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Jankowski M, Stefańska K, Suchodolski M, Dompe C, Wąsiatycz G, Kempisty B, Nowicki M, Roszak M. Differential regulation of apoptosis-related genes during long-term culture and differentiation of canine adipose-derived stem cells - a functional bioinformatical analysis. Front Genet 2025; 15:1515778. [PMID: 39834550 PMCID: PMC11743971 DOI: 10.3389/fgene.2024.1515778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 12/11/2024] [Indexed: 01/22/2025] Open
Abstract
Introduction Stem cells derived from adipose tissue are gaining popularity in the field of regenerative medicine due to their adaptability and clinical potential. Their rapid growth, ability to differentiate, and easy extraction with minimal complications make adipose-derived stem cells (ADSCs) a promising option for many treatments, particularly those targeting bone-related diseases. This study analyzed gene expression in canine ADSCs subjected to long-term culture and osteogenic differentiation. Methods ADSCs were isolated from discarded surgical waste and cultured for 14 days with and without differentiation media to assess osteogenic changes. RNA sequencing (RNA-seq) and bioinformatical analysis were performed to obtain comprehensive transcriptomic data. A total of 17793 genes were detected and GO enrichment analysis was performed on the differentially expressed genes to identify significantly up- and downregulated Biological Process (BP) GO terms across each comparison. Results The upregulation of apoptosis-regulating genes and genes related to circulatory system development suggest an induction of these processes, while the downregulation of neurogenesis and gliogenesis genes points to reciprocal regulation during osteogenic differentiation of canine ADSCs. Discussion These findings underscore the potential of ADSCs in bone regeneration and offer valuable insights for advancing tissue engineering, however further studies, including proteomic analyses, are needed to confirm these patterns and their biological significance.
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Affiliation(s)
- Maurycy Jankowski
- Department of Computer Science and Statistics, Poznan University of Medical Sciences, Poznan, Poland
- Deparment of Histology and Embryology, Poznan University of Medical Sciences, Poznan, Poland
- Greater Poland Center of Digital Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Katarzyna Stefańska
- Department of Computer Science and Statistics, Poznan University of Medical Sciences, Poznan, Poland
| | - Michał Suchodolski
- Greater Poland Center of Digital Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Claudia Dompe
- Department of Immunology, Poznan University of Medical Sciences, Poznan, Poland
- Doctoral School, Poznan University of Medical Sciences, Poznan, Poland
| | - Grzegorz Wąsiatycz
- Department of Human Morphology and Embryology, Division of Anatomy, Faculty of Medicine, Wrocław Medical University, Wrocław, Poland
| | - Bartosz Kempisty
- Department of Human Morphology and Embryology, Division of Anatomy, Faculty of Medicine, Wrocław Medical University, Wrocław, Poland
- Institute of Veterinary Medicine, Nicolaus Copernicus University, Torun, Poland
- Physiology Graduate Faculty, North Carolina State University, Raleigh, NC, United States
- Center of Assisted Reproduction, Department of Obstetrics and Gynecology, University Hospital and Masaryk University, Brno, Czechia
| | - Michał Nowicki
- Deparment of Histology and Embryology, Poznan University of Medical Sciences, Poznan, Poland
| | - Magdalena Roszak
- Department of Computer Science and Statistics, Poznan University of Medical Sciences, Poznan, Poland
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Lu K, He L, Guo Z, Li M, Cheng X, Liu S, Zhang T, Chen Q, Zhao R, Yang L, Wu X, Cheng K, Cao P, Wu L, Shahzad M, Zheng M, Jiao L, Wu Y, Li D. PDCD4 deficiency in hepatocytes exacerbates nonalcoholic steatohepatitis through enhanced MHC class II transactivator expression. Metabolism 2024; 161:156036. [PMID: 39342987 DOI: 10.1016/j.metabol.2024.156036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 09/01/2024] [Accepted: 09/17/2024] [Indexed: 10/01/2024]
Abstract
Nonalcoholic steatohepatitis (NASH) is a primary cause of liver cirrhosis and hepatocellular carcinoma, presenting a significant and unmet medical challenge. The necessity to investigate the molecular mechanisms underlying NASH is highlighted by the observed decrease in programmed cell death 4 (PDCD4) expression in NASH patients, suggesting that PDCD4 may play a protective role in maintaining liver health. In this study, we identify PDCD4 as a natural inhibitor of NASH development in mice. The absence of PDCD4 leads to the spontaneous progression of NASH. Notably, PDCD4-deficient hepatocytes display elevated major histocompatibility complex class II (MHCII) expression due to CIITA activation, indicating that PCDC4 prevents the abnormal transformation of hepatocytes into antigen-presenting cells (APCs). Cell co-culture experiments reveal that hepatocytes lacking PDCD4, which resemble APCs, can directly activate CD4+ T cells by presenting multiple peptides, resulting in the release of inflammatory factors. Additionally, both cellular and animal studies show that CIITA promotes lipid accumulation in hepatocytes and exacerbates NASH progression. In summary, our findings reveal a novel role of PDCD4 in regulating CIITA and MHCII expression during NASH development, offering new therapeutic approaches for NASH treatment.
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Affiliation(s)
- Kaikai Lu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Xi'an Jiaotong University, Xi'an, Shaan Xi 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, Shaan Xi, 710061, China
| | - Lei He
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Xi'an Jiaotong University, Xi'an, Shaan Xi 710061, China; Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center of China, Beijing 100034, China
| | - Zizhen Guo
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Mengda Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Xi'an Jiaotong University, Xi'an, Shaan Xi 710061, China; Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xiaona Cheng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Xi'an Jiaotong University, Xi'an, Shaan Xi 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, Shaan Xi, 710061, China
| | - Sitong Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Xi'an Jiaotong University, Xi'an, Shaan Xi 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, Shaan Xi, 710061, China
| | - Tianyun Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Xi'an Jiaotong University, Xi'an, Shaan Xi 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, Shaan Xi, 710061, China; School of Software Engineering, Xi'an Jiaotong University Faculty of Electronic and Information Engineering, Xi'an, Shaan Xi 710049, China
| | - Qian Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Xi'an Jiaotong University, Xi'an, Shaan Xi 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, Shaan Xi, 710061, China
| | - Rong Zhao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Xi'an Jiaotong University, Xi'an, Shaan Xi 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, Shaan Xi, 710061, China
| | - Luyun Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Xi'an Jiaotong University, Xi'an, Shaan Xi 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, Shaan Xi, 710061, China
| | - Xiaodan Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Xi'an Jiaotong University, Xi'an, Shaan Xi 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, Shaan Xi, 710061, China
| | - Kexin Cheng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Xi'an Jiaotong University, Xi'an, Shaan Xi 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, Shaan Xi, 710061, China
| | - Peihai Cao
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaan Xi 710061, China
| | - Litao Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Xi'an Jiaotong University, Xi'an, Shaan Xi 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, Shaan Xi, 710061, China
| | - Muhammad Shahzad
- Department of Pharmacology, University of Health Sciences, Lahore 54600, Pakistan
| | - Minghua Zheng
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou 325000, China
| | - Lianying Jiao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Xi'an Jiaotong University, Xi'an, Shaan Xi 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, Shaan Xi, 710061, China
| | - Yue Wu
- Department of Cardiology, Cardiometabolic Innovation Center of Ministry of Education, First Affiliated Hospital, Xi'an, Shaan Xi 710061, China
| | - Dongmin Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Xi'an Jiaotong University, Xi'an, Shaan Xi 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, Shaan Xi, 710061, China; Department of Cardiology, Cardiometabolic Innovation Center of Ministry of Education, First Affiliated Hospital, Xi'an, Shaan Xi 710061, China.
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Stefańska K, Nemcova L, Blatkiewicz M, Pieńkowski W, Ruciński M, Zabel M, Mozdziak P, Podhorska-Okołów M, Dzięgiel P, Kempisty B. Apoptosis Related Human Wharton's Jelly-Derived Stem Cells Differentiation into Osteoblasts, Chondrocytes, Adipocytes and Neural-like Cells-Complete Transcriptomic Assays. Int J Mol Sci 2023; 24:10023. [PMID: 37373173 DOI: 10.3390/ijms241210023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 05/31/2023] [Accepted: 06/09/2023] [Indexed: 06/29/2023] Open
Abstract
Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) exhibit multilineage differentiation potential, adhere to plastic, and express a specific set of surface markers-CD105, CD73, CD90. Although there are relatively well-established differentiation protocols for WJ-MSCs, the exact molecular mechanisms involved in their in vitro long-term culture and differentiation remain to be elucidated. In this study, the cells were isolated from Wharton's jelly of umbilical cords obtained from healthy full-term deliveries, cultivated in vitro, and differentiated towards osteogenic, chondrogenic, adipogenic and neurogenic lineages. RNA samples were isolated after the differentiation regimen and analyzed using an RNA sequencing (RNAseq) assay, which led to the identification of differentially expressed genes belonging to apoptosis-related ontological groups. ZBTB16 and FOXO1 were upregulated in all differentiated groups as compared to controls, while TGFA was downregulated in all groups. In addition, several possible novel marker genes associated with the differentiation of WJ-MSCs were identified (e.g., SEPTIN4, ITPR1, CNR1, BEX2, CD14, EDNRB). The results of this study provide an insight into the molecular mechanisms involved in the long-term culture in vitro and four-lineage differentiation of WJ-MSCs, which is crucial to utilize WJ-MSCs in regenerative medicine.
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Affiliation(s)
- Katarzyna Stefańska
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland
- Cellivia 3 S.A., 61-623 Poznan, Poland
| | - Lucie Nemcova
- Institute of Animal Physiology and Genetics of the Czech Academy of Sciences, 27721 Libechov, Czech Republic
| | - Małgorzata Blatkiewicz
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland
| | - Wojciech Pieńkowski
- Division of Perinatology and Women's Diseases, Poznan University of Medical Sciences, 60-535 Poznan, Poland
| | - Marcin Ruciński
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland
| | - Maciej Zabel
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
- Division of Anatomy and Histology, University of Zielona Góra, 65-046 Zielona Góra, Poland
| | - Paul Mozdziak
- Prestage Department of Poultry Sciences, North Carolina State University, Raleigh, NC 27695, USA
| | - Marzenna Podhorska-Okołów
- Division of Ultrastructural Research, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
| | - Piotr Dzięgiel
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
| | - Bartosz Kempisty
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
- Division of Anatomy, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
- Department of Obstetrics and Gynecology, University Hospital and Masaryk University, 60177 Brno, Czech Republic
- Physiology Graduate Faculty, North Carolina State University, Raleigh, NC 27695, USA
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IGFBP-6 Alters Mesenchymal Stromal Cell Phenotype Driving Dasatinib Resistance in Chronic Myeloid Leukemia. Life (Basel) 2023; 13:life13020259. [PMID: 36836615 PMCID: PMC9960877 DOI: 10.3390/life13020259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 12/27/2022] [Accepted: 01/14/2023] [Indexed: 01/18/2023] Open
Abstract
Chronic myeloid leukemia (CML), BCR-ABL1-positive, is classified as a myeloproliferative characterized by Philadelphia chromosome/translocation t(9;22) and proliferating granulocytes. Despite the clinical success of tyrosine kinase inhibitors (TKi) agents in the treatment of CML, most patients have minimal residual disease contained in the bone marrow microenvironment, within which stromal cells assume a pro-inflammatory phenotype that determines their transformation in cancer-associated fibroblasts (CAF) which, in turn can play a fundamental role in resistance to therapy. Insulin-like Growth Factor Binding Protein-6 (IGFBP-6) is expressed during tumor development, and is involved in immune-escape and inflammation as well, providing a potential additional target for CML therapy. Here, we aimed at investigating the role of IGFBP-6/SHH/TLR4 axis in TKi response. We used a CML cell line, LAMA84-s, and healthy bone marrow stromal cells, HS-5, in mono- or co-culture. The two cell lines were treated with Dasatinib and/or IGFBP-6, and the expression of inflammatory markers was tested by qRT-PCR; furthermore, expression of IGFBP-6, TLR4 and Gli1 were evaluated by Western blot analysis and immumocytochemistry. The results showed that both co-culture and Dasatinib exposure induce inflammation in stromal and cancer cells so that they modulate the expression of TLR4, and these effects were more marked following IGFBP-6 pre-treatment suggesting that this molecule may confer resistance through the inflammatory processes. This phenomenon was coupled with sonic hedgehog (SHH) signaling. Indeed, our data also demonstrate that HS-5 treatment with PMO (an inducer of SHH) induces significant modulation of TLR4 and overexpression of IGFPB-6 suggesting that the two pathways are interconnected with each other and with the TLR-4 pathway. Finally, we demonstrated that pretreatment with IGFBP-6 and/or PMO restored LAMA-84 cell viability after treatment with Dasatinib, suggesting that both IGFBP-6 and SHH are involved in the resistance mechanisms induced by the modulation of TLR-4, thus indicating that the two pathways may be considered as potential therapeutic targets.
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Denaro S, D’Aprile S, Alberghina C, Pavone AM, Torrisi F, Giallongo S, Longhitano L, Mannino G, Lo Furno D, Zappalà A, Giuffrida R, Tibullo D, Li Volti G, Vicario N, Parenti R. Neurotrophic and immunomodulatory effects of olfactory ensheathing cells as a strategy for neuroprotection and regeneration. Front Immunol 2022; 13:1098212. [PMID: 36601122 PMCID: PMC9806219 DOI: 10.3389/fimmu.2022.1098212] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 12/06/2022] [Indexed: 12/23/2022] Open
Abstract
Accumulating evidence sustains glial cells as critical players during central nervous system (CNS) development, homeostasis and disease. Olfactory ensheathing cells (OECs), a type of specialized glia cells sharing properties with both Schwann cells and astrocytes, are of critical importance in physiological condition during olfactory system development, supporting its regenerative potential throughout the adult life. These characteristics prompted research in the field of cell-based therapy to test OEC grafts in damaged CNS. Neuroprotective mechanisms exerted by OEC grafts are not limited to axonal regeneration and cell differentiation. Indeed, OEC immunomodulatory properties and their phagocytic potential encourage OEC-based approaches for tissue regeneration in case of CNS injury. Herein we reviewed recent advances on the immune role of OECs, their ability to modulate CNS microenvironment via bystander effects and the potential of OECs as a cell-based strategy for tissue regeneration.
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Affiliation(s)
- Simona Denaro
- Section of Physiology, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Simona D’Aprile
- Section of Physiology, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Cristiana Alberghina
- Section of Physiology, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Anna Maria Pavone
- Section of Physiology, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Filippo Torrisi
- Section of Physiology, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Sebastiano Giallongo
- Section of Biochemistry, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Lucia Longhitano
- Section of Biochemistry, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Giuliana Mannino
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy
| | - Debora Lo Furno
- Section of Physiology, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Agata Zappalà
- Section of Physiology, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Rosario Giuffrida
- Section of Physiology, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Daniele Tibullo
- Section of Biochemistry, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Giovanni Li Volti
- Section of Biochemistry, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Nunzio Vicario
- Section of Physiology, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy,*Correspondence: Nunzio Vicario, ; Rosalba Parenti,
| | - Rosalba Parenti
- Section of Physiology, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy,*Correspondence: Nunzio Vicario, ; Rosalba Parenti,
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The Role of Epigenetics in Neuroinflammatory-Driven Diseases. Int J Mol Sci 2022; 23:ijms232315218. [PMID: 36499544 PMCID: PMC9740629 DOI: 10.3390/ijms232315218] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 11/24/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022] Open
Abstract
Neurodegenerative disorders are characterized by the progressive loss of central and/or peripheral nervous system neurons. Within this context, neuroinflammation comes up as one of the main factors linked to neurodegeneration progression. In fact, neuroinflammation has been recognized as an outstanding factor for Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and multiple sclerosis (MS). Interestingly, neuroinflammatory diseases are characterized by dramatic changes in the epigenetic profile, which might provide novel prognostic and therapeutic factors towards neuroinflammatory treatment. Deep changes in DNA and histone methylation, along with histone acetylation and altered non-coding RNA expression, have been reported at the onset of inflammatory diseases. The aim of this work is to review the current knowledge on this field.
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IFN- γ Licensing Does Not Enhance the Reduced Immunomodulatory Potential and Migratory Ability of Differentiation-Induced Porcine Bone Marrow-Derived Mesenchymal Stem Cells in an In Vitro Xenogeneic Application. BIOMED RESEARCH INTERNATIONAL 2021; 2021:4604856. [PMID: 34527737 PMCID: PMC8437647 DOI: 10.1155/2021/4604856] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 08/12/2021] [Accepted: 08/14/2021] [Indexed: 01/10/2023]
Abstract
IFN-γ licensing to mesenchymal stem cells (MSCs) is applied to enhance the therapeutic potential of MSCs. However, although the features of MSCs are affected by several stimuli, little information is available on changes to the therapeutic potential of IFN-γ-licensed differentiated MSCs during xenogeneic applications. Therefore, the present study is aimed at clarifying the effects of adipogenic/osteogenic differentiation and IFN-γ licensing on the in vitro immunomodulatory and migratory properties of porcine bone marrow-derived MSCs in xenogeneic applications using human peripheral blood mononuclear cells (PBMCs). IFN-γ licensing in differentiated MSCs lowered lineage-specific gene expression but did not affect MSC-specific cell surface molecules. Although indoleamine 2,3 deoxygenase (IDO) activity and expression were increased after IFN-γ licensing in undifferentiated MSCs, they were reduced after differentiation. IFN-γ licensing to differentiated MSCs elevated the reduced IDO expression in differentiated MSCs; however, the increase was not sufficient to reach to the level achieved by undifferentiated MSCs. During a mixed lymphocyte reaction with quantification of TNF-α concentration, proliferation and activation of xenogeneic PBMCs were suppressed by undifferentiated MSCs but inhibited to a lesser extent by differentiated MSCs. IFN-γ licensing increasingly suppressed proliferation of PBMCs in undifferentiated MSCs but it was incapable of elevating the reduced immunosuppressive ability of differentiated MSCs. Migratory ability through a scratch assay and gene expression study was reduced in differentiated MSCs than their undifferentiated counterparts; IFN-γ licensing was unable to enhance the reduced migratory ability in differentiated MSCs. Similar results were found in a Transwell system with differentiated MSCs in the upper chamber toward xenogeneic PBMCs in the lower chamber, despite IFN-γ licensing increased the migratory ability of undifferentiated MSCs. Overall, IFN-γ licensing did not enhance the reduced immunomodulatory and migratory properties of differentiated MSCs in a xenogeneic application. This study provides a better understanding of the ways in which MSC therapy can be applied.
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Zhao SF, Ye YX, Xu JD, He Y, Zhang DW, Xia ZY, Wang S. Long non-coding RNA KCNQ1OT1 increases the expression of PDCD4 by targeting miR-181a-5p, contributing to cardiomyocyte apoptosis in diabetic cardiomyopathy. Acta Diabetol 2021; 58:1251-1267. [PMID: 33907874 DOI: 10.1007/s00592-021-01713-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 03/26/2021] [Indexed: 12/19/2022]
Abstract
AIMS Diabetic cardiomyopathy (DCM) is a specific myocardial alteration in patients with diabetics. LncRNA KCNQ1OT1 has been previously demonstrated to be involved in various diabetic complications. Our aims are to further investigate the underlying regulatory mechanisms/pathways of KCNQ1OT1 in DCM. METHODS In vitro and in vivo models of DCM were established in high glucose (HG)-treated human cardiomyocytes and in streptozotocin (STZ)-induced diabetic mice, respectively. Gene and protein expressions were examined by qPCR, western blotting and ELISA. Cell proliferation and apoptosis were determined by CCK8 assay, flow cytometry and TUNEL staining. The association between KCNQ1OT1 and miR-181a-5p, miR-181a-5p and PDCD4 was predicted using bioinformatics methods and subsequently confirmed by dual luciferase reporter and RNA immunoprecipitation assays. Mouse cardiac tissues were collected and analysed using HE staining, Masson's staining and immunohistochemical analysis. RESULTS KCNQ1OT1 and PDCD4 were upregulated in HG-treated human cardiomyocytes, while miR-181a-5p was downregulated. In addition, KCNQ1OT1 could negatively regulate miR-181a-5p expression; meanwhile, miR-181a-5p also negatively regulated PDCD4 expression. KCNQ1OT1 silencing suppressed the expression of inflammatory cytokines and cell apoptosis in vitro, whereas inhibition of miR-181a-5p abrogated those effects of KCNQ1OT1 knockdown. Moreover, overexpressed PDCD4 abolished the inhibition on inflammation and apoptosis caused by miR-181a-5p overexpression. Finally, KCNQ1OT1 knockdown reduced the expression of PDCD4 via regulating miR-181a-5p and inhibited myocardial inflammation and cardiomyocyte apoptosis in the in vivo DCM model. CONCLUSIONS Our findings suggest that KCNQ1OT1 and its target gene miR-181a-5p regulate myocardial inflammation and cardiomyocyte apoptosis by modulating PDCD4 in DCM.
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Affiliation(s)
- Shuo-Fang Zhao
- Department of Anesthesiology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences and Guangdong Cardiovascular Institute, No.102, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080, Guangdong Province, People's Republic of China
| | - Ying-Xian Ye
- Department of Anesthesiology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences and Guangdong Cardiovascular Institute, No.102, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080, Guangdong Province, People's Republic of China
| | - Jin-Dong Xu
- Department of Anesthesiology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences and Guangdong Cardiovascular Institute, No.102, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080, Guangdong Province, People's Republic of China
| | - Yi He
- Department of Anesthesiology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences and Guangdong Cardiovascular Institute, No.102, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080, Guangdong Province, People's Republic of China
| | - Deng-Wen Zhang
- Department of Anesthesiology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences and Guangdong Cardiovascular Institute, No.102, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080, Guangdong Province, People's Republic of China
| | - Zheng-Yuan Xia
- Department of Anesthesiology, The University of Hong Kong, Pok Fu Lam, 999077, Hong Kong SAR, People's Republic of China
| | - Sheng Wang
- Department of Anesthesiology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences and Guangdong Cardiovascular Institute, No.102, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080, Guangdong Province, People's Republic of China.
- Department of Anesthesiology, Linzhi People's Hospital, Linzhi, Tibet, People's Republic of China.
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Jiang Y, Li S, Zhou Q, Liu S, Liu X, Xiao J, Jiang W, Xu Y, Kong D, Wang F, Wei F, Zheng C. PDCD4 Negatively Regulated Osteogenic Differentiation and Bone Defect Repair of Mesenchymal Stem Cells Through GSK-3β/β-Catenin Pathway. Stem Cells Dev 2021; 30:806-815. [PMID: 34088227 DOI: 10.1089/scd.2021.0041] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have been shown to be involved in bone injury repair. Programmed cell death 4 (PDCD4) is not only a tumor suppressor gene but also plays roles in the regulation of MSC function. The aim of the study was to uncover PDCD4 potential regulatory roles and mechanisms in the osteogenic differentiation and bone defect repair of MSCs. shRNA technique was used to knock down PDCD4 expression in umbilical cord-derived mesenchymal stem cells (shPDCD4-UCMSCs). Their phenotype was characterized by flow cytometry and the differentiation potential was verified. We found that PDCD4 knockdown did not affect the surface molecule expression of UCMSCs, but significantly enhanced their osteogenic differentiation and osteogenesis-related molecule expression. Mechanistically, glycogen synthase kinase-3β (GSK-3β) phosphorylation and β-catenin expression were significantly increased in shPDCD4-UCMSCs during the osteogenic differentiation process. The β-catenin inhibitor PNU-74654 reversed shPDCD4-increased osteogenesis and osteogenesis-related molecule expression. The results of animal experiments showed that shPDCD4-UCMSCs markedly improved the defect healing in rabbits. Our findings suggest that PDCD4 acts as a negative regulator of MSC osteogenic differentiation through GSK-3β/β-catenin pathway. Targeting PDCD4 may be a way to improve MSC-mediated therapeutic effects on bone injury.
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Affiliation(s)
- Yang Jiang
- Hematology Department, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Institute of Biotherapy for Hematological Malignancies, Shandong University, Jinan, China.,Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, China
| | - Shuo Li
- Hematology Department, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Hematology Department, Binzhou Medical University Hospital, Binzhou, China
| | - Qian Zhou
- Hematology Department, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Hematology Department, Linyi Central Hospital, Yishui, China
| | - Shenghou Liu
- Department of Joint Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xiaoli Liu
- Hematology Department, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Institute of Biotherapy for Hematological Malignancies, Shandong University, Jinan, China.,Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, China
| | - Juan Xiao
- Hematology Department, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Institute of Biotherapy for Hematological Malignancies, Shandong University, Jinan, China.,Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, China
| | - Wen Jiang
- Hematology Department, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Institute of Medical Sciences, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yaqi Xu
- Hematology Department, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Institute of Biotherapy for Hematological Malignancies, Shandong University, Jinan, China.,Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, China
| | - Dexiao Kong
- Hematology Department, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Institute of Biotherapy for Hematological Malignancies, Shandong University, Jinan, China.,Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, China
| | - Fang Wang
- Institute of Medical Sciences, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Fengtao Wei
- Department of Cardiology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chengyun Zheng
- Hematology Department, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Institute of Biotherapy for Hematological Malignancies, Shandong University, Jinan, China.,Shandong University-Karolinska Institute Collaborative Laboratory for Stem Cell Research, Shandong University, Jinan, China
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10
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Russo C, Mannino G, Patanè M, Parrinello NL, Pellitteri R, Stanzani S, Giuffrida R, Lo Furno D, Russo A. Ghrelin peptide improves glial conditioned medium effects on neuronal differentiation of human adipose mesenchymal stem cells. Histochem Cell Biol 2021; 156:35-46. [PMID: 33728539 PMCID: PMC8277640 DOI: 10.1007/s00418-021-01980-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/01/2021] [Indexed: 12/20/2022]
Abstract
The influences of ghrelin on neural differentiation of adipose-derived mesenchymal stem cells (ASCs) were investigated in this study. The expression of typical neuronal markers, such as protein gene product 9.5 (PGP9.5) and Microtubule Associated Protein 2 (MAP2), as well as glial Fibrillary Acid Protein (GFAP) as a glial marker was evaluated in ASCs in different conditions. In particular, 2 µM ghrelin was added to control ASCs and to ASCs undergoing neural differentiation. For this purpose, ASCs were cultured in Conditioned Media obtained from Olfactory Ensheathing cells (OEC-CM) or from Schwann cells (SC-CM). Data on marker expression were gathered after 1 and 7 days of culture by fluorescence immunocytochemistry and flow cytometry. Results show that only weak effects were induced by the addition of only ghrelin. Instead, dynamic ghrelin-induced modifications were detected on the increased marker expression elicited by glial conditioned media. In fact, the combination of ghrelin and conditioned media consistently induced a further increase of PGP9.5 and MAP2 expression, especially after 7 days of treatment. The combination of ghrelin with SC-CM produced the most evident effects. Weak or no modifications were found on conditioned medium-induced GFAP increases. Observations on the ghrelin receptor indicate that its expression in control ASCs, virtually unchanged by the addition of only ghrelin, was considerably increased by CM treatment. These increases were enhanced by combining ghrelin and CM treatment, especially at 7 days. Overall, it can be assumed that ghrelin favors a neuronal rather than a glial ASC differentiation.
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Affiliation(s)
- Cristina Russo
- Physiology Section, Department of Biomedical and Biotechnological Sciences, University of Catania, via S. Sofia, 97, 95123 Catania, Italy
| | - Giuliana Mannino
- Physiology Section, Department of Biomedical and Biotechnological Sciences, University of Catania, via S. Sofia, 97, 95123 Catania, Italy
| | - Martina Patanè
- Physiology Section, Department of Biomedical and Biotechnological Sciences, University of Catania, via S. Sofia, 97, 95123 Catania, Italy
| | | | - Rosalia Pellitteri
- Institute for Biomedical Research and Innovation, Italian National Research Council, Via P. Gaifami, 18, 95126 Catania, Italy
| | - Stefania Stanzani
- Physiology Section, Department of Biomedical and Biotechnological Sciences, University of Catania, via S. Sofia, 97, 95123 Catania, Italy
| | - Rosario Giuffrida
- Physiology Section, Department of Biomedical and Biotechnological Sciences, University of Catania, via S. Sofia, 97, 95123 Catania, Italy
| | - Debora Lo Furno
- Physiology Section, Department of Biomedical and Biotechnological Sciences, University of Catania, via S. Sofia, 97, 95123 Catania, Italy
| | - Antonella Russo
- Physiology Section, Department of Biomedical and Biotechnological Sciences, University of Catania, via S. Sofia, 97, 95123 Catania, Italy
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11
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Mannino G, Russo C, Longo A, Anfuso CD, Lupo G, Lo Furno D, Giuffrida R, Giurdanella G. Potential therapeutic applications of mesenchymal stem cells for the treatment of eye diseases. World J Stem Cells 2021; 13:632-644. [PMID: 34249232 PMCID: PMC8246249 DOI: 10.4252/wjsc.v13.i6.632] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 05/07/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023] Open
Abstract
Stem cell-based treatments have been extensively explored in the last few decades to develop therapeutic strategies aimed at providing effective alternatives for those human pathologies in which surgical or pharmacological therapies produce limited effects. Among stem cells of different sources, mesenchymal stem cells (MSCs) offer several advantages, such as the absence of ethical concerns, easy harvesting, low immunogenicity and reduced tumorigenesis risks. Other than a multipotent differentiation ability, MSCs can release extracellular vesicles conveying proteins, mRNA and microRNA. Thanks to these properties, new therapeutic approaches have been designed for the treatment of various pathologies, including ocular diseases. In this review, the use of different MSCs and different administration strategies are described for the treatment of diabetic retinopathy, glaucoma, and retinitis pigmentosa. In a large number of investigations, positive results have been obtained by in vitro experiments and by MSC administration in animal models. Most authors agree that beneficial effects are likely related to MSC paracrine activity. Based on these considerations, many clinical trials have already been carried out. Overall, although some adverse effects have been described, promising outcomes are reported. It can be assumed that in the near future, safer and more effective protocols will be developed for more numerous clinical applications to improve the quality of life of patients affected by eye diseases.
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Affiliation(s)
- Giuliana Mannino
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania 95123, Italy
| | - Cristina Russo
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania 95123, Italy
| | - Anna Longo
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania 95123, Italy
| | - Carmelina Daniela Anfuso
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania 95123, Italy
| | - Gabriella Lupo
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania 95123, Italy
| | - Debora Lo Furno
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania 95123, Italy.
| | - Rosario Giuffrida
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania 95123, Italy
| | - Giovanni Giurdanella
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania 95123, Italy
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12
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Effects of High Glucose Concentration on Pericyte-Like Differentiated Human Adipose-Derived Mesenchymal Stem Cells. Int J Mol Sci 2021; 22:ijms22094604. [PMID: 33925714 PMCID: PMC8125146 DOI: 10.3390/ijms22094604] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/19/2021] [Accepted: 04/24/2021] [Indexed: 02/07/2023] Open
Abstract
A pericyte-like differentiation of human adipose-derived mesenchymal stem cells (ASCs) was tested in in vitro experiments for possible therapeutic applications in cases of diabetic retinopathy (DR) to replace irreversibly lost pericytes. For this purpose, pericyte-like ASCs were obtained after their growth in a specific pericyte medium. They were then cultured in high glucose conditions to mimic the altered microenvironment of a diabetic eye. Several parameters were monitored, especially those particularly affected by disease progression: cell proliferation, viability and migration ability; reactive oxygen species (ROS) production; inflammation-related cytokines and angiogenic factors. Overall, encouraging results were obtained. In fact, even after glucose addition, ASCs pre-cultured in the pericyte medium (pmASCs) showed high proliferation rate, viability and migration ability. A considerable increase in mRNA expression levels of the anti-inflammatory cytokines transforming growth factor-β1 (TGF-β1) and interleukin-10 (IL-10) was observed, associated with reduction in ROS production, and mRNA expression of pro-inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), and angiogenic factors. Finally, a pmASC-induced better organization of tube-like formation by retinal endothelial cells was observed in three-dimensional co-culture. The pericyte-like ASCs obtained in these experiments represent a valuable tool for the treatment of retinal damages occurring in diabetic patients.
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13
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Lu K, Chen Q, Li M, He L, Riaz F, Zhang T, Li D. Programmed cell death factor 4 (PDCD4), a novel therapy target for metabolic diseases besides cancer. Free Radic Biol Med 2020; 159:150-163. [PMID: 32745771 DOI: 10.1016/j.freeradbiomed.2020.06.016] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Revised: 06/05/2020] [Accepted: 06/06/2020] [Indexed: 02/06/2023]
Abstract
Programmed cell death factor 4 (PDCD4) is originally described as a tumor suppressor gene that exerts antineoplastic effects by promoting apoptosis and inhibiting tumor cell proliferation, invasion, and metastasis. Several investigations have probed the aberrant expression of PDCD4 with the progression of metabolic diseases, such as polycystic ovary syndrome (PCOS), obesity, diabetes, and atherosclerosis. It has been ascertained that PDCD4 causes glucose and lipid metabolism disorders, insulin resistance, oxidative stress, chronic inflammatory response, and gut flora disorders to regulate the progression of metabolic diseases. This review aims to summarize the latest researches to uncover the structure, expression regulation, and biological functions of PDCD4 and to elucidate the regulatory mechanism of the development of tumors and metabolic diseases. This review has emphasized the understanding of the PDCD4 role and to provide new ideas for the research, diagnosis, and treatment of tumors and metabolic diseases.
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Affiliation(s)
- Kaikai Lu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, 710061, PR China
| | - Qian Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, 710061, PR China
| | - Mengda Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, 710061, PR China
| | - Lei He
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, 710061, PR China
| | - Farooq Riaz
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, 710061, PR China
| | - Tianyun Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, 710061, PR China
| | - Dongmin Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, PR China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, 710061, PR China.
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14
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Ghayour-Mobarhan M, Ferns GA, Moghbeli M. Genetic and molecular determinants of prostate cancer among Iranian patients: An update. Crit Rev Clin Lab Sci 2020; 57:37-53. [PMID: 31895010 DOI: 10.1080/10408363.2019.1657061] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Prostate cancer (PCa) is one of the most common age-related cancers among men. Various environmental and genetic factors are involved in the development and progression of PCa. In most cases, the primary symptoms of disease are not severe. Therefore, it is common for patients to be referred with severe clinical manifestations at advanced stages of disease. Since this malignancy is age related and Iran will face a significant increase in the number of seniors, it is expected that the prevalence of PCa among Iranian men will rise. PCa progression has been observed to be associated with genetic and ethnic factors. It may therefore be clinically useful to determine a panel of genetic markers, in addition to routine diagnostic methods, to detect tumors in the early stages. In the present review, we have summarized the reported genetic markers in PCa Iranian patients to pave the way for the determination of an ethnic specific genetic marker panel for the early detection of PCa. To understand the genetic and molecular biology of PCa among Iranians, we have categorized these genetic markers based on their cellular functions.
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Affiliation(s)
- Majid Ghayour-Mobarhan
- Metabolic Syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Division of Medical Education, Brighton & Sussex Medical School, Brighton, UK
| | - Meysam Moghbeli
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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15
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Alteration of Apoptosis during Differentiation in Human Dental Pulp-Derived Mesenchymal Stem Cell. JOURNAL OF ANIMAL REPRODUCTION AND BIOTECHNOLOGY 2019. [DOI: 10.12750/jarb.34.1.2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
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16
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Lo Furno D, Mannino G, Pellitteri R, Zappalà A, Parenti R, Gili E, Vancheri C, Giuffrida R. Conditioned Media From Glial Cells Promote a Neural-Like Connexin Expression in Human Adipose-Derived Mesenchymal Stem Cells. Front Physiol 2018; 9:1742. [PMID: 30555356 PMCID: PMC6282092 DOI: 10.3389/fphys.2018.01742] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 11/19/2018] [Indexed: 12/12/2022] Open
Abstract
The expression of neuronal and glial connexins (Cxs) has been evaluated in adipose-derived mesenchymal stem cells (ASCs) whose neural differentiation was promoted by a conditioned medium (CM) obtained from cultures of olfactory ensheathing cells (OECs) or Schwann cells (SCs). By immunocytochemistry and flow cytometer analysis it was found that Cx43 was already considerably expressed in naïve ASCs and further increased after 24 h and 7 days from CM exposition. Cx32 and Cx36 were significantly improved in conditioned cultures compared to control ASCs, whereas a decreased expression was noticed in the absence of CM treatments. Cx47 was virtually absent in any conditions. Altogether, high basal levels and induced increases of Cx43 expression suggest a potential attitude of ASCs toward an astrocyte differentiation, whereas the lack of Cx47 would indicate a poor propensity of ASCs to become oligodendrocytes. CM-evoked Cx32 and Cx36 increases showed that a neuronal- or a SC-like differentiation can be promoted by using this strategy. Results further confirm that environmental cues can favor an ASC neural differentiation, either as neuronal or glial elements. Of note, the use of glial products present in CM rather than the addition of chemical agents to achieve such differentiation would resemble "more physiological" conditions of differentiation. As a conclusion, the overexpression of typical neural Cxs would indicate the potential capability of neural-like ASCs to interact with neighboring neural cells and microenvironment.
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Affiliation(s)
- Debora Lo Furno
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania, Italy
| | - Giuliana Mannino
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania, Italy
| | - Rosalia Pellitteri
- Institute of Neurological Sciences, National Research Council, Catania, Italy
| | - Agata Zappalà
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania, Italy
| | - Rosalba Parenti
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania, Italy
| | - Elisa Gili
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Carlo Vancheri
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Rosario Giuffrida
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania, Italy
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17
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Casado-Díaz A, Anter J, Müller S, Winter P, Quesada-Gómez JM, Dorado G. Transcriptomic analyses of the anti-adipogenic effects of oleuropein in human mesenchymal stem cells. Food Funct 2017; 8:1254-1270. [PMID: 28243663 DOI: 10.1039/c7fo00045f] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Extra virgin olive oil has positive effects on health. Oleuropein is a polyphenolic compound present in olive-tree leaves, fruits (olives) and olive oil. It is responsible for the relevant organoleptic and biological properties of olive oil, including antiadipogenic properties. Thus, the effects of oleuropein on the adipogenesis of human bone-marrow mesenchymal stem cells were studied by transcriptomics and differential gene-expression analyses. Oleuropein could upregulate expression of 60% of adipogenesis-repressed genes. Besides, it could activate signaling pathways such as Rho and β-catenin, maintaining cells at an undifferentiated stage. Our data suggest that mitochondrial activity is reduced by oleuropein, mostly during adipogenic differentiation. These results shed light on oleuropein activity on cells, with potential application as a "nutraceutical" for the prevention and treatment of diseases such as obesity and osteoporosis.
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Affiliation(s)
- Antonio Casado-Díaz
- Unidad de Gestión Clínica de Endocrinología y Nutrición, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain. and CIBER de Fragilidad y Envejecimiento Saludable, Spain
| | - Jaouad Anter
- Dep. Genética, Universidad de Córdoba, Campus Rabanales C5-1-O1, 14071 Córdoba, Spain
| | - Sören Müller
- GenXPro, Altenhoferallee 3, 60438 Frankfurt Main, Germany
| | - Peter Winter
- GenXPro, Altenhoferallee 3, 60438 Frankfurt Main, Germany
| | - José Manuel Quesada-Gómez
- Unidad de Gestión Clínica de Endocrinología y Nutrición, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain. and CIBER de Fragilidad y Envejecimiento Saludable, Spain
| | - Gabriel Dorado
- Dep. Bioquímica y Biología Molecular, Campus Rabanales C6-1-E17, Campus de Excelencia Internacional Agroalimentario (ceiA3), Universidad de Córdoba, 14071 Córdoba, Spain and CIBER de Fragilidad y Envejecimiento Saludable, Spain
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18
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Li JZH, Gao W, Ho WK, Lei WB, Wei WI, Chan JYW, Wong TS. The clinical association of programmed cell death protein 4 (PDCD4) with solid tumors and its prognostic significance: a meta-analysis. CHINESE JOURNAL OF CANCER 2016; 35:95. [PMID: 27852288 PMCID: PMC5112731 DOI: 10.1186/s40880-016-0158-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Accepted: 04/15/2016] [Indexed: 12/26/2022]
Abstract
Background Programmed cell death protein 4 (PDCD4) is a novel tumor suppressor protein involved in programmed cell death. Its association with cancer progression has been observed in multiple tumor models, but evidence supporting its association with solid tumors in humans remains controversial. This study aimed to determine the clinical significance and prognostic value of PDCD4 in solid tumors. Methods A systematic literature review was performed to retrieve publications with available clinical information and survival data. The eligibility of the selected articles was based on the criteria of the Dutch Cochrane Centre proposed by the Meta-analysis Of Observational Studies in Epidemiology group. Pooled odds ratios (ORs), hazard ratios (HRs), and 95% confidence intervals (CIs) for survival analysis were calculated. Publication bias was examined by Begg’s and Egger’s tests. Results Clinical data of 2227 cancer patients with solid tumors from 23 studies were evaluated. PDCD4 expression was significantly associated with the differentiation status of head and neck cancer (OR 4.25, 95% CI 1.87–9.66) and digestive system cancer (OR 2.87, 95% CI 1.84–4.48). Down-regulation of PDCD4 was significantly associated with short overall survival of patients with head and neck (HR: 3.44, 95% CI 2.38–4.98), breast (HR: 1.86, 95% CI 1.36–2.54), digestive system (HR: 2.12, 95% CI 1.75–2.56), and urinary system cancers (HR: 3.16, 95% CI 1.06–9.41). Conclusions The current evidence suggests that PDCD4 down-regulation is involved in the progression of several types of solid tumor and is a potential marker for solid tumor prognoses. Its clinical usefulness should be confirmed by large-scale prospective studies.
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Affiliation(s)
- John Zeng Hong Li
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong, SAR, P. R. China
| | - Wei Gao
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong, SAR, P. R. China
| | - Wai-Kuen Ho
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong, SAR, P. R. China
| | - Wen Bin Lei
- Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510080, P. R. China
| | - William Ignace Wei
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong, SAR, P. R. China
| | - Jimmy Yu-Wai Chan
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong, SAR, P. R. China
| | - Thian-Sze Wong
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong, SAR, P. R. China.
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19
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Lo Furno D, Mannino G, Cardile V, Parenti R, Giuffrida R. Potential Therapeutic Applications of Adipose-Derived Mesenchymal Stem Cells. Stem Cells Dev 2016; 25:1615-1628. [PMID: 27520311 DOI: 10.1089/scd.2016.0135] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Stem cells are subdivided into two main categories: embryonic and adult stem cells. In principle, pluripotent embryonic stem cells might differentiate in any cell types of the organism, whereas the potential of adult stem cells would be more restricted. Although adult stem cells from bone marrow have been initially the most extensively studied, those derived from human adipose tissue have been lately more widely investigated, because of several advantages. First, they can be easily obtained in large amounts from subcutaneous adipose tissue, with minimal pain and morbidity for the patients during harvesting. In addition, they feature low immunogenicity and can differentiate not only in cells of mesodermal lineage (adipocytes, osteoblasts, chondrocytes and muscle cells), but also in cells of other germ layers, such as neural or epithelial cells. As their multilineage differentiation capabilities are increasingly highlighted, their possible use in cell-based regenerative medicine is now broadly explored. In fact, starting from in vitro observations, many studies have already entered the preclinical and clinical phases. In this review, because of our main scientific interest, adipogenic, osteogenic, chondrogenic, and neurogenic differentiation abilities of adipose-derived mesenchymal stem cells, as well as their possible therapeutic applications, are chiefly focused. In addition, their ability to differentiate toward muscle, epithelial, pancreatic, and hepatic cells is briefly reported.
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Affiliation(s)
- Debora Lo Furno
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania , Catania, Italy
| | - Giuliana Mannino
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania , Catania, Italy
| | - Venera Cardile
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania , Catania, Italy
| | - Rosalba Parenti
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania , Catania, Italy
| | - Rosario Giuffrida
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania , Catania, Italy
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20
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Jia Z, Wang J, Shi Q, Liu S, Wang W, Tian Y, Lu Q, Chen P, Ma K, Zhou C. SOX6 and PDCD4 enhance cardiomyocyte apoptosis through LPS-induced miR-499 inhibition. Apoptosis 2016; 21:174-83. [PMID: 26659076 PMCID: PMC4712245 DOI: 10.1007/s10495-015-1201-6] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Sepsis-induced cardiac apoptosis is one of the major pathogenic factors in myocardial dysfunction. As it enhances numerous proinflammatory factors, lipopolysaccharide (LPS) is considered the principal mediator in this pathological process. However, the detailed mechanisms involved are unclear. In this study, we attempted to explore the mechanisms involved in LPS-induced cardiomyocyte apoptosis. We found that LPS stimulation inhibited microRNA (miR)-499 expression and thereby upregulated the expression of SOX6 and PDCD4 in neonatal rat cardiomyocytes. We demonstrate that SOX6 and PDCD4 are target genes of miR-499, and they enhance LPS-induced cardiomyocyte apoptosis by activating the BCL-2 family pathway. The apoptosis process enhanced by overexpression of SOX6 or PDCD4, was rescued by the cardiac-abundant miR-499. Overexpression of miR-499 protected the cardiomyocytes against LPS-induced apoptosis. In brief, our results demonstrate the existence of a miR-499-SOX6/PDCD4-BCL-2 family pathway in cardiomyocytes in response to LPS stimulation.
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Affiliation(s)
- Zhuqing Jia
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China, Peking University, No. 38, Xueyuan Road, Haidian District, Beijing, China
| | - Jiaji Wang
- Beijing Jianhua Experimental School, Yuquan Road 66, Haidian District, Beijing, China
| | - Qiong Shi
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China, Peking University, No. 38, Xueyuan Road, Haidian District, Beijing, China
| | - Siyu Liu
- Department of Epidemiology, Rollins School of Public Health, Emory University, 1518 Clifton Road NE, Atlanta, GA, 30322, USA
| | - Weiping Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China, Peking University, No. 38, Xueyuan Road, Haidian District, Beijing, China
| | - Yuyao Tian
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China, Peking University, No. 38, Xueyuan Road, Haidian District, Beijing, China
| | - Qin Lu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China, Peking University, No. 38, Xueyuan Road, Haidian District, Beijing, China
| | - Ping Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China, Peking University, No. 38, Xueyuan Road, Haidian District, Beijing, China
| | - Kangtao Ma
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China, Peking University, No. 38, Xueyuan Road, Haidian District, Beijing, China
| | - Chunyan Zhou
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China, Peking University, No. 38, Xueyuan Road, Haidian District, Beijing, China.
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21
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Lo Furno D, Graziano ACE, Avola R, Giuffrida R, Perciavalle V, Bonina F, Mannino G, Cardile V. A Citrus bergamia Extract Decreases Adipogenesis and Increases Lipolysis by Modulating PPAR Levels in Mesenchymal Stem Cells from Human Adipose Tissue. PPAR Res 2016; 2016:4563815. [PMID: 27403151 PMCID: PMC4926019 DOI: 10.1155/2016/4563815] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 05/25/2016] [Indexed: 02/06/2023] Open
Abstract
The aim of this research was to assess the impact of a well-characterized extract from Citrus bergamia juice on adipogenesis and/or lipolysis using mesenchymal stem cells from human adipose tissue as a cell model. To evaluate the effects on adipogenesis, some cell cultures were treated with adipogenic medium plus 10 or 100 μg/mL of extract. To determine the properties on lipolysis, additional mesenchymal stem cells were cultured with adipogenic medium for 14 days and after this time added with Citrus bergamia for further 14 days. To verify adipogenic differentiation, oil red O staining at 7, 14, 21, and 28 days was performed. Moreover, the expression of peroxisome proliferator-activated receptor gamma (PPAR-γ), adipocytes fatty acid-binding protein (A-FABP), adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), monoglyceride lipase (MGL), 5'-adenosine monophosphate-activated protein kinase (AMPK)α1/2, and pAMPKα1/2 was evaluated by Western blot analysis and the release of glycerol by colorimetric assay. Citrus bergamia extract suppressed the accumulation of intracellular lipids in mesenchymal stem cells during adipogenic differentiation and promoted lipolysis by repressing the expression of adipogenic genes and activating lipolytic genes. Citrus bergamia extract could be a useful natural product for improving adipose mobilization in obesity-related disorders.
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Affiliation(s)
- Debora Lo Furno
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Via S. Sofia 65, 95125 Catania, Italy
| | - Adriana Carol Eleonora Graziano
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Via S. Sofia 65, 95125 Catania, Italy
| | - Rosanna Avola
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Via S. Sofia 65, 95125 Catania, Italy
| | - Rosario Giuffrida
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Via S. Sofia 65, 95125 Catania, Italy
| | - Vincenzo Perciavalle
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Via S. Sofia 65, 95125 Catania, Italy
| | - Francesco Bonina
- Department of Drug Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
| | - Giuliana Mannino
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Via S. Sofia 65, 95125 Catania, Italy
| | - Venera Cardile
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Via S. Sofia 65, 95125 Catania, Italy
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22
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Comparison of Cellular Alterations in Fat Cells Harvested With Laser-Assisted Liposuction and Suction-Assisted Liposuction. J Craniofac Surg 2016; 27:631-5. [DOI: 10.1097/scs.0000000000002589] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
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23
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Wang W, Kratz K, Behl M, Yan W, Liu Y, Xu X, Baudis S, Li Z, Kurtz A, Lendlein A, Ma N. The interaction of adipose-derived human mesenchymal stem cells and polyether ether ketone. Clin Hemorheol Microcirc 2015; 61:301-21. [DOI: 10.3233/ch-152001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Weiwei Wang
- Institute of Biomaterial Science and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, Teltow, Germany
| | - Karl Kratz
- Institute of Biomaterial Science and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, Teltow, Germany
- Helmholtz Virtual Institute - Multifunctional Materials in Medicine, Berlin and Teltow, Teltow, Germany
| | - Marc Behl
- Institute of Biomaterial Science and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, Teltow, Germany
| | - Wan Yan
- Institute of Biomaterial Science and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, Teltow, Germany
- Institute of Chemistry, University of Potsdam, Potsdam, Germany
| | - Yue Liu
- Institute of Biomaterial Science and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, Teltow, Germany
- Institute of Chemistry, University of Potsdam, Potsdam, Germany
| | - Xun Xu
- Institute of Biomaterial Science and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, Teltow, Germany
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
| | - Stefan Baudis
- Institute of Biomaterial Science and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, Teltow, Germany
| | - Zhengdong Li
- Institute of Biomaterial Science and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, Teltow, Germany
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
| | - Andreas Kurtz
- Berlin-Brandenburg Center for Regenerative Therapies, Charité - University Medicine Berlin, Berlin, Germany
- College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Gwangk-ro 1, Gwanak-gu, Seoul, Korea
| | - Andreas Lendlein
- Institute of Biomaterial Science and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, Teltow, Germany
- Helmholtz Virtual Institute - Multifunctional Materials in Medicine, Berlin and Teltow, Teltow, Germany
- Institute of Chemistry, University of Potsdam, Potsdam, Germany
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
| | - Nan Ma
- Institute of Biomaterial Science and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, Teltow, Germany
- Helmholtz Virtual Institute - Multifunctional Materials in Medicine, Berlin and Teltow, Teltow, Germany
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
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24
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Puzio-Kuter AM, Laddha SV, Castillo-Martin M, Sun Y, Cordon-Cardo C, Chan CS, Levine AJ. Involvement of tumor suppressors PTEN and p53 in the formation of multiple subtypes of liposarcoma. Cell Death Differ 2015; 22:1785-91. [PMID: 25822339 PMCID: PMC4648325 DOI: 10.1038/cdd.2015.27] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Revised: 01/21/2015] [Accepted: 02/12/2015] [Indexed: 12/26/2022] Open
Abstract
Liposarcoma (LPS) is a type of soft tissue sarcoma that mostly occurs in adults, and in humans is characterized by amplifications of MDM2 and CDK4. The molecular pathogenesis of this malignancy is still poorly understood and, therefore, we developed a mouse model with conditional inactivation of PTEN and p53 to investigate these pathways in the progression of the disease. We show that deletion of these two tumor suppressors cooperate in the formation of multiple subtypes of LPS (from well-differentiated LPS to pleomorphic LPS). In addition, progression of the tumors is further characterized by the expression of D cyclins and CDK4/6, which allow for continued cell division. Microarray analysis also revealed novel genes that are differentially expressed between different subtypes of LPS, which could aid in understanding the disease and to unravel potential new therapeutic targets.
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Affiliation(s)
- A M Puzio-Kuter
- Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA
| | - S V Laddha
- Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA
| | - M Castillo-Martin
- Icahn School of Medicine at Mount Sinai, Mount Sinai School of Medicine, New York, USA
| | - Y Sun
- Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA
| | - C Cordon-Cardo
- Icahn School of Medicine at Mount Sinai, Mount Sinai School of Medicine, New York, USA
| | - C S Chan
- Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA.,Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Jersey, USA
| | - A J Levine
- Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA.,Institute for Advanced Study, Princeton, New Jersey, USA
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25
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Wang X, Yang P, Liu J, Wu H, Yu W, Zhang T, Fu H, Liu Y, Hai C. RARγ-C-Fos-PPARγ2 signaling rather than ROS generation is critical for all-trans retinoic acid-inhibited adipocyte differentiation. Biochimie 2014; 106:121-30. [PMID: 25173565 DOI: 10.1016/j.biochi.2014.08.009] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Accepted: 08/19/2014] [Indexed: 11/18/2022]
Abstract
Obesity has become a worldwide public health problem, which is mainly determined by excess energy intake and adipose tissue expansion. Adipose tissue expansion can occur through hyperplasia (adipocyte differentiation) or hypertrophy. Retinoic acid was shown to inhibit adipocyte differentiation. However, the molecular mechanism is unclear. In the study, we found that all-trans-retinoic acid (ATRA) inhibited 3T3-L1 adipocyte differentiation. We did not observe significant apoptosis in differentiated adipocytes treated by ATRA. ATRA increased ROS generation and disturbed redox balance. However, antioxidant treatment did not ameliorate the reduction of lipid accumulation induced by ATRA, indicating that ROS generation was not involved in ATRA-inhibited adipocyte differentiation. ATRA reduced C/EBPα, PPARγ and its target gene expression. In the presence of ATRA, retinoic acid receptor (RAR) α/γ expression was increased. Inhibition of RARγ, but not RARα, blocked ATRA-induced reduction of PPARγ2 expression. ATRA induced a profound interaction between RARγ and C-Fos protein, reflected by Co-IP results. C-Fos was found to exhibit a differentiation-dependent DNA binding activity to PPARγ2 promoter. RARγ inhibitor significantly suppressed ATRA-inhibited DNA binding activity of C-Fos to PPARγ2 promoter, indicating that downregulation of C-Fos activity mediated activation of RARγ-exerted reduction of PPARγ2 expression and thus inhibition of adipocyte differentiation induced by ATRA. Taken together, these data demonstrates that RARγ-C-Fos-PPARγ2 signaling rather than ROS generation is critical for ATRA-inhibited adipocyte differentiation.
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Affiliation(s)
- Xin Wang
- Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China.
| | - Peng Yang
- Department of Health Statistics, School of Public Health, Fourth Military Medical University, Xi'an 710032, China
| | - Jiangzheng Liu
- Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China
| | - Hao Wu
- Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China
| | - Weihua Yu
- Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China
| | - Tao Zhang
- Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China
| | - Han Fu
- Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China
| | - Ying Liu
- Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China
| | - Chunxu Hai
- Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China.
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26
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Zhao Y, Gao J, Lu F. Human adipose-derived stem cell adipogenesis induces paracrine regulation of the invasive ability of MCF-7 human breast cancer cells in vitro.. Exp Ther Med 2013; 6:937-942. [PMID: 24137293 PMCID: PMC3797295 DOI: 10.3892/etm.2013.1237] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2013] [Accepted: 07/11/2013] [Indexed: 11/21/2022] Open
Abstract
The aim of this study was to determine the effects of paracrine regulation on the invasive ability of MCF-7 human breast cancer cells through human adipose-derived stem cell (hADSC) adipogenesis. hADSC differentiation of the third and fourth passages of cells was induced in different induction media: osteogenic, adipogenic and chondrogenic. Transwell migration assays in the differently conditioned media, flow cytometry, enzyme-linked immunosorbent assay and western blot analysis for selected cytokines were performed. The flow cytometric analysis demonstrated positive expression of CD29, CD44 and CD105, while expression of CD34 and CD45 was not identified. The transwell migration assay showed that the invasive ability of MCF-7 cells was significantly enhanced during hADSC adipogenesis. hADSCs exerted a significantly positive effect on the invasive activity of MCF-7 cells during adipo-genesis. The results indicate that the high expression levels of activating protein 2 (aP2) in MCF-7 and adipocytes induced for 12 days may be associated with cell growth, invasion and metastasis. Peroxisome proliferator-activated receptor γ may be involved in fatty syntheses during adipogenic initiation and following adipogenic differentiation, possibly acting as a protection factor resulting in cell maturation and differentiation. This study also demonstrated that the expression of vascular endothelial growth factor was repressed by hADSCs, while that of matrix metalloproteinase-2 and urokinase-type plasminogen activator was increased to a significant level.
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Affiliation(s)
- Yang Zhao
- Department of Plastic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
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