University Yamaguchi Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology Niigata University Graduate School of Medical and Dental Sciences, Niigata University Niigata Japan
| | - Yasuho Taura
- Department of Veterinary Surgery Joint Faculty of Veterinary Medicine, Yamaguchi University Yamaguchi Japan
| | - Isao Sakaida
- Department of Gastroenterology & Hepatology Yamaguchi University Graduate School of Medicine Yamaguchi Japan.,Center for Reparative MedicineYamaguchi University Graduate School of Medicine, Yamaguchi University Yamaguchi Japan
| |
Collapse
|
15
|
Liver Cells Proliferation and Apoptosis in Patients with Alcoholic Liver Disease After Autologous Hematopoietic Stem Cell Transplantation. BIONANOSCIENCE 2017. [DOI: 10.1007/s12668-016-0354-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
|
16
|
Kim JK, Kim SJ, Kim Y, Chung YE, Park YN, Kim HO, Kim JS, Park MS, Sakaida I, Kim DY, Lee JI, Ahn SH, Lee KS, Han KH. Long-Term Follow-Up of Patients After Autologous Bone Marrow Cell Infusion for Decompensated Liver Cirrhosis. Cell Transplant 2017; 26:1059-1066. [PMID: 28120743 DOI: 10.3727/096368917x694778] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Although several human clinical trials using various bone marrow-derived cell types for cirrhotic or decompensated patients have reported a short-term benefit, long-term follow-up data are limited. We analyzed the long-term clinical outcomes of autologous bone marrow cell infusion (ABMI) for decompensated liver cirrhosis (LC). Patients enrolled in a pilot single-armed ABMI study were followed up more than 5 years. Bone marrow-derived mononuclear cells (BM-MNCs) from decompensated LC were harvested and after processing were infused into a peripheral vein. The laboratory test results and long-term clinical course including liver transplantation (LT), development of cancer, cause of death, and survival after ABMI were analyzed. Nineteen patients were followed up for a median of 66 months after ABMI. Liver function, including serum levels of albumin and Child-Pugh (CP) score, was improved at the 1-year follow-up. Liver volume was significantly greater, cirrhosis was sustained, and collagen content was decreased at the 6-month follow-up. Five years after ABMI, five patients (26.3%) maintained CP class A without LT or death, and five patients (26.3%) had undergone elective LT. Hepatocellular carcinoma (HCC) occurred in five patients (26.3%), and lymphoma and colon cancer occurred in one patient each. Three patients (15.8%) were lost to follow-up at months 22, 31, and 33, respectively, but maintained CP class A until their last follow-up. Five patients expired due to infection. While improved liver function was maintained in some patients for more than 5 years after ABMI, other patients developed HCC. Further studies of long-term follow-up cohorts after cell therapy for LC are warranted.
Collapse
|
17
|
Matsumoto T, Takami T, Sakaida I. Cell transplantation as a non-invasive strategy for treating liver fibrosis. Expert Rev Gastroenterol Hepatol 2017; 10:639-48. [PMID: 26691057 DOI: 10.1586/17474124.2016.1134313] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Advancements in antiviral drugs have enabled control of viral hepatitis; yet, many patients with liver cirrhosis (LC) are awaiting liver transplants. Liver transplantation yields dramatic therapeutic effects, but problems such as shortage of donors, surgical invasiveness, immunological rejection and costs, limit the number of transplantations. Advances in liver regeneration therapy through cell transplantation as a non-invasive treatment for cirrhosis will supplement these restrictions to the number of liver transplants. Clinical trials for LC have included hematopoietic stem cell mobilization by administration of granulocyte colony-stimulating factor, infusion of autologous bone marrow cells, and administration of autologous mesenchymal stem cells derived from bone marrow or umbilical cord. Several recently reported randomized controlled studies have shown the effectiveness of these approaches. However, to promote implementation of new liver regeneration therapies, it is important to develop a system whereby cell therapies with ensured safety can be approved quickly.
Collapse
Affiliation(s)
- Toshihiko Matsumoto
- a Department of Gastroenterology & Hepatology , Yamaguchi University Graduate School of Medicine , Yamaguchi , Japan.,b Department of Oncology and Laboratory Medicine , Yamaguchi University Graduate School of Medicine , Yamaguchi , Japan
| | - Taro Takami
- a Department of Gastroenterology & Hepatology , Yamaguchi University Graduate School of Medicine , Yamaguchi , Japan
| | - Isao Sakaida
- a Department of Gastroenterology & Hepatology , Yamaguchi University Graduate School of Medicine , Yamaguchi , Japan
| |
Collapse
|
18
|
Alessio N, Özcan S, Tatsumi K, Murat A, Peluso G, Dezawa M, Galderisi U. The secretome of MUSE cells contains factors that may play a role in regulation of stemness, apoptosis and immunomodulation. Cell Cycle 2017; 16:33-44. [PMID: 27463232 PMCID: PMC5270533 DOI: 10.1080/15384101.2016.1211215] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 07/01/2016] [Accepted: 07/01/2016] [Indexed: 01/10/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) are a heterogeneous population, which contain several cell phenotypes: mesenchymal stem cells, progenitor cells, fibroblasts and other type of cells. Previously, we identified unique stem cells that we named multilineage-differentiating stress enduring (Muse) cells as one to several percent of MSCs of the bone marrow, adipose tissue and dermis. Among different cell populations in MSCs, Muse cells, positive for pluripotent surface marker SSEA-3, may represent cells responsible for pluripotent-like property of MSCs, since they express pluripotency genes, able to differentiated into triploblastic cells from a single cells and are self-renewable. MSCs release biologically active factors that have profound effects on local cellular dynamics. A thorough examination of MSC secretome seems essential for understanding the physiological functions exerted by these cells in our organism and also for rational cellular therapy design. In this setting, studies on secretome of Muse cells may shed light on pathways that are associated with their specific features. Our findings evidenced that secretomes of MSCs and Muse cells contain factors that regulate extracellular matrix remodeling, ox-redox activities and immune system. Muse cells appear to secrete factors that may preserve their stem cell features, allow survival under stress conditions and may contribute to their immunomodulation capacity. In detail, the proteins belonging to protein kinase A signaling, FXR/RXR activation and LXR/RXR activation pathways may play a role in regulation of Muse stem cell features. These last 2 pathways together with proteins associated with antigen presentation pathway and coagulation system may play a role in immunomodulation.
Collapse
Affiliation(s)
- Nicola Alessio
- Department of Experimental Medicine, Biotechnology and Molecular Biology Section, Second University of Naples, Naples, Italy
| | - Servet Özcan
- Genome and Stem Cell Center (GENKOK), Erciyes University, Kayseri, Turkey
- Graduate School of Health Sciences, Erciyes Universty, Kayseri, Turkey
| | - Kazuki Tatsumi
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan
- Tohoku Laboratory Non-clinical Research Division, Clio, Inc., Sendai, Japan
| | - Ayşegül Murat
- Graduate School of Health Sciences, Erciyes Universty, Kayseri, Turkey
| | | | - Mari Dezawa
- Tohoku Laboratory Non-clinical Research Division, Clio, Inc., Sendai, Japan
| | - Umberto Galderisi
- Department of Experimental Medicine, Biotechnology and Molecular Biology Section, Second University of Naples, Naples, Italy
- Genome and Stem Cell Center (GENKOK), Erciyes University, Kayseri, Turkey
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Temple University, Philadelphia, PA, USA
| |
Collapse
|
19
|
Iseki M, Kushida Y, Wakao S, Akimoto T, Mizuma M, Motoi F, Asada R, Shimizu S, Unno M, Chazenbalk G, Dezawa M. Muse Cells, Nontumorigenic Pluripotent-Like Stem Cells, Have Liver Regeneration Capacity Through Specific Homing and Cell Replacement in a Mouse Model of Liver Fibrosis. Cell Transplant 2016; 26:821-840. [PMID: 27938474 DOI: 10.3727/096368916x693662] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Muse cells, a novel type of nontumorigenic pluripotent-like stem cells, reside in the bone marrow, skin, and adipose tissue and are collectable as cells positive for pluripotent surface marker SSEA-3. They are able to differentiate into cells representative of all three germ layers. The capacity of intravenously injected human bone marrow-derived Muse cells to repair an immunodeficient mouse model of liver fibrosis was evaluated in this study. The cells exhibited the ability to spontaneously differentiate into hepatoblast/hepatocyte lineage cells in vitro. They demonstrated a high migration capacity toward the serum and liver section of carbon tetrachloride-treated mice in vitro. In vivo, they specifically accumulated in the liver, but not in other organs except, to a lesser extent, in the lungs at 2 weeks after intravenous injection in the liver fibrosis model. After homing, Muse cells spontaneously differentiated in vivo into HepPar-1 (71.1 ± 15.2%), human albumin (54.3 ± 8.2%), and anti-trypsin (47.9 ± 4.6%)-positive cells without fusing with host hepatocytes, and expressed mature functional markers such as human CYP1A2 and human Glc-6-Pase at 8 weeks after injection. Recovery in serum, total bilirubin, and albumin and significant attenuation of fibrosis were recognized with statistical differences between the Muse cell-transplanted group and the control groups, which received the vehicle or the same number of a non-Muse cell population of MSCs (MSCs in which Muse cells were eliminated). Thus, unlike ESCs and iPSCs, Muse cells are unique in their efficient migration and integration into the damaged liver after intravenous injection, nontumorigenicity, and spontaneous differentiation into hepatocytes, rendering induction into hepatocytes prior to transplantation unnecessary. They may repair liver fibrosis by two simple steps: expansion after collection from the bone marrow and intravenous injection. A therapeutic strategy such as this is feasible and may provide significant advancements toward liver regeneration in patients with liver disease.
Collapse
|
20
|
Andreone P, Catani L, Margini C, Brodosi L, Lorenzini S, Sollazzo D, Nicolini B, Giordano R, Montemurro T, Rizzi S, Dan E, Giudice V, Viganò M, Casadei A, Foschi FG, Malvi D, Bernardi M, Conti F, Lemoli RM. Reinfusion of highly purified CD133+ bone marrow-derived stem/progenitor cells in patients with end-stage liver disease: A phase I clinical trial. Dig Liver Dis 2015; 47:1059-1066. [PMID: 26427587 DOI: 10.1016/j.dld.2015.08.018] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Revised: 08/24/2015] [Accepted: 08/29/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Bone marrow stem/progenitor cells seem to be effective in liver regeneration after tissue injury. AIM To evaluate the feasibility and safety of the mobilization and reinfusion of CD133+ stem/progenitor cells in patients with end-stage liver disease. METHODS Autologous CD133+ stem/progenitor cells, mobilized with granulocyte-colony stimulating factor, were collected by leukapheresis and reinfused at increasing doses through the hepatic artery starting from 5×10(4)/kg up to 1×10(6)/kg. RESULTS 16 subjects with Model for End-stage Liver Disease (MELD) score between 17 and 25 were enrolled, 14 mobilized an adequate number of CD133+ stem/progenitor cells and 12 were reinfused. No severe adverse events related to the procedure were reported. MELD score significantly worsened during mobilization in Child Turcotte Pugh-C patients. A significant improvement of liver function was observed 2 months after reinfusion (MELD 19.5 vs. 16; P=0.045). Overall, 5 patients underwent liver transplantation within 12 months from reinfusion and 2 died because of progressive liver failure. CONCLUSIONS CD133+ stem/progenitor cells reinfusion in patients with end-stage liver disease is feasible and safe. A worsening of liver function was observed during mobilization in Child Turcotte Pugh-C patients. The temporary improvement of MELD score after reinfusion suggests that stem cells therapy may be a "bridge to transplant" approach for these patients.
Collapse
Affiliation(s)
- Pietro Andreone
- Department of Medical and Surgical Sciences, Bologna University, Bologna, Italy.
| | - Lucia Catani
- Department of Specialty Diagnostic and Experimental Medicine, Bologna University, Bologna, Italy
| | - Cristina Margini
- Department of Medical and Surgical Sciences, Bologna University, Bologna, Italy
| | - Lucia Brodosi
- Department of Medical and Surgical Sciences, Bologna University, Bologna, Italy
| | - Stefania Lorenzini
- Department of Medical and Surgical Sciences, Bologna University, Bologna, Italy
| | - Daria Sollazzo
- Department of Specialty Diagnostic and Experimental Medicine, Bologna University, Bologna, Italy
| | - Benedetta Nicolini
- Department of Specialty Diagnostic and Experimental Medicine, Bologna University, Bologna, Italy
| | - Rosaria Giordano
- Cell Factory, Unit of Cell Therapy and Cryobiology, Fondazione IRCCS Ca' Granda, Maggiore Hospital, Milano, Italy
| | | | - Simonetta Rizzi
- Department of Specialty Diagnostic and Experimental Medicine, Bologna University, Bologna, Italy
| | - Elisa Dan
- Department of Specialty Diagnostic and Experimental Medicine, Bologna University, Bologna, Italy
| | - Valeria Giudice
- Transfusion Medicine Unit, Bologna University Hospital, Policlinico S. Orsola-Malpighi, Bologna, Italy
| | - Mariele Viganò
- Department of Regenerative Medicine, Maggiore Hospital, Milano, Italy
| | - Andrea Casadei
- Zompatori Radiology Unit, Bologna University Hospital, Policlinico S. Orsola-Malpighi, Bologna, Italy
| | | | - Deborah Malvi
- "F. Addarii" Institute of Oncology and Transplantation, Bologna University Hospital, Policlinico S. Orsola-Malpighi, Bologna, Italy
| | - Mauro Bernardi
- Department of Medical and Surgical Sciences, Bologna University, Bologna, Italy
| | - Fabio Conti
- Department of Medical and Surgical Sciences, Bologna University, Bologna, Italy
| | - Roberto M Lemoli
- Haematology Clinic, Internal Medicine Department, Genoa University, Genoa, Italy
| |
Collapse
|
21
|
Eom YW, Kim G, Baik SK. Mesenchymal stem cell therapy for cirrhosis: Present and future perspectives. World J Gastroenterol 2015; 21:10253-10261. [PMID: 26420953 PMCID: PMC4579873 DOI: 10.3748/wjg.v21.i36.10253] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Revised: 06/01/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Cirrhosis occurs as a result of various chronic liver injuries, which may be caused by viral infections, alcohol abuse and the administration of drugs and chemicals. Recently, bone marrow cells (BMCs), hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) have been used for developing treatments for cirrhosis. Clinical trials have investigated the therapeutic potential of BMCs, HSCs and MSCs for the treatment of cirrhosis based on their potential to differentiate into hepatocytes. Although the therapeutic mechanisms of BMC, HSC and MSC treatments are still not fully characterized, the evidence thus far has indicated that the potential therapeutic mechanisms of MSCs are clearer than those of BMCs or HSCs with respect to liver regenerative medicine. MSCs suppress inflammatory responses, reduce hepatocyte apoptosis, increase hepatocyte regeneration, reverse liver fibrosis and enhance liver functionality. This paper summarizes the clinical studies that have used BMCs, HSCs and MSCs in patients with liver failure or cirrhosis. We also present the potential therapeutic mechanisms of BMCs, HSCs and MSCs for the improvement of liver function.
Collapse
|
22
|
Pankaj P, Zhang Q, Bai XL, Liang TB. Autologous bone marrow transplantation in decompensated liver: Systematic review and meta-analysis. World J Gastroenterol 2015; 21:8697-8710. [PMID: 26229412 PMCID: PMC4515851 DOI: 10.3748/wjg.v21.i28.8697] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2014] [Revised: 03/27/2015] [Accepted: 04/28/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the efficacy of autologous bone marrow mononuclear cell transplantation in decompensated liver disease.
METHODS: Medline, EMBASE, PubMed, Science Direct, and the Cochrane Library were searched for relevant studies. Retrospective case-control studies were included along with randomized clinical trials. Meta-analysis was performed in line with recommendations from the Cochrane Collaboration software review manager. Heterogeneity was assessed using a random-effects model.
RESULTS: Four randomized controlled trials and four retrospective studies were included. Cell transplantation increased serum albumin level by 1.96 g/L (95%CI: 0.74-3.17; P = 0.002], 2.55 g/L (95%CI: 0.32-4.79; P = 0.03), and 3.65 g/L (95%CI: 0.76-6.54; P = 0.01) after 1, 3, and 6 mo, respectively. Patients who had undergone cell transplantation also had a lower level of total bilirubin [mean difference (MD): -1.37 mg/dL; 95%CI: -2.68-(-0.06); P = 0.04] after 6 mo. This decreased after 1 year when compared to standard treatment (MD: -1.26; 95%CI: -2.48-(-0.03); P = 0.04]. A temporary decrease in alanine transaminase and aspartate transaminase were significant in the cell transplantation group. However, after 6 mo treatment, patients who had undergone cell transplantation had a slightly longer prothrombin time (MD: 5.66 s, 95%CI: 0.04-11.28; P = 0.05). Changes in the model for end-stage liver disease score and Child-Pugh score were not statistically significant.
CONCLUSION: Autologous bone marrow transplantation showed some benefits in patients with decompensated liver disease. However, further studies are still needed to verify its role in clinical treatment for end-stage liver disease.
Collapse
|
23
|
Wakao S, Dezawa M. [Current status and future prospects of Muse cell research
]. Nihon Yakurigaku Zasshi 2015; 145:299-305. [PMID: 26063152 DOI: 10.1254/fpj.145.299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
|
24
|
Li T, Xia M, Gao Y, Chen Y, Xu Y. Human umbilical cord mesenchymal stem cells: an overview of their potential in cell-based therapy. Expert Opin Biol Ther 2015; 15:1293-306. [PMID: 26067213 DOI: 10.1517/14712598.2015.1051528] [Citation(s) in RCA: 174] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Human umbilical cord mesenchymal stem cells (HUC-MSCs) are one of the typical adult stem cells; they have superiorities including low immunogenicity, non-invasive harvest procedure, easy expansion in vitro, and ethical access compared with stem cells from other sources. Therefore, HUC-MSCs are a promising candidate for cell-based therapy. AREAS COVERED Here we reviewed the development of stem cell-based therapy, the manufacturing and banking process of HUC-MSCs, the emerging clinical studies in the field of cancer, central nervous system diseases, liver diseases and graft-versus-host disease, the potential therapeutic mechanisms, as well as challenges of HUC-MSCs in clinical translation. EXPERT OPINION HUC-MSCs seem to be an optimal choice for stem cell-based therapy. However, before the cells translate from basic to clinical research, some problems still remain to be solved: i) building regulatory guidelines as well as an efficient and safe manufacturing procedure; ii) establishing donor's genetic testing and long-term closely monitoring system; iii) conducting further clinical trials to determine the optimum and standard dosage, time, route, frequency and many other technical issues of HUC-MSCs transplantation.
Collapse
Affiliation(s)
- Tan Li
- Drum Tower Hospital, Medical School of Nanjing University, Department of Neurology , 321 Zhongshan Road, Nanjing City, Jiangsu Province 210008 , China +86 25 6818 2212 ; +86 25 8310 5208 ; ;
| | | | | | | | | |
Collapse
|
25
|
Irfan A, Ahmed I. Could Stem Cell Therapy be the Cure in Liver Cirrhosis? J Clin Exp Hepatol 2015; 5:142-6. [PMID: 26155042 PMCID: PMC4491605 DOI: 10.1016/j.jceh.2014.03.042] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Accepted: 03/03/2014] [Indexed: 12/12/2022] Open
Abstract
Over the past five decades, liver cirrhosis has become an increasingly prevalent disease and one that will often require considerable medical intervention. However, current treatment options have demonstrated severe problems that have prompted research to provide a suitable alternative. These treatments are scarcely available, very expensive and present at a huge cost to the patient's quality of life. The introduction of stem cell therapy into liver disease has been heralded as the future of personalized medicine and may be the alternative that the healthcare system desperately seeks. To truly determine the scientific basis surrounding this excitement, a literature search was carried out in January 2013 to determine all the data that was present in this topic area. All articles also underwent full cross-referencing to ensure no data was missed. 11 clinical trials were found to meet this criteria and trials were included in both English and non-English languages. The sporadic nature of the data across the trials, with various methods and stem cell types, made comparisons difficult. The basic trends from the data were positive and the majority deemed the use of stem cells safe and feasible in patients presenting with cirrhotic liver disease. However, there is a clear requirement for more research, not only to determine the most efficacious technique and stem cell type but also to further understand stem cells to enhance progress. There may also be a requirement for a framework that future stem cell trials can be based on, which would allow future data to be comparative and allow valid conclusions to be drawn which may propel this therapy into standard clinical practice.
Collapse
Affiliation(s)
- Ahmer Irfan
- University of Edinburgh, Edinburgh, United Kingdom,Address for correspondence: Ahmer Irfan, University of Edinburgh Medical School, 47 Little France Crescent, Edinburgh, EH16 4TJ, United Kingdom.
| | - Irfan Ahmed
- University of Aberdeen, Aberdeen, United Kingdom
| |
Collapse
|
26
|
AlAhmari LS, AlShenaifi JY, AlAnazi RA, Abdo AA. Autologous bone marrow-derived cells in the treatment of liver disease patients. Saudi J Gastroenterol 2015; 21:5-10. [PMID: 25672232 PMCID: PMC4355864 DOI: 10.4103/1319-3767.151211] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Liver transplantation is universally accepted as a "cure" procedure, and yet is not universally applicable for the treatment of end-stage liver diseases (ESLD) because of the shortage of donors, operative complications, risk of rejection, and high cost. Bioartificial liver device is an option to temporarily improve the liver function and to bridge the patients to liver transplantation. However, bioartificial liver device has many problems in clinical application, such as hepatocyte allograft rejection and maintenance of hepatocyte viability and function. Another therapeutic option is stem cell transplantation. There are two broad types of stem cells: Embryonic stem cells and adult stem cells. The latter are sourced from bone marrow (BM), adipose tissue, and blood. This review will concentrate on BM-derived cells. BM-derived cell transplantation, although not ideal, is theoretically an optimal modality for the treatment of ESLD. Autologous BM-derived cells have no graft rejection, have the capability of regeneration and self-renewal, and are multipotent stem cells that can differentiate into a variety of cell types which include hepatocytes. The pathway from BM-derived cell to hepatocyte is well documented. The present review summarizes the delivery routes of BM-derived cells to the liver, the evidences of engraftment of BM-derived cells in the liver, and the possible mechanisms of BM-derived cells in liver repair and regeneration, and finally, updates the clinical applications.
Collapse
Affiliation(s)
- Leenah S. AlAhmari
- Liver Disease Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Jumanah Y. AlShenaifi
- Liver Disease Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Reema A. AlAnazi
- Liver Disease Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Ayman A. Abdo
- Liver Disease Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia,Address for correspondence: Prof. Ayman A. Abdo, Department of Medicine, College of Medicine, King Saud University, Saudi Arabia. E-mail:
| |
Collapse
|
27
|
Wakao S, Akashi H, Kushida Y, Dezawa M. Muse cells, newly found non-tumorigenic pluripotent stem cells, reside in human mesenchymal tissues. Pathol Int 2014; 64:1-9. [PMID: 24471964 DOI: 10.1111/pin.12129] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Accepted: 12/13/2013] [Indexed: 01/09/2023]
Abstract
Mesenchymal stem cells (MSCs) have been presumed to include a subpopulation of pluripotent-like cells as they differentiate not only into the same mesodermal-lineage cells but also into ectodermal- and endodermal-lineage cells and exert tissue regenerative effects in a wide variety of tissues. A novel type of pluripotent stem cell, Multilineage-differentiating stress enduring (Muse) cells, was recently discovered in mesenchymal tissues such as the bone marrow, adipose tissue, dermis and connective tissue of organs, as well as in cultured fibroblasts and bone marrow-MSCs. Muse cells are able to differentiate into all three germ layers from a single cell and to self-renew, and yet exhibit non-tumorigenic and low telomerase activities. They can migrate to and target damaged sites in vivo, spontaneously differentiate into cells compatible with the targeted tissue, and contribute to tissue repair. Thus, Muse cells may account for the wide variety of differentiation abilities and tissue repair effects that have been observed in MSCs. Muse cells are unique in that they are pluripotent stem cells that belong in the living body, and are thus assumed to play an important role in 'regenerative homeostasis' in vivo.
Collapse
Affiliation(s)
- Shohei Wakao
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | | | | | | |
Collapse
|
28
|
Behbahan IS, Keating A, Gale RP. Concise review: bone marrow autotransplants for liver disease? Stem Cells 2014; 31:2313-29. [PMID: 23939914 DOI: 10.1002/stem.1510] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2013] [Revised: 07/08/2013] [Accepted: 07/15/2013] [Indexed: 12/11/2022]
Abstract
There are increasing reports of using bone marrow-derived stem cells to treat advanced liver disease. We consider several critical issues that underlie this approach. For example, are there multipotent stem cell populations in human adult bone marrow? Can they develop into liver cells or supporting cell types? What are stromal stem/progenitor cells, and can they promote tissue repair without replacing hepatocytes? Does reversal of end-stage liver disease require new hepatocytes, a new liver microenvironment, both, neither or something else? Although many of these questions are unanswered, we consider the conceptual and experimental bases underlying these issues and critically analyze results of clinical trials of stem cell therapy of end-stage liver disease.
Collapse
Affiliation(s)
- Iman Saramipoor Behbahan
- Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
| | | | | |
Collapse
|
29
|
Xu L, Gong Y, Wang B, Shi K, Hou Y, Wang L, Lin Z, Han Y, Lu L, Chen D, Lin X, Zeng Q, Feng W, Chen Y. Randomized trial of autologous bone marrow mesenchymal stem cells transplantation for hepatitis B virus cirrhosis: regulation of Treg/Th17 cells. J Gastroenterol Hepatol 2014; 29:1620-8. [PMID: 24942592 DOI: 10.1111/jgh.12653] [Citation(s) in RCA: 82] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/17/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Liver cirrhosis is one of the major consequences of hepatitis B virus (HBV) infection, and transplantation of autologous bone marrow mesenchymal stem cells (ABMSCs) is one of promising therapies for patients with HBV-related liver cirrhosis (HBV-LC). However, the mechanism is unclear. The aim of the current study was to explore the role of Treg/Th17 cells in ABMSCs transplantation in patients with HBV-LC. METHODS In this prospective study, 56 patients were enrolled and randomly assigned to transplantation group and control group. After 24-week follow-up, 39 patients completed the study (20 cases in transplantation group and 19 cases in control group). The Model for End-Stage Liver Disease scores, liver function, changes of Treg/Th17 cells, as well as related transcription factors and serum cytokines, were determined. RESULTS Although patients in both groups showed significant improvement after Entecavir treatment, ABMSC transplantation further improved patients' liver function. Moreover, there was a significant increase in Treg cells and a marked decrease in Th17 cells in the transplantation group compared with control, leading to an increased Treg/Th17 ratio. Furthermore, mRNA levels of Treg-related transcription factor (Foxp3) and Th17-related transcription factor (RORγt) were increased and decreased, respectively. In addition, serum transforming growth factor-β levels were significantly higher at early weeks of transplantation, while serum levels of interleukin-17, tumor necrosis factor-α, and interleukin-6 were significantly lower in patients in the transplantation group compared with control. CONCLUSION ABMSCs transplantation was effective in improving liver function in patients with HBV-LC, which was mediated, at least in part, through the regulation of Treg/Th17 cell balance.
Collapse
Affiliation(s)
- Lanman Xu
- Department of Infection and Liver Diseases of the First Affiliated Hospital and Liver Research Center, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
30
|
Margini C, Vukotic R, Brodosi L, Bernardi M, Andreone P. Bone marrow derived stem cells for the treatment of end-stage liver disease. World J Gastroenterol 2014; 20:9098-9105. [PMID: 25083082 PMCID: PMC4112892 DOI: 10.3748/wjg.v20.i27.9098] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 02/27/2014] [Accepted: 04/15/2014] [Indexed: 02/06/2023] Open
Abstract
End-stage disease due to liver cirrhosis is an important cause of death worldwide. Cirrhosis results from progressive, extensive fibrosis and impaired hepatocyte regeneration. The only curative treatment is liver transplantation, but due to the several limitations of this procedure, the interest in alternative therapeutic strategies is increasing. In particular, the potential of bone marrow stem cell (BMSC) therapy in cirrhosis has been explored in different trials. In this article, we evaluate the results of 18 prospective clinical trials, and we provide a descriptive overview of recent advances in the research on hepatic regenerative medicine. The main message from the currently available data in the literature is that BMSC therapy is extremely promising in the context of liver cirrhosis. However, its application should be further explored in randomized, controlled trials with large cohorts and long follow-ups.
Collapse
|
31
|
Peng SY, Chou CJ, Cheng PJ, Ko IC, Kao YJ, Chen YH, Cheng WTK, Shaw SWS, Wu SC. Therapeutic potential of amniotic-fluid-derived stem cells on liver fibrosis model in mice. Taiwan J Obstet Gynecol 2014; 53:151-157. [PMID: 25017258 DOI: 10.1016/j.tjog.2014.04.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Accepted: 02/10/2014] [Indexed: 01/18/2023] Open
Abstract
OBJECTIVE Liver fibrosis results from the wound healing response to chronic liver damage. Advanced liver fibrosis results in cirrhosis and liver failure, and liver transplantation is often the only option for effective therapy; however, the shortage of available donor livers limits this treatment. Thus, new therapies for advanced liver fibrosis are essential. MATERIALS AND METHODS Amniotic fluid contains an abundance of stem cells, which are derived from all three germ layers of the developing fetus. These cells do not induce teratomas in vivo and do not pose any ethical concerns. To generate liver fibrosis models, male ICR mice were treated with CCl4 via oral gavage for 4 weeks, and the serum levels of glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, and albumin were higher than in the control group following chemical induction. To assess the potential of amniotic-fluid-derived stem cells (mAFSCs) to ameliorate liver fibrosis in vivo, mAFSCs were isolated from amniotic fluid of 13.5-day-old transgenic mice, which globally express the fluorescent protein, enhanced green fluorescent protein (EGFP), for tracing purposes (EGFP-mAFSCs). Single cells were injected via the mesentery (1 × 10(6) cells/mouse) of transplanted mice with liver fibrosis. RESULTS Four weeks after EGFP-mAFSC transplantation, the serum glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, and albumin levels of recipient mice in the EGFP-mAFSC-injected group were significantly decreased when compared with mice in the saline-injected group. Additionally, fibrotic tissues were evaluated using Masson's trichrome staining 4 weeks after cell transplantation. Shrinkage of the fibrotic area was observed in the EGFP-mAFSC-injected group. The tissue-repair effects were also confirmed by hydroxyproline content analysis. CONCLUSION The possible repair mechanism from our data revealed that EGFP-mAFSCs may fuse with the recipient liver cells. Overall, EGFP-mAFSCs can ameliorate liver fibrosis in mice, thus providing insight into the future development of regenerative medicine.
Collapse
Affiliation(s)
- Shao-Yu Peng
- Institute of Biotechnology, National Taiwan University, Taipei, Taiwan
| | - Chih-Jen Chou
- Institute of Biotechnology, National Taiwan University, Taipei, Taiwan
| | - Po-Jen Cheng
- Department of Obstetrics and Gynaecology, Chang Gung Memorial Hospital at Linkou and Chang Gung University, College of Medicine, Taoyuan, Taiwan
| | - I-Chen Ko
- Department of Animal Science and Technology, National Taiwan University, Taipei, Taiwan
| | - Yi-Jung Kao
- Department of Animal Science and Technology, National Taiwan University, Taipei, Taiwan
| | - Yu-Hsu Chen
- Institute of Biotechnology, National Taiwan University, Taipei, Taiwan; Department of Surgery, Hualien Armed Forces General Hospital, Hualien, Taiwan
| | - Winston Teng-Kui Cheng
- Department of Animal Science and Technology, National Taiwan University, Taipei, Taiwan; Department of Animal Science and Biotechnology, Tunghai University, Taichung, Taiwan
| | - S W Steven Shaw
- Department of Obstetrics and Gynaecology, Chang Gung Memorial Hospital at Linkou and Chang Gung University, College of Medicine, Taoyuan, Taiwan; Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan; Prenatal Cell and Gene Therapy Group, Institute for Women's Health, University College London, London, UK.
| | - Shinn-Chih Wu
- Institute of Biotechnology, National Taiwan University, Taipei, Taiwan; Department of Animal Science and Technology, National Taiwan University, Taipei, Taiwan.
| |
Collapse
|
32
|
Effect of transplantation route on stem cell migration to fibrotic liver of rats via cellular magnetic resonance imaging. Cytotherapy 2014; 15:1266-74. [PMID: 23993301 DOI: 10.1016/j.jcyt.2013.05.023] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2013] [Revised: 05/29/2013] [Accepted: 05/30/2013] [Indexed: 10/26/2022]
Abstract
BACKGROUND AIMS Assessing mesenchymal stromal cells (MSCs) after grafting is essential for understanding their migration and differentiation processes. The present study sought to evaluate via cellular magnetic resonance imaging (MRI) if transplantation route may have an effect on MSCs engrafting to fibrotic liver of rats. METHODS Rat MSCs were prepared, labeled with superparamagnetic iron oxide and scanned with MRI. Labeled MSCs were transplanted via the portal vein or vena caudalis to rats with hepatic fibrosis. MRI was performed in vitro before and after transplantation. Histologic examination was performed. MRI scan and imaging parameter optimization in vitro and migration under in vivo conditions were demonstrated. RESULTS Strong MRI susceptibility effects could be found on gradient echo-weighted, or T2∗-weighted, imaging sequences from 24 h after labeling to passage 4 of labeled MSCs in vitro. In vivo, MRI findings of the portal vein group indicated lower signal in liver on single shot fast spin echo-weighted, or T2-weighted, imaging and T2∗-weighted imaging sequences. The low liver MRI signal increased gradually from 0-3 h and decreased gradually from 3 h to 14 days post-transplantation. The distribution pattern of labeled MSCs in liver histologic sections was identical to that of MRI signal. It was difficult to find MSCs in tissues near the portal area on day 14 after transplantation; labeled MSCs appeared in fibrous tuberculum at the edge of the liver. No MRI signal change and a positive histologic examination were observed in the vena caudalis group. CONCLUSIONS The portal vein route seemed to be more beneficial than the vena caudalis on MSC migration to fibrotic liver of rats via MRI.
Collapse
|
33
|
Terai S, Takami T, Yamamoto N, Fujisawa K, Ishikawa T, Urata Y, Tanimoto H, Iwamoto T, Mizunaga Y, Matsuda T, Oono T, Marumoto M, Burganova G, Fernando Quintanilha L, Hidaka I, Marumoto Y, Saeki I, Uchida K, Yamasaki T, Tani K, Taura Y, Fujii Y, Nishina H, Okita K, Sakaida I. Status and prospects of liver cirrhosis treatment by using bone marrow-derived cells and mesenchymal cells. TISSUE ENGINEERING PART B-REVIEWS 2014; 20:206-10. [PMID: 24450831 DOI: 10.1089/ten.teb.2013.0527] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In 2003, we started autologous bone marrow cell infusion (ABMi) therapy for treating liver cirrhosis. ABMi therapy uses 400 mL of autologous bone marrow obtained under general anesthesia and infused mononuclear cells from the peripheral vein. The clinical study expanded and we treated liver cirrhosis induced by HCV and HBV infection and alcohol consumption. We found that the ABMi therapy was effective for cirrhosis patients and now we are treating patients with combined HIV and HCV infection and with metabolic syndrome-induced liver cirrhosis. Currently, to substantiate our findings that liver cirrhosis can be successfully treated by the ABMi therapy, we are conducting randomized multicenter clinical studies designated "Advanced medical technology B" for HCV-related liver cirrhosis in Japan. On the basis of our clinical study, we developed a proof-of-concept showing that infusion of bone marrow cells (BMCs) improved liver fibrosis and sequentially activated proliferation of hepatic progenitor cells and hepatocytes, further promoting restoration of liver functions. To treat patients with severe forms of liver cirrhosis, we continued translational research to develop less invasive therapies by using mesenchymal stem cells derived from bone marrow. We obtained a small quantity of BMCs under local anesthesia and expanded them into mesenchymal stem cells that will then be used for treating cirrhosis. In this review, we present our strategy to apply the results of our laboratory research to clinical studies.
Collapse
Affiliation(s)
- Shuji Terai
- 1 Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine , Yamaguchi, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
34
|
Bone marrow cell-based regenerative therapy for liver cirrhosis. World J Methodol 2013; 3:65-9. [PMID: 25237624 PMCID: PMC4145572 DOI: 10.5662/wjm.v3.i4.65] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 11/06/2013] [Accepted: 12/12/2013] [Indexed: 02/06/2023] Open
Abstract
Bone marrow cells are capable of differentiation into liver cells. Therefore, transplantation of bone marrow cells has considerable potential as a future therapy for regeneration of damaged liver tissue. Autologous bone marrow infusion therapy has been applied to patients with liver cirrhosis, and improvement of liver function parameters has been demonstrated. In this review, we summarize clinical trials of regenerative therapy using bone marrow cells for advanced liver diseases including cirrhosis, as well as topics pertaining to basic in vitro or in vivo approaches in order to outline the essentials of this novel treatment modality.
Collapse
|
35
|
Kuroda Y, Dezawa M. Mesenchymal stem cells and their subpopulation, pluripotent muse cells, in basic research and regenerative medicine. Anat Rec (Hoboken) 2013; 297:98-110. [PMID: 24293378 DOI: 10.1002/ar.22798] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2013] [Accepted: 09/13/2013] [Indexed: 12/13/2022]
Abstract
Mesenchymal stem cells (MSCs) have gained a great deal of attention for regenerative medicine because they can be obtained from easy accessible mesenchymal tissues, such as bone marrow, adipose tissue, and the umbilical cord, and have trophic and immunosuppressive effects to protect tissues. The most outstanding property of MSCs is their potential for differentiation into cells of all three germ layers. MSCs belong to the mesodermal lineage, but they are known to cross boundaries from mesodermal to ectodermal and endodermal lineages, and differentiate into a variety of cell types both in vitro and in vivo. Such behavior is exceptional for tissue stem cells. As observed with hematopoietic and neural stem cells, tissue stem cells usually generate cells that belong to the tissue in which they reside, and do not show triploblastic differentiation. However, the scientific basis for the broad multipotent differentiation of MSCs still remains an enigma. This review summarizes the properties of MSCs from representative mesenchymal tissues, including bone marrow, adipose tissue, and the umbilical cord, to demonstrate their similarities and differences. Finally, we introduce a novel type of pluripotent stem cell, multilineage-differentiating stress-enduring (Muse) cells, a small subpopulation of MSCs, which can explain the broad spectrum of differentiation ability in MSCs.
Collapse
Affiliation(s)
- Yasumasa Kuroda
- Department of Anatomy and Anthropology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | | |
Collapse
|
36
|
De Schauwer C, Van de Walle GR, Van Soom A, Meyer E. Mesenchymal stem cell therapy in horses: useful beyond orthopedic injuries? Vet Q 2013; 33:234-41. [DOI: 10.1080/01652176.2013.800250] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
|
37
|
Seo KW, Sohn SY, Bhang DH, Nam MJ, Lee HW, Youn HY. Therapeutic effects of hepatocyte growth factor-overexpressing human umbilical cord blood-derived mesenchymal stem cells on liver fibrosis in rats. Cell Biol Int 2013; 38:106-16. [PMID: 24115681 DOI: 10.1002/cbin.10186] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Accepted: 08/26/2013] [Indexed: 01/18/2023]
Abstract
Fibrosis is a common end stage for a variety of liver diseases, including most chronic liver diseases, and results from an imbalance between collagen deposition and degradation. Mesenchymal stem cells (MSCs) have the ability to migrate into fibrotic livers and differentiate into hepatocytes. Hepatocyte growth factor (HGF) has potent anti-apoptotic and mitogenic effects on hepatocytes during liver injury and plays an essential role in the development and regeneration of the liver. In this study, human HGF-overexpressing human umbilical cord blood-derived MSCs (hHGF-HUCB-MSCs) were prepared using the pMEX Expression System, and the upregulation of hHGF expression was confirmed by RT-PCR and ELISA. HGF expressed by hHGF-HUCB-MSCs exerted a stimulatory effect on hepatocyte proliferation in vitro. hHGF-HUCB-MSCs were transplanted to investigate the therapeutic effects of these cells on carbon tetrachloride (CCL4)-induced liver fibrosis in a rat model. After 4 weeks of cell treatment once per week with 2 × 10(6) cells, biochemical analysis of the serum and histopathological analysis of the liver tissue were performed. The results of the biochemical analysis of the serum show that the hHGF-HUCB-MSC-treated group had higher levels of alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase, indicating the improvement of liver function. Histopathology showed that the hHGF-HUCB-MSC-treated group had reduction in the density of collagen fibres. Thus hHGF-HUCB-MSCs can enhance liver regeneration and could be useful for the treatment of patients with liver fibrosis or cirrhosis.
Collapse
Affiliation(s)
- Kyoung-Won Seo
- Department of Veterinary Internal Medicine, College of Veterinary Medicine, Chungnam National University, 99 Daehakro, Yuseoung gu, Daejon, 305-764, Republic of Korea
| | | | | | | | | | | |
Collapse
|
38
|
Tanimoto H, Terai S, Taro T, Murata Y, Fujisawa K, Yamamoto N, Sakaida I. Improvement of liver fibrosis by infusion of cultured cells derived from human bone marrow. Cell Tissue Res 2013; 354:717-28. [PMID: 24104560 DOI: 10.1007/s00441-013-1727-2] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Accepted: 08/29/2013] [Indexed: 01/12/2023]
Abstract
We develop "autologous bone marrow cell infusion (ABMi) therapy" for the treatment of human decompensated liver cirrhosis and confirm the efficacy and safety of this treatment in multicenter clinical studies. With the goal of further expanding the applications of ABMi, we first cultured human bone marrow cells and then determined whether a cell fraction found to be effective in improving liver fibrosis can be amplified. Cells harvested after two passages (P2 cells) consistently contained approximately 94% mesenchymal stem cells (MSCs); conversely, the cells harvested after only medium change (P0 cells) contained many macrophages. MSCs (2.8 × 10(8)) in P2 cells were harvested from 3.8 × 10(8) bone marrow-derived mononuclear cells after 22 days. DNA-chip analysis also showed during the culturing step that bone marrow-derived cells decreased with macrophage phenotype. The infused 5 × 10(5) P2 cells significantly improved liver fibrosis in the nonobese diabetic/severe combined immunodeficient (NOD-SCID) mouse carbon tetrachloride (CCl4) liver cirrhosis model and induced the expression of matrix metalloproteinase (MMP)-9 and suppressed expressions of alpha smooth muscle actin (αSMA), tumor necrosis factor alpha (TNFα) and transforming growth factor beta (TGFβ) in the liver. Cultured human bone marrow-derived cells (P2 cells) significantly inhibited liver fibrosis. The increase of MMP-9 and suppressed activation of hepatic stellate cells (HSCs) through the regulation of humoral factors (TNFα and TGFβ) contribute to the improvement of liver fibrosis by MSCs comprising about 94% of P2 cells. MSCs in cultured human bone marrow-derived mono-nuclear cells (BM-MNCs) proliferate sufficiently in cell therapy, so we believe our cultured bone marrow-derived cell therapy can lead to expanded clinical applications and enable outpatient therapy.
Collapse
Affiliation(s)
- Haruko Tanimoto
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Minami-Kogushi 1-1-1, Ube, Yamaguchi, 755-8505, Japan
| | | | | | | | | | | | | |
Collapse
|
39
|
Asgari S, Moslem M, Bagheri-Lankarani K, Pournasr B, Miryounesi M, Baharvand H. Differentiation and transplantation of human induced pluripotent stem cell-derived hepatocyte-like cells. Stem Cell Rev Rep 2013; 9:493-504. [PMID: 22076752 DOI: 10.1007/s12015-011-9330-y] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The generation of human induced pluripotent stem cells (hiPSCs) with a high differentiation potential provided a new source for hepatocyte generation not only for drug discovery and in vitro disease models, but also for cell replacement therapy. However, the reported hiPSC-derived hepatocyte-like cells (HLCs) were not well characterized and their transplantation, as the most promising clue of cell function was not reported. Here, we performed a growth factor-mediated differentiation of functional HLCs from hiPSCs and evaluated their potential for recovery of a carbon tetrachloride (CCl4)-injured mouse liver following transplantation. The hiPSC-derived hepatic lineage cells expressed hepatocyte-specific markers, showed glycogen and lipid storage activity, secretion of albumin (ALB), alpha-fetoprotein (AFP), urea, and CYP450 metabolic activity in addition to low-density lipoprotein (LDL) and indocyanin green (ICG) uptake. Similar results were observed with human embryonic stem cell (hESC)-derived HLCs. The transplantation of hiPSC-HLCs into a CCl4-injured liver showed incorporation of the hiPSC-HLCs into the mouse liver which resulted in a significant enhancement in total serum ALB after 1 week. A reduction of total serum LDH and bilirubin was seen when compared with the control and sham groups 1 and 5 weeks post-transplantation. Additionally, we detected human serum ALB and ALB-positive transplanted cells in both the host serum and livers, respectively, which showed functional integration of transplanted cells within the mouse livers. Therefore, our results have opened up a proof of concept that functional HLCs can be generated from hiPSCs, thus improving the general condition of a CCl4-injured mouse liver after their transplantation. These results may bring new insights in the clinical applications of hiPSCs once safety issues are overcome.
Collapse
Affiliation(s)
- Samira Asgari
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, PO Box 19395-4644, Tehran, Iran
| | | | | | | | | | | |
Collapse
|
40
|
Kato T, Hisasue M, Segawa K, Fujimoto A, Makiishi E, Neo S, Yasuno K, Kobayashi R, Tsuchiya R. Accumulation of xenotransplanted canine bone marrow cells in NOD/SCID/γc(null) mice with acute hepatitis induced by CCl4. J Vet Med Sci 2013; 75:847-55. [PMID: 23411484 DOI: 10.1292/jvms.12-0530] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Bone marrow cell infusion (BMI) has recently been suggested as an effective therapy for refractory liver disease; however, the efficiency of BMI using canine bone marrow cells (cBMCs) has not been reported. We evaluated the accumulation potential of cBMCs in a mouse model of acute liver failure. Acute hepatitis was induced by carbon tetrachloride (CCl4) treatment in NOD/SCID/γc(null)(NOG) mice and wild-type (WT) C57BL mice, and the characteristics of liver dysfunction and the degree of hepatic injury and regeneration were compared between the two mouse models. Next, female CCl4-treated NOG mice were xenotransplanted with male PKH26-labeled cBMCs, and the potential of cBMCs to accumulate in injured liver tissue compartments was examined. Fluorescence microscopy was performed to histologically detect the infused cBMCs, and DNA polymerase chain reaction was performed for detection of the male Y chromosome (SRY gene) in the recipient female NOG mice. The number of PKH26-positive cBMCs transplanted in the liver tissue gradually increased in the NOG mice. The infused cBMCs were located in the necrotic area of the liver at an early stage after transplantation, and most had accumulated a week after transplantation. However, the therapeutic efficacy of the xenotransplantation remained unclear, because no significant differences were observed concerning the extent liver injury and regeneration between the cBMC-transplanted and saline control mice. These results suggest that cBMCs will specifically accumulate in injured liver tissue and that BMC transplantation may have the potential to repair liver deficiency.
Collapse
Affiliation(s)
- Takashi Kato
- Laboratory of Internal Medicine II, School of Veterinary Medicine, Azabu University, 1-17-71 Fuchinobe, Chuoku, Sagamihara, Kanagawa 252-5201, Japan
| | | | | | | | | | | | | | | | | |
Collapse
|
41
|
Amin MA, Sabry D, Rashed LA, Aref WM, el-Ghobary MA, Farhan MS, Fouad HA, Youssef YAA. Short-term evaluation of autologous transplantation of bone marrow-derived mesenchymal stem cells in patients with cirrhosis: Egyptian study. Clin Transplant 2013; 27:607-612. [PMID: 23923970 DOI: 10.1111/ctr.12179] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/21/2013] [Indexed: 02/05/2023]
Abstract
BACKGROUND Stem cell-based therapy has received attention as a possible alternative to organ transplantation. The aim of this study was to assess the safety and efficacy of autologous transplantation of bone marrow (BM)-derived stromal cells in post-HCV liver cirrhosis patients. METHODOLOGY 10 × 10(6) of isolated human bone marrow (HBM)-stromal cells in 10 mL normal saline were injected in the spleen of 20 patients with end-stage liver cirrhosis guided by the ultrasonography, and then patients were followed up on monthly basis for six months. RESULTS A statistically significant decrease was detected in the total bilirubin, aspartate transaminase (AST), alanine transaminase (ALT) (p-value<0.01), prothrombin time (PT), and international normalized ratio (INR) levels (p-value<0.05), while a statistically significant increase in the albumin and PC (p-value<0.05) after follow-up. CONCLUSION This study suggested the safety, feasibility, and efficacy of the intrasplenic injection of autologous BM stromal cells in improving liver function in Egyptian patients with cirrhosis.
Collapse
Affiliation(s)
- Mona A Amin
- Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
| | | | | | | | | | | | | | | |
Collapse
|
42
|
Zhong Y, Xu J, Deng M, Liu B, Zhang F, Yuan Y, Yang X, Xu R. Generation of a human bone marrow-derived mesenchymal stem cell line expressing and secreting high levels of bioactive -melanocyte-stimulating hormone. J Biochem 2013; 153:371-379. [DOI: 10.1093/jb/mvt003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
|
43
|
Iwamoto T, Terai S, Hisanaga T, Takami T, Yamamoto N, Watanabe S, Sakaida I. Bone-marrow-derived cells cultured in serum-free medium reduce liver fibrosis and improve liver function in carbon-tetrachloride-treated cirrhotic mice. Cell Tissue Res 2012. [PMID: 23183782 DOI: 10.1007/s00441-012-1528-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
We have previously developed autologous bone marrow cell infusion (ABMi) therapy for liver cirrhosis patients. One problem associated with ABMi therapy is that general anesthesia is required to obtain 400 ml bone marrow fluid from liver cirrhosis patients. However, many patients with decompensated cirrhosis do not meet the criteria, because of decreased liver function or an increased bleeding tendency. To overcome these issues, our aim is to derive liver repair cells from small amounts of autologous bone marrow aspirates obtained under local anesthesia and to use these cells in liver cirrhosis patients. Here, we conducted, by using a mouse model, basic research aimed at achieving novel liver regeneration therapy. We cultured bone marrow cells aspirated from the femurs of C57 BL/6 Tg14 (act-EGFP) OsbY01 mice (green fluoresent protein [GFP]-transgenic mice). After 14 days of culture with serum-free medium (good manufacturing practice grade), the obtained spindle-shaped GFP-positive cells were injected (1×10(4) cells) via the caudal vein into mice with carbon tetrachloride (CCl4)-induced cirrhosis. Numerous cultured macrophages and some mesenchymal stem cells repopulated the cirrhotic liver. The results showed that serum albumin, liver fibrosis and liver function were significantly improved in the group treated with cultured bone marrow cells (P<0.01). Moreover, matrix metalloproteinase-9 expression was increased in the liver (P<0.01). Thus, infusion of bone-marrow-derived cultured cells improved liver function and liver fibrosis in mice with CCl4-induced cirrhosis.
Collapse
Affiliation(s)
- Takuya Iwamoto
- Department of Gastroenterology & Hepatology, Yamaguchi University Graduate School of Medicine, Minami Kogushi 1-1-1, Ube, Yamaguchi, 755-8505, Japan
| | | | | | | | | | | | | |
Collapse
|
44
|
Suh YG, Kim JK, Byun JS, Yi HS, Lee YS, Eun HS, Kim SY, Han KH, Lee KS, Duester G, Friedman SL, Jeong WI. CD11b(+) Gr1(+) bone marrow cells ameliorate liver fibrosis by producing interleukin-10 in mice. Hepatology 2012; 56:1902-12. [PMID: 22544759 PMCID: PMC3427419 DOI: 10.1002/hep.25817] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2012] [Accepted: 04/25/2012] [Indexed: 02/06/2023]
Abstract
UNLABELLED Clinical trials and animal models suggest that infusion of bone marrow cells (BMCs) is effective therapy for liver fibrosis, but the underlying mechanisms are obscure, especially those associated with early effects of BMCs. Here, we analyzed the early impact of BMC infusion and identified the subsets of BMCs showing antifibrotic effects in mice with carbon tetrachloride-induced liver fibrosis. An interaction between BMCs and activated hepatic stellate cells (HSCs) was investigated using an in vitro coculturing system. Within 24 hours, infused BMCs were in close contact with activated HSCs, which was associated with reduced liver fibrosis, enhanced hepatic expression of interleukin (IL)-10, and expanded regulatory T cells but decreased macrophage infiltration in the liver at 24 hours after BMC infusion. In contrast, IL-10-deficient (IL-10(-/-) ) BMCs failed to reproduce these effects in fibrotic livers. Intriguingly, in isolated cells, CD11b(+) Gr1(high) F4/80(-) and CD11b(+) Gr1(+) F4/80(+) BMCs expressed more IL-10 after coculturing with activated HSCs, leading to suppressed expression of collagen and α-smooth muscle actin in HSCs. Moreover, these effects were either enhanced or abrogated, respectively, when BMCs were cocultured with IL-6(-/-) and retinaldehyde dehydrogenase 1(-/-) HSCs. Similar to murine data, human BMCs expressed more IL-10 after coculturing with human HSC lines (LX-2 or hTERT), and serum IL-10 levels were significantly elevated in patients with liver cirrhosis after autologous BMC infusion. CONCLUSION Activated HSCs increase IL-10 expression in BMCs (CD11b(+) Gr1(high) F4/80(-) and CD11b(+) Gr1(+) F4/80(+) cells), which in turn ameliorates liver fibrosis. Our findings could enhance the design of BMC therapy for liver fibrosis.
Collapse
Affiliation(s)
- Yang-Gun Suh
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea
| | - Ja Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Jin-Seok Byun
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea
| | - Hyon-Seung Yi
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea
| | - Young-Sun Lee
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea
| | - Hyuk Soo Eun
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea
| | - So Yeon Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Kwan Sik Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Gregg Duester
- Sanford-Burnham Medical Research Institute, La Jolla, CA, USA
| | - Scott L. Friedman
- Division of Liver Diseases, Mount Sinai School of Medicine, New York, New York, USA
| | - Won-Il Jeong
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea
| |
Collapse
|
45
|
Fang TC, Pang CY, Chiu SC, Ding DC, Tsai RK. Renoprotective effect of human umbilical cord-derived mesenchymal stem cells in immunodeficient mice suffering from acute kidney injury. PLoS One 2012; 7:e46504. [PMID: 23029541 PMCID: PMC3459926 DOI: 10.1371/journal.pone.0046504] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2012] [Accepted: 09/03/2012] [Indexed: 11/19/2022] Open
Abstract
It is unknown whether human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) can improve the renal function of patients suffering from acute kidney injury. Moreover, before beginning clinical trials, it is necessary to investigate this renoprotective effect of hUC-MSCs in a xenogeneic model of acute kidney injury. However, no previous studies have examined the application of hUC-MSCs to immunodeficient mice suffering from acute kidney injury. The objectives of this study were to examine whether hUC-MSCs could improve renal function in nonobese diabetic-severe combined immune deficiency (NOD-SCID) mice suffering from acute kidney injury, and to investigate the mechanism(s) for hUC-MSCs to improve renal function in this xenogeneic model. Early (3 hr) and late (12 hr) administrations of hUC-MSCs (106 cells) were performed via the external jugular vein into NOD-SCID mice suffering from either folic acid (FA) (250 mg/kg body weight) or vehicle. The results showed that early administration of hUC-MSCs improved the renal function of NOD-SCID mice suffering from FA-induced acute kidney injury, as evidenced by decreased serum urea nitrogen and serum creatinine levels, as well as a reduced tubular injury score. The beneficial effects of hUC-MSCs were through reducing apoptosis and promoting proliferation of renal tubular cells. These benefits were independent of inflammatory cytokine effects and transdifferentiation. Furthermore, this study is the first one to show that the reduced apoptosis of renal tubular cells by hUC-MSCs in this xenogeneic model is mediated through the mitochondrial pathway, and through the increase of Akt phosphorylation.
Collapse
Affiliation(s)
- Te-Chao Fang
- Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan.
| | | | | | | | | |
Collapse
|
46
|
Zhou WL, Medine CN, Zhu L, Hay DC. Stem cell differentiation and human liver disease. World J Gastroenterol 2012; 18:2018-25. [PMID: 22563188 PMCID: PMC3342599 DOI: 10.3748/wjg.v18.i17.2018] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2011] [Revised: 02/08/2012] [Accepted: 02/26/2012] [Indexed: 02/06/2023] Open
Abstract
Human stem cells are scalable cell populations capable of cellular differentiation. This makes them a very attractive in vitro cellular resource and in theory provides unlimited amounts of primary cells. Such an approach has the potential to improve our understanding of human biology and treating disease. In the future it may be possible to deploy novel stem cell-based approaches to treat human liver diseases. In recent years, efficient hepatic differentiation from human stem cells has been achieved by several research groups including our own. In this review we provide an overview of the field and discuss the future potential and limitations of stem cell technology.
Collapse
|
47
|
Abstract
PURPOSE OF REVIEW To provide an overview of the current status of liver regeneration therapies for liver cirrhosis and future prospects. RECENT FINDINGS Various clinical studies for liver disease have been reported, including hepatic administration of autologous CD34-positive cells induced by granulocyte colony-stimulating factor, portal vein administration of CD133-positive mononuclear cells, and administration of autologous bone marrow-derived mesenchymal stem cells. Effectiveness of these approaches has been shown in some patients. We have also reported improved liver fibrosis and function with infusion of autologous bone marrow cells in a basic study with mice, and on the basis of those results started autologous bone marrow cell infusion (ABMi) therapy for liver cirrhosis. The efficacy and safety of ABMi therapy has also been reported by other institutions. SUMMARY Results of recent clinical studies strongly suggest that liver function-improving effects can be achieved using infusion of bone marrow (stem) cells for cirrhosis. New treatment methods using less-invasive bone marrow-derived cultured cells need to be developed.
Collapse
|
48
|
Terai S, Tanimoto H, Maeda M, Zaitsu J, Hisanaga T, Iwamoto T, Fujisawa K, Mizunaga Y, Matsumoto T, Urata Y, Marumoto Y, Hidaka I, Ishikawa T, Yokoyama Y, Aoyama K, Tsuchiya M, Takami T, Omori K, Yamamoto N, Segawa M, Uchida K, Yamasaki T, Okita K, Sakaida I. Timeline for development of autologous bone marrow infusion (ABMi) therapy and perspective for future stem cell therapy. J Gastroenterol 2012; 47:491-7. [PMID: 22488349 DOI: 10.1007/s00535-012-0580-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2012] [Accepted: 03/06/2012] [Indexed: 02/04/2023]
Abstract
Liver cirrhosis patients generally progress to liver failure. To cure this progressive disease, we developed a novel cell therapy using bone marrow cells; autologous bone marrow cell infusion (ABMi) therapy. We previously described the possible action mechanism of ABMi therapy in the cirrhotic liver, and showed the timeline and results of clinical studies of ABMi therapy. We have also carried out other clinical studies using bone marrow cells and granulocyte colony-stimulating factor. Here, we report a new randomized clinical trial to evaluate the effects of ABMi therapy. However, ABMi therapy may not be possible in patients who are unable to undergo general anesthesia; therefore, we have started to develop a next-generation stem cell therapy using cultured mesenchymal stem cells.
Collapse
Affiliation(s)
- Shuji Terai
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Minami-Kogushi 1-1-1, Ube, Yamaguchi, 755-8505, Japan.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
49
|
Mizunaga Y, Terai S, Yamamoto N, Uchida K, Yamasaki T, Nishina H, Fujita Y, Shinoda K, Hamamoto Y, Sakaida I. Granulocyte colony-stimulating factor and interleukin-1β are important cytokines in repair of the cirrhotic liver after bone marrow cell infusion: comparison of humans and model mice. Cell Transplant 2012; 21:2363-75. [PMID: 22507241 DOI: 10.3727/096368912x638856] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
We previously described the effectiveness of autologous bone marrow cell infusion (ABMi) therapy for patients with liver cirrhosis (LC). We analyzed chronological changes in 19 serum cytokines as well as levels of specific cytokines in patients after ABMi therapy and in a mouse model of cirrhosis generated using green fluorescent protein (GFP)/carbon tetrachloride (CCl4). We measured expression profiles of cytokines in serum samples collected from 13 patients before and at 1 day and 1 week after ABMi. Child-Pugh scores significantly improved in all of these patients. To analyze the meaning of early cytokine change, we infused GFP-positive bone marrow cells (BMCs) into mice with CCl4-induced LC and obtained serum and tissue samples at 1 day and as well as at 1, 2, 3, and 4 weeks later. We compared chronological changes in serum cytokine expression in humans and in the model mice at 1 day and 1 week after BMC infusion. Among 19 cytokine, both granulocyte colony-stimulating factor (G-CSF) and interleukin-1β(IL-1β) in serum was found to show the same chronological change pattern between human and mice model. Next, we examined changes in cytokine expression in cirrhosis liver before and at 1, 2, 3, and 4 weeks after BMC infusion. Both G-CSF and IL-1β were undetectable in the liver tissues before and at 1 week after BMC infusion but increased at 2 weeks and continued until 4 weeks after infusion. The infused BMCs induced an early decrease of both G-CSF and IL-1β in serum and an increase in the model mice with LC. These dynamic cytokine changes might be important to repair liver cirrhosis after BMC infusion.
Collapse
Affiliation(s)
- Yuko Mizunaga
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | | | | | | | | | | | | | | | | | | |
Collapse
|
50
|
Maeda M, Takami T, Terai S, Sakaida I. Autologous bone marrow cell infusions suppress tumor initiation in hepatocarcinogenic mice with liver cirrhosis. J Gastroenterol Hepatol 2012; 27 Suppl 2:104-11. [PMID: 22320927 DOI: 10.1111/j.1440-1746.2011.07016.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
We have previously reported the efficacy and safety of autologous bone marrow cell infusion (ABMi) therapy for liver cirrhosis patients without hepatocellular carcinoma in a multicenter clinical trial. However, since liver cirrhosis is highly oncogenic, evaluation of the effects of ABMi on the mechanisms of hepatocarcinogenesis is of great importance. Therefore, frequent ABMi was performed in hepatocarcinogenic mice, and its effects on hepatocarcinogenesis were analyzed. The N-nitrosodiethylamine (DEN)/green fluorescent protein (GFP)-carbon tetrachloride (CCl(4) ) model was developed by administering DEN once, followed by repeated administration of CCl(4) intraperitoneally as for the control group. In the administration (ABMi) group, GFP-positive bone marrow cells were infused through a tail vein. The kinetics of hepatocarcinogenesis were evaluated histologically 4.5 months after DEN treatment. At 4.5 months, there was significantly lower incidence of foci and tumors in the ABMi group, and they were smaller in number, while their size was almost equal. No GFP-positive tumors were found in ABMi livers. Moreover, ABMi livers showed significantly reduced liver fibrosis, consistent with significantly lower 8-hydroxy-2'-deoxyguanosine levels, higher superoxide dismutase activity, and increased nuclear translocation of nuclear factor-erythroid 2 p45-related factor 2. These results demonstrate that frequent ABMi might contribute to suppressed tumor initiation during stages of hepatocarcinogenesis, consistent with improvements in liver fibrosis and stabilization of redox homeostasis.
Collapse
Affiliation(s)
- Masaki Maeda
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | | | | | | |
Collapse
|