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Zhou Y, Cheng JT, Feng ZX, Wang YY, Zhang Y, Cai WQ, Han ZW, Wang XW, Xiang Y, Yang HY, Liu BR, Peng XC, Cui SZ, Xin HW. Could gastrointestinal tumor-initiating cells originate from cell-cell fusion in vivo? World J Gastrointest Oncol 2021; 13:92-108. [PMID: 33643526 PMCID: PMC7896421 DOI: 10.4251/wjgo.v13.i2.92] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 12/25/2020] [Accepted: 01/28/2021] [Indexed: 02/06/2023] Open
Abstract
Tumor-initiating cells (TICs) or cancer stem cells are believed to be responsible for gastrointestinal tumor initiation, progression, metastasis, and drug resistance. It is hypothesized that gastrointestinal TICs (giTICs) might originate from cell-cell fusion. Here, we systemically evaluate the evidence that supports or opposes the hypothesis of giTIC generation from cell-cell fusion both in vitro and in vivo. We review giTICs that are capable of initiating tumors in vivo with 5000 or fewer in vivo fused cells. Under this restriction, there is currently little evidence demonstrating that giTICs originate from cell-cell fusion in vivo. However, there are many reports showing that tumor generation in vitro occurs with more than 5000 fused cells. In addition, the mechanisms of giTIC generation via cell-cell fusion are poorly understood, and thus, we propose its potential mechanisms of action. We suggest that future research should focus on giTIC origination from cell-cell fusion in vivo, isolation or enrichment of giTICs that have tumor-initiating capabilities with 5000 or less in vivo fused cells, and further clarification of the underlying mechanisms. Our review of the current advances in our understanding of giTIC origination from cell-cell fusion may have significant implications for the understanding of carcinogenesis and future cancer therapeutic strategies targeting giTICs.
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Affiliation(s)
- Yang Zhou
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Jun-Ting Cheng
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Zi-Xian Feng
- Department of Oncology and Haematology, Lianjiang People's Hospital, Guangzhou 524400, Guangdong Province, China
| | - Ying-Ying Wang
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Ying Zhang
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Wen-Qi Cai
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Zi-Wen Han
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Xian-Wang Wang
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Ying Xiang
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Hui-Yu Yang
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan Province, China
| | - Bing-Rong Liu
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan Province, China
| | - Xiao-Chun Peng
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
- Department of Pathophysiology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Shu-Zhong Cui
- State Key Laboratory of Respiratory Disease, Affiliated Cancer Hospital Institute of Guangzhou Medical University, Guangzhou 510095, Guangdong Province, China
| | - Hong-Wu Xin
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
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Ramadan R, Vermeulen L. Confusion on Cell Fusion. Cell Mol Gastroenterol Hepatol 2020; 11:304-306. [PMID: 33191154 PMCID: PMC7768611 DOI: 10.1016/j.jcmgh.2020.07.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 05/28/2020] [Accepted: 07/20/2020] [Indexed: 12/10/2022]
Affiliation(s)
| | - Louis Vermeulen
- Correspondence Address correspondence to: Louis Vermeulen, PhD, Amsterdam University Medical Centers, Laboratory for Experimental Oncology and Radiobiology, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
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Sutton TL, Walker BS, Wong MH. Rebuttal to: Confusion on Cell Fusion. Cell Mol Gastroenterol Hepatol 2020; 11:307-308. [PMID: 33068772 PMCID: PMC7768553 DOI: 10.1016/j.jcmgh.2020.09.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Revised: 09/10/2020] [Accepted: 09/14/2020] [Indexed: 12/10/2022]
Affiliation(s)
| | | | - Melissa H Wong
- Department of Cell, Developmental and Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.
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Tin(IV) compounds of tridentate thiosemicarbazone Schiff bases: Synthesis, characterization, in-silico analysis and in vitro cytotoxicity. Polyhedron 2020. [DOI: 10.1016/j.poly.2020.114729] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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5
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Liau LL, Al-Masawa ME, Koh B, Looi QH, Foo JB, Lee SH, Cheah FC, Law JX. The Potential of Mesenchymal Stromal Cell as Therapy in Neonatal Diseases. Front Pediatr 2020; 8:591693. [PMID: 33251167 PMCID: PMC7672022 DOI: 10.3389/fped.2020.591693] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 10/05/2020] [Indexed: 12/18/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) can be derived from various tissue sources, such as the bone marrow (BMSCs), adipose tissue (ADSCs), umbilical cord (UC-MSCs) and umbilical cord blood (UCB-MSCs). Clinical trials have been conducted to investigate the potential of MSCs in ameliorating neonatal diseases, including bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH) and necrotizing enterocolitis (NEC). In preclinical studies, MSC therapy has been tested for the treatment of various neonatal diseases affecting the heart, eye, gut, and brain as well as sepsis. Up to date, the number of clinical trials using MSCs to treat neonatal diseases is still limited. The data reported thus far positioned MSC therapy as safe with positive outcomes. However, most of these trials are still preliminary and generally smaller in scale. Larger trials with more appropriate controls and a longer follow-up period need to be conducted to prove the safety and efficacy of the therapy more conclusively. This review discusses the current application of MSCs in treating neonatal diseases, its mechanism of action and future direction of this novel therapy, including the potential of using MSC-derived extracellular vesicles instead of the cells to treat various clinical conditions in the newborn.
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Affiliation(s)
- Ling Ling Liau
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Maimonah Eissa Al-Masawa
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Benson Koh
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Qi Hao Looi
- Future Cytohealth Sdn Bhd, Bandar Seri Petaling, Kuala Lumpur, Malaysia
| | - Jhi Biau Foo
- School of Pharmacy, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Malaysia
| | - Sau Har Lee
- School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Malaysia
| | - Fook Choe Cheah
- Department of Paediatrics, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Jia Xian Law
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
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Sung J, Sodhi CP, Voltaggio L, Hou X, Jia H, Zhou Q, Čiháková D, Hackam DJ. The recruitment of extra-intestinal cells to the injured mucosa promotes healing in radiation enteritis and chemical colitis in a mouse parabiosis model. Mucosal Immunol 2019; 12:503-517. [PMID: 30617302 PMCID: PMC6445662 DOI: 10.1038/s41385-018-0123-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Revised: 11/05/2018] [Accepted: 11/20/2018] [Indexed: 02/04/2023]
Abstract
Mucosal healing occurs through migration and proliferation of cells within injured epithelium, yet these processes may be inadequate for mucosal healing after significant injury where the mucosa is denuded. We hypothesize that extra-intestinal cells can contribute to mucosal healing after injury to the small and large intestine. We generated parabiotic pairs between wild-type and tdTomato mice, which were then subjected to radiation-induced enteritis and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. We now show that as compared with singleton mice, mice with a parabiotic partner were protected against intestinal damage as revealed by significantly reduced weight loss, reduced expression of pro-inflammatory cytokines, reduced enterocyte apoptosis, and improved crypt proliferation. Donor cells expressed CD45-, Sca-1+, c-kit+, and CXCR4+ and accumulated around the injured crypts but did not transdifferentiate into epithelia, suggesting that extra-intestinal cells play a paracrine role in the healing response, while parabiotic pairings with Rag1-/- mice showed improved healing, indicating that adaptive immune cells were dispensable for mucosal healing. Strikingly, ablation of the bone marrow of the donor parabionts removed the protective effects. These findings reveal that the recruitment of extra-intestinal, bone marrow-derived cells into the injured intestinal mucosa can promote mucosal healing, suggesting novel therapeutic approaches for severe intestinal disease.
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Affiliation(s)
- J Sung
- Institute of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - C P Sodhi
- Division of Pediatric Surgery, Johns Hopkins Children's Center and Department of Surgery, Baltimore, MD, USA
| | - L Voltaggio
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - X Hou
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | - H Jia
- Division of Pediatric Surgery, Johns Hopkins Children's Center and Department of Surgery, Baltimore, MD, USA
| | - Q Zhou
- Division of Pediatric Surgery, Johns Hopkins Children's Center and Department of Surgery, Baltimore, MD, USA
| | - D Čiháková
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - D J Hackam
- Institute of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
- Division of Pediatric Surgery, Johns Hopkins Children's Center and Department of Surgery, Baltimore, MD, USA.
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Hypoxia Enhances Fusion of Oral Squamous Carcinoma Cells and Epithelial Cells Partly via the Epithelial-Mesenchymal Transition of Epithelial Cells. BIOMED RESEARCH INTERNATIONAL 2018; 2018:5015203. [PMID: 29581976 PMCID: PMC5822897 DOI: 10.1155/2018/5015203] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Accepted: 01/03/2018] [Indexed: 01/06/2023]
Abstract
Increasing evidence and indications showed that cell fusion is crucial in tumor development and metastasis, and hypoxia, a closely linked factor to tumor microenvironment, which can lead to EMT, induces angiogenesis and metastasis in tumor growth. However, the relationship between hypoxia and fusion has not been reported yet. EMT will change some proteins in the epithelial cell surface and the changes of proteins in cell surface may increase cell fusion. This study found that hypoxia promotes the spontaneous cell fusion between Oral Squamous Carcinoma Cells (OSCCs) and Human Immortalized Oral Epithelial Cells (HIOECs). At the same time, Hypoxia can lead to EMT, and hypoxia-pretreated HIOECs increased fusion rate with OSCC, while the fusion rate was significantly reduced by DAPT, a kind of EMT blocker. Therefore, epithelial cells can increase spontaneously cell fusion with OSCC by EMT. Our study may provide a new insight to link among tumor microenvironment, cell fusion, and cancer.
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Drucker NA, McCulloh CJ, Li B, Pierro A, Besner GE, Markel TA. Stem cell therapy in necrotizing enterocolitis: Current state and future directions. Semin Pediatr Surg 2018; 27:57-64. [PMID: 29275819 PMCID: PMC5745058 DOI: 10.1053/j.sempedsurg.2017.11.011] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Stem cell therapy is a promising treatment modality for necrotizing enterocolitis. Among the many promising stem cells identified to date, it is likely that mesenchymal stem cells will be the most useful and practical cell-based therapies for this condition. Using acellular components such as exosomes or other paracrine mediators are promising as well. Multiple mechanisms are likely at play in the positive effects provided by these cells, and further research is underway to further elucidate these effects.
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Affiliation(s)
- Natalie A. Drucker
- Department of Surgery, Section of Pediatric Surgery, Riley Hospital for Children, Indianapolis, IN
| | - Christopher J. McCulloh
- Department of Pediatric Surgery, Center for Perinatal Research, Nationwide Children’s Hospital, Columbus, OH
| | - Bo Li
- Division of General and Thoracic Surgery, Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - Agostino Pierro
- Division of General and Thoracic Surgery, Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - Gail E. Besner
- Department of Pediatric Surgery, Center for Perinatal Research, Nationwide Children’s Hospital, Columbus, OH
| | - Troy A. Markel
- Department of Surgery, Section of Pediatric Surgery, Riley Hospital for Children, Indianapolis, IN
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9
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Yan TL, Wang M, Xu Z, Huang CM, Zhou XC, Jiang EH, Zhao XP, Song Y, Song K, Shao Z, Liu K, Shang ZJ. Up-regulation of syncytin-1 contributes to TNF-α-enhanced fusion between OSCC and HUVECs partly via Wnt/β-catenin-dependent pathway. Sci Rep 2017; 7:40983. [PMID: 28112190 PMCID: PMC5256027 DOI: 10.1038/srep40983] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Accepted: 12/13/2016] [Indexed: 12/19/2022] Open
Abstract
Accumulating evidence implies that cell fusion is one of the driving forces of cancer invasion and metastasis. However, considerably less is still known about the triggering factors and underlying mechanisms associated with cancer-host cell fusion, particularly in inflammatory tumor microenvironment. In this study, we confirmed that inflammatory factor TNF-α could enhance fusion between squamous cell carcinoma cells 9 (SCC-9) and human umbilical vein endothelial cells (HUVEC). Further study revealed that TNF-α could promote up-regulation of syncytin-1 in SCC-9 and its receptor neutral amino acid transporter type 2 (ASCT-2) in HUVEC. Syncytin-1 acted as an important downstream effector in TNF-α-enhanced cancer-endothelial cell fusion. TNF-α treatment also led to the activation of Wnt/β-catenin signal pathway in SCC-9. The activation of Wnt/β-catenin signal pathway was closely associated with the up-regulation of syncytin-1 in SCC-9 and increased fusion between SCC-9 and HUVEC while blocking of Wnt/β-catenin signal pathway resulted in the corresponding down-regulation of syncytin-1 accompanied by sharp decrease of cancer-endothelial cell fusion. Taking together, our results suggest that Wnt/β-catenin signal pathway activation-dependent up-regulation of syncytin-1 contributes to the pro-inflammatory factor TNF-α-enhanced fusion between oral squamous cell carcinoma cells and endothelial cells.
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Affiliation(s)
- Ting-Lin Yan
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) &Key Laboratory for Oral Biomedicine Ministry of Education, Wuhan University, Wuhan, China
| | - Meng Wang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) &Key Laboratory for Oral Biomedicine Ministry of Education, Wuhan University, Wuhan, China
| | - Zhi Xu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) &Key Laboratory for Oral Biomedicine Ministry of Education, Wuhan University, Wuhan, China
| | - Chun-Ming Huang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) &Key Laboratory for Oral Biomedicine Ministry of Education, Wuhan University, Wuhan, China
| | - Xiao-Cheng Zhou
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) &Key Laboratory for Oral Biomedicine Ministry of Education, Wuhan University, Wuhan, China
| | - Er-Hui Jiang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) &Key Laboratory for Oral Biomedicine Ministry of Education, Wuhan University, Wuhan, China
| | - Xiao-Ping Zhao
- Center of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yong Song
- Department of Stomatology, Liuzhou People's Hospital, Guangxi, China
| | - Kai Song
- Department of Oral and Maxillofacial Surgery, The Affliated Hospital of Qingdao University, Qingdao, China
| | - Zhe Shao
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) &Key Laboratory for Oral Biomedicine Ministry of Education, Wuhan University, Wuhan, China.,Department of Oromaxillofacial &Head NeckOncology, School &Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Ke Liu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) &Key Laboratory for Oral Biomedicine Ministry of Education, Wuhan University, Wuhan, China.,Department of Oromaxillofacial &Head NeckOncology, School &Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Zheng-Jun Shang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) &Key Laboratory for Oral Biomedicine Ministry of Education, Wuhan University, Wuhan, China.,Department of Oromaxillofacial &Head NeckOncology, School &Hospital of Stomatology, Wuhan University, Wuhan, China
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Doster DL, Jensen AR, Khaneki S, Markel TA. Mesenchymal stromal cell therapy for the treatment of intestinal ischemia: Defining the optimal cell isolate for maximum therapeutic benefit. Cytotherapy 2016; 18:1457-1470. [PMID: 27745788 DOI: 10.1016/j.jcyt.2016.08.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 07/16/2016] [Accepted: 08/02/2016] [Indexed: 02/06/2023]
Abstract
Intestinal ischemia is a devastating intraabdominal emergency that often necessitates surgical intervention. Mortality rates can be high, and patients who survive often have significant long-term morbidity. The implementation of traditional medical therapies to prevent or treat intestinal ischemia have been sparse over the last decade, and therefore, the use of novel therapies are becoming more prevalent. Cellular therapy using mesenchymal stromal cells is one such treatment modality that is attracting noteworthy attention in the scientific community. Several groups have seen benefit with cellular therapy, but the optimal cell line has not been identified. The purpose of this review is to: 1) Review the mechanism of intestinal ischemia and reperfusion injury, 2) Identify the mechanisms of how cellular therapy may be therapeutic for this disease, and 3) Compare various MSC tissue sources to maximize potential therapeutic efficacy in the treatment of intestinal I/R diseases.
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Affiliation(s)
- Dominique L Doster
- Department of Surgery, Indiana University Health, Indianapolis, IN, USA; The Indiana University School of Medicine, Indianapolis, IN, USA
| | - Amanda R Jensen
- Department of Surgery, Indiana University Health, Indianapolis, IN, USA; The Indiana University School of Medicine, Indianapolis, IN, USA
| | - Sina Khaneki
- Department of Surgery, Indiana University Health, Indianapolis, IN, USA; The Indiana University School of Medicine, Indianapolis, IN, USA
| | - Troy A Markel
- Department of Surgery, Indiana University Health, Indianapolis, IN, USA; The Indiana University School of Medicine, Indianapolis, IN, USA; Section of Pediatric Surgery, Indiana University Health, Indianapolis, IN, USA; Riley Hospital for Children, Indiana University Health, Indianapolis, IN, USA.
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11
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Xu W, Chen J, Liu X, Li H, Qi X, Guo X. Autologous bone marrow stromal cell transplantation as a treatment for acute radiation enteritis induced by a moderate dose of radiation in dogs. Transl Res 2016; 171:38-51. [PMID: 26763584 DOI: 10.1016/j.trsl.2015.12.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Revised: 11/23/2015] [Accepted: 12/16/2015] [Indexed: 02/07/2023]
Abstract
Radiation enteritis is one of the most common complications of cancer radiotherapy, and the development of new and effective measures for its prevention and treatment is of great importance. Adult bone marrow stromal stem cells (ABMSCs) are capable of self-renewal and exhibit low immunogenicity. In this study, we investigated ABMSC transplantation as a treatment for acute radiation enteritis. We developed a dog model of acute radiation enteritis using abdominal intensity-modulated radiation therapy in a single X-ray dose of 14 Gy. ABMSCs were cultured in vitro, identified via immunofluorescence and flow cytometry, and double labeled with CM-Dil and superparamagnetic iron oxide (SPIO) before transplantation, which took place 48 hours after abdominal irradiation in a single fraction. The dog model of acute radiation enteritis was transplanted with cultured ABMSCs labeled with CM-Dil and SPIO into the mesenteric artery through the femoral artery. Compared with untreated control groups, dogs treated with ABMSCs exhibited substantially longer survival time and improved relief of clinical symptoms. ABMSC transplantation induced the regeneration of the intestinal epithelium and the recovery of intestinal function. Furthermore, ABMSC transplantation resulted in elevated serum levels of the anti-inflammatory cytokine interleukin-11 (IL10) and intestinal radioprotective factors, such as keratinocyte growth factor, basic fibroblast growth factor-2, and platelet-derived growth factor-B while reducing the serum level of the inflammatory cytokine IL17. ABMSCs induced the regeneration of the intestinal epithelium and regulated the secretion of serum cytokines and the expression of radioprotective proteins and thus could be beneficial in the development of novel and effective mitigators of and protectors against acute radiation enteritis.
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Affiliation(s)
- Wenda Xu
- Department of Gastroenterology, The 251st Hospital of PLA, Zhangjiakou, China
| | - Jiang Chen
- Department of Gastroenterology, Shenyang General Hospital of PLA, Shenyang, China
| | - Xu Liu
- Department of Gastroenterology, Shenyang General Hospital of PLA, Shenyang, China
| | - Hongyu Li
- Department of Gastroenterology, Shenyang General Hospital of PLA, Shenyang, China
| | - Xingshun Qi
- Department of Gastroenterology, Shenyang General Hospital of PLA, Shenyang, China
| | - Xiaozhong Guo
- Department of Gastroenterology, Shenyang General Hospital of PLA, Shenyang, China.
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12
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Altarche-Xifro W, di Vicino U, Muñoz-Martin MI, Bortolozzi A, Bové J, Vila M, Cosma MP. Functional Rescue of Dopaminergic Neuron Loss in Parkinson's Disease Mice After Transplantation of Hematopoietic Stem and Progenitor Cells. EBioMedicine 2016; 8:83-95. [PMID: 27428421 PMCID: PMC4919540 DOI: 10.1016/j.ebiom.2016.04.016] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 04/14/2016] [Indexed: 01/24/2023] Open
Abstract
Parkinson's disease is a common neurodegenerative disorder, which is due to the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and for which no definitive cure is currently available. Cellular functions in mouse and human tissues can be restored after fusion of bone marrow (BM)-derived cells with a variety of somatic cells. Here, after transplantation of hematopoietic stem and progenitor cells (HSPCs) in the SNpc of two different mouse models of Parkinson's disease, we significantly ameliorated the dopaminergic neuron loss and function. We show fusion of transplanted HSPCs with neurons and with glial cells in the ventral midbrain of Parkinson's disease mice. Interestingly, the hybrids can undergo reprogramming in vivo and survived up to 4 weeks after transplantation, while acquiring features of mature astroglia. These newly generated astroglia produced Wnt1 and were essential for functional rescue of the dopaminergic neurons. Our data suggest that glial-derived hybrids produced upon fusion of transplanted HSPCs in the SNpc can rescue the Parkinson's disease phenotype via a niche-mediated effect, and can be exploited as an efficient cell-therapy approach.
Transplantation of HSPCs into the substantia nigra of PD mice ameliorates dopaminergic neuron loss and function. Hybrids generated after fusion of transplanted HSPCs undergo reprogramming in vivo and acquire features of mature astroglia. Newly generated astroglia produced Wnt1 and can functionally rescue the dopaminergic neuron loss. A definitive therapy for Parkinson's disease is not available. Here, we transplanted hematopoietic stem and progenitor cells into the substantia nigra of brains of two different mouse models of Parkinson's disease. These transplanted cells fused with neurons and glial cells of the recipient mice. Four weeks after transplantation, the hybrids acquired features of mature astroglia, secreted Wnt1, and functionally ameliorated dopaminergic neuron loss. Current cell therapy approaches are being pursued in the striatum with the aim to increase dopamine levels. Here we show that the loss of dopaminergic neurons can be protected against by direct actions in the substantia nigra.
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Affiliation(s)
- Wassim Altarche-Xifro
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain; Universitat Pompeu Fabra (UPF), Dr Aiguader 88, 08003 Barcelona, Spain
| | - Umberto di Vicino
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain; Universitat Pompeu Fabra (UPF), Dr Aiguader 88, 08003 Barcelona, Spain
| | - Maria Isabel Muñoz-Martin
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain; Universitat Pompeu Fabra (UPF), Dr Aiguader 88, 08003 Barcelona, Spain
| | - Analía Bortolozzi
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain; Department of Neurochemistry and Neuropharmacology, IIBB-CSIC (Consejo Superior de Investigaciones Científicas), Barcelona, Spain
| | - Jordi Bové
- Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute and Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain
| | - Miquel Vila
- Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute and Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain; Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona (UAB), Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain
| | - Maria Pia Cosma
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain; Universitat Pompeu Fabra (UPF), Dr Aiguader 88, 08003 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain.
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Barone M, Scavo MP, Licinio R, Piombino M, De Tullio N, Mallamaci R, Di Leo A. Role of Bone Marrow-Derived Stem Cells in Polyps Development in Mice with Apc(Min/+) Mutation. Stem Cells Int 2015; 2015:354193. [PMID: 26167184 PMCID: PMC4488009 DOI: 10.1155/2015/354193] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2015] [Accepted: 05/30/2015] [Indexed: 02/07/2023] Open
Abstract
We explored the hypothesis that an altered microenvironment (intestinal adenomatous polyp) could modify the differentiation program of bone marrow-derived stem cells (BMSCs), involving them in colon carcinogenesis. Sublethally irradiated 8-week-old female Apc(Min/+) mice were transplanted with bone marrow (BM) cells obtained from either male age-matched Apc(Min/+) (Apc-Tx-Apc) or wild type (WT) (WT-Tx-Apc) mice. At 4 and 7 weeks after transplantation, BM-derived colonocytes were recognized by colocalization of Y-chromosome and Cdx2 protein (specific colonocyte marker). Polyp number, volume, and grade of dysplasia were not influenced by irradiation/transplantation procedures since they were similar in both untreated female Apc(Min/+) and Apc-Tx-Apc mice. At 4 and 7 weeks after transplantation, a progressive significant reduction of polyp number and volume was observed in WT-Tx-Apc mice. Moreover, the number of WT-Tx-Apc mice with a high-grade dysplastic polyps significantly decreased as compared to Apc-Tx-Apc mice. Finally, at 4 and 7 weeks after transplantation, WT-Tx-Apc mice showed a progressive significant increase of Y+/Cdx2+ cells in "normal" mucosa, whereas, in the adenomatous tissue, Y+/Cdx2+ cells remained substantially unvaried. Our findings demonstrate that WT BMSCs do not participate in polyp development but rather inhibit their growth. The substitution of genotypically altered colonocytes with Y+/Cdx2+ cells probably contributes to this process.
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Affiliation(s)
- Michele Barone
- 1Gastroenterology Unit, Department of Emergency and Organ Transplantation, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy
| | - Maria Principia Scavo
- 1Gastroenterology Unit, Department of Emergency and Organ Transplantation, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy
- 2Methodist Research Institute, 6670 Bertner Avenue, Houston, TX 77030, USA
| | - Raffaele Licinio
- 1Gastroenterology Unit, Department of Emergency and Organ Transplantation, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy
| | - Michele Piombino
- 3Radiotherapy Unit, Diagnostic Imaging Department, Polyclinic Hospital, Piazza G. Cesare 11, 70124 Bari, Italy
| | - Nicola De Tullio
- 1Gastroenterology Unit, Department of Emergency and Organ Transplantation, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy
| | - Rosanna Mallamaci
- 4Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari, Via E. Orabona 4, 70124 Bari, Italy
| | - Alfredo Di Leo
- 1Gastroenterology Unit, Department of Emergency and Organ Transplantation, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy
- *Alfredo Di Leo:
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14
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Vermeulen L, Morrissey E, van der Heijden M, Nicholson AM, Sottoriva A, Buczacki S, Kemp R, Tavaré S, Winton DJ. Defining stem cell dynamics in models of intestinal tumor initiation. Science 2013; 342:995-8. [PMID: 24264992 DOI: 10.1126/science.1243148] [Citation(s) in RCA: 310] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Cancer is a disease in which cells accumulate genetic aberrations that are believed to confer a clonal advantage over cells in the surrounding tissue. However, the quantitative benefit of frequently occurring mutations during tumor development remains unknown. We quantified the competitive advantage of Apc loss, Kras activation, and P53 mutations in the mouse intestine. Our findings indicate that the fate conferred by these mutations is not deterministic, and many mutated stem cells are replaced by wild-type stem cells after biased, but still stochastic events. Furthermore, P53 mutations display a condition-dependent advantage, and especially in colitis-affected intestines, clones harboring mutations in this gene are favored. Our work confirms the previously theoretical notion that the tissue architecture of the intestine suppresses the accumulation of mutated lineages.
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Affiliation(s)
- Louis Vermeulen
- Cancer Research UK, Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK
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15
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Puglisi MA, Tesori V, Lattanzi W, Gasbarrini GB, Gasbarrini A. Colon cancer stem cells: Controversies and perspectives. World J Gastroenterol 2013; 19:2997-3006. [PMID: 23716979 PMCID: PMC3662939 DOI: 10.3748/wjg.v19.i20.2997] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2013] [Revised: 03/25/2013] [Accepted: 04/04/2013] [Indexed: 02/06/2023] Open
Abstract
Tumors have long been viewed as a population in which all cells have the equal propensity to form new tumors, the so called conventional stochastic model. The cutting-edge theory on tumor origin and progression, tends to consider cancer as a stem cell disease. Stem cells are actively involved in the onset and maintenance of colon cancer. This review is intended to examine the state of the art on colon cancer stem cells (CSCs), with regard to the recent achievements of basic research and to the corresponding translational consequences. Specific prominence is given to the hypothesized origin of CSCs and to the methods for their identification. The growing understanding of CSC biology is driving the optimization of novel anti-cancer targeted drugs.
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Grudzinska MK, Kurzejamska E, Hagemann N, Bojakowski K, Soin J, Lehmann MH, Reinecke H, Murry CE, Soderberg-Naucler C, Religa P. Monocyte chemoattractant protein 1-mediated migration of mesenchymal stem cells is a source of intimal hyperplasia. Arterioscler Thromb Vasc Biol 2013; 33:1271-9. [PMID: 23599443 DOI: 10.1161/atvbaha.112.300773] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
OBJECTIVE Intimal hyperplasia is considered to be a healing response and is a major cause of vessel narrowing after injury, where migration of vascular progenitor cells contributes to pathological events, including transplant arteriosclerosis. APPROACH AND RESULTS In this study, we used a rat aortic-allograft model to identify the predominant cell types associated with transplant arteriosclerosis and to identify factors important in their recruitment into the graft. Transplantation of labeled adventitial tissues allowed us to identify the adventitia as a major source of cells migrating to the intima. RNA microarrays revealed a potential role for monocyte chemoattractant protein 1 (MCP-1), stromal cell-derived factor 1, regulated on activation, normal T cell expressed and secreted, and interferon-inducible protein 10 in the induced vasculopathy. MCP-1 induced migration of adventitial fibroblast cells. CCR2, the receptor for MCP-1, was coexpressed with CD90, CD44, NG2, or sca-1 on mesenchymal stem cells. In vivo experiments using MCP-1-deficient and CCR2-deficient mice confirmed an important role of MCP-1 in the formation of intimal hyperplasia in a mouse model of vascular injury. CONCLUSIONS The adventitia is a potentially important cellular source that contributes to intimal hyperplasia, and MCP-1 is a potent chemokine for the recruitment of adventitial vascular progenitor cells to intimal lesions.
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Affiliation(s)
- Monika K Grudzinska
- Experimental Cardiovascular Research Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
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