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1
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Podsednik A, Xu HN, Li LZ. Passage dependence of NADH redox status and reactive oxygen species level in vitro in triple-negative breast cancer cell lines with different invasiveness. TRANSLATIONAL BREAST CANCER RESEARCH : A JOURNAL FOCUSING ON TRANSLATIONAL RESEARCH IN BREAST CANCER 2024; 5:27. [PMID: 39534579 PMCID: PMC11557164 DOI: 10.21037/tbcr-24-36] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024]
Abstract
Background The redox status of nicotinamide adenine dinucleotide (NAD; including oxidized form NAD+ and reduced form NADH) plays key roles in both health and disease and has been actively studied to develop cancer biomarkers and therapeutic strategies. With the optical redox imaging (ORI) technique, we have been investigating the relationship of NADH redox status, reactive oxygen species (ROS), and invasiveness in breast cancer cell cultures, and have associated higher invasiveness with more oxidized NADH redox state. However, the cell cultures may have phenotypic drift and metabolic change with increased passage numbers. Methods We investigated the passage-dependence of NADH redox status and ROS levels in two triple-negative breast cancer (TNBC) cell cultures: the more invasive/metastatic MDA-MB-231 and the less invasive/metastatic HCC1806 cell lines. We measured the NADH redox status, redox plasticity, and cytoplasmic and mitochondrial ROS levels under the basal condition and metabolic perturbations of the mitochondrial electron transport chain. We evaluated the dependence of redox and ROS profiles on the cell passage number by comparing the early (<20 passages) with the late (>60 passages) passage cells. Results (I) NADH redox and ROS baselines are stable and independent of cell passage number, but can vary with passage number under metabolic perturbations depending on specific perturbation and cell line; (II) NADH redox status and intracellular ROS levels can change discordantly in cancer cells; (III) under both basal and metabolically perturbed conditions, the more invasive cell line has a more oxidized NADH redox status with a higher basal cytoplasmic ROS level than the less invasive line, regardless of passage number. Conclusions The general correlation between redox, ROS, and invasiveness in studied TNBC cells is not very sensitive to passage number. These results indicate that NADH redox and basal ROS status in TNBC likely reflect the intrinsic progressive nature of TNBC cells.
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Affiliation(s)
- Allison Podsednik
- Britton Chance Laboratory of Redox Imaging, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - He N Xu
- Britton Chance Laboratory of Redox Imaging, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Lin Z Li
- Britton Chance Laboratory of Redox Imaging, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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2
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Cheng Y, Lian S, Li S, Lu Y, Wang J, Deng X, Zhai S, Jia L. Combination of Se-methylselenocysteine, D-α-tocopheryl succinate, β-carotene, and l-lysine can prevent cancer metastases using as an adjuvant therapy. J Zhejiang Univ Sci B 2022; 23:943-956. [DOI: 10.1631/jzus.b2200232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Han KH, Kim MH, Jeong GJ, Kim AK, Chang JW, Kim DI. FGF-17 from Hypoxic Human Wharton's Jelly-Derived Mesenchymal Stem Cells Is Responsible for Maintenance of Cell Proliferation at Late Passages. Int J Stem Cells 2019; 12:279-290. [PMID: 31022995 PMCID: PMC6657939 DOI: 10.15283/ijsc18042] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2018] [Revised: 02/27/2019] [Accepted: 03/04/2019] [Indexed: 11/09/2022] Open
Abstract
Background and Objectives Although it is well known that hypoxic culture conditions enhance proliferation of human mesenchymal stem cells, the exact mechanism is not fully understood. In this study, we investigated the effect of fibroblast growth factor (FGF)-17 from hypoxic human Wharton's Jelly-derived mesenchymal stem cells (hWJ-MSCs) on cell proliferation at late passages. Methods and Results hWJ-MSCs were cultured in α-MEM medium supplemented with 10% fetal bovine serum (FBS) in normoxic (21% O2) and hypoxic (1% O2) conditions. Protein antibody array was performed to analyze secretory proteins in conditioned medium from normoxic and hypoxic hWJ-MSCs at passage 10. Cell proliferation of hypoxic hWJ-MSCs was increased compared with normoxic hWJ-MSCs from passage 7 to 10, and expression of secretory FGF-17 was highly increased in conditioned medium from hypoxic hWJ-MSCs at passage 10. Knockdown of FGF-17 in hypoxic and normoxic hWJ-MSCs decreased cell proliferation, whereas treatment of hypoxic and normoxic hWJ-MSCs with recombinant protein FGF-17 increased their proliferation. Signal transduction of FGF-17 in hypoxic and normoxic hWJ-MSCs involved the ERK1/2 pathway. Cell phenotypes were not changed under either condition. Differentiation-related genes adiponectin, Runx2, and chondroadherin were downregulated in normoxic hWJ-MSCs treated with rFGF-17, and upregulated by siFGF-17. Expression of alkaline phosphatase (ALP), Runx2, and chondroadherin was upregulated in hypoxic hWJ-MSCs, and this effect was rescued by transfection with siFGF-17. Only chondroadherin was upregulated in hypoxic hWJ-MSCs with rFGF-17. Conclusions In hypoxic culture conditions, FGF-17 from hypoxic hWJ-MSCs contributes to the maintenance of high proliferation at late passages through the ERK1/2 pathway.
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Affiliation(s)
- Kyu-Hyun Han
- Division of Vascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Min-Hee Kim
- Division of Vascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Gun-Jae Jeong
- Division of Vascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ae-Kyeong Kim
- Division of Vascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jong Wook Chang
- Stem Cell & Regenerative Medicine Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea
| | - Dong-Ik Kim
- Division of Vascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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4
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Yokoyama T, Yagi Mendoza H, Tanaka T, Ii H, Takano R, Yaegaki K, Ishikawa H. Regulation of CCl 4-induced liver cirrhosis by hepatically differentiated human dental pulp stem cells. Hum Cell 2019; 32:125-140. [PMID: 30637566 DOI: 10.1007/s13577-018-00234-0] [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: 11/01/2018] [Accepted: 12/09/2018] [Indexed: 02/07/2023]
Abstract
Liver transplantation is the most effective treatment for treating liver cirrhosis. However, a limited number of donors, graft rejection, and other complications can undermine transplant success. It is considered that cell transplantation is an alternative approach of liver transplantation. We previously developed a protocol for hepatic differentiation of cluster of differentiation 117+ stem cells isolated from human exfoliated deciduous tooth pulp (SHEDs) under hydrogen sulfide exposure. These cells showed excellent hepatic function. Here, we investigated whether hepatocyte-like cell transplantation is effective for treating carbon tetrachloride (CCl4)-induced liver cirrhosis. SHEDs were hepatically differentiated, which was confirmed via immunological analyses and albumin concentration determination in the medium. Rats were intraperitoneally injected with CCl4 for and the differentiated cells were injected into rat spleen. Histopathological and immunohistochemical analyses were performed. Liver functions were serologically and pathologically determined. Quantitative real-time-polymerase chain reaction was implemented to clarify the treatment procedure of liver cirrhosis. In vitro-differentiated hepatocyte-like cells were positive for all examined hepatic markers. SHED-derived hepatocyte transplantation eliminated liver fibrosis and restored liver structure in rats. Liver immunohistochemical analyses showed the presence of human-specific hepatic markers, i.e., a large amount of human hepatic cells were very active in the liver and spleen. Serological tests revealed significant liver function recovery in the transplantation group. Expression of genes promoting fibrosis increased after cirrhosis induction but was suppressed after transplantation. Our results suggest that xenotransplantation of hepatocyte-like cells of human origin can treat cirrhosis. Moreover, cell-based therapy of chronic liver conditions may be an effective option.
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Affiliation(s)
- Tomomi Yokoyama
- Department of Oral Health, The Nippon Dental University School of Life Dentistry at Tokyo, 1-9-20 Fujimi, Chiyoda-ku, Tokyo, 102-8159, Japan
| | - Hiromi Yagi Mendoza
- Department of Oral Health, The Nippon Dental University School of Life Dentistry at Tokyo, 1-9-20 Fujimi, Chiyoda-ku, Tokyo, 102-8159, Japan
| | - Tomoko Tanaka
- Department of Oral Health, The Nippon Dental University School of Life Dentistry at Tokyo, 1-9-20 Fujimi, Chiyoda-ku, Tokyo, 102-8159, Japan
| | - Hisataka Ii
- Department of Oral Health, The Nippon Dental University School of Life Dentistry at Tokyo, 1-9-20 Fujimi, Chiyoda-ku, Tokyo, 102-8159, Japan
| | - Riya Takano
- Department of Oral Health, The Nippon Dental University School of Life Dentistry at Tokyo, 1-9-20 Fujimi, Chiyoda-ku, Tokyo, 102-8159, Japan
| | - Ken Yaegaki
- Department of Oral Health, The Nippon Dental University School of Life Dentistry at Tokyo, 1-9-20 Fujimi, Chiyoda-ku, Tokyo, 102-8159, Japan.
| | - Hiroshi Ishikawa
- Department of Oral Health, The Nippon Dental University School of Life Dentistry at Tokyo, 1-9-20 Fujimi, Chiyoda-ku, Tokyo, 102-8159, Japan.,Laboratory of Clinical Regenerative Medicine, Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, Laboratory of Advanced Research D # 326, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
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Kouroupis D, Sanjurjo-Rodriguez C, Jones E, Correa D. Mesenchymal Stem Cell Functionalization for Enhanced Therapeutic Applications. TISSUE ENGINEERING PART B-REVIEWS 2018; 25:55-77. [PMID: 30165783 DOI: 10.1089/ten.teb.2018.0118] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
IMPACT STATEMENT Culture expansion of MSCs has detrimental effects on various cell characteristics and attributes (e.g., phenotypic changes and senescence), which, in addition to inherent interdonor variability, negatively impact the standardization and reproducibility of their therapeutic potential. The identification of innate distinct functional MSC subpopulations, as well as the description of ex vivo protocols aimed at maintaining phenotypes and enhancing specific functions have the potential to overcome these limitations. The incorporation of those approaches into cell-based therapy would significantly impact the field, as more reproducible clinical outcomes may be achieved.
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Affiliation(s)
- Dimitrios Kouroupis
- 1 Department of Orthopedics, UHealth Sports Medicine Institute, University of Miami Miller School of Medicine, Miami, Florida.,2 Diabetes Research Institute & Cell Transplant Center, University of Miami Miller School of Medicine, Miami, Florida
| | - Clara Sanjurjo-Rodriguez
- 3 Leeds Institute of Rheumatic and Musculoskeletal Disease, Saint James University Hospital, University of Leeds, Leeds, United Kingdom.,4 Department of Biomedical Sciences, Medicine and Physiotherapy, University of A Coruña, CIBER-BBN-Institute of Biomedical Research of A Coruña (INIBIC), A Coruña, Spain
| | - Elena Jones
- 3 Leeds Institute of Rheumatic and Musculoskeletal Disease, Saint James University Hospital, University of Leeds, Leeds, United Kingdom
| | - Diego Correa
- 1 Department of Orthopedics, UHealth Sports Medicine Institute, University of Miami Miller School of Medicine, Miami, Florida.,2 Diabetes Research Institute & Cell Transplant Center, University of Miami Miller School of Medicine, Miami, Florida
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6
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Hu C, Zhao L, Peng C, Li L. Regulation of the mitochondrial reactive oxygen species: Strategies to control mesenchymal stem cell fates ex vivo and in vivo. J Cell Mol Med 2018; 22:5196-5207. [PMID: 30160351 PMCID: PMC6201215 DOI: 10.1111/jcmm.13835] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 07/11/2018] [Indexed: 12/18/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are broadly used in cell‐based regenerative medicine because of their self‐renewal and multilineage potencies in vitro and in vivo. To ensure sufficient amounts of MSCs for therapeutic purposes, cells are generally cultured in vitro for long‐term expansion or specific terminal differentiation until cell transplantation. Although physiologically up‐regulated reactive oxygen species (ROS) production is essential for maintenance of stem cell activities, abnormally high levels of ROS can harm MSCs both in vitro and in vivo. Overall, additional elucidation of the mechanisms by which physiological and pathological ROS are generated is necessary to better direct MSC fates and improve their therapeutic effects by controlling external ROS levels. In this review, we focus on the currently revealed ROS generation mechanisms and the regulatory routes for controlling their rates of proliferation, survival, senescence, apoptosis, and differentiation. A promising strategy in future regenerative medicine involves regulating ROS generation via various means to augment the therapeutic efficacy of MSCs, thus improving the prognosis of patients with terminal diseases.
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Affiliation(s)
- Chenxia Hu
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Lingfei Zhao
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, China
| | - Conggao Peng
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Lanjuan Li
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
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7
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Hypoxic culture enhances the expansion of rat bone marrow-derived mesenchymal stem cells via the regulatory pathways of cell division and apoptosis. In Vitro Cell Dev Biol Anim 2018; 54:666-676. [PMID: 30136033 DOI: 10.1007/s11626-018-0281-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 07/12/2018] [Indexed: 02/07/2023]
Abstract
This study aimed to examine the proliferative behavior and molecular mechanisms of rat bone marrow-derived MSCs (rBMSCs) cultured under three different oxygen concentrations. Passaged rBMSCs exhibited significantly greater proliferation rates at 1% O2 and 5% O2 than those at 18% O2 and the cells exposed to 1% O2 showed the highest proliferative potential, which was evidenced by the growth curves, colony-forming efficiencies, and CCK-8 absorbance values. The rBMSCs grown under hypoxic culture conditions (1% O2 and 5% O2) had the increased percentage of cells in S + G2/M-phase and the decreased apoptotic index, compared with normoxia (18% O2). It was revealed for the first time that there were more phosphohistone H3 (PHH3)-positive cells and higher expressions of proliferating cell nuclear antigen (PCNA) in the hypoxic cultures of rBMSCs than in the normoxic culture. Hypoxia upregulated the anti-apoptotic protein Bcl-2 and downregulated the pro-apoptotic proteins Bax and the cleaved caspase-3 in cultured rBMSCs. The levels of hypoxia-inducible factor-1α (HIF-1α) and phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) were increased in the hypoxic-cultured rBMSCs. Nevertheless, no significant difference was observed in p53 level of rBMSCs between different oxygen concentrations. In conclusion, the hypoxia exerts a promoting effect on the in vitro expansion of rBMSCs via several signaling and molecular pathways involved in the control of cell cycle and apoptosis.
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8
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Labusca L, Herea DD, Mashayekhi K. Stem cells as delivery vehicles for regenerative medicine-challenges and perspectives. World J Stem Cells 2018. [PMID: 29849930 DOI: : 10.4252/wjsc.v10.i5.43] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The use of stem cells as carriers for therapeutic agents is an appealing modality for targeting tissues or organs of interest. Combined delivery of cells together with various information molecules as therapeutic agents has the potential to enhance, modulate or even initiate local or systemic repair processes, increasing stem cell efficiency for regenerative medicine applications. Stem-cell-mediated delivery of genes, proteins or small molecules takes advantage of the innate capability of stem cells to migrate and home to injury sites. As the native migratory properties are affected by in vitro expansion, the existent methods for enhancing stem cell targeting capabilities (modified culture methods, genetic modification, cell surface engineering) are described. The role of various nanoparticles in equipping stem cells with therapeutic small molecules is revised together with their class-specific advantages and shortcomings. Modalities to circumvent common challenges when designing a stem-cell-mediated targeted delivery system are described as well as future prospects in using this approach for regenerative medicine applications.
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Affiliation(s)
- Luminita Labusca
- Orthopedics and Traumatology Clinic, Emergency County Hospital Saint Spiridon Iasi Romania, Iasi 700000, Romania
| | - Dumitru Daniel Herea
- Stem Cell Laboratory, National Institute of Research and Development for Technical Physics (NIRDTP), Iasi 700349, Romania
| | - Kaveh Mashayekhi
- Systems Bioinformatics and Modelling SBIM, Frankfurt 45367, Germany
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9
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Labusca L, Herea DD, Mashayekhi K. Stem cells as delivery vehicles for regenerative medicine-challenges and perspectives. World J Stem Cells 2018; 10:43-56. [PMID: 29849930 PMCID: PMC5973910 DOI: 10.4252/wjsc.v10.i5.43] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 04/26/2018] [Accepted: 05/09/2018] [Indexed: 02/06/2023] Open
Abstract
The use of stem cells as carriers for therapeutic agents is an appealing modality for targeting tissues or organs of interest. Combined delivery of cells together with various information molecules as therapeutic agents has the potential to enhance, modulate or even initiate local or systemic repair processes, increasing stem cell efficiency for regenerative medicine applications. Stem-cell-mediated delivery of genes, proteins or small molecules takes advantage of the innate capability of stem cells to migrate and home to injury sites. As the native migratory properties are affected by in vitro expansion, the existent methods for enhancing stem cell targeting capabilities (modified culture methods, genetic modification, cell surface engineering) are described. The role of various nanoparticles in equipping stem cells with therapeutic small molecules is revised together with their class-specific advantages and shortcomings. Modalities to circumvent common challenges when designing a stem-cell-mediated targeted delivery system are described as well as future prospects in using this approach for regenerative medicine applications.
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Affiliation(s)
- Luminita Labusca
- Orthopedics and Traumatology Clinic, Emergency County Hospital Saint Spiridon Iasi Romania, Iasi 700000, Romania
| | - Dumitru Daniel Herea
- Stem Cell Laboratory, National Institute of Research and Development for Technical Physics (NIRDTP), Iasi 700349, Romania
| | - Kaveh Mashayekhi
- Systems Bioinformatics and Modelling SBIM, Frankfurt 45367, Germany
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10
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Balikov DA, Crowder SW, Lee JB, Lee Y, Ko UH, Kang ML, Kim WS, Shin JH, Sung HJ. Aging Donor-Derived Human Mesenchymal Stem Cells Exhibit Reduced Reactive Oxygen Species Loads and Increased Differentiation Potential Following Serial Expansion on a PEG-PCL Copolymer Substrate. Int J Mol Sci 2018; 19:ijms19020359. [PMID: 29370101 PMCID: PMC5855581 DOI: 10.3390/ijms19020359] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 01/22/2018] [Accepted: 01/23/2018] [Indexed: 12/13/2022] Open
Abstract
Human mesenchymal stem cells (hMSCs) have been widely studied for therapeutic development in tissue engineering and regenerative medicine. They can be harvested from human donors via tissue biopsies, such as bone marrow aspiration, and cultured to reach clinically relevant cell numbers. However, an unmet issue lies in the fact that the hMSC donors for regenerative therapies are more likely to be of advanced age. Their stem cells are not as potent compared to those of young donors, and continue to lose healthy, stemness-related activities when the hMSCs are serially passaged in tissue culture plates. Here, we have developed a cheap, scalable, and effective copolymer film to culture hMSCs obtained from aged human donors over several passages without loss of reactive oxygen species (ROS) handling or differentiation capacity. Assays of cell morphology, reactive oxygen species load, and differentiation potential demonstrate the effectiveness of copolymer culture on reduction in senescence-related activities of aging donor-derived hMSCs that could hinder the therapeutic potential of autologous stem cell therapies.
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Affiliation(s)
- Daniel A Balikov
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA.
| | - Spencer W Crowder
- Department of Materials and Department of Bioengineering, Imperial College London, London SW7 2AZ, UK.
| | - Jung Bok Lee
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA.
- Severance Biomedical Science Institute, College of Medicine, Yonsei University, Seoul 03722, Korea.
| | - Yunki Lee
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA.
- Department of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.
| | - Ung Hyun Ko
- Department of Mechanical Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea.
| | - Mi-Lan Kang
- Severance Biomedical Science Institute, College of Medicine, Yonsei University, Seoul 03722, Korea.
| | - Won Shik Kim
- Department of Otorhinolaryngology, College of Medicine, Yonsei University, Seoul 03722, Korea.
| | - Jennifer H Shin
- Department of Mechanical Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea.
| | - Hak-Joon Sung
- Severance Biomedical Science Institute, College of Medicine, Yonsei University, Seoul 03722, Korea.
- Department of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.
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11
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Yu J, Shi J, Zhang Y, Zhang Y, Huang Y, Chen Z, Yang J. The replicative senescent mesenchymal stem / stromal cells defect in DNA damage response and anti-oxidative capacity. Int J Med Sci 2018; 15:771-781. [PMID: 30008586 PMCID: PMC6036081 DOI: 10.7150/ijms.24635] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Accepted: 04/27/2018] [Indexed: 01/11/2023] Open
Abstract
Replicative senescence and potential malignant transformation are great limitations in the clinical application of bone marrow-derived mesenchymal stem / stromal cells (MSCs). An abnormal DNA damage response may result in genomic instability, which is an integral component of aging and tumorigenesis. However, the effect of aging on the DNA damage response in MSCs is currently unknown. In the present study, we evaluated the DNA damage response induced by oxidative stress and DNA double-strand breaks in human bone marrow-derived MSCs. After long-term cell culture, replicative senescent MSCs (sMSCs) were characterized by a poor proliferation rate, high senescence-associated β-galactosidase activity, and enhanced expression of P53 and P16. Features of the DNA damage response in these sMSCs were then compared with those from early-passage MSCs. The sMSCs were more sensitive to hydrogen peroxide and bleomycin treatment with respect to cell viability and apoptosis induction. Combined with the comet assay, γH2AX foci characterization and reactive oxygen species detection were used to demonstrate that the antioxidant and DNA repair ability of sMSCs are attenuated. This result could be explained, at least in part, by the downregulation of anti-oxidation and DNA repair genes, including Cu/Zn-SOD, GPX, CAT, OGG1, XRCC1, Ku70, BRCA2 and XRCC4. In conclusion, MSCs aging is associated with a reduction in the DNA repair and anti-oxidative capacity.
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Affiliation(s)
- Jin Yu
- Department of Cell Biology, Army Medical University (The Third Military Medical University), Chongqing 400038, China
| | - Jiazhong Shi
- Department of Cell Biology, Army Medical University (The Third Military Medical University), Chongqing 400038, China
| | - Yue Zhang
- Department of Cell Biology, Army Medical University (The Third Military Medical University), Chongqing 400038, China.,Department of Pathology, The 451th hospital of PLA, Xi'an 710000, China
| | - Yi Zhang
- Department of Cell Biology, Army Medical University (The Third Military Medical University), Chongqing 400038, China
| | - Yaqin Huang
- Department of Cell Biology, Army Medical University (The Third Military Medical University), Chongqing 400038, China
| | - Zhiwen Chen
- Urology Institute of PLA, Southwest Hospital, Army Medical University (The Third Military Medical University), Chongqing 400038, China
| | - Jin Yang
- Department of Cell Biology, Army Medical University (The Third Military Medical University), Chongqing 400038, China
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13
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Barhanpurkar-Naik A, Mhaske ST, Pote ST, Singh K, Wani MR. Interleukin-3 enhances the migration of human mesenchymal stem cells by regulating expression of CXCR4. Stem Cell Res Ther 2017; 8:168. [PMID: 28705238 PMCID: PMC5512829 DOI: 10.1186/s13287-017-0618-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Revised: 06/06/2017] [Accepted: 06/23/2017] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) represent an important source for cell therapy in regenerative medicine. MSCs have shown promising results for repair of damaged tissues in various degenerative diseases in animal models and also in human clinical trials. However, little is known about the factors that could enhance the migration and tissue-specific engraftment of exogenously infused MSCs for successful regenerative cell therapy. Previously, we have reported that interleukin-3 (IL-3) prevents bone and cartilage damage in animal models of rheumatoid arthritis and osteoarthritis. Also, IL-3 promotes the differentiation of human MSCs into functional osteoblasts and increases their in-vivo bone regenerative potential in immunocompromised mice. However, the role of IL-3 in migration of MSCs is not yet known. In the present study, we investigated the role of IL-3 in migration of human MSCs under both in-vitro and in-vivo conditions. METHODS MSCs isolated from human bone marrow, adipose and gingival tissues were used for in-vitro cell migration, motility and wound healing assays in the presence or absence of IL-3. The effect of IL-3 preconditioning on expression of chemokine receptors and integrins was examined by flow cytometry and real-time PCR. The in-vivo migration of IL-3-preconditioned MSCs was investigated using a subcutaneous matrigel-releasing stromal cell-derived factor-1 alpha (SDF-1α) model in immunocompromised mice. RESULTS We observed that human MSCs isolated from all three sources express IL-3 receptor-α (IL-3Rα) both at gene and protein levels. IL-3 significantly enhances in-vitro migration, motility and wound healing abilities of MSCs. Moreover, IL-3 preconditioning upregulates expression of chemokine (C-X-C motif) receptor 4 (CXCR4) on MSCs, which leads to increased migration of cells towards SDF-1α. Furthermore, CXCR4 antagonist AMD3100 decreases the migration of IL-3-treated MSCs towards SDF-1α. Importantly, IL-3 also induces in-vivo migration of MSCs towards subcutaneously implanted matrigel-releasing-SDF-1α in immunocompromised mice. CONCLUSIONS The present study demonstrates for the first time that IL-3 has an important role in enhancing the migration of human MSCs through regulation of the CXCR4/SDF-1α axis. These findings suggest a potential role of IL-3 in improving the efficacy of MSCs in regenerative cell therapy.
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Affiliation(s)
| | - Suhas T. Mhaske
- National Centre for Cell Science, S. P. Pune University Campus, Pune, 411 007 India
| | - Satish T. Pote
- National Centre for Cell Science, S. P. Pune University Campus, Pune, 411 007 India
| | - Kanupriya Singh
- National Centre for Cell Science, S. P. Pune University Campus, Pune, 411 007 India
| | - Mohan R. Wani
- National Centre for Cell Science, S. P. Pune University Campus, Pune, 411 007 India
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14
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Ahn SH, Cho SH, Song JE, Kim S, Oh SS, Jung S, Cho KA, Lee TH. Caveolin-1 serves as a negative effector in senescent human gingival fibroblasts during Fusobacterium nucleatum infection. Mol Oral Microbiol 2016; 32:236-249. [PMID: 27315395 DOI: 10.1111/omi.12167] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/15/2016] [Indexed: 12/11/2022]
Abstract
It is well established that aging is associated with increased susceptibility to infectious diseases. Fusobacterium nucleatum is a well-known bacterial species that plays a central bridging role between early and late colonizers in the human oral cavity. Further, the ability of F. nucleatum to invade gingival fibroblasts (GFs) is critical to the development of periodontal diseases. However, the mechanisms underlying the age-related infection of GFs by F. nucleatum remain unknown. We used young (fourth passage) and senescent (22nd passage) GFs to investigate the mechanisms of F. nucleatum infection in aged GFs and first observed increased invasion of F. nucleatum in senescent GFs. We also found that the co-localization of caveolin-1 (Cav-1), a protein marker of aging, with F. nucleatum and the knockdown of Cav-1 in GFs reduced F. nucleatum invasion. Additionally, F. nucleatum infection triggered the production of reactive oxygen species (ROS) through activation of NADPH oxidase in GFs, but senescent GFs exhibited significantly lower levels of NADPH oxidase activity and ROS production compared with young GFs in both the uninfected and infected conditions. Also, senescent GFs exhibited a decline in proinflammatory cytokine production and extracellular signal regulated kinase (ERK) phosphorylation following F. nucleatum infection. Interestingly, the knockdown of Cav-1 in senescent GFs increased NADPH oxidase activity and caused the upregulation of interleukin-6 and interleukin-8 and the phosphorylation of ERK. Collectively, the increased expression of Cav-1 might play a critical role in F. nucleatum invasion and could hinder the host response in senescent GFs.
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Affiliation(s)
- S H Ahn
- Department of Oral Biochemistry, Dental Science Research Institute, Medical Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju, Korea
| | - S-H Cho
- Department of Molecular Medicine (BK21plus), Chonnam National University Graduate School, Gwangju, Korea
| | - J-E Song
- Department of Molecular Medicine (BK21plus), Chonnam National University Graduate School, Gwangju, Korea
| | - S Kim
- Department of Oral Biochemistry, Dental Science Research Institute, Medical Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju, Korea.,Department of Molecular Medicine (BK21plus), Chonnam National University Graduate School, Gwangju, Korea
| | - S S Oh
- Department of Oral Biochemistry, Dental Science Research Institute, Medical Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju, Korea
| | - S Jung
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Chonnam National University, Gwangju, Korea
| | - K A Cho
- Department of Biochemistry, Chonnam National University Medical School, Gwangju, Korea
| | - T-H Lee
- Department of Oral Biochemistry, Dental Science Research Institute, Medical Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju, Korea.,Department of Molecular Medicine (BK21plus), Chonnam National University Graduate School, Gwangju, Korea
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15
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Bianco J, De Berdt P, Deumens R, des Rieux A. Taking a bite out of spinal cord injury: do dental stem cells have the teeth for it? Cell Mol Life Sci 2016; 73:1413-37. [PMID: 26768693 PMCID: PMC11108394 DOI: 10.1007/s00018-015-2126-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Revised: 12/16/2015] [Accepted: 12/22/2015] [Indexed: 12/15/2022]
Abstract
Dental stem cells are an emerging star on a stage that is already quite populated. Recently, there has been a lot of hype concerning these cells in dental therapies, especially in regenerative endodontics. It is fitting that most research is concentrated on dental regeneration, although other uses for these cells need to be explored in more detail. Being a true mesenchymal stem cell, their capacities could also prove beneficial in areas outside their natural environment. One such field is the central nervous system, and in particular, repairing the injured spinal cord. One of the most formidable challenges in regenerative medicine is to restore function to the injured spinal cord, and as yet, a cure for paralysis remains to be discovered. A variety of approaches have already been tested, with graft-based strategies utilising cells harbouring appropriate properties for neural regeneration showing encouraging results. Here we present a review focusing on properties of dental stem cells that endorse their use in regenerative medicine, with particular emphasis on repairing the damaged spinal cord.
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Affiliation(s)
- John Bianco
- Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Université catholique de Louvain, Avenue Mounier, 73, B1 73.12, 1200, Brussels, Belgium.
- Integrated Center for Cell Therapy and Regenerative Medicine, International Clinical Research Center (FNUSA-ICRC), St. Anne's University Hospital Brno, Pekařská 53, 656 91, Brno, Czech Republic.
| | - Pauline De Berdt
- Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Université catholique de Louvain, Avenue Mounier, 73, B1 73.12, 1200, Brussels, Belgium
| | - Ronald Deumens
- Institute of Neuroscience, Université catholique de Louvain, Avenue Hippocrate B1.54.10, 1200, Brussels, Belgium
| | - Anne des Rieux
- Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Université catholique de Louvain, Avenue Mounier, 73, B1 73.12, 1200, Brussels, Belgium
- Institute of Condensed Matter and Nanosciences, Université catholique de Louvain, 1348, Louvain-La-Neuve, Belgium
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16
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Prasad S, Gupta SC, Tyagi AK. Reactive oxygen species (ROS) and cancer: Role of antioxidative nutraceuticals. Cancer Lett 2016; 387:95-105. [PMID: 27037062 DOI: 10.1016/j.canlet.2016.03.042] [Citation(s) in RCA: 627] [Impact Index Per Article: 69.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Revised: 03/22/2016] [Accepted: 03/23/2016] [Indexed: 12/21/2022]
Abstract
Extensive research over the past half a century indicates that reactive oxygen species (ROS) play an important role in cancer. Although low levels of ROS can be beneficial, excessive accumulation can promote cancer. One characteristic of cancer cells that distinguishes them from normal cells is their ability to produce increased numbers of ROS and their increased dependence on an antioxidant defense system. ROS are produced as a byproduct intracellularly by mitochondria and other cellular elements and exogenously by pollutants, tobacco, smoke, drugs, xenobiotics, and radiation. ROS modulate various cell signaling pathways, which are primarily mediated through the transcription factors NF-κB and STAT3, hypoxia-inducible factor-1α, kinases, growth factors, cytokines and other proteins, and enzymes; these pathways have been linked to cellular transformation, inflammation, tumor survival, proliferation, invasion, angiogenesis, and metastasis of cancer. ROS are also associated with epigenetic changes in genes, which is helpful in diagnosing diseases. This review considers the role of ROS in the various stages of cancer development. Finally, we provide evidence that nutraceuticals derived from Mother Nature are highly effective in eliminating cancer cells.
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Affiliation(s)
- Sahdeo Prasad
- Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
| | - Subash C Gupta
- Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Amit K Tyagi
- Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
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17
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De Becker A, Riet IV. Homing and migration of mesenchymal stromal cells: How to improve the efficacy of cell therapy? World J Stem Cells 2016; 8:73-87. [PMID: 27022438 PMCID: PMC4807311 DOI: 10.4252/wjsc.v8.i3.73] [Citation(s) in RCA: 351] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Revised: 12/24/2015] [Accepted: 01/29/2016] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) are currently being investigated for use in a wide variety of clinical applications. For most of these applications, systemic delivery of the cells is preferred. However, this requires the homing and migration of MSCs to a target tissue. Although MSC homing has been described, this process does not appear to be highly efficacious because only a few cells reach the target tissue and remain there after systemic administration. This has been ascribed to low expression levels of homing molecules, the loss of expression of such molecules during expansion, and the heterogeneity of MSCs in cultures and MSC culture protocols. To overcome these limitations, different methods to improve the homing capacity of MSCs have been examined. Here, we review the current understanding of MSC homing, with a particular focus on homing to bone marrow. In addition, we summarize the strategies that have been developed to improve this process. A better understanding of MSC biology, MSC migration and homing mechanisms will allow us to prepare MSCs with optimal homing capacities. The efficacy of therapeutic applications is dependent on efficient delivery of the cells and can, therefore, only benefit from better insights into the homing mechanisms.
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18
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p53-Dependent Senescence in Mesenchymal Stem Cells under Chronic Normoxia Is Potentiated by Low-Dose γ-Irradiation. Stem Cells Int 2015; 2016:6429853. [PMID: 26788069 PMCID: PMC4695678 DOI: 10.1155/2016/6429853] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 11/02/2015] [Indexed: 12/28/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are a source of adult multipotent cells important in tissue regeneration. Murine MSCs are known to proliferate poorly in vitro under normoxia. The aim of this study is to analyze the interaction of nonphysiological high oxygen and low-dose γ-irradiation onto growth, senescence, and DNA damage. Tri-potent bone marrow-derived MSCs from p53 wildtype and p53−/− mice were cultured under either 21% or 2% O2. Long-term observations revealed a decreasing ability of wildtype mMSCs to proliferate and form colonies under extended culture in normoxia. This was accompanied by increased senescence under normoxia but not associated with telomere shortening. After low-dose γ-irradiation, the normoxic wildtype cells further increased the level of senescence. The number of radiation-induced γH2AX DNA repair foci was higher in mMSCs kept under normoxia but not in p53−/− cells. P53-deficient MSCs additionally showed higher clonogeneity, lower senescence levels, and fewer γH2AX repair foci per cell as compared to their p53 wildtype counterparts irrespective of oxygen levels. These results reveal that oxygen levels together with γ-irradiation and p53 status are interconnected factors modulating growth capacity of BM MSCs in long-term culture. These efforts help to better understand and optimize handling of MSCs prior to their therapeutic use.
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19
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Chun YW, Balikov DA, Feaster TK, Williams CH, Sheng CC, Lee JB, Boire TC, Neely MD, Bellan LM, Ess KC, Bowman AB, Sung HJ, Hong CC. Combinatorial polymer matrices enhance in vitro maturation of human induced pluripotent stem cell-derived cardiomyocytes. Biomaterials 2015. [PMID: 26204225 DOI: 10.1016/j.biomaterials.2015.07.004] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Cardiomyocytes derived from human induced pluripotent stem cells (iPSC-CMs) hold great promise for modeling human heart diseases. However, iPSC-CMs studied to date resemble immature embryonic myocytes and therefore do not adequately recapitulate native adult cardiomyocyte phenotypes. Since extracellular matrix plays an essential role in heart development and maturation in vivo, we sought to develop a synthetic culture matrix that could enhance functional maturation of iPSC-CMs in vitro. In this study, we employed a library of combinatorial polymers comprising of three functional subunits - poly-ε-caprolacton (PCL), polyethylene glycol (PEG), and carboxylated PCL (cPCL) - as synthetic substrates for culturing human iPSC-CMs. Of these, iPSC-CMs cultured on 4%PEG-96%PCL (each % indicates the corresponding molar ratio) exhibit the greatest contractility and mitochondrial function. These functional enhancements are associated with increased expression of cardiac myosin light chain-2v, cardiac troponin I and integrin alpha-7. Importantly, iPSC-CMs cultured on 4%PEG-96%PCL demonstrate troponin I (TnI) isoform switch from the fetal slow skeletal TnI (ssTnI) to the postnatal cardiac TnI (cTnI), the first report of such transition in vitro. Finally, culturing iPSC-CMs on 4%PEG-96%PCL also significantly increased expression of genes encoding intermediate filaments known to transduce integrin-mediated mechanical signals to the myofilaments. In summary, our study demonstrates that synthetic culture matrices engineered from combinatorial polymers can be utilized to promote in vitro maturation of human iPSC-CMs through the engagement of critical matrix-integrin interactions.
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Affiliation(s)
- Young Wook Chun
- Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA
| | - Daniel A Balikov
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA
| | - Tromondae K Feaster
- Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Charles H Williams
- Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Calvin C Sheng
- Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Jung-Bok Lee
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA
| | - Timothy C Boire
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA
| | - M Diana Neely
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Leon M Bellan
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA; Department of Mechanical Engineering, Vanderbilt University, Nashville, TN 37235, USA
| | - Kevin C Ess
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Aaron B Bowman
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Hak-Joon Sung
- Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA.
| | - Charles C Hong
- Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Research Medicine, Veterans Affairs TVHS, Nashville, TN 37212, USA.
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20
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Casey SC, Vaccari M, Al-Mulla F, Al-Temaimi R, Amedei A, Barcellos-Hoff MH, Brown DG, Chapellier M, Christopher J, Curran CS, Forte S, Hamid RA, Heneberg P, Koch DC, Krishnakumar PK, Laconi E, Maguer-Satta V, Marongiu F, Memeo L, Mondello C, Raju J, Roman J, Roy R, Ryan EP, Ryeom S, Salem HK, Scovassi AI, Singh N, Soucek L, Vermeulen L, Whitfield JR, Woodrick J, Colacci A, Bisson WH, Felsher DW. The effect of environmental chemicals on the tumor microenvironment. Carcinogenesis 2015; 36 Suppl 1:S160-S183. [PMID: 26106136 PMCID: PMC4565612 DOI: 10.1093/carcin/bgv035] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2014] [Revised: 11/24/2014] [Accepted: 11/28/2014] [Indexed: 12/11/2022] Open
Abstract
Potentially carcinogenic compounds may cause cancer through direct DNA damage or through indirect cellular or physiological effects. To study possible carcinogens, the fields of endocrinology, genetics, epigenetics, medicine, environmental health, toxicology, pharmacology and oncology must be considered. Disruptive chemicals may also contribute to multiple stages of tumor development through effects on the tumor microenvironment. In turn, the tumor microenvironment consists of a complex interaction among blood vessels that feed the tumor, the extracellular matrix that provides structural and biochemical support, signaling molecules that send messages and soluble factors such as cytokines. The tumor microenvironment also consists of many host cellular effectors including multipotent stromal cells/mesenchymal stem cells, fibroblasts, endothelial cell precursors, antigen-presenting cells, lymphocytes and innate immune cells. Carcinogens can influence the tumor microenvironment through effects on epithelial cells, the most common origin of cancer, as well as on stromal cells, extracellular matrix components and immune cells. Here, we review how environmental exposures can perturb the tumor microenvironment. We suggest a role for disrupting chemicals such as nickel chloride, Bisphenol A, butyltins, methylmercury and paraquat as well as more traditional carcinogens, such as radiation, and pharmaceuticals, such as diabetes medications, in the disruption of the tumor microenvironment. Further studies interrogating the role of chemicals and their mixtures in dose-dependent effects on the tumor microenvironment could have important general mechanistic implications for the etiology and prevention of tumorigenesis.
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Affiliation(s)
- Stephanie C Casey
- Division of Oncology, Departments of Medicine and Pathology, Stanford University, Stanford, CA 94305, USA, Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, 40126 Bologna, Italy, Department of Pathology, Kuwait University, 13110 Safat, Kuwait, Department of Experimental and Clinical Medicine, University of Firenze, 50134 Florence, Italy, Department of Radiation Oncology, NYU School of Medicine, New York, NY 10016, USA, Department of Environmental and Radiological Health Sciences, Colorado State University/ Colorado School of Public Health, Fort Collins, CO 80523-1680, USA, Centre De Recherche En Cancerologie De Lyon, U1052-UMR5286, Université de Lyon, 69007 Lyon, France, Cancer Research UK, Cambridge Institute, University of Cambridge, Robinson Way, CB2 0RE Cambridge, UK, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA, Mediterranean Institute of Oncology, 95029 Viagrande, Italy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, 43400 Selangor, Malaysia, Charles University in Prague, Third Faculty of Medicine, 100 00 Prague 10, Czech Republic, Center for Environment and Water, Research Institute, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia, Department of Science and Biomedical Technology, University of Cagliari, 09124 Cagliari, Italy, Pathology Unit, Mediterranean Institute of Oncology, 95029 Viagrande, Italy, Institute of Molecular Genetics, National Research Council, 27100 Pavia, Italy, Regulatory Toxicology Research Division, Bureau of Chemical Safety Food Directorate, Health Products and Food Branch Health Canada, Ottawa, Ontario K1A0K9, Canada, Department of Medicine, University of Louisville, Louisville, KY 40202, USA, Molecular Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC 20057, USA, University of Pennsylvania School of Medicine
| | - Monica Vaccari
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, 40126 Bologna, Italy
| | - Fahd Al-Mulla
- Department of Pathology, Kuwait University, 13110 Safat, Kuwait
| | | | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Firenze, 50134 Florence, Italy
| | | | - Dustin G Brown
- Department of Environmental and Radiological Health Sciences, Colorado State University/ Colorado School of Public Health, Fort Collins, CO 80523-1680, USA
| | - Marion Chapellier
- Centre De Recherche En Cancerologie De Lyon, U1052-UMR5286, Université de Lyon, 69007 Lyon, France
| | - Joseph Christopher
- Cancer Research UK, Cambridge Institute, University of Cambridge, Robinson Way, CB2 0RE Cambridge, UK
| | - Colleen S Curran
- School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Stefano Forte
- Mediterranean Institute of Oncology, 95029 Viagrande, Italy
| | - Roslida A Hamid
- Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, 43400 Selangor, Malaysia
| | - Petr Heneberg
- Charles University in Prague, Third Faculty of Medicine, 100 00 Prague 10, Czech Republic
| | - Daniel C Koch
- Division of Oncology, Departments of Medicine and Pathology, Stanford University, Stanford, CA 94305, USA, Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, 40126 Bologna, Italy, Department of Pathology, Kuwait University, 13110 Safat, Kuwait, Department of Experimental and Clinical Medicine, University of Firenze, 50134 Florence, Italy, Department of Radiation Oncology, NYU School of Medicine, New York, NY 10016, USA, Department of Environmental and Radiological Health Sciences, Colorado State University/ Colorado School of Public Health, Fort Collins, CO 80523-1680, USA, Centre De Recherche En Cancerologie De Lyon, U1052-UMR5286, Université de Lyon, 69007 Lyon, France, Cancer Research UK, Cambridge Institute, University of Cambridge, Robinson Way, CB2 0RE Cambridge, UK, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA, Mediterranean Institute of Oncology, 95029 Viagrande, Italy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, 43400 Selangor, Malaysia, Charles University in Prague, Third Faculty of Medicine, 100 00 Prague 10, Czech Republic, Center for Environment and Water, Research Institute, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia, Department of Science and Biomedical Technology, University of Cagliari, 09124 Cagliari, Italy, Pathology Unit, Mediterranean Institute of Oncology, 95029 Viagrande, Italy, Institute of Molecular Genetics, National Research Council, 27100 Pavia, Italy, Regulatory Toxicology Research Division, Bureau of Chemical Safety Food Directorate, Health Products and Food Branch Health Canada, Ottawa, Ontario K1A0K9, Canada, Department of Medicine, University of Louisville, Louisville, KY 40202, USA, Molecular Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC 20057, USA, University of Pennsylvania School of Medicine
| | - P K Krishnakumar
- Center for Environment and Water, Research Institute, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia
| | - Ezio Laconi
- Department of Science and Biomedical Technology, University of Cagliari, 09124 Cagliari, Italy
| | - Veronique Maguer-Satta
- Centre De Recherche En Cancerologie De Lyon, U1052-UMR5286, Université de Lyon, 69007 Lyon, France
| | - Fabio Marongiu
- Department of Science and Biomedical Technology, University of Cagliari, 09124 Cagliari, Italy
| | - Lorenzo Memeo
- Pathology Unit, Mediterranean Institute of Oncology, 95029 Viagrande, Italy
| | - Chiara Mondello
- Institute of Molecular Genetics, National Research Council, 27100 Pavia, Italy
| | - Jayadev Raju
- Regulatory Toxicology Research Division, Bureau of Chemical Safety Food Directorate, Health Products and Food Branch Health Canada, Ottawa, Ontario K1A0K9, Canada
| | - Jesse Roman
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
| | - Rabindra Roy
- Molecular Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC 20057, USA
| | - Elizabeth P Ryan
- Department of Environmental and Radiological Health Sciences, Colorado State University/ Colorado School of Public Health, Fort Collins, CO 80523-1680, USA
| | - Sandra Ryeom
- University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
| | - Hosni K Salem
- Urology Department, Kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo 11562, Egypt
| | - A Ivana Scovassi
- Institute of Molecular Genetics, National Research Council, 27100 Pavia, Italy
| | - Neetu Singh
- Centre for Advanced Research, King George's Medical University, Chowk, Lucknow, Uttar Pradesh 226003, India
| | - Laura Soucek
- Vall d'Hebron Institute of Oncology (VHIO) and Institució Catalana de Recerca i Estudis Avançats (ICREA), 08035 Barcelona, Spain
| | - Louis Vermeulen
- Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Jonathan R Whitfield
- Vall d'Hebron Institute of Oncology (VHIO) and Institució Catalana de Recerca i Estudis Avançats (ICREA), 08035 Barcelona, Spain
| | - Jordan Woodrick
- Molecular Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC 20057, USA
| | - Annamaria Colacci
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, 40126 Bologna, Italy
| | - William H Bisson
- Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331, USA, and
| | - Dean W Felsher
- Division of Oncology, Departments of Medicine and Pathology, Stanford University, Stanford, CA 94305, USA
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21
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Ishkitiev N, Yaegaki K, Imai T, Tanaka T, Fushimi N, Mitev V, Okada M, Tominaga N, Ono S, Ishikawa H. Novel management of acute or secondary biliary liver conditions using hepatically differentiated human dental pulp cells. Tissue Eng Part A 2014; 21:586-93. [PMID: 25234861 DOI: 10.1089/ten.tea.2014.0162] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The current definitive treatment for acute or chronic liver condition, that is, cirrhosis, is liver transplantation from a limited number of donors, which might cause complications after donation. Hence, bone marrow stem cell transplantation has been developed, but the risk of carcinogenesis remains. We have recently developed a protocol for hepatic differentiation of CD117(+) stem cells from human exfoliated deciduous teeth (SHED). In the present study, we examine whether SHED hepatically differentiated (hd) in vitro could be used to treat acute liver injury (ALI) and secondary biliary cirrhosis. The CD117(+) cell fraction was magnetically separated from SHED and then differentiated into hepatocyte-like cells in vitro. The cells were transplanted into rats with either ALI or induced secondary biliary cirrhosis. Engraftment of human liver cells was determined immunohistochemically and by in situ hybridization. Recovery of liver function was examined by means of histochemical and serological tests. Livers of transplanted animals were strongly positive for human immunohistochemical factors, and in situ hybridization confirmed engraftment of human hepatocytes. The tests for recovery of liver function confirmed the presence of human hepatic markers in the animals' blood serum and lack of fibrosis and functional integration of transplanted human cells into livers. No evidence of malignancy was found. We show that in vitro hdSHED engraft morphologically and functionally into the livers of rats having acute injury or secondary biliary cirrhosis. SHED are readily accessible adult stem cells, capable of proliferating in large numbers before differentiating in vitro. This makes SHED an appropriate and safe stem cell source for regenerative medicine.
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Affiliation(s)
- Nikolay Ishkitiev
- 1 Department of Oral Health, School of Life Dentistry at Tokyo, Nippon Dental University , Tokyo, Japan
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22
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Abstract
Nickel is widely applied in industrial settings and Ni(II) compounds have been classified as group one human carcinogens. The molecular basis of Ni(II) carcinogenicity has proved complex, for many stress response pathways are activated and yield unexpected Ni(II)-specific toxicology profile. Ni(II)-induced toxicogenomic change has been associated with altered activity of HIF, p53, c-MYC, NFκB and iron and 2-oxoglutarate-dependent dioxygenases. Advancing high-throughput technology has indicated the toxicogenome of Ni(II) involves crosstalk between HIF, p53, c-MYC, NFκB and dioxygenases. This paper is intended to review the network of Ni(II)-induced common transcription-factor-governed pathways by discussing transcriptome alteration, its governing transcription factors and the underlying mechanism. Finally, we propose a putative target network of Ni(II) as a human carcinogen.
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Affiliation(s)
- Yixin Yao
- Department of Environmental Medicine, New York University Langone Medical Center, 57 Old Forge Road, Tuxedo, NY, 10987, USA,
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23
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Kavanagh DPJ, Robinson J, Kalia N. Mesenchymal Stem Cell Priming: Fine-tuning Adhesion and Function. Stem Cell Rev Rep 2014; 10:587-99. [DOI: 10.1007/s12015-014-9510-7] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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24
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Okada M, Ishkitiev N, Yaegaki K, Imai T, Tanaka T, Fukuda M, Ono S, Haapasalo M. Hydrogen sulphide increases hepatic differentiation of human tooth pulp stem cells compared with human bone marrow stem cells. Int Endod J 2014; 47:1142-50. [PMID: 24517624 DOI: 10.1111/iej.12262] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Accepted: 02/05/2014] [Indexed: 12/11/2022]
Abstract
AIM To determine the differences in stem cell properties, in hepatic differentiation and in the effects of hydrogen sulphide (H2 S) on hepatic differentiation between human bone marrow stem cells (hBMC) and stem cells from human exfoliated primary tooth pulp (SHED). METHODOLOGY CD117(+) cells were magnetically separated and subjected to hepatic differentiation. CD117(+) cell lineages were characterized for transcription factors indicative of stem cells by qRT-PCR. For the last 9 days of the differentiation, the test cells were exposed to 0.1 ng mL(-1) H2 S. Immunocytochemistry and flow cytometry of albumin, alpha-fetoprotein and carbamoyl phosphate synthetase were carried out after differentiation. Urea concentration and glycogen synthesis were also determined. RESULTS Genes expressed in SHED were also expressed in BMC. No difference in expression level of hepatic markers was shown by immunofluorescence. SHED showed more positive cells than hBMC (P < 0.01). H2 S increased the number of positive cells in both cultures (P < 0.01). Urea concentration and glycogen synthesis increased significantly after H2 S exposure (P < 0.001 and P < 0.05, respectively). Real-time PCR data were analysed by RT(2) profiler RT-PCR Array Data Analysis version 3.5 (Qiagen), and ELISA data were analysed by Bonferroni's multiple comparison using Windows spss version 16 (SPSS Inc, Chicago, IL, USA). Bonferroni's multiple comparison test was also carried out after angle transformation for the percentage data of flow cytometer using Windows spss(®) version 16 (SPSS Inc). Statistical significance was accepted at P < 0.05. CONCLUSIONS Stem cells from human exfoliated primary tooth pulp and BMC have similar properties. The level of hepatic differentiation in SHED compared with BMC was the same or higher. H2 S increased the level of hepatic differentiation.
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Affiliation(s)
- M Okada
- Department of Oral Health, Nippon Dental University, Tokyo, Japan
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Rajamani K, Li YS, Hsieh DK, Lin SZ, Harn HJ, Chiou TW. Genetic and epigenetic instability of stem cells. Cell Transplant 2014; 23:417-33. [PMID: 24622296 DOI: 10.3727/096368914x678472] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Recently, research on stem cells has been receiving an increasing amount of attention, both for its advantages and disadvantages. Genetic and epigenetic instabilities among stem cells have been a recurring obstacle to progress in regenerative medicine using stem cells. Various reports have stated that these instabilities can transform stem cells when transferred in vivo and thus have the potential to develop tumors. Previous research has shown that various extrinsic and intrinsic factors can contribute to the stability of stem cells. The extrinsic factors include growth supplements, growth factors, oxygen tension, passage technique, and cryopreservation. Controlling these factors based on previous reports may assist researchers in developing strategies for the production and clinical application of "safe" stem cells. On the other hand, the intrinsic factors can be unpredictable and uncontrollable; therefore, to ensure the successful use of stem cells in regenerative medicine, it is imperative to develop and implement appropriate strategies and technique for culturing stem cells and to confirm the genetic and epigenetic safety of these stem cells before employing them in clinical trials.
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Affiliation(s)
- Karthyayani Rajamani
- Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan
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Crowder SW, Balikov DA, Hwang YS, Sung HJ. Cancer Stem Cells under Hypoxia as a Chemoresistance Factor in Breast and Brain. CURRENT PATHOBIOLOGY REPORTS 2014; 2:33-40. [PMID: 24587979 DOI: 10.1007/s40139-013-0035-6] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Over the last fifteen years, basic science and clinical studies have aimed to identify cancer stem cells (CSCs) in multiple types of cancer in order to unravel their mechanistic roles in cancer recurrence for therapeutic exploitation. Exposure of cells and tissues to hypoxia, or sub-atmospheric concentrations of oxygen (< 21% O2), stimulates various stress response pathways that bias the cells towards a self-preserving, anti-apoptotic phenotype. Despite major advances in our understanding of hypoxia, CSCs, and their interrelated nature, some of the most promising cancer therapies have shown limited efficacy in clinic for the past few years, in part due to the inherently hypoxic nature of growing tumors. In the present article, we discuss recent findings regarding the behavior of breast and brain CSCs under hypoxia, as well as the mechanisms that have been shown to drive their chemo-/radioresistance and metastatic potential.
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Affiliation(s)
- Spencer W Crowder
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA ; Center for Stem Cell Biology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Daniel A Balikov
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA ; Center for Stem Cell Biology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Yu-Shik Hwang
- Department of Maxillofacial Biomedical Engineering, School of Dentistry, Kyung Hee University, Seoul, South Korea
| | - Hak-Joon Sung
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA ; Center for Stem Cell Biology, Vanderbilt University Medical Center, Nashville, TN, USA ; Department of Maxillofacial Biomedical Engineering, School of Dentistry, Kyung Hee University, Seoul, South Korea
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Abstract
Thyroid cancer cells were believed to be generated by multi-step carcinogenesis, in which cancer cells are derived from thyrocytes, via multiple incidences of damage to their genome, especially in oncogenes or anti-oncogenes that accelerate proliferation or foster malignant phenotypes, such as the ability to invade the surrounding tissue or metastasize to distant organs, until a new hypothesis, fetal cell carcinogenesis, was presented. In fetal cell carcinogenesis, thyroid tumor cells are assumed to be derived from three types of fetal thyroid cell which only exist in fetuses or young children, namely, thyroid stem cells (TSCs), thyroblasts and prothyrocytes, by proliferation without differentiation. Genomic alternations, such as RET/PTC and PAX8-PPARγ1 rearrangements and a mutation in the BRAF gene, play an oncogenic role by preventing thyroid fetal cells from differentiating. Fetal cell carcinogenesis effectively explains recent molecular and clinical evidence regarding thyroid cancer, including thyroid cancer initiating cells (TCICs), and it underscores the importance of identifying a stem cells and clarifying the molecular mechanism of organ development in cancer research. It introduces three important concepts, the reverse approach, stem cell crisis and mature and immature cancers. Further, it implies that analysis of a small population of cells in a cancer tissue will be a key technique in establishing future laboratory tests. In the contrary, mass analysis such as gene expression profiling, whole genomic scan, and proteomics analysis may have definite limitations since they can only provide information based on many cells.
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Affiliation(s)
- Toru Takano
- Department of Laboratory Medicine, Osaka University Graduate School of Medicine, Suita 565-0871, Japan
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