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1
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Kang DY, Bae SW, Jang KJ. Natural bioactive gallic acid shows potential anticancer effects by inhibiting the proliferation and invasiveness behavior in human embryonic carcinoma cells. Mol Med Rep 2025; 31:151. [PMID: 40211726 PMCID: PMC11997742 DOI: 10.3892/mmr.2025.13516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 02/06/2025] [Indexed: 04/16/2025] Open
Abstract
Embryonic cancer stem cells (CSCs), referred to as self‑renewable cells, are commonly found in liquid and solid cancers and can also be attributed to tumor onset, resistance, expansion, recurrence and metastasis following treatment. Cancer therapy targeting CSCs using natural bioactive products is an optimal option for inhibiting cancer recurrence, thereby improving prognosis. Several natural compounds and extracts have been used to identify direct or indirect therapy effects that reduce the pathological activities of CSCs. Natural gallic acid (GA) is noted to have anticancer properties for oncogene expression, cycle arrest, apoptosis, angiogenesis, migration and metastasis in various cancers. The present study demonstrated that GA has various anticancer activities in NTERA‑2 and NCCIT human embryonic carcinoma cells. In two types of embryonic CSCs, GA effectively induced cell death via late apoptosis. Furthermore, GA showed the G0/G1 cell cycle arrest activity in embryonic CSCs by inducing the increase of p21, p27 and p53 expression and the decrease of CDK4, cyclin E and cyclin D1 expression. The present study showed that GA inhibited the expression levels of mRNA and protein for stem cell markers, such as SOX2, NANOG and OCT4, in NTERA‑2 and NCCIT cells. The induction of cellular and mitochondrial reactive oxygen species by GA also activated the cellular DNA damage response pathway by raising the phosphorylated‑BRCA1, ATM, Chk1, Chk2 and histone. Finally, GA inhibited CSCs invasion and migration by inhibiting the expression of matrix metalloproteinase by the downregulation of EGFR/JAK2/STAT5 signaling pathway. Thus, it is hypothesized that GA could be a potential inhibitor of cancer emergence by suppressing CSC properties.
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Affiliation(s)
- Dong Young Kang
- Department of Immunology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Chungju. Chungcheong 27478, Republic of Korea
| | - Se Won Bae
- Department of Chemistry and Cosmetics, Jeju National University, Jeju, Jejudo 63243, Republic of Korea
| | - Kyoung-Jin Jang
- Department of Integrative Biological Sciences and Industry, College of Life Science, Sejong University, Seoul 05006, Republic of Korea
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Hill M, Andrews-Pfannkoch C, Atherton E, Knudsen T, Trncic E, Marmorstein AD. Detection of Residual iPSCs Following Differentiation of iPSC-Derived Retinal Pigment Epithelial Cells. J Ocul Pharmacol Ther 2024; 40:680-687. [PMID: 39358867 PMCID: PMC11698679 DOI: 10.1089/jop.2024.0130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 09/09/2024] [Indexed: 10/04/2024] Open
Abstract
Purpose: The goal of this study was to develop a lot release assay for iPSC residuals following directed differentiation of iPSCs to retinal pigment epithelial (RPE) cells. Methods: RNA Sequencing (RNA Seq) of iPSCs and RPE derived from them was used to identify pluripotency markers downregulated in RPE cells. Quantitative real time PCR (qPCR) was then applied to assess iPSC residuals in iPSC-derived RPE. The limit of detection (LOD) of the assay was determined by performing spike-in assays with known quantities of iPSCs serially diluted into an RPE suspension. Results: ZSCAN10 and LIN28A were among 8 pluripotency markers identified by RNA Seq as downregulated in RPE. Based on copy number and expression of pseudogenes and lncRNAs ZSCAN10 and LIN28A were chosen for use in qPCR assays for residual iPSCs. Reverse transcription PCR indicated generally uniform expression of ZSCAN10 and LIN28A in 21 clones derived from 8 iPSC donors with no expression of either in RPE cells derived from 5 donor lines. Based on qPCR, ZSCAN10, and LIN28A expression in iPSCs was generally uniform. The LOD for ZSCAN10 and LIN28A in qPCR assays was determined using spike in assays of RPE derived from 2 iPSC lines. Analysis of ΔΔCt found the limit of detection to be <0.01% of cells, equivalent to <1 iPSC/10,000 RPE cells in both iPSC lines. Conclusions: qPCR for ZSCAN10 and LIN28A detects <1 in 10,000 residual iPSCs in a population of iPSC-derived RPE providing an adequate LOD of iPSC residuals for lot release testing.
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Affiliation(s)
- Matthew Hill
- Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Evan Atherton
- Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, USA
| | - Travis Knudsen
- Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, USA
| | - Emma Trncic
- Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, USA
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3
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Liu S, Ren J, Hu Y, Zhou F, Zhang L. TGFβ family signaling in human stem cell self-renewal and differentiation. CELL REGENERATION (LONDON, ENGLAND) 2024; 13:26. [PMID: 39604763 PMCID: PMC11602941 DOI: 10.1186/s13619-024-00207-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 10/16/2024] [Accepted: 11/01/2024] [Indexed: 11/29/2024]
Abstract
Human stem cells are undifferentiated cells with the capacity for self-renewal and differentiation into distinct cell lineages, playing important role in the development and maintenance of diverse tissues and organs. The microenvironment of stem cell provides crucial factors and components that exert significant influence over the determination of cell fate. Among these factors, cytokines from the transforming growth factor β (TGFβ) superfamily, including TGFβ, bone morphogenic protein (BMP), Activin and Nodal, have been identified as important regulators governing stem cell maintenance and differentiation. In this review, we present a comprehensive overview of the pivotal roles played by TGFβ superfamily signaling in governing human embryonic stem cells, somatic stem cells, induced pluripotent stem cells, and cancer stem cells. Furthermore, we summarize the latest research and advancements of TGFβ family in various cancer stem cells and stem cell-based therapy, discussing their potential clinical applications in cancer therapy and regeneration medicine.
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Affiliation(s)
- Sijia Liu
- International Biomed-X Research Center, Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Jiang Ren
- The First Affiliated Hospital, MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Institute of Biomedical Innovation, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Yanmei Hu
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Fangfang Zhou
- The First Affiliated Hospital, the Institutes of Biology and Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, China.
| | - Long Zhang
- International Biomed-X Research Center, Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.
- The First Affiliated Hospital, MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Institute of Biomedical Innovation, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China.
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China.
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4
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Pignatti E, Maccaferri M, Pisciotta A, Carnevale G, Salvarani C. A comprehensive review on the role of mesenchymal stromal/stem cells in the management of rheumatoid arthritis. Expert Rev Clin Immunol 2024; 20:463-484. [PMID: 38163928 DOI: 10.1080/1744666x.2023.2299729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 12/21/2023] [Indexed: 01/03/2024]
Abstract
INTRODUCTION Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease with systemic manifestations. Although the success of immune modulatory drug therapy is considerable, about 40% of patients do not respond to treatment. Mesenchymal stromal/stem cells (MSCs) have been demonstrated to have therapeutic potential for inflammatory diseases. AREAS COVERED This review provides an update on RA disease and on pre-clinical and clinical studies using MSCs from bone marrow, umbilical cord, adipose tissue, and dental pulp, to regulate the immune response. Moreover, the clinical use, safety, limitations, and future perspective of MSCs in RA are discussed. Using the PubMed database and ClincalTrials.gov, peer-reviewed full-text papers, abstracts and clinical trials were identified from 1985 through to April 2023. EXPERT OPINION MSCs demonstrated a satisfactory safety profile and potential for clinical efficacy. However, it is mandatory to deepen the investigations on how MSCs affect the proinflammatory deregulated RA patients' cells. MSCs are potentially good candidates for severe RA patients not responding to conventional therapies but a long-term follow-up after stem cells treatment and standardized protocols are needed. Future research should focus on well-designed multicenter randomized clinical trials with adequate sample sizes and properly selected patients satisfying RA criteria for a valid efficacy evaluation.
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Affiliation(s)
- Elisa Pignatti
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Monia Maccaferri
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Alessandra Pisciotta
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Gianluca Carnevale
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Carlo Salvarani
- Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
- Rheumatology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
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5
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Kim J, Kim J, Kim D, Bello AB, Kim BJ, Cha B, Lee S. Therapeutic potential of mesenchymal stem cells from human iPSC-derived teratomas for osteochondral defect regeneration. Bioeng Transl Med 2024; 9:e10629. [PMID: 38435815 PMCID: PMC10905541 DOI: 10.1002/btm2.10629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 11/08/2023] [Accepted: 11/14/2023] [Indexed: 03/05/2024] Open
Abstract
Human induced pluripotent stem cells (iPSCs) hold great promise for personalized medicine, as they can be differentiated into specific cell types, especially mesenchymal stem cells (MSCs). Therefore, our study sought to assess the feasibility of deriving MSCs from teratomas generated from human iPSCs. Teratomas serve as a model to mimic multilineage human development, thus enriching specific somatic progenitors and stem cells. Here, we discovered a small, condensed mass of MSCs within iPSC-generated teratomas. Afterward, we successfully isolated MSCs from this condensed mass, which was a byproduct of teratoma development. To evaluate the characteristics and cell behaviors of iPSC-derived MSCs (iPSC-MSCs), we conducted comprehensive assessments using qPCR, immunophenotype analysis, and cell proliferation-related assays. Remarkably, iPSC-MSCs exhibited an immunophenotype resembling that of conventional MSCs, and they displayed robust proliferative capabilities, similar to those of higher pluripotent stem cell-derived MSCs. Furthermore, iPSC-MSCs demonstrated the ability to differentiate into multiple lineages in vitro. Finally, we evaluated the therapeutic potential of iPSC-MSCs using an osteochondral defect model. Our findings demonstrated that teratomas are a promising source for the isolation of condensed MSCs. More importantly, our results suggest that iPSC-MSCs derived from teratomas possess the capacity for tissue regeneration, highlighting their promise for future therapeutic applications.
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Affiliation(s)
- Jiseong Kim
- Department of Biomedical TechnologyDongguk UniversityGoyang‐siRepublic of Korea
| | - Jin‐Su Kim
- Department of Biomedical ScienceCHA UniversitySeongnam‐siRepublic of Korea
- Biomaterials Research CenterCELLINBIO Co., Ltd.Suwon‐siGyeonggi‐doRepublic of Korea
| | - Dohyun Kim
- Department of Biomedical TechnologyDongguk UniversityGoyang‐siRepublic of Korea
| | - Alvin Bacero Bello
- Department of Biomedical TechnologyDongguk UniversityGoyang‐siRepublic of Korea
- Department of Integrative EngineeringChung‐Ang UniversitySeoulRepublic of Korea
| | - Byoung Ju Kim
- Department of Rearch & Development teamATEMsSeoulRepublic of Korea
| | - Byung‐Hyun Cha
- Division of Biomedical ConvergenceCollege of Biomedical Science, Kangwon National UniversityChuncheon‐siRepublic of Korea
| | - Soo‐Hong Lee
- Department of Biomedical TechnologyDongguk UniversityGoyang‐siRepublic of Korea
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6
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Lee SY, Lee DY, Yun SH, Lee J, Mariano E, Park J, Choi Y, Han D, Kim JS, Hur SJ. Current technology and industrialization status of cell-cultivated meat. JOURNAL OF ANIMAL SCIENCE AND TECHNOLOGY 2024; 66:1-30. [PMID: 38618028 PMCID: PMC11007461 DOI: 10.5187/jast.2023.e107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 10/05/2023] [Accepted: 10/09/2023] [Indexed: 04/16/2024]
Abstract
Interest and investment in cultivated meat are increasing because of the realization that it can effectively supply sufficient food resources and reduce the use of livestock. Nevertheless, accurate information on the specific technologies used for cultivated meat production and the characteristics of cultivated meat is lacking. Authorization for the use of cultivated meat is already underway in the United States, Singapore, and Israel, and other major countries are also expected to approve cultivated meat as food once the details of the intricate process of producing cultivated meat, which encompasses stages such as cell proliferation, differentiation, maturation, and assembly, is thoroughly established. The development and standardization of mass production processes and safety evaluations must precede the industrialization and use of cultivated meat as food. However, the technology for the industrialization of cultivated meat is still in its nascent stage, and the mass production process has not yet been established. The mass production process of cultivated meat may not be easy to disclose because it is related to the interests of several companies or research teams. However, the overall research flow shows that equipment development for mass production and cell acquisition, proliferation, and differentiation, as well as for three-dimensional production supports and bioreactors have not yet been completed. Therefore, additional research on the mass production process and safety of cultivated meat is essential. The consumer's trust in the cultivated meat products and production technologies recently disclosed by some companies should also be analyzed and considered for guiding future developments in this industry. Furthermore, close monitoring by academia and the government will be necessary to identify fraud in the cultivated meat industry.
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Affiliation(s)
- Seung Yun Lee
- Division of Animal Science, Division of
Applied Life Science (BK21 Four), Institute of Agriculture & Life
Science, Gyeongsang National University, Jinju 52828,
Korea
| | - Da Young Lee
- Department of Animal Science and
Technology, Chung-Ang University, Anseong 17546, Korea
| | - Seung Hyeon Yun
- Department of Animal Science and
Technology, Chung-Ang University, Anseong 17546, Korea
| | - Juhyun Lee
- Department of Animal Science and
Technology, Chung-Ang University, Anseong 17546, Korea
| | - Ermie Mariano
- Department of Animal Science and
Technology, Chung-Ang University, Anseong 17546, Korea
| | - Jinmo Park
- Department of Animal Science and
Technology, Chung-Ang University, Anseong 17546, Korea
| | - Yeongwoo Choi
- Department of Animal Science and
Technology, Chung-Ang University, Anseong 17546, Korea
| | - Dahee Han
- Department of Animal Science and
Technology, Chung-Ang University, Anseong 17546, Korea
| | - Jin Soo Kim
- Department of Animal Science and
Technology, Chung-Ang University, Anseong 17546, Korea
| | - Sun Jin Hur
- Department of Animal Science and
Technology, Chung-Ang University, Anseong 17546, Korea
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7
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Yadav D, Sharma PK, Mishra PS, Malviya R. The Potential of Stem Cells in Treating Breast Cancer. Curr Stem Cell Res Ther 2024; 19:324-333. [PMID: 37132308 DOI: 10.2174/1574888x18666230428094056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 11/26/2022] [Accepted: 12/29/2022] [Indexed: 05/04/2023]
Abstract
There has been a lot of interest in stem cell therapy as a means of curing disease in recent years. Despite extensive usage of stem cell therapy in the treatment of a wide range of medical diseases, it has been hypothesized that it plays a key part in the progression of cancer. Breast cancer is still the most frequent malignancy in women globally. However, the latest treatments, such as stem cell targeted therapy, are considered to be more effective in preventing recurrence, metastasis, and chemoresistance of breast cancer than older methods like chemotherapy and radiation. This review discusses the characteristics of stem cells and how stem cells may be used to treat breast cancer.
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Affiliation(s)
- Deepika Yadav
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Pramod Kumar Sharma
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Prem Shankar Mishra
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Rishabha Malviya
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
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8
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Jiang M, Jang SE, Zeng L. The Effects of Extrinsic and Intrinsic Factors on Neurogenesis. Cells 2023; 12:cells12091285. [PMID: 37174685 PMCID: PMC10177620 DOI: 10.3390/cells12091285] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 04/18/2023] [Accepted: 04/25/2023] [Indexed: 05/15/2023] Open
Abstract
In the mammalian brain, neurogenesis is maintained throughout adulthood primarily in two typical niches, the subgranular zone (SGZ) of the dentate gyrus and the subventricular zone (SVZ) of the lateral ventricles and in other nonclassic neurogenic areas (e.g., the amygdala and striatum). During prenatal and early postnatal development, neural stem cells (NSCs) differentiate into neurons and migrate to appropriate areas such as the olfactory bulb where they integrate into existing neural networks; these phenomena constitute the multistep process of neurogenesis. Alterations in any of these processes impair neurogenesis and may even lead to brain dysfunction, including cognitive impairment and neurodegeneration. Here, we first summarize the main properties of mammalian neurogenic niches to describe the cellular and molecular mechanisms of neurogenesis. Accumulating evidence indicates that neurogenesis plays an integral role in neuronal plasticity in the brain and cognition in the postnatal period. Given that neurogenesis can be highly modulated by a number of extrinsic and intrinsic factors, we discuss the impact of extrinsic (e.g., alcohol) and intrinsic (e.g., hormones) modulators on neurogenesis. Additionally, we provide an overview of the contribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection to persistent neurological sequelae such as neurodegeneration, neurogenic defects and accelerated neuronal cell death. Together, our review provides a link between extrinsic/intrinsic factors and neurogenesis and explains the possible mechanisms of abnormal neurogenesis underlying neurological disorders.
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Affiliation(s)
- Mei Jiang
- Department of Human Anatomy, Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, Dongguan Campus, Guangdong Medical University, Dongguan 523808, China
| | - Se Eun Jang
- Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, Singapore 308433, Singapore
| | - Li Zeng
- Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, Singapore 308433, Singapore
- Neuroscience and Behavioral Disorders Program, DUKE-NUS Graduate Medical School, Singapore 169857, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technology University, Novena Campus, 11 Mandalay Road, Singapore 308232, Singapore
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9
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Exposing intracellular molecular changes during the differentiation of human-induced pluripotent stem cells into erythropoietin-producing cells using Raman spectroscopy and imaging. Sci Rep 2022; 12:20454. [PMID: 36443362 PMCID: PMC9705388 DOI: 10.1038/s41598-022-24725-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 11/18/2022] [Indexed: 11/29/2022] Open
Abstract
The objective of this study was to explore intracellular molecular changes during the differentiation of human-induced pluripotent stem cells (iPSCs) into erythropoietin (EPO)-producing cells using Raman spectroscopy and imaging. Raman imaging data of fixed cells at four stages of cell differentiation were analyzed by a partial least squares (PLS) regression model, and the variations in the intracellular molecular compositions with cell differentiation were investigated. As a result, three biomarkers characterizing the cell phases were identified: dimethyl sulfoxide (DMSO), fatty acids with a low grade of unsaturation, and glycoproteins. The uptake of DMSO by EPO-producing cells, which was added into a culture medium as an inducer for cell differentiation, was detected, and the increase in unsaturated fatty acid concentrations was revealed that lipid metabolism changed over the course of cell differentiation. The decrease in the glycoprotein concentration after the cell phase during which iPSCs differentiated into EPO-producing cells was also made clear. Raman imaging successfully visualized chemical images of these three biomarkers in two dimensions, where the biomarker concentrations independently varied during cell differentiation. These results demonstrated the application potential of the proposed method to regenerative medicine for monitoring cell differentiation and discriminating cell maturation in situ at the molecular level.
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10
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Friesen M, Khalil AS, Barrasa MI, Jeppesen JF, Mooney DJ, Jaenisch R. Development of a physiological insulin resistance model in human stem cell-derived adipocytes. SCIENCE ADVANCES 2022; 8:eabn7298. [PMID: 35714187 PMCID: PMC9205586 DOI: 10.1126/sciadv.abn7298] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 05/04/2022] [Indexed: 05/20/2023]
Abstract
Adipocytes are key regulators of human metabolism, and their dysfunction in insulin signaling is central to metabolic diseases including type II diabetes mellitus (T2D). However, the progression of insulin resistance into T2D is still poorly understood. This limited understanding is due, in part, to the dearth of suitable models of insulin signaling in human adipocytes. Traditionally, adipocyte models fail to recapitulate in vivo insulin signaling, possibly due to exposure to supraphysiological nutrient and hormone conditions. We developed a protocol for human pluripotent stem cell-derived adipocytes that uses physiological nutrient conditions to produce a potent insulin response comparable to in vivo adipocytes. After systematic optimization, this protocol allows robust insulin-stimulated glucose uptake and transcriptional insulin response. Furthermore, exposure of sensitized adipocytes to physiological hyperinsulinemia dampens insulin-stimulated glucose uptake and dysregulates insulin-responsive transcription. Overall, our methodology provides a novel platform for the mechanistic study of insulin signaling and resistance using human pluripotent stem cell-derived adipocytes.
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Affiliation(s)
- Max Friesen
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
| | - Andrew S. Khalil
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
- Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02142, USA
- Wyss Institute for Biologically Inspired Engineering, Cambridge, MA 02142, USA
| | | | | | - David J. Mooney
- Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02142, USA
- Wyss Institute for Biologically Inspired Engineering, Cambridge, MA 02142, USA
| | - Rudolf Jaenisch
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
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11
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Antitumor Effects of Natural Bioactive Ursolic Acid in Embryonic Cancer Stem Cells. JOURNAL OF ONCOLOGY 2022; 2022:6737248. [PMID: 35222644 PMCID: PMC8866021 DOI: 10.1155/2022/6737248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 01/22/2022] [Indexed: 11/17/2022]
Abstract
Embryonic cancer cells (CSCs) could cause different types of cancer, a skill that makes them even more dangerous than other cancer cells. Identifying CSCs using natural products is a good option as it inhibits the recurrence of cancer with moderate various effects. Ursolic acid (UA) is a pentacyclic triterpenoid extracted from fruit and herbal remedies and has known anticancer functions against various cancer cells. However, its potential against CSCs remains uncertain. This study was planned to examine the induction of cell apoptosis by the UA. For cell signaling studies, we performed experiments, which are real-time qPCR and immunoblotting. Also, various cellular processes were analyzed using flow cytometry. The results raised a barrier to cell proliferation by the UA in NTERA-2 and NCCIT cells. Morphological studies also confirmed the UA's ability to cause cell death in embryonic CSCs. Examination of cell death importation showed that the UA formed the expression of the iNOS and thus the cell generation and mitochondrial reactive oxygen generation, which created a reaction to cellular DNA damage by raising the protein levels of phospho-histone ATR and ATM. In addition, the UA created the binding of the G0/G1 cell cycle to NTERA-2 and NCCIT cells, improved the expression levels of p21 and p27, and reduced the expression levels of CDK4, cyclin D1, and cyclin E, confirming the UA's ability to initiate cell cycle arrest. Finally, the UA created an internal mechanism of apoptosis in the embryonic CSC using BAX and cytochrome c regulation as well as the regulation of BCL-xL and BCL-2 proteins. Therefore, UA could be the best candidate for targeting CSCs and thus suppressing the emergence of cancer.
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12
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Klein SG, Alsolami SM, Arossa S, Ramos-Mandujano G, Parry AJ, Steckbauer A, Duarte CM, Li M. In situ monitoring reveals cellular environmental instabilities in human pluripotent stem cell culture. Commun Biol 2022; 5:119. [PMID: 35136190 PMCID: PMC8826360 DOI: 10.1038/s42003-022-03065-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 01/20/2022] [Indexed: 12/26/2022] Open
Abstract
Mammalian cell cultures are a keystone resource in biomedical research, but the results of published experiments often suffer from reproducibility challenges. This has led to a focus on the influence of cell culture conditions on cellular responses and reproducibility of experimental findings. Here, we perform frequent in situ monitoring of dissolved O2 and CO2 with optical sensor spots and contemporaneous evaluation of cell proliferation and medium pH in standard batch cultures of three widely used human somatic and pluripotent stem cell lines. We collate data from the literature to demonstrate that standard cell cultures consistently exhibit environmental instability, indicating that this may be a pervasive issue affecting experimental findings. Our results show that in vitro cell cultures consistently undergo large departures of environmental parameters during standard batch culture. These findings should catalyze further efforts to increase the relevance of experimental results to the in vivo physiology and enhance reproducibility.
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Affiliation(s)
- Shannon G Klein
- Red Sea Research Center (RSRC) and Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology, Thuwal, 23955, Saudi Arabia
| | - Samhan M Alsolami
- Biological and Environmental Science and Engineering Division (BESE), King Abdullah University of Science and Technology, Thuwal, 23955, Saudi Arabia
| | - Silvia Arossa
- Red Sea Research Center (RSRC) and Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology, Thuwal, 23955, Saudi Arabia
| | - Gerardo Ramos-Mandujano
- Biological and Environmental Science and Engineering Division (BESE), King Abdullah University of Science and Technology, Thuwal, 23955, Saudi Arabia
| | - Anieka J Parry
- Red Sea Research Center (RSRC) and Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology, Thuwal, 23955, Saudi Arabia
| | - Alexandra Steckbauer
- Red Sea Research Center (RSRC) and Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology, Thuwal, 23955, Saudi Arabia
| | - Carlos M Duarte
- Red Sea Research Center (RSRC) and Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology, Thuwal, 23955, Saudi Arabia.
| | - Mo Li
- Biological and Environmental Science and Engineering Division (BESE), King Abdullah University of Science and Technology, Thuwal, 23955, Saudi Arabia.
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Sp N, Kang DY, Jo ES, Lee JM, Bae SW, Jang KJ. Pivotal Role of Iron Homeostasis in the Induction of Mitochondrial Apoptosis by 6-Gingerol Through PTEN Regulated PD-L1 Expression in Embryonic Cancer Cells. Front Oncol 2021; 11:781720. [PMID: 34804985 PMCID: PMC8595921 DOI: 10.3389/fonc.2021.781720] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 10/15/2021] [Indexed: 01/07/2023] Open
Abstract
Embryonic cancer stem cells (CSCs) can differentiate into any cancer type. Targeting CSCs with natural compounds is a promising approach as it suppresses cancer recurrence with fewer adverse effects. 6-Gingerol is an active component of ginger, which exhibits well-known anti-cancer activities. This study determined the mechanistic aspects of cell death induction by 6-gingerol. To analyze cellular processes, we used Western blot and real-time qPCR for molecular signaling studies and conducted flow cytometry. Our results suggested an inhibition of CSC marker expression and Wnt/β-catenin signaling by 6-gingerol in NCCIT and NTERA-2 cells. 6-Gingerol induced reactive oxygen species generation, the DNA damage response, cell cycle arrest, and the intrinsic pathway of apoptosis in embryonic CSCs. Furthermore, 6-gingerol inhibited iron metabolism and induced PTEN, which both played vital roles in the induction of cell death. The activation of PTEN resulted in the inhibition of PD-L1 expression through PI3K/AKT/p53 signaling. The induction of PTEN also mediated the downregulation of microRNAs miR-20b, miR-21, and miR-130b to result in PD-L1 suppression by 6-gingerol. Hence, 6-gingerol may be a promising candidate to target CSCs by regulating PTEN-mediated PD-L1 expression.
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Affiliation(s)
- Nipin Sp
- Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Chungju, South Korea
| | - Dong Young Kang
- Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Chungju, South Korea
| | - Eun Seong Jo
- Pharmacological Research Division, National Institute of Food and Drug Safety Evaluation, Osong Health Technology Administration Complex, Cheongju-si, South Korea
| | - Jin-Moo Lee
- Pharmacological Research Division, National Institute of Food and Drug Safety Evaluation, Osong Health Technology Administration Complex, Cheongju-si, South Korea.,SK Bioscience, Seongnam-si, South Korea
| | - Se Won Bae
- Department of Chemistry and Cosmetics, Jeju National University, Jeju, South Korea
| | - Kyoung-Jin Jang
- Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Chungju, South Korea
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14
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Ebrahimie E, Rahimirad S, Tahsili M, Mohammadi-Dehcheshmeh M. Alternative RNA splicing in stem cells and cancer stem cells: Importance of transcript-based expression analysis. World J Stem Cells 2021; 13:1394-1416. [PMID: 34786151 PMCID: PMC8567453 DOI: 10.4252/wjsc.v13.i10.1394] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 06/21/2021] [Accepted: 09/14/2021] [Indexed: 02/06/2023] Open
Abstract
Alternative ribonucleic acid (RNA) splicing can lead to the assembly of different protein isoforms with distinctive functions. The outcome of alternative splicing (AS) can result in a complete loss of function or the acquisition of new functions. There is a gap in knowledge of abnormal RNA splice variants promoting cancer stem cells (CSCs), and their prospective contribution in cancer progression. AS directly regulates the self-renewal features of stem cells (SCs) and stem-like cancer cells. Notably, octamer-binding transcription factor 4A spliced variant of octamer-binding transcription factor 4 contributes to maintaining stemness properties in both SCs and CSCs. The epithelial to mesenchymal transition pathway regulates the AS events in CSCs to maintain stemness. The alternative spliced variants of CSCs markers, including cluster of differentiation 44, aldehyde dehydrogenase, and doublecortin-like kinase, α6β1 integrin, have pivotal roles in increasing self-renewal properties and maintaining the pluripotency of CSCs. Various splicing analysis tools are considered in this study. LeafCutter software can be considered as the best tool for differential splicing analysis and identification of the type of splicing events. Additionally, LeafCutter can be used for efficient mapping splicing quantitative trait loci. Altogether, the accumulating evidence re-enforces the fact that gene and protein expression need to be investigated in parallel with alternative splice variants.
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Affiliation(s)
- Esmaeil Ebrahimie
- School of Animal and Veterinary Sciences, The University of Adelaide, Adelaide 5005, South Australia, Australia
- La Trobe Genomics Research Platform, School of Life Sciences, College of Science, Health and Engineering, La Trobe University, Melbourne 3086, Australia
- School of Biosciences, The University of Melbourne, Melbourne 3010, Australia,
| | - Samira Rahimirad
- Department of Medical Genetics, National Institute of Genetic Engineering and Biotechnology, Tehran 1497716316, Iran
- Division of Urology, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal H4A 3J1, Quebec, Canada
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15
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Sp N, Kang DY, Jo ES, Lee JM, Jang KJ. Iron Metabolism as a Potential Mechanism for Inducing TRAIL-Mediated Extrinsic Apoptosis Using Methylsulfonylmethane in Embryonic Cancer Stem Cells. Cells 2021; 10:cells10112847. [PMID: 34831070 PMCID: PMC8616102 DOI: 10.3390/cells10112847] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 10/11/2021] [Accepted: 10/21/2021] [Indexed: 02/07/2023] Open
Abstract
Embryonic cancer stem cells (CSCs) can differentiate into any cancer type. Targeting CSC using natural compounds is a good approach as it suppresses cancer recurrence with fewer adverse effects, and methylsulfonylmethane (MSM) is a sulfur-containing compound with well-known anticancer activities. This study determined the mechanistic aspects of the anticancer activity of MSM. We used Western blotting and real-time qPCR for molecular signaling studies and conducted flow cytometry for analyzing the processes in cells. Our results suggested an inhibition in the expression of CSC markers and Wnt/β-catenin signaling. MSM induced TRAIL-mediated extrinsic apoptosis in NCCIT and NTERA-2 cells rather than an intrinsic pathway. Inhibition of iron metabolism-dependent reactive oxygen species (ROS) generation takes part in TRAIL-mediated apoptosis induction by MSM. Suppressing iron metabolism by MSM also regulated p38/p53/ERK signaling and microRNA expressions, such as upregulating miR-130a and downregulating miR-221 and miR-222, which resulted in TRAIL induction and thereby extrinsic pathway of apoptosis. Hence, MSM could be a good candidate for neoadjuvant therapy by targeting CSCs by inhibiting iron metabolism.
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Affiliation(s)
- Nipin Sp
- Department of Pathology, Institute of Biomedical Science and Technology, School of Medicine, Konkuk University, Chungju 27478, Korea; (N.S.); (D.Y.K.)
| | - Dong Young Kang
- Department of Pathology, Institute of Biomedical Science and Technology, School of Medicine, Konkuk University, Chungju 27478, Korea; (N.S.); (D.Y.K.)
| | - Eun Seong Jo
- Pharmacological Research Division, National Institute of Food and Drug Safety Evaluation, Osong Health Technology Administration Complex, Cheongju-si 28159, Korea; (E.S.J.); (J.-M.L.)
| | - Jin-Moo Lee
- Pharmacological Research Division, National Institute of Food and Drug Safety Evaluation, Osong Health Technology Administration Complex, Cheongju-si 28159, Korea; (E.S.J.); (J.-M.L.)
- SK Bioscience, Seongnam-si 13493, Korea
| | - Kyoung-Jin Jang
- Department of Pathology, Institute of Biomedical Science and Technology, School of Medicine, Konkuk University, Chungju 27478, Korea; (N.S.); (D.Y.K.)
- Correspondence: ; Tel.: +82-2-2030-7839
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16
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Ding H, Zhao Y, Yu X, Chen L, Han J, Feng J. Tolerable upper intake level of iron damages the liver of weaned piglets. J Anim Physiol Anim Nutr (Berl) 2021; 105:668-677. [PMID: 33683742 DOI: 10.1111/jpn.13521] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 11/25/2020] [Accepted: 02/15/2021] [Indexed: 01/03/2023]
Abstract
Iron is one of the essential trace elements, which is often supplemented as an additive to meet the growing needs of toddlers and young animals. Recommended nutrient intake (RNI) and tolerable upper intake levels (UL) are always set when the iron is supplemented. The purpose of this study was to evaluate the subacute (28 days) toxicity of UL iron to weaned piglet liver. Thirty 23-day-old weaned piglets were divided into three groups and, respectively, supplemented with 100, 300 or 3000 (UL) mg/kg iron. UL iron caused significant weight loss in 4th week (p < 0.05). Divalent metal transporter 1(DMT1) decreased significantly, ferroportin 1 and ferritin increased significantly in the liver of UL iron group (p < 0.05). Although there was no significant effect on liver morphology, UL iron significantly increased hepatic iron, reactive oxygen species (ROS), malondialdehyde (MDA) and protein carbonyl (p < 0.05). UL iron significantly reduced glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), catalase (CAT) and total anti-oxidation capacity (T-AOC) in the liver (p < 0.05). Nuclear factor erythroid 2-related factor 2 (Nrf2) activated subunits of glutamate cysteine ligase (Gclc) and glutathione S-transferase A1 (Gsta1) upregulation in the UL iron group liver, thereby increasing resistance to oxidative stress. In conclusion, UL iron supplementation altered iron metabolism, generated free radicals, reduced antioxidant enzyme activity and activated Nrf2 signalling pathway in the weaned piglet liver.
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Affiliation(s)
- Haoxuan Ding
- College of Animal Sciences, Zhejiang University, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou, China
| | - Yang Zhao
- College of Animal Sciences, Zhejiang University, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou, China
| | - Xiaonan Yu
- College of Animal Sciences, Zhejiang University, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou, China
| | - Lingjun Chen
- College of Animal Sciences, Zhejiang University, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou, China
| | - Jianan Han
- College of Animal Sciences, Zhejiang University, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou, China
| | - Jie Feng
- College of Animal Sciences, Zhejiang University, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou, China
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17
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Ko CCH, Chia WK, Selvarajah GT, Cheah YK, Wong YP, Tan GC. The Role of Breast Cancer Stem Cell-Related Biomarkers as Prognostic Factors. Diagnostics (Basel) 2020; 10:721. [PMID: 32961774 PMCID: PMC7555329 DOI: 10.3390/diagnostics10090721] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 09/13/2020] [Accepted: 09/16/2020] [Indexed: 02/06/2023] Open
Abstract
Breast cancer is one of the leading causes of cancer-related deaths in women worldwide, and its incidence is on the rise. A small fraction of cancer stem cells was identified within the tumour bulk, which are regarded as cancer-initiating cells, possess self-renewal and propagation potential, and a key driver for tumour heterogeneity and disease progression. Cancer heterogeneity reduces the overall efficacy of chemotherapy and contributes to treatment failure and relapse. The cell-surface and subcellular biomarkers related to breast cancer stem cell (BCSC) phenotypes are increasingly being recognised. These biomarkers are useful for the isolation of BCSCs and can serve as potential therapeutic targets and prognostic tools to monitor treatment responses. Recently, the role of noncoding microRNAs (miRNAs) has extensively been explored as novel biomarker molecules for breast cancer diagnosis and prognosis with high specificity and sensitivity. An in-depth understanding of the biological roles of miRNA in breast carcinogenesis provides insights into the pathways of cancer development and its utility for disease prognostication. This review gives an overview of stem cells, highlights the biomarkers expressed in BCSCs and describes their potential role as prognostic indicators.
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Affiliation(s)
- Clarence Ching Huat Ko
- Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Kuala Lumpur, Malaysia; (C.C.H.K.); (W.K.C.)
- Department of Biomedical Science, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Malaysia;
| | - Wai Kit Chia
- Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Kuala Lumpur, Malaysia; (C.C.H.K.); (W.K.C.)
| | - Gayathri Thevi Selvarajah
- Department of Veterinary Clinical Studies, Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400 Serdang, Malaysia;
- Institute of Biosciences, Universiti Putra Malaysia, 43400 UPM, Serdang, Malaysia
| | - Yoke Kqueen Cheah
- Department of Biomedical Science, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Malaysia;
- Institute of Biosciences, Universiti Putra Malaysia, 43400 UPM, Serdang, Malaysia
| | - Yin Ping Wong
- Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Kuala Lumpur, Malaysia; (C.C.H.K.); (W.K.C.)
| | - Geok Chin Tan
- Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Kuala Lumpur, Malaysia; (C.C.H.K.); (W.K.C.)
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18
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Andrejew R, Glaser T, Oliveira-Giacomelli Á, Ribeiro D, Godoy M, Granato A, Ulrich H. Targeting Purinergic Signaling and Cell Therapy in Cardiovascular and Neurodegenerative Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1201:275-353. [PMID: 31898792 DOI: 10.1007/978-3-030-31206-0_14] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Extracellular purines exert several functions in physiological and pathophysiological mechanisms. ATP acts through P2 receptors as a neurotransmitter and neuromodulator and modulates heart contractility, while adenosine participates in neurotransmission, blood pressure, and many other mechanisms. Because of their capability to differentiate into mature cell types, they provide a unique therapeutic strategy for regenerating damaged tissue, such as in cardiovascular and neurodegenerative diseases. Purinergic signaling is pivotal for controlling stem cell differentiation and phenotype determination. Proliferation, differentiation, and apoptosis of stem cells of various origins are regulated by purinergic receptors. In this chapter, we selected neurodegenerative and cardiovascular diseases with clinical trials using cell therapy and purinergic receptor targeting. We discuss these approaches as therapeutic alternatives to neurodegenerative and cardiovascular diseases. For instance, promising results were demonstrated in the utilization of mesenchymal stem cells and bone marrow mononuclear cells in vascular regeneration. Regarding neurodegenerative diseases, in general, P2X7 and A2A receptors mostly worsen the degenerative state. Stem cell-based therapy, mainly through mesenchymal and hematopoietic stem cells, showed promising results in improving symptoms caused by neurodegeneration. We propose that purinergic receptor activity regulation combined with stem cells could enhance proliferative and differentiation rates as well as cell engraftment.
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Affiliation(s)
- Roberta Andrejew
- Neuroscience Laboratory, Institute of Chemistry, Department of Biochemistry, University of São Paulo, São Paulo, Brazil
| | - Talita Glaser
- Neuroscience Laboratory, Institute of Chemistry, Department of Biochemistry, University of São Paulo, São Paulo, Brazil
| | - Ágatha Oliveira-Giacomelli
- Neuroscience Laboratory, Institute of Chemistry, Department of Biochemistry, University of São Paulo, São Paulo, Brazil
| | - Deidiane Ribeiro
- Neuroscience Laboratory, Institute of Chemistry, Department of Biochemistry, University of São Paulo, São Paulo, Brazil
| | - Mariana Godoy
- Neuroscience Laboratory, Institute of Chemistry, Department of Biochemistry, University of São Paulo, São Paulo, Brazil.,Laboratory of Neurodegenerative Diseases, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Alessandro Granato
- Neuroscience Laboratory, Institute of Chemistry, Department of Biochemistry, University of São Paulo, São Paulo, Brazil
| | - Henning Ulrich
- Neuroscience Laboratory, Institute of Chemistry, Department of Biochemistry, University of São Paulo, São Paulo, Brazil.
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19
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Sp N, Kang DY, Jo ES, Rugamba A, Kim WS, Park YM, Hwang DY, Yoo JS, Liu Q, Jang KJ, Yang YM. Tannic Acid Promotes TRAIL-Induced Extrinsic Apoptosis by Regulating Mitochondrial ROS in Human Embryonic Carcinoma Cells. Cells 2020; 9:E282. [PMID: 31979292 PMCID: PMC7072125 DOI: 10.3390/cells9020282] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 01/17/2020] [Accepted: 01/22/2020] [Indexed: 12/12/2022] Open
Abstract
: Human embryonic carcinoma (EC; NCCIT) cells have self-renewal ability and pluripotency. Cancer stem cell markers are highly expressed in NCCIT cells, imparting them with the pluripotent nature to differentiate into other cancer types, including breast cancer. As one of the main cancer stem cell pathways, Wnt/β-catenin is also overexpressed in NCCIT cells. Thus, inhibition of these pathways defines the ability of a drug to target cancer stem cells. Tannic acid (TA) is a natural polyphenol present in foods, fruits, and vegetables that has anti-cancer activity. Through Western blotting and PCR, we demonstrate that TA inhibits cancer stem cell markers and the Wnt/β-catenin signaling pathway in NCCIT cells and through a fluorescence-activated cell sorting analysis we demonstrated that TA induces sub-G1 cell cycle arrest and apoptosis. The mechanism underlying this is the induction of mitochondrial reactive oxygen species (ROS) (mROS), which then induce the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated extrinsic apoptosis pathway instead of intrinsic mitochondrial apoptosis pathway. Moreover, ribonucleic acid sequencing data with TA in NCCIT cells show an elevation in TRAIL-induced extrinsic apoptosis, which we confirm by Western blotting and real-time PCR. The induction of human TRAIL also proves that TA can induce extrinsic apoptosis in NCCIT cells by regulating mROS.
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Affiliation(s)
- Nipin Sp
- Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 05029, Korea; (N.S.); (D.Y.K.); (E.S.J.); (A.R.); (W.S.K.)
| | - Dong Young Kang
- Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 05029, Korea; (N.S.); (D.Y.K.); (E.S.J.); (A.R.); (W.S.K.)
| | - Eun Seong Jo
- Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 05029, Korea; (N.S.); (D.Y.K.); (E.S.J.); (A.R.); (W.S.K.)
| | - Alexis Rugamba
- Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 05029, Korea; (N.S.); (D.Y.K.); (E.S.J.); (A.R.); (W.S.K.)
| | - Wan Seop Kim
- Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 05029, Korea; (N.S.); (D.Y.K.); (E.S.J.); (A.R.); (W.S.K.)
| | - Yeong-Min Park
- Department of Immunology, School of Medicine, Konkuk University, Chungju 27478, Korea;
| | - Dae-Yong Hwang
- Department of Surgery, School of Medicine, Konkuk University, Seoul 05029, Korea;
| | - Ji-Seung Yoo
- Department of Immunology, Hokkaido University Graduate School of Medicine, Sapporo 060-0808, Japan;
| | - Qing Liu
- Jilin Green food Engineering Research Institute, Changchun 130000, Jilin, China;
| | - Kyoung-Jin Jang
- Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 05029, Korea; (N.S.); (D.Y.K.); (E.S.J.); (A.R.); (W.S.K.)
| | - Young Mok Yang
- Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 05029, Korea; (N.S.); (D.Y.K.); (E.S.J.); (A.R.); (W.S.K.)
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20
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Topal T, Kim BC, Villa-Diaz LG, Deng CX, Takayama S, Krebsbach PH. Rapid translocation of pluripotency-related transcription factors by external uniaxial forces. Integr Biol (Camb) 2019; 11:41-52. [PMID: 30809641 PMCID: PMC6428113 DOI: 10.1093/intbio/zyz003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 01/22/2019] [Indexed: 11/14/2022]
Abstract
Human embryonic stem cells subjected to a one-time uniaxial stretch for as short as 30-min on a flexible substrate coated with Matrigel experienced rapid and irreversible nuclear-to-cytoplasmic translocation of NANOG and OCT4, but not Sox2. Translocations were directed by intracellular transmission of biophysical signals from cell surface integrins to nuclear CRM1 and were independent of exogenous soluble factors. On E-CADHERIN-coated substrates, presumably with minimal integrin engagement, mechanical strain-induced rapid nuclear-to-cytoplasmic translocation of the three transcription factors. These findings might provide fundamental insights into early developmental processes and may facilitate mechanotransduction-mediated bioengineering approaches to influencing stem cell fate determination.
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Affiliation(s)
- Tuğba Topal
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA
| | - Byoung Choul Kim
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA
- Division of Nano-Bioengineering, Incheon National University, Incheon, Republic of Korea
| | - Luis G Villa-Diaz
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA
- Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI, USA
- Department of Biological Sciences, Oakland University, Rochester, MI, USA
| | - Cheri X Deng
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Shuichi Takayama
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA
- Wallace H Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory School of Medicine, Atlanta, GA, USA
| | - Paul H Krebsbach
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA
- Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI, USA
- Section of Periodontics, University of California, Los Angeles School of Dentistry, Los Angeles, CA, USA
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21
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Sellers ZP, Bujko K, Schneider G, Kucia M, Ratajczak MZ. Novel evidence that pituitary sex hormones regulate migration, adhesion, and proliferation of embryonic stem cells and teratocarcinoma cells. Oncol Rep 2018; 39:851-859. [PMID: 29207191 PMCID: PMC5783624 DOI: 10.3892/or.2017.6108] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 11/07/2017] [Indexed: 12/22/2022] Open
Abstract
The pituitary sex hormones (SexHs): follicle‑stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL) regulate several functions crucial for reproduction, including oogenesis, spermatogenesis, and lactation. An important source of prolactin-like hormones, known as lactogens, is the placenta, and lactogens bind to the PRL receptor (PRLR) with high affinity and thereby mimic the actions of PRL. Recently, it has been demonstrated that pituitary SexHs were involved in metastatic lung cancer, certain sarcomas, and leukemia. In the present study we aimed to investigate whether FSH, LH, and PRL were able to stimulate stem cells involved in early development. To address this issue we employed a murine embryonic stem cell line (ES-D3) as well as two teratocarcinoma cell lines, P19 (murine) and NTera2 (human). We determined that all these cells expressed SexH receptors at the mRNA and protein levels and that stimulation of these receptors induced phosphorylation of p42/44 MAPK, p38 MAPK, and AKT. Moreover, ES-D3, P19, and NTera2 cells responded with increased migration and adhesion to physiological concentrations of pituitary SexHs. In view of these findings we proposed that maternal-derived pituitary SexHs regulate the biology of stem cells involved in early development.
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Affiliation(s)
- Zachariah Payne Sellers
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA
| | - Kamila Bujko
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA
| | - Gabriela Schneider
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA
| | - Magdalena Kucia
- Department of Regenerative Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Mariusz Z. Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA
- Department of Regenerative Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland
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22
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Chen TY, Lee SH, Dhar SS, Lee MG. Protein arginine methyltransferase 7-mediated microRNA-221 repression maintains Oct4, Nanog, and Sox2 levels in mouse embryonic stem cells. J Biol Chem 2018; 293:3925-3936. [PMID: 29378844 DOI: 10.1074/jbc.ra117.000425] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Revised: 01/09/2018] [Indexed: 11/06/2022] Open
Abstract
The stemness maintenance of embryonic stem cells (ESCs) requires pluripotency transcription factors, including Oct4, Nanog, and Sox2. We have previously reported that protein arginine methyltransferase 7 (PRMT7), an epigenetic modifier, is an essential pluripotency factor that maintains the stemness of mouse ESCs, at least in part, by down-regulating the expression of the anti-stemness microRNA (miRNA) miR-24-2. To gain greater insight into the molecular basis underlying PRMT7-mediated maintenance of mouse ESC stemness, we searched for new PRMT7-down-regulated anti-stemness miRNAs. Here, we show that miR-221 gene-encoded miR-221-3p and miR-221-5p are anti-stemness miRNAs whose expression levels in mouse ESCs are directly repressed by PRMT7. Notably, both miR-221-3p and miR-221-5p targeted the 3' untranslated regions of mRNA transcripts of the major pluripotency factors Oct4, Nanog, and Sox2 to antagonize mouse ESC stemness. Moreover, miR-221-5p silenced also the expression of its own transcriptional repressor PRMT7. Transfection of miR-221-3p and miR-221-5p mimics induced spontaneous differentiation of mouse ESCs. CRISPR-mediated deletion of the miR-221 gene, as well as specific antisense inhibitors of miR-221-3p and miR-221-5p, inhibited the spontaneous differentiation of PRMT7-depleted mouse ESCs. Taken together, these findings reveal that the PRMT7-mediated repression of miR-221-3p and miR-221-5p expression plays a critical role in maintaining mouse ESC stemness. Our results also establish miR-221-3p and miR-221-5p as anti-stemness miRNAs that target Oct4, Nanog, and Sox2 mRNAs in mouse ESCs.
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Affiliation(s)
- Tsai-Yu Chen
- From the Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030 and.,Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030
| | - Sung-Hun Lee
- From the Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030 and
| | - Shilpa S Dhar
- From the Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030 and
| | - Min Gyu Lee
- From the Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030 and .,Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030
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Ee MT, Thébaud B. The Therapeutic Potential of Stem Cells for Bronchopulmonary Dysplasia: "It's About Time" or "Not so Fast" ? Curr Pediatr Rev 2018; 14:227-238. [PMID: 30205800 PMCID: PMC6416190 DOI: 10.2174/1573396314666180911100503] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 08/09/2018] [Accepted: 09/10/2018] [Indexed: 12/23/2022]
Abstract
OBJECTIVE While the survival of extremely premature infants has improved over the past decades, the rate of complications - especially for bronchopulmonary dysplasia (BPD) - remains unacceptably high. Over the past 50 years, no safe therapy has had a substantial impact on the incidence and severity of BPD. METHODS This may stem from the multifactorial disease pathogenesis and the increasing lung immaturity. Mesenchymal Stromal Cells (MSCs) display pleiotropic effects and show promising results in neonatal rodents in preventing or rescuing lung injury without adverse effects. Early phase clinical trials are now underway to determine the safety and efficacy of this therapy in extremely premature infants. RESULTS AND CONCLUSION This review summarizes our current knowledge about MSCs, their mechanism of action and the results of preclinical studies that provide the rationale for early phase clinical trials and discuss remaining gaps in our knowledge.
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Affiliation(s)
- Mong Tieng Ee
- Division of Neonatology, Department of Pediatrics, Children's Hospital of Eastern Ontario (CHEO) and CHEO Research Institute, Ottawa, ON, Canada
| | - Bernard Thébaud
- Division of Neonatology, Department of Pediatrics, Children's Hospital of Eastern Ontario (CHEO) and CHEO Research Institute, Ottawa, ON, Canada.,Sinclair Centre for Regenerative Medicine, Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada.,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
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Mandal C, Kim SH, Chai JC, Lee YS, Jung KH, Chai YG. Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro 2017; 46:66-76. [PMID: 28986285 DOI: 10.1016/j.tiv.2017.10.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 08/18/2017] [Accepted: 10/02/2017] [Indexed: 11/17/2022]
Abstract
During the differentiation process, various epigenetic factors regulate the precise expression of important genes and control cellular fate. During this stage, the differentiating cells become vulnerable to external stimuli. Here, we used an early neural differentiation model to observe ethanol-mediated transcriptional alterations. Our objective was to identify important molecular regulators of ethanol-related alterations in the genome during differentiation. A transcriptomic analysis was performed to profile the mRNA expression in differentiating embryoid bodies with or without ethanol treatment. In total, 147 differentially expressed genes were identified in response to 50mM ethanol. Of these differentially expressed genes, 78 genes were up-regulated and 69 genes were down-regulated. Our analysis revealed a strong association among the transcript signatures of the important modulators which were involved in protein modification, protein synthesis and gene expression. Additionally, ethanol-mediated activation of DNA transcription was observed. We also profiled ethanol-responsive transcription factors (TFs), upstream transcriptional regulators and TF-binding motifs in the differentiating embryoid bodies. In this study, we established a platform that we hope will help other researchers determine the ethanol-mediated changes that occur during cellular differentiation.
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Affiliation(s)
- Chanchal Mandal
- Department of Molecular and Life Science, Hanyang University, Ansan, Republic of Korea
| | - Sun Hwa Kim
- Department of Molecular and Life Science, Hanyang University, Ansan, Republic of Korea
| | - Jin Choul Chai
- Department of Molecular and Life Science, Hanyang University, Ansan, Republic of Korea
| | - Young Seek Lee
- Department of Molecular and Life Science, Hanyang University, Ansan, Republic of Korea
| | - Kyoung Hwa Jung
- Institute of Natural Science and Technology, Hanyang University, Ansan, Republic of Korea.
| | - Young Gyu Chai
- Department of Molecular and Life Science, Hanyang University, Ansan, Republic of Korea; Department of Bionanotechnology, Hanyang University, Seoul, Republic of Korea.
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Blits B, Boer GJ, Verhaagen J. Pharmacological, Cell, and Gene Therapy Strategies to Promote Spinal Cord Regeneration. Cell Transplant 2017. [DOI: 10.3727/000000002783985521] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
In this review, recent studies using pharmacological treatment, cell transplantation, and gene therapy to promote regeneration of the injured spinal cord in animal models will be summarized. Pharmacological and cell transplantation treatments generally revealed some degree of effect on the regeneration of the injured ascending and descending tracts, but further improvements to achieve a more significant functional recovery are necessary. The use of gene therapy to promote repair of the injured nervous system is a relatively new concept. It is based on the development of methods for delivering therapeutic genes to neurons, glia cells, or nonneural cells. Direct in vivo gene transfer or gene transfer in combination with (neuro)transplantation (ex vivo gene transfer) appeared powerful strategies to promote neuronal survival and axonal regrowth following traumatic injury to the central nervous system. Recent advances in understanding the cellular and molecular mechanisms that govern neuronal survival and neurite outgrowth have enabled the design of experiments aimed at viral vector-mediated transfer of genes encoding neurotrophic factors, growth-associated proteins, cell adhesion molecules, and antiapoptotic genes. Central to the success of these approaches was the development of efficient, nontoxic vectors for gene delivery and the acquirement of the appropriate (genetically modified) cells for neurotransplantation. Direct gene transfer in the nervous system was first achieved with herpes viral and E1-deleted adenoviral vectors. Both vector systems are problematic in that these vectors elicit immunogenic and cytotoxic responses. Adeno-associated viral vectors and lentiviral vectors constitute improved gene delivery systems and are beginning to be applied in neuroregeneration research of the spinal cord. Ex vivo approaches were initially based on the implantation of genetically modified fibroblasts. More recently, transduced Schwann cells, genetically modified pieces of peripheral nerve, and olfactory ensheathing glia have been used as implants into the injured spinal cord.
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Affiliation(s)
- Bas Blits
- Graduate School Neurosciences Amsterdam, Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam-ZO, The Netherlands
| | - Gerard J. Boer
- Graduate School Neurosciences Amsterdam, Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam-ZO, The Netherlands
| | - Joost Verhaagen
- Graduate School Neurosciences Amsterdam, Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam-ZO, The Netherlands
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Parmar MS, Mishra SR, Somal A, Pandey S, Kumar GS, Sarkar M, Chandra V, Sharma GT. Expression and secretory profile of buffalo fetal fibroblasts and Wharton's jelly feeder layers. Anim Reprod Sci 2017; 180:66-77. [PMID: 28363499 DOI: 10.1016/j.anireprosci.2017.02.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Revised: 02/16/2017] [Accepted: 02/19/2017] [Indexed: 11/25/2022]
Abstract
The present study examined the comparative expression and secretory profile of vital signaling molecules in buffalo fetal fibroblasts (BFF) and Wharton's jelly (BWJ) feeder layers at different passages. Both feeder layers were expanded up to 8th passage. Signaling molecules viz. bone morphogenetic protein 4 (BMP4), fibroblast growth factor 2 (FGF2), leukemia inhibitory factor (LIF) and transforming growth factor beta 1 (TGFB1) and pluripotency-associated transcriptional factors (POU5F1, SOX2, NANOG, KLF4, MYC and FOXD3) were immunolocalized in the both feeder types. A clear variation in the expression pattern of key signaling molecules with passaging was registered in both feeders compared to primary culture (0 passage). The conditioned media (CM) was collected from different passages (2, 4, 6, 8) of both the feeder layers and was quantified using enzyme-linked immunosorbent assay (ELISA). Concomitant to expression profile, protein quantification also revealed differences in the concentration of signaling molecules at different time points. Conjointly, expression and secretory profile revealed that 2nd passage of BFF and 6th passage of BWJ exhibit optimal levels of key signaling molecules thus may be selected as best passages for embryonic stem cells (ESCs) propagation. Further, the effect of mitomycin-C (MMC) treatment on the expression profile of signaling molecules in the selected passages of BFF and BWJ revealed that MMC modulates the expression profile of these molecules. In conclusion, the results indicate that feeder layers vary in expression and secretory pattern of vital signaling molecules with passaging. Based on these findings, the appropriate feeder passages may be selected for the quality propagation of buffalo ESCs.
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Affiliation(s)
- Mehtab S Parmar
- Reproductive Physiology Laboratory, Division of Physiology and Climatology, ICAR-Indian Veterinary Research Institute, Izatnagar-243 122, Bareilly, UP, India
| | - Smruti Ranjan Mishra
- Reproductive Physiology Laboratory, Division of Physiology and Climatology, ICAR-Indian Veterinary Research Institute, Izatnagar-243 122, Bareilly, UP, India
| | - Anjali Somal
- Reproductive Physiology Laboratory, Division of Physiology and Climatology, ICAR-Indian Veterinary Research Institute, Izatnagar-243 122, Bareilly, UP, India
| | - Sriti Pandey
- Reproductive Physiology Laboratory, Division of Physiology and Climatology, ICAR-Indian Veterinary Research Institute, Izatnagar-243 122, Bareilly, UP, India
| | - G Sai Kumar
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar-243 122, Bareilly, UP, India
| | - Mihir Sarkar
- Reproductive Physiology Laboratory, Division of Physiology and Climatology, ICAR-Indian Veterinary Research Institute, Izatnagar-243 122, Bareilly, UP, India
| | - Vikash Chandra
- Reproductive Physiology Laboratory, Division of Physiology and Climatology, ICAR-Indian Veterinary Research Institute, Izatnagar-243 122, Bareilly, UP, India
| | - G Taru Sharma
- Reproductive Physiology Laboratory, Division of Physiology and Climatology, ICAR-Indian Veterinary Research Institute, Izatnagar-243 122, Bareilly, UP, India.
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Lindner M, Bauer G. Accelerating practical applications of cutting edge human iPS cell technologies. Nihon Yakurigaku Zasshi 2017; 149:115-118. [PMID: 28260740 DOI: 10.1254/fpj.149.115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Abstract
The translationally controlled tumor protein (TCTP) is a highly conserved protein that is regulated due to a high number of extracellular stimuli. TCTP has an important role for cell cycle and normal development. On the other side, tumor reversion and malignant transformation have been associated with TCTP. TCTP has been found among the 12 genes that are differentially expressed during mouse oocyte maturation, and an overexpression of this gene was reported in a wide variety of different cancer types. Its antiapoptotic effect is indicated by the interaction with several proapoptotic proteins of the Bcl-2 family and the p53 tumor suppressor protein. In this article, we draw attention to the role of TCTP in cancer, especially, focusing on cell differentiation and tumor reversion, a biological process by which highly tumorigenic cells lose their malignant phenotype. This protein has been shown to be the most strongly downregulated protein in revertant cells compared to the parental cancer cells. Decreased expression of TCTP results either in the reprogramming of cancer cells into reversion or apoptosis. As conventional chemotherapy is frequently associated with the development of drug resistance and high toxicity, the urge for the development of new or additional scientific approaches falls into place. Differentiation therapy aims at reinducing differentiation backward to the nonmalignant cellular state. Here, different approaches have been reported such as the induction of retinoid pathways and the use of histone deacetylase inhibitors. Also, PPARγ agonists and the activation of the vitamin D receptor have been reported as potential targets in differentiation therapy. As TCTP is known as the histamine-releasing factor, antihistaminic drugs have been shown to target this protein. Antihistaminic compounds, hydroxyzine and promethazine, inhibited cell growth of cancer cells and decreased TCTP expression of breast cancer and leukemia cells. Recently, we found that two antihistaminics, levomepromazine and buclizine, inhibited cancer cell growth by direct binding to TCTP and induction of cell differentiation. These data confirmed that TCTP is an exquisite target for anticancer differentiation therapy and antihistaminics have potential to be lead compounds for the direct interaction with TCTP as new inhibitors of human TCTP and tumor growth.
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Affiliation(s)
- Ean-Jeong Seo
- Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128, Mainz, Germany
| | - Nicolas Fischer
- Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128, Mainz, Germany
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128, Mainz, Germany.
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Abstract
The derivation of human embryonic stem (hES) cells heralds a new era in stem cell research, generating excitement for their therapeutic potential in regenerative medicine. Pioneering work of embryologists, developmental biologists, and reproductive medicine practitioners in in vitro fertilization clinics has facilitated hES cell research. This review summarizes current research focused on optimizing hES cell culture conditions for good manufacturing practice, directing hES cell differentiation toward trophectoderm and germ cells, and approaches used to reprogram cells for pluripotent cell derivation. The identification of germ stem cells in the testis and the recent controversy over their existence in the ovary raise the possibility of harnessing them for treating young cancer survivors. There is also the potential to harvest fetal stem cells with pluripotent cell-like properties from discarded placental tissues. The recent identification of adult stem/progenitor cell activity in the human endometrium offers a new understanding of common gynecological diseases. Discoveries resulting from research into embryonic, germ, fetal, and adult stem cells are highly relevant to human reproduction.
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Affiliation(s)
- Caroline E Gargett
- Centre for Women's Health Research, Monash Institute of Medical Research, and Monash University Department of Obstetrics and Gynaecology, Monash Medical Centre, Clayton, Victoria, Australia.
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31
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Elhusseini FM, Saad MAAA, Anber N, Elghannam D, Sobh MA, Alsayed A, El-Dusoky S, Sheashaa H, Abdel-Ghaffar H, Sobh M. Long Term Study of Protective Mechanisms of Human Adipose Derived Mesenchymal Stem Cells on Cisplatin Induced Kidney injury in Sprague-Dawley Rats. J Stem Cells Regen Med 2016. [PMID: 27398000 PMCID: PMC4929892 DOI: 10.46582/jsrm.1201006] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND/AIMS Long-term evaluation of cisplatin induced nephrotoxicity and the probable renal protective activities of stem cells are lacking up until now. We evaluated the early and long-term role of human adipose derived mesenchymal stem cells (ADMSCs) in prevention or amelioration of cisplatin induced acute kidney injury (AKI) in Sprague-Dawley rats. For this, we determined the kidney tissue level of oxidative stress markers in conjugation with a renal histopathological scoring system of both acute and chronic renal changes. METHODS This study used eighty Sprague-Dawley (SD) rats weighing 250-300g. They were assigned into four equal groups (each group n=20): (I) Negative control group, rats injected with single dose of 1 ml normal saline. (II) Positive control cisplatin, rats injected with a single dose of 5 mg/kg I.P in 1 ml saline. (III) Cisplatin and culture media group, rats injected with 0.5 ml of culture media single dose into the tail vein and (IV) Cisplatin and ADMSCs group, rats injected with a single dose of 0.5 ml of culture media containing 5 x10(6)ADMSCs into the tail vein one day after cisplatin administration. Each main group was further divided according to the timing of sacrifice into four subgroups (each subgroup n=5). Rats in the subgroup A were sacrificed after 4 days; subgroup B were sacrificed after 7 days; subgroup C were sacrificed after 11 days; and subgroup D were sacrificed after 30 days. Before sacrifice, 24 hrs.-urine was collected using a metabolic cage. Renal function was evaluated through blood urea nitrogen (BUN), serum creatinine and creatinine clearance. Kidney tissue homogenate oxidative stress parameters, Malondialdehyde (MDA), Superoxide dismutase (SOD) and Glutathione (GSH) were determined. In addition, histopathological analysis for active injury, regenerative and chronic changes was performed. RESULTS ADMSCs were characterized and their capability of differentiation was proved. Cisplatin induced a significant increase in plasma creatinine and tissue MDA and induced a decrease in SOD, GSH and creatinine clearance. ADMSCs attenuated these changes. Cisplatin resulted in prominent histopathological changes in the term of tubular necrosis, atrophy, inflammatory cells infiltration and fibrosis. ADMSCs significantly lowered the injury score at day 4, 7, 11 and 30 with marked regenerative changes starting from day 4 and limited fibrotic score at day 30. CONCLUSION ADMSCs have both protective and regenerative abilities with consequent limitation of the development of renal fibrosis after the cisplatin induced acute tubular necrosis, largely through an anti-oxidative activity.
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Affiliation(s)
| | | | | | | | | | - Aziza Alsayed
- Medical Experimental Research Center (MERC), Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Sara El-Dusoky
- Medical Experimental Research Center (MERC), Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | | | | | - Mohamed Sobh
- Urology and Nephrology Center; Medical Experimental Research Center (MERC), Faculty of Medicine, Mansoura University, Mansoura, Egypt
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RNA Sequencing Reveals the Alteration of the Expression of Novel Genes in Ethanol-Treated Embryoid Bodies. PLoS One 2016; 11:e0149976. [PMID: 26930486 PMCID: PMC4773011 DOI: 10.1371/journal.pone.0149976] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Accepted: 02/08/2016] [Indexed: 12/11/2022] Open
Abstract
Fetal alcohol spectrum disorder is a collective term representing fetal abnormalities associated with maternal alcohol consumption. Prenatal alcohol exposure and related anomalies are well characterized, but the molecular mechanism behind this phenomenon is not well characterized. In this present study, our aim is to profile important genes that regulate cellular development during fetal development. Human embryonic carcinoma cells (NCCIT) are cultured to form embryoid bodies and then treated in the presence and absence of ethanol (50 mM). We employed RNA sequencing to profile differentially expressed genes in the ethanol-treated embryoid bodies from NCCIT vs. EB, NCCIT vs. EB+EtOH and EB vs. EB+EtOH data sets. A total of 632, 205 and 517 differentially expressed genes were identified from NCCIT vs. EB, NCCIT vs. EB+EtOH and EB vs. EB+EtOH, respectively. Functional annotation using bioinformatics tools reveal significant enrichment of differential cellular development and developmental disorders. Furthermore, a group of 42, 15 and 35 transcription factor-encoding genes are screened from all of the differentially expressed genes obtained from NCCIT vs. EB, NCCIT vs. EB+EtOH and EB vs. EB+EtOH, respectively. We validated relative gene expression levels of several transcription factors from these lists by quantitative real-time PCR. We hope that our study substantially contributes to the understanding of the molecular mechanism underlying the pathology of alcohol-mediated anomalies and ease further research.
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Sheashaa H, Lotfy A, Elhusseini F, Aziz AA, Baiomy A, Awad S, Alsayed A, El-Gilany AH, Saad MAAA, Mahmoud K, Zahran F, Salem DA, Sarhan A, Ghaffar HA, Sobh M. Protective effect of adipose-derived mesenchymal stem cells against acute kidney injury induced by ischemia-reperfusion in Sprague-Dawley rats. Exp Ther Med 2016; 11:1573-1580. [PMID: 27168775 PMCID: PMC4840483 DOI: 10.3892/etm.2016.3109] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2014] [Accepted: 12/01/2015] [Indexed: 01/20/2023] Open
Abstract
Acute kidney injury (AKI) is a complex clinical condition associated with significant morbidity and mortality and lacking effective management. Ischemia-reperfusion injury (IRI) remains one of the leading causes of AKI in native and transplanted kidneys. The aim of this study was to evaluate the efficacy of adipose-derived mesenchymal stem cells (ADSCs) in the prevention of renal IRI in rats. The study was conducted on male Sprague-Dawley rats (n=72) weighing 250-300 g. Rats were randomly assigned to three main groups: i) Sham-operated control group (n=24); ii) positive control group, in which rats were subjected to IRI and were administered culture media following 4 h of IRI (n=24); and iii) ADSC group (n=24), in which rats were administered 1×106 ADSCs via the tail vein following 4 h of IRI. Each main group was further divided according to the timing after IRI into four equal-sized subgroups. Renal function was tested via the measurement of serum creatinine levels and creatinine clearance. In addition, malondialdehyde (MDA) levels were determined in serum and renal tissue homogenate as an indicator of oxidative stress. Histopathological changes were analyzed in different regions of the kidney, namely the cortex, outer stripe of the outer medulla (OSOM), inner stripe of the outer medulla (ISOM) and inner medulla. In each region, the scoring system considered active injury changes, regenerative changes and chronic changes. The ADSCs were assessed and their differentiation capability was verified. IRI resulted in a significant increase in serum creatinine, serum and tissue MDA levels and a significant reduction in creatinine clearance compared with those in sham-operated rats,. These changes were attenuated by the use of ADSCs. The prominent histopathological changes in the cortex, ISOM and OSOM were reflected in the injury score, which was significantly evident in the positive control group. The use of ADSCs was associated with significantly lowered injury scores at days 1 and 3; however, no significant effect was observed on day 7. These results indicate that the use of ADSCs ameliorates renal injury and dysfunction associated with IRI in rats.
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Affiliation(s)
- Hussein Sheashaa
- Urology and Nephrology Center, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Ahmed Lotfy
- Medical Experimental Research Center (MERC), Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Fatma Elhusseini
- Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Azza Abdel Aziz
- Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Azza Baiomy
- Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Samah Awad
- Medical Experimental Research Center (MERC), Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Aziza Alsayed
- Medical Experimental Research Center (MERC), Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Abdel-Hady El-Gilany
- Department of Public Health, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Mohamed-Ahdy A A Saad
- Department of Pharmacology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Khaled Mahmoud
- Urology and Nephrology Center, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Faten Zahran
- Biochemistry Department, Faculty of Science, Zagazig University, Zagazig 44516, Egypt
| | - Dalia A Salem
- Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Ahmed Sarhan
- Urology and Nephrology Center, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Hassan Abdel Ghaffar
- Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Mohamed Sobh
- Urology and Nephrology Center, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt; Medical Experimental Research Center (MERC), Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
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Regenerative Applications Using Tooth Derived Stem Cells in Other Than Tooth Regeneration: A Literature Review. Stem Cells Int 2015; 2016:9305986. [PMID: 26798366 PMCID: PMC4699044 DOI: 10.1155/2016/9305986] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2015] [Revised: 09/03/2015] [Accepted: 09/08/2015] [Indexed: 12/13/2022] Open
Abstract
Tooth derived stem cells or dental stem cells are categorized according to the location from which they are isolated and represent a promising source of cells for regenerative medicine. Originally, as one kind of mesenchymal stem cells, they are considered an alternative of bone marrow stromal cells. They share many commonalties but maintain differences. Considering their original function in development and the homeostasis of tooth structures, many applications of these cells in dentistry have aimed at tooth structure regeneration; however, the application in other than tooth structures has been attempted extensively. The availability from discarded or removed teeth can be an innate benefit as a source of autologous cells. Their origin from the neural crest results in exploitation of neurological and numerous other applications. This review briefly highlights current and future perspectives of the regenerative applications of tooth derived stem cells in areas beyond tooth regeneration.
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Ouyang J, Yu W, Liu J, Zhang N, Florens L, Chen J, Liu H, Washburn M, Pei D, Xie T. Cyclin-dependent kinase-mediated Sox2 phosphorylation enhances the ability of Sox2 to establish the pluripotent state. J Biol Chem 2015; 290:22782-94. [PMID: 26139602 DOI: 10.1074/jbc.m115.658195] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Indexed: 11/06/2022] Open
Abstract
Sox2 is a key factor in maintaining self-renewal of embryonic stem cells (ESCs) and adult stem cells as well as in reprogramming differentiated cells back into pluripotent or multipotent stem cells. Although previous studies have shown that Sox2 is phosphorylated in human ESCs, the biological significance of Sox2 phosphorylation in ESC maintenance and reprogramming has not been well understood. In this study we have identified new phosphorylation sites on Sox2 and have further demonstrated that Cdk2-mediated Sox2 phosphorylation at Ser-39 and Ser-253 is required for establishing the pluripotent state during reprogramming but is dispensable for ESC maintenance. Mass spectrometry analysis of purified Sox2 protein has identified new phosphorylation sites on two tyrosine and six serine/Threonine residues. Cdk2 physically interacts with Sox2 and phosphorylates Sox2 at Ser-39 and Ser-253 in vitro. Surprisingly, Sox2 phosphorylation at Ser-39 and Ser-253 is dispensable for ESC self-renewal and cell cycle progression. In addition, Sox2 phosphorylation enhances its ability to establish the pluripotent state during reprogramming by working with Oct4 and Klf4. Finally, Cdk2 can also modulate the ability of Oct4, Sox2, and Klf4 in reprogramming fibroblasts back into pluripotent stem cells. Therefore, this study has for the first time demonstrated that Sox2 phosphorylation by Cdk2 promotes the establishment but not the maintenance of the pluripotent state. It might also help explain why the inactivation of CDK inhibitors such as p53, p21, and Arf/Ink4 promotes the induction of pluripotent stem cells.
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Affiliation(s)
- Juan Ouyang
- From the Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China, Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530 Guangzhou, China
| | - Wei Yu
- Stowers Institute for Medical Research, Kansas City, Missouri 64110
| | - Jing Liu
- Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530 Guangzhou, China
| | - Nian Zhang
- Stowers Institute for Medical Research, Kansas City, Missouri 64110
| | - Laurence Florens
- Stowers Institute for Medical Research, Kansas City, Missouri 64110
| | - Jiekai Chen
- Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530 Guangzhou, China
| | - He Liu
- Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530 Guangzhou, China
| | - Michael Washburn
- Stowers Institute for Medical Research, Kansas City, Missouri 64110, Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, Kansas 66160, and
| | - Duanqing Pei
- Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530 Guangzhou, China,
| | - Ting Xie
- Stowers Institute for Medical Research, Kansas City, Missouri 64110, Department of Anatomy and Cell Biology, University of Kansas School of Medicine, Kansas City, Kansas 66160
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Subbarao RB, Ullah I, Kim EJ, Jang SJ, Lee WJ, Jeon RH, Kang D, Lee SL, Park BW, Rho GJ. Characterization and evaluation of neuronal trans-differentiation with electrophysiological properties of mesenchymal stem cells isolated from porcine endometrium. Int J Mol Sci 2015; 16:10934-51. [PMID: 26006231 PMCID: PMC4463684 DOI: 10.3390/ijms160510934] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Accepted: 05/11/2015] [Indexed: 12/31/2022] Open
Abstract
Endometrial stromal cells (EMSCs) obtained from porcine uterus (n = 6) were positive for mesenchymal stem cell markers (CD29, CD44 and CD90), and negative for epithelial marker CD9 and hematopoietic markers CD34, CD45 analyzed by flow cytometry. Further the cells were positive for expression of mesenchymal markers, CD105, CD140b, and CD144 by PCR. Pluripotent markers OCT4, SOX2, and NANOG were positively expressed in EMSCs analyzed by Western blotting and PCR. Further, differentiation into adipocytes and osteocytes was confirmed by cytochemical staining and lineage specific gene expression by quantitative realtime-PCR. Adipocyte (FABP, LPL, AP2) and osteocyte specific genes (ON, BG, RUNX2) in differentiated EMSCs showed significant (p < 0.05) increase in expression compared to undifferentiated control cells. Neurogenic transdifferentiation of EMSCs exhibited distinctive dendritic morphology with axon projections and neuronal specific genes, NFM, NGF, MBP, NES, B3T and MAP2 and proteins, B3T, NFM, NGF, and TRKA were positively expressed in neuronal differentiated cells. Functional analysis of neuronal differentiated EMSCs displayed voltage-dependence and kinetics for transient outward K+ currents (Ito), at holding potential of -80 mV, Na+ currents and during current clamp, neuronal differentiated EMSCs was more negative than that of control EMSCs. Porcine EMSCs is a suitable model for studying molecular mechanism of transdifferentiation, assessment of electrophysiological properties and their efficiency during in vivo transplantation.
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Affiliation(s)
- Raghavendra Baregundi Subbarao
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine, Gyeongsang National University, Jinju 660-701, Korea.
| | - Imran Ullah
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine, Gyeongsang National University, Jinju 660-701, Korea.
| | - Eun-Jin Kim
- Department of Physiology and Institute of Health Sciences, School of Medicine, Gyeongsang National University, Jinju 660-751, Korea.
| | - Si-Jung Jang
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine, Gyeongsang National University, Jinju 660-701, Korea.
| | - Won-Jae Lee
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine, Gyeongsang National University, Jinju 660-701, Korea.
| | - Ryoung Hoon Jeon
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine, Gyeongsang National University, Jinju 660-701, Korea.
| | - Dawon Kang
- Department of Physiology and Institute of Health Sciences, School of Medicine, Gyeongsang National University, Jinju 660-751, Korea.
| | - Sung-Lim Lee
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine, Gyeongsang National University, Jinju 660-701, Korea.
| | - Bong-Wook Park
- Department of Oral and Maxillofacial Surgery, Institute of Health Science, School of Medicine, Gyeongsang National University, Jinju 660-751, Korea.
| | - Gyu-Jin Rho
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine, Gyeongsang National University, Jinju 660-701, Korea.
- Research Institute of Life Sciences, Gyeongsang National University, Jinju 660-701, Korea.
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Mandal C, Jung KH, Kang SC, Choi MR, Park KS, Chung IY, Chai YG. Knocking down of UTX in NCCIT cells enhance cell attachment and promote early neuronal cell differentiation. BIOCHIP JOURNAL 2015. [DOI: 10.1007/s13206-015-9302-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Krylova TA, Musorina AS, Zenin VV, Yakovleva TK, Poljanskaya GG. A comparative analysis of mesenchymal stem-cell lines derived from bone marrow and limb muscle of early human embryos. ACTA ACUST UNITED AC 2014. [DOI: 10.1134/s1990519x14060042] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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39
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Do EK, Cheon HC, Jang IH, Choi EJ, Heo SC, Kang KT, Bae KH, Cho YS, Seo JK, Yoon JH, Lee TG, Kim JH. Reptin Regulates Pluripotency of Embryonic Stem Cells and Somatic Cell Reprogramming Through Oct4-Dependent Mechanism. Stem Cells 2014; 32:3126-36. [DOI: 10.1002/stem.1827] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Accepted: 07/16/2014] [Indexed: 01/25/2023]
Affiliation(s)
- Eun kyoung Do
- Department of Physiology, School of Medicine; Pusan National University; Yangsan Gyeongsangnam-do Republic of Korea
| | - Hyo Cheon Cheon
- Department of Physiology, School of Medicine; Pusan National University; Yangsan Gyeongsangnam-do Republic of Korea
| | - Il Ho Jang
- Department of Physiology, School of Medicine; Pusan National University; Yangsan Gyeongsangnam-do Republic of Korea
| | - Eun Jung Choi
- Department of Physiology, School of Medicine; Pusan National University; Yangsan Gyeongsangnam-do Republic of Korea
| | - Soon Chul Heo
- Department of Physiology, School of Medicine; Pusan National University; Yangsan Gyeongsangnam-do Republic of Korea
| | - Kyung Taek Kang
- Department of Physiology, School of Medicine; Pusan National University; Yangsan Gyeongsangnam-do Republic of Korea
| | - Kwang Hee Bae
- Research Center for Integrated Cellulomics; Korea Research Institute of Bioscience and Biotechnology; Daejeon Republic of Korea
| | - Yee Sook Cho
- Stem Cell Research Center; Korea Research Institute of Bioscience and Biotechnology; Daejeon Republic of Korea
| | - Jeong Kon Seo
- UNIST Central Research Facility; Ulsan National Institute of Science and Technology; Ulsan Republic of Korea
| | | | | | - Jae Ho Kim
- Department of Physiology, School of Medicine; Pusan National University; Yangsan Gyeongsangnam-do Republic of Korea
- Research Institute of Convergence Biomedical Science and Technology, Pusan National University Yangsan Hospital; Yangsan Gyeongsangnam-do Republic of Korea
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40
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Cell therapies and regenerative medicine. Hepatol Int 2014. [PMID: 26202498 DOI: 10.1007/s12072-013-9512-6] [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: 10/25/2022]
Abstract
Molecular and cell biology has resulted in major advances in our understanding of disease pathogenesis as well as in novel strategies for the diagnosis, therapy and prevention of human diseases. Based on modern molecular, genetic and biochemical methodologies, it is on the one hand possible to identify disease-related point mutations and single nucleotide polymorphisms, for example. On the other hand, using high throughput array and other technologies, it is for example possible to simultaneously analyze thousands of genes or gene products (RNA and proteins), resulting in an individual gene or gene expression profile ('signature'). Such data increasingly allow defining the individual disposition for a given disease and predicting disease prognosis as well as the efficacy of therapeutic strategies in the individual patient ('personalized medicine'). At the same time, the basic discoveries in cell biology, including embryonic and adult stem cells, induced pluripotent stem cells, genetically modified cells and others, have moved regenerative medicine into the center of biomedical research worldwide with a major translational impact on tissue engineering as well as transplantation medicine. All these aspects have greatly contributed to the recent advances in regenerative medicine and the development of novel concepts for the treatment of many human diseases, including liver diseases.
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41
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Acunzo J, Baylot V, So A, Rocchi P. TCTP as therapeutic target in cancers. Cancer Treat Rev 2014; 40:760-9. [PMID: 24650927 DOI: 10.1016/j.ctrv.2014.02.007] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 02/19/2014] [Accepted: 02/21/2014] [Indexed: 01/07/2023]
Abstract
The translationally controlled tumor protein (TCTP) is a highly conserved protein present in eukaryotic organisms. This protein, located both in the cytoplasmic and the nucleus, is expressed in various tissues and is regulated in response to a wide range of extracellular stimuli. TCTP interacts with itself and other protein including MCL1 and p53. TCTP has been shown to play an important role in physiological events, such as cell proliferation, cell death and immune responses but also in stress response and tumor reversion. Moreover, TCTP expression is associated with malignancy and chemoresistance. In this review, we will evaluate pathways regulated by TCTP and current inhibitory strategy to target TCTP in cancerous diseases.
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Affiliation(s)
- Julie Acunzo
- (a)Inserm, U1068, CRCM, Marseille F-13009, France; (b)Institut Paoli-Calmettes, Marseille F-13009, France; (c)Aix-Marseille Univ., Marseille F-13284, France; (d)CNRS, UMR7258, Marseille F-13009, France
| | - Virginie Baylot
- (a)Inserm, U1068, CRCM, Marseille F-13009, France; (b)Institut Paoli-Calmettes, Marseille F-13009, France; (c)Aix-Marseille Univ., Marseille F-13284, France; (d)CNRS, UMR7258, Marseille F-13009, France
| | - Alan So
- (e)University of British Columbia, The Vancouver Prostate Centre 2660- Oak St Vancouver, BC V6H3Z6, Canada
| | - Palma Rocchi
- (a)Inserm, U1068, CRCM, Marseille F-13009, France; (b)Institut Paoli-Calmettes, Marseille F-13009, France; (c)Aix-Marseille Univ., Marseille F-13284, France; (d)CNRS, UMR7258, Marseille F-13009, France.
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42
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Blum HE. Advances in individualized and regenerative medicine. Adv Med Sci 2014; 59:7-12. [PMID: 24797966 DOI: 10.1016/j.advms.2013.12.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2013] [Accepted: 12/11/2013] [Indexed: 12/25/2022]
Abstract
Molecular and cell biology have resulted in major advances in our understanding of disease pathogenesis as well as in novel strategies for the diagnosis, therapy and prevention of human diseases. Based on modern molecular, genetic and biochemical methodologies it is on the one hand possible to identify for example disease-related point mutations and single nucleotide polymorphisms. On the other hand, using high throughput array and other technologies, it is for example possible to simultaneously analyze thousands of genes or gene products (RNA and proteins), resulting in an individual gene or gene expression profile ('signature'). Such data increasingly allow to define the individual disposition for a given disease and to predict disease prognosis as well as the efficacy of therapeutic strategies in the individual patient ('individualized medicine'). At the same time, the basic discoveries in cell biology, including embryonic and adult stem cells, induced pluripotent stem cells, genetically modified cells and others, have moved regenerative medicine into the center of biomedical research worldwide with a major translational impact on tissue engineering as well as transplantation medicine. All these aspects have greatly contributed to the recent advances in regenerative medicine and the development novel concepts for the treatment of many human diseases, including liver diseases.
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43
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Babczyk P, Conzendorf C, Klose J, Schulze M, Harre K, Tobiasch E. Stem Cells on Biomaterials for Synthetic Grafts to Promote Vascular Healing. J Clin Med 2014; 3:39-87. [PMID: 26237251 PMCID: PMC4449663 DOI: 10.3390/jcm3010039] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2013] [Revised: 10/28/2013] [Accepted: 11/16/2013] [Indexed: 12/25/2022] Open
Abstract
This review is divided into two interconnected parts, namely a biological and a chemical one. The focus of the first part is on the biological background for constructing tissue-engineered vascular grafts to promote vascular healing. Various cell types, such as embryonic, mesenchymal and induced pluripotent stem cells, progenitor cells and endothelial- and smooth muscle cells will be discussed with respect to their specific markers. The in vitro and in vivo models and their potential to treat vascular diseases are also introduced. The chemical part focuses on strategies using either artificial or natural polymers for scaffold fabrication, including decellularized cardiovascular tissue. An overview will be given on scaffold fabrication including conventional methods and nanotechnologies. Special attention is given to 3D network formation via different chemical and physical cross-linking methods. In particular, electron beam treatment is introduced as a method to combine 3D network formation and surface modification. The review includes recently published scientific data and patents which have been registered within the last decade.
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Affiliation(s)
- Patrick Babczyk
- Department of Natural Science, Bonn-Rhein-Sieg University of Applied Science, Von-Liebig-Street 20, Rheinbach 53359, Germany.
| | - Clelia Conzendorf
- Faculty of Mechanical Engineering/Process Engineering, University of Applied Science Dresden, Friedrich-List-Platz 1, Dresden 01069, Germany.
| | - Jens Klose
- Faculty of Mechanical Engineering/Process Engineering, University of Applied Science Dresden, Friedrich-List-Platz 1, Dresden 01069, Germany.
| | - Margit Schulze
- Department of Natural Science, Bonn-Rhein-Sieg University of Applied Science, Von-Liebig-Street 20, Rheinbach 53359, Germany.
| | - Kathrin Harre
- Faculty of Mechanical Engineering/Process Engineering, University of Applied Science Dresden, Friedrich-List-Platz 1, Dresden 01069, Germany.
| | - Edda Tobiasch
- Department of Natural Science, Bonn-Rhein-Sieg University of Applied Science, Von-Liebig-Street 20, Rheinbach 53359, Germany.
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44
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Pulianmackal AJ, Kareem AVK, Durgaprasad K, Trivedi ZB, Prasad K. Competence and regulatory interactions during regeneration in plants. FRONTIERS IN PLANT SCIENCE 2014; 5:142. [PMID: 24782880 PMCID: PMC3990048 DOI: 10.3389/fpls.2014.00142] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Accepted: 03/25/2014] [Indexed: 05/08/2023]
Abstract
The ability to regenerate is widely exploited by multitudes of organisms ranging from unicellular bacteria to multicellular plants for their propagation and repair. But the levels of competence for regeneration vary from species to species. While variety of living cells of a plant display regeneration ability, only a few set of cells maintain their stemness in mammals. This highly pliable nature of plant cells in-terms of regeneration can be attributed to their high developmental plasticity. De novo organ initiation can be relatively easily achieved in plants by proper hormonal regulations. Elevated levels of plant hormone auxin induces the formation of proliferating mass of pluripotent cells called callus, which predominantly express lateral root meristem markers and hence is having an identity similar to lateral root primordia. Organ formation can be induced from the callus by modulating the ratio of hormones. An alternative for de novo organogenesis is by the forced expression of plant specific transcription factors. The mechanisms by which plant cells attain competence for regeneration on hormonal treatment or forced expression remain largely elusive. Recent studies have provided some insight into how the epigenetic modifications in plants affect this competence. In this review we discuss the present understanding of regenerative biology in plants and scrutinize the future prospectives of this topic. While discussing about the regeneration in the sporophyte of angiosperms which is well studied, here we outline the regenerative biology of the gametophytic phase and discuss about various strategies of regeneration that have evolved in the domain of life so that a common consensus on the entire process of regeneration can be made.
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Affiliation(s)
| | | | | | | | - Kalika Prasad
- *Correspondence: Kalika Prasad, School of Biology Indian Institute of Science Education and Research, Thiruvananthapuram, India e-mail:
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45
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Wagner RT, Cooney AJ. Minireview: the diverse roles of nuclear receptors in the regulation of embryonic stem cell pluripotency. Mol Endocrinol 2013; 27:864-78. [PMID: 23504955 PMCID: PMC3656235 DOI: 10.1210/me.2012-1383] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Accepted: 02/01/2013] [Indexed: 11/19/2022] Open
Abstract
Extensive research has been devoted to the goal of understanding how a single cell of embryonic origin can give rise to every somatic cell type and the germ cell lineage, a hallmark defined as "pluripotency." The aggregate of this work supports fundamentally important roles for the gene transcription networks inherent to the pluripotent cell. Transcription networks have been identified that are both required for pluripotency, as well as sufficient to reprogram somatic cells to a naive pluripotent state. Several members of the nuclear receptor (NR) superfamily of transcription factors have been identified to play diverse roles in the regulation of pluripotency. The ligand-responsive nature of NRs coupled with the abundance of genetic models available has led to a significant advance in the understanding of NR roles in embryonic stem cell pluripotency. Furthermore, the presence of a ligand-binding domain may lead to development of small molecules for a wide range of therapeutic and research applications, even in cases of NRs that are not known to respond to physiologic ligands. Presented here is an overview of NR regulation of pluripotency with a focus on the transcriptional, proteomic, and epigenetic mechanisms by which they promote or suppress the pluripotent state.
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Affiliation(s)
- Ryan T Wagner
- Department of Cell Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston TX 77030-3498, USA
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46
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Lam J, Segura T. The modulation of MSC integrin expression by RGD presentation. Biomaterials 2013; 34:3938-3947. [PMID: 23465825 PMCID: PMC3650837 DOI: 10.1016/j.biomaterials.2013.01.091] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2013] [Accepted: 01/26/2013] [Indexed: 12/29/2022]
Abstract
Biomaterials designed to mimic the intricate native extracellular matrix (ECM) can use a variety of techniques to control the behavior of encapsulated cells. Common methods include controlling the mechanical properties of the material, incorporating bioactive signals, spatially patterning bioactive signals, and controlling the time-release of bioactive signals. Further design parameters like bioactive signal distribution can be used to manipulate cell behavior. Efforts on clustering adhesion peptides have focused on seeding cells on top of a biomaterial. Here we report the effect of clustering the adhesion peptide RGD on mouse mesenchymal stem cells encapsulated inside three-dimensional hyaluronic acid hydrogels. The clustered bioactive signals resulted in significant differences in both cell spreading and integrin expression. These results indicate that signal RGD peptide clustering is an additional hydrogel design parameter can be used to influence and guide the behavior of encapsulated cells.
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Affiliation(s)
- Jonathan Lam
- University of California Los Angeles, Bioengineering Department, USA
| | - Tatiana Segura
- University of California Los Angeles, Bioengineering Department, USA; University of California Los Angeles, Chemical and Biomolecular Engineering Department, USA.
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47
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Bagul A, Frost JH, Drage M. Stem cells and their role in renal ischaemia reperfusion injury. Am J Nephrol 2013; 37:16-29. [PMID: 23295823 DOI: 10.1159/000345731] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2012] [Accepted: 11/07/2012] [Indexed: 01/03/2023]
Abstract
BACKGROUND Ischaemia-reperfusion injury (IRI) remains one of the leading causes of acute kidney injury (AKI). IRI is an underlying multifactorial pathophysiological process which affects the outcome in both native and transplanted patients. The high morbidity and mortality associated with IRI/AKI and disappointing results from current available clinical therapeutic approaches prompt further research. Stem cells (SC) are undifferentiated cells that can undergo both renewal and differentiation into one or more cell types which can possibly ameliorate IRI. AIM To carry out a detailed literature analysis and construct a comprehensive literature review addressing the role of SC in AKI secondary to IRI. METHODS Evidence favouring the role of SC in renal IRI and evidence showing no benefits of SC in renal IRI are the two main aspects to be studied. The search strategy was based on an extensive search addressing MESH terms and free text terms. RESULTS The majority of studies in the field of renal IRI and stem cell therapy show substantial benefits. CONCLUSIONS Studies were mostly conducted in small animal models, thus underscoring the need for further pre-clinical studies in larger animal models, and results should be taken with caution. SC therapy may be promising though controversy exists in the exact mechanism. Thorough scientific exploration is required to assess mechanism, safety profile, reproducibility and methods to monitor administered SC.
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Affiliation(s)
- Atul Bagul
- Department of Transplantation, MRC Centre for Transplantation, Guys and St. Thomas' NHS Foundation Trust, London, UK.
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48
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Spaas JH, Guest DJ, Van de Walle GR. Tendon Regeneration in Human and Equine Athletes. Sports Med 2012; 42:871-90. [DOI: 10.1007/bf03262300] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Kashir J, Jones C, Child T, Williams SA, Coward K. Viability Assessment for Artificial Gametes: The Need for Biomarkers of Functional Competency1. Biol Reprod 2012; 87:114. [DOI: 10.1095/biolreprod.112.103853] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
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50
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Bhatia H, Sharma R, Dawes J, Khillan JS. Maintenance of feeder free anchorage independent cultures of ES and iPS cells by retinol/vitamin A. J Cell Biochem 2012; 113:3002-10. [DOI: 10.1002/jcb.24177] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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