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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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Li YY, Qian FC, Zhang GR, Li XC, Zhou LW, Yu ZM, Liu W, Wang QY, Li CQ. FunlncModel: integrating multi-omic features from upstream and downstream regulatory networks into a machine learning framework to identify functional lncRNAs. Brief Bioinform 2024; 26:bbae623. [PMID: 39602828 PMCID: PMC11601888 DOI: 10.1093/bib/bbae623] [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: 08/26/2024] [Revised: 10/26/2024] [Accepted: 11/14/2024] [Indexed: 11/29/2024] Open
Abstract
Accumulating evidence indicates that long noncoding RNAs (lncRNAs) play important roles in molecular and cellular biology. Although many algorithms have been developed to reveal their associations with complex diseases by using downstream targets, the upstream (epi)genetic regulatory information has not been sufficiently leveraged to predict the function of lncRNAs in various biological processes. Therefore, we present FunlncModel, a machine learning-based interpretable computational framework, which aims to screen out functional lncRNAs by integrating a large number of (epi)genetic features and functional genomic features from their upstream/downstream multi-omic regulatory networks. We adopted the random forest method to mine nearly 60 features in three categories from >2000 datasets across 11 data types, including transcription factors (TFs), histone modifications, typical enhancers, super-enhancers, methylation sites, and mRNAs. FunlncModel outperformed alternative methods for classification performance in human embryonic stem cell (hESC) (0.95 Area Under Curve (AUROC) and 0.97 Area Under the Precision-Recall Curve (AUPRC)). It could not only infer the most known lncRNAs that influence the states of stem cells, but also discover novel high-confidence functional lncRNAs. We extensively validated FunlncModel's efficacy by up to 27 cancer-related functional prediction tasks, which involved multiple cancer cell growth processes and cancer hallmarks. Meanwhile, we have also found that (epi)genetic regulatory features, such as TFs and histone modifications, serve as strong predictors for revealing the function of lncRNAs. Overall, FunlncModel is a strong and stable prediction model for identifying functional lncRNAs in specific cellular contexts. FunlncModel is available as a web server at https://bio.liclab.net/FunlncModel/.
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Affiliation(s)
- Yan-Yu Li
- The First Affiliated Hospital & National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
- Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang, Hunan, 421001, China
- School of Computer, University of South China, Hengyang, Hunan, 421001, China
- Institute of Biochemistry and Molecular Biology, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Feng-Cui Qian
- The First Affiliated Hospital & National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
- Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang, Hunan, 421001, China
- School of Computer, University of South China, Hengyang, Hunan, 421001, China
- Institute of Biochemistry and Molecular Biology, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Guo-Rui Zhang
- Institute of Biochemistry and Molecular Biology, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Xue-Cang Li
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, 163000, China
| | - Li-Wei Zhou
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Zheng-Min Yu
- School of Computer, University of South China, Hengyang, Hunan, 421001, China
| | - Wei Liu
- College of Science, Heilongjiang Institute of Technology, Harbin, Heilongjiang, 150000, China
| | - Qiu-Yu Wang
- The First Affiliated Hospital & National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
- Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang, Hunan, 421001, China
- School of Computer, University of South China, Hengyang, Hunan, 421001, China
- Institute of Biochemistry and Molecular Biology, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Chun-Quan Li
- The First Affiliated Hospital & National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
- Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang, Hunan, 421001, China
- Key Laboratory of Rare Pediatric Diseases, Ministry of Education, University of South China, Hengyang, Hunan, 421001, China
- School of Computer, University of South China, Hengyang, Hunan, 421001, China
- Institute of Biochemistry and Molecular Biology, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
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Cao L, Liu Q, Ma Y, Wang S. Identification of immune-related signature with prognosis in children with stage 4 and 4S neuroblastoma. Clin Transl Oncol 2024; 26:905-916. [PMID: 37709978 DOI: 10.1007/s12094-023-03320-4] [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: 04/29/2023] [Accepted: 08/29/2023] [Indexed: 09/16/2023]
Abstract
OBJECTIVE Spontaneous regression of tumors is an attractive phenomenon that most commonly occurs in stage 4S neuroblastoma (NB). However, the mechanism underlying this phenomenon remains unclear. METHODS Datasets correlated with NB were downloaded from online public databases, the differentially expressed genes (DEGs) between stage 4 and 4S associated with immunity were identified, and functional enrichment analysis was utilized to explore the potential functions and signaling pathways of these DEGs. In addition, based on these DEGs, a prognostic signature was constructed and validated, and differences in immune cell infiltration were analyzed. RESULTS A total of 13 DEGs were finally identified, and functional enrichment analysis revealed that these DEGs were primarily enriched in the positive regulation of neuron differentiation and TGF-β signaling pathway. The signature successfully stratifies patients into two risk score groups and performs well in judging prognosis and predicting overall survival time. In addition, the prognostic value of the risk score calculated by the signature was independent of clinical factors. The results of immune cell infiltration showed that patients with a high infiltration of resting CD4 + memory T cells had a better prognosis, while plasma cells had a worse prognosis. CONCLUSION The results of the functional enrichment analysis of these identified DEGs suggested that these DEGs may be related to spontaneous regression of NB. In addition, the prognostic signature has the potential to create new risk stratification in patients with NB.
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Affiliation(s)
- Lijian Cao
- Department of Pediatric Surgical Oncology, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University and the National Clinical Research Center for Child Health and Disorders, Chongqing, 400014, People's Republic of China
| | - Qingqing Liu
- Department of Pediatric Surgical Oncology, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University and the National Clinical Research Center for Child Health and Disorders, Chongqing, 400014, People's Republic of China
| | - Yue Ma
- Department of Pediatric Surgical Oncology, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University and the National Clinical Research Center for Child Health and Disorders, Chongqing, 400014, People's Republic of China
| | - Shan Wang
- Department of Pediatric Surgical Oncology, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University and the National Clinical Research Center for Child Health and Disorders, Chongqing, 400014, People's Republic of China.
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Xu J, Fang S, Wang N, Li B, Huang Y, Fan Q, Shi J, Liu H, Shao Z. Dual-specificity Tyrosine Phosphorylation-regulated Kinase Inhibitor ID-8 Promotes Human Somatic Cell Reprogramming by Activating PDK4 Expression. Stem Cell Rev Rep 2022; 18:2074-2087. [PMID: 35080746 DOI: 10.1007/s12015-021-10294-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/27/2021] [Indexed: 10/19/2022]
Abstract
BACKGROUND Human induced pluripotent stem cells (hiPSCs) hold great potentials in disease modeling, drug screening and cell therapy. However, efficiency and costs of hiPSCs preparation still need to be improved. METHODS We screened the compounds that target signaling pathways, epigenetic modifications or metabolic-process regulation to replace the growth factors. After small molecule treatment, TRA-1-60, which is a cell surface antigen expressed by human embryonic stem cells (hESCs), staining was performed to quantify the efficiency of somatic cell reprogramming. Next, small molecule cocktail-induced ESCs or iPSCs were examined with pluripotent markers expression. Finally, Genome-wide gene expression profile was analyzed by RNA-seq to illustrate the mechanism of human somatic cell reprogramming. RESULT Here, we found that a dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) inhibitor ID-8 robustly enhanced human somatic cell reprogramming by upregulation of pyruvate dehydrogenase kinase 4 (PDK4) and activation of glycolysis. Furthermore, we identified a novel growth-factor-free hiPSC generation system using small molecules ID-8 (I) and TGFβ signal pathway agonist Kartogenin (K). Importantly, we developed IK medium combined with low-dose bFGF to support the long-term expansion of human pluripotent stem cells. IK-iPSCs showed pluripotency and normal karyotype. CONCLUSIONS Our studies may provide a novel growth-factor-free culture system to facilitate the generation of hiPSCs for multiple applications in regenerative medicine. In Brief Xu et at. found that a dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) inhibitor ID-8 robustly enhanced human somatic cell reprogramming by upregulation of PDK4 and activation of glycolysis. Furthermore, we established a novel growth-factor-free hiPSC generation system using small molecules ID-8/Kartogenin (IK). IK medium combined with Low-dose bFGF (IKB medium) supported the long-term expansion of human pluripotent stem cells. Highlights ID-8 Enhanced Reprogramming of Human Fibroblasts and Astrocytes Establishment of the Growth-factor-free Reprogramming System Using Small Molecule Compounds IK IKB Medium Maintained the Long-term Expansion of Human Pluripotent Stem Cells ID-8 Promoted Human Somatic Cell Reprogramming by Activating PDK4 Expression.
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Affiliation(s)
- Jinhong Xu
- Fujian Provincial Key Laboratory of Neurodegenerative, Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
- Institute for Translational Brain Research, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200032, China
| | - Shi Fang
- Fujian Provincial Key Laboratory of Neurodegenerative, Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
- Institute for Translational Brain Research, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200032, China
| | - Naweng Wang
- Institute for Translational Brain Research, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200032, China
| | - Bo Li
- Key Laboratory of Biomedical Engineering of Fujian Province, Research Center of Biomedical Engineering of Xiamen, Department of Biomaterials, College of Materials, Xiamen University, Xiamen, 361005, People's Republic of China
| | - Yongheng Huang
- Fujian Provincial Key Laboratory of Neurodegenerative, Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China
- Institute for Translational Brain Research, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200032, China
| | - Qi Fan
- Institute for Translational Brain Research, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200032, China
| | - Jingyi Shi
- Institute for Translational Brain Research, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200032, China
| | - Huihui Liu
- Institute for Translational Brain Research, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200032, China
| | - Zhicheng Shao
- Fujian Provincial Key Laboratory of Neurodegenerative, Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, 361005, Fujian, China.
- Institute for Translational Brain Research, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200032, China.
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Spontaneously and reversibly forming phospholipid polymer hydrogels as a matrix for cell engineering. Biomaterials 2020; 230:119628. [DOI: 10.1016/j.biomaterials.2019.119628] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 11/11/2019] [Accepted: 11/11/2019] [Indexed: 12/16/2022]
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Ginsenoside Rb1 promotes the growth of mink hair follicle via PI3K/AKT/GSK-3β signaling pathway. Life Sci 2019; 229:210-218. [PMID: 31102746 DOI: 10.1016/j.lfs.2019.05.033] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Revised: 04/29/2019] [Accepted: 05/13/2019] [Indexed: 12/20/2022]
Abstract
AIMS Hair follicles play a critical role in the process of hair growth. The dermal papilla cells (DPCs) are an important component in the hair follicle regeneration and growth. This study investigated the effects of ginsenoside Rb1 on the growth of cultured mink hair follicles and DPCs. MAIN METHODS The mink hair follicles were treated with ginsenoside Rb1 for 9 days and their lengths were measured every three days. Real-time PCR was used to determine the mRNA expression of vascularization endothelial growth factor A (VEGF-A), VEGF receptor 2 (VEGF-R2) and TGF-β1. In addition, the levels of proteins were detected by western blot. Cell proliferation was determined by immunofluorescence staining of proliferation marker Ki-67 and cell cycle analysis was performed on flow cytometry. Moreover, cell migration was evaluated by wound healing assay. KEY FINDINGS Ginsenoside Rb1 promoted the growth of hair follicles, and proliferation and migration of DPCs. Ginsenoside Rb1 improved the expression levels of VEGFA and VEGF-R2, while attenuated the TGF-β1 expression both in hair follicles and DPCs. Furthermore, ginsenoside Rb1 facilitated the activation of PI3K/AKT/GSK-3β signaling pathway in hair follicles and DPCs. SIGNIFICANCE The results reveals a crucial role of PI3K/AKT/GSK-3β signaling pathway in ginsenoside Rb1-induced growth of hair follicles and DPCs.
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A Survey of Strategies to Modulate the Bone Morphogenetic Protein Signaling Pathway: Current and Future Perspectives. Stem Cells Int 2016; 2016:7290686. [PMID: 27433166 PMCID: PMC4940573 DOI: 10.1155/2016/7290686] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Accepted: 05/24/2016] [Indexed: 12/14/2022] Open
Abstract
Bone morphogenetic proteins (BMPs) constitute the largest subdivision of the TGF-β family of ligands and are unequivocally involved in regulating stem cell behavior. Appropriate regulation of canonical BMP signaling is critical for the development and homeostasis of numerous human organ systems, as aberrations in the BMP pathway or its regulation are increasingly associated with diverse human pathologies. In this review, we provide a wide-perspective on strategies that increase or decrease BMP signaling. We briefly outline the current FDA-approved approaches, highlight emerging next-generation technologies, and postulate prospective avenues for future investigation. We also detail how activating other pathways may indirectly modulate BMP signaling, with a particular emphasis on the relationship between the BMP and Activin/TGF-β pathways.
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Kim MO, Ryu JM, Suh HN, Park SH, Oh YM, Lee SH, Han HJ. cAMP Promotes Cell Migration Through Cell Junctional Complex Dynamics and Actin Cytoskeleton Remodeling: Implications in Skin Wound Healing. Stem Cells Dev 2015; 24:2513-24. [PMID: 26192163 DOI: 10.1089/scd.2015.0130] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Stem cells have attracted great interest for their therapeutic capacity in tissue regeneration. Cyclic adenosine 3',5'-monophosphate (cAMP), existing in high concentration at wound sites, mediated various signaling pathways such as cytoskeleton dynamics, cell adhesion, and cell migration in stem cells, which suggest the critical roles of cAMP in the wound healing process through functional regulation of stem cells. However, the mechanisms behind the effect of cAMP on mouse embryonic stem cell (mESC) motility and its roles on skin wound healing remain to be fully elucidated. In the present study, 8-Bromo cAMP-treated mESCs showed significant wound closure and improved neovascularization. Moreover, 8-Bromo cAMP stimulated mESC migration into the wound bed. 8-Bromo cAMP also increased ESC motility in in vitro migration assay. 8-Bromo cAMP induced myosin light chain phosphorylation through Rac1 and Cdc42 signaling, which were involved in 8-Bromo cAMP-induced decrease in expression of junction proteins (connexin 43, E-cadherin, and occludin) at the plasma membrane. Subsequently, 8-Bromo cAMP induced the disruption of cell junctions (including gap junctions, adherens junctions, and tight junctions), which reduced the function of the gap junctions and cell adhesion. In addition, 8-Bromo cAMP-induced Rac1 and Cdc42 activation increased Arp3, TOCA, PAK, and N-WASP expression, but decreased cofilin phosphorylation level, which elicited actin cytoskeleton remodeling. In contrast to the control, 8-Bromo cAMP evoked a substantial migration of cells into the denuded area, which was blocked by the small interfering RNAs of the signaling pathway-related molecules or by inhibitors. In conclusion, cAMP enhanced the migration of mESCs through effective coordination of junctional disruption and actin cytoskeleton remodeling, which increased the wound healing capacity of ESCs.
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Affiliation(s)
- Mi Ok Kim
- 1 Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University , Seoul, Republic of Korea.,2 BK21 PLUS Creative Veterinary Research Center, Seoul National University , Seoul, Republic of Korea
| | - Jung Min Ryu
- 1 Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University , Seoul, Republic of Korea.,2 BK21 PLUS Creative Veterinary Research Center, Seoul National University , Seoul, Republic of Korea
| | - Han Na Suh
- 1 Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University , Seoul, Republic of Korea.,2 BK21 PLUS Creative Veterinary Research Center, Seoul National University , Seoul, Republic of Korea
| | - Soo Hyun Park
- 3 College of Veterinary Medicine, Chonnam National University , Gwangju, Republic of Korea
| | - Yeon-Mok Oh
- 4 Department of Pulmonary and Critical Care Medicine, and Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Republic of Korea
| | - Sang Hun Lee
- 5 Medical Science Research Institute, Soonchunhyang University Seoul Hospital , Seoul, Republic of Korea
| | - Ho Jae Han
- 1 Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University , Seoul, Republic of Korea.,2 BK21 PLUS Creative Veterinary Research Center, Seoul National University , Seoul, Republic of Korea
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Zhu G, Fei T, Li Z, Yan X, Chen YG. Activin Regulates Self-renewal and Differentiation of Trophoblast Stem Cells by Down-regulating the X Chromosome Gene Bcor. J Biol Chem 2015. [PMID: 26221038 DOI: 10.1074/jbc.m115.674127] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The development of a functional placenta is largely dependent upon proper proliferation and differentiation of trophoblast stem cells (TSCs). Activin signaling has long been regarded to play important roles during this process, but the exact mechanism is largely unknown. Here, we demonstrate that the X chromosome gene BCL-6 corepressor (Bcor) is a critical downstream effector of activin to fine-tune mouse TSC fate decision. Bcor was specifically down-regulated by activin A in TSCs in a dose-dependent manner, and immediately up-regulated upon TSC differentiation. Knockdown of Bcor partially compensated for the absence of activin A in maintaining the self-renewal of TSCs together with FGF4, while promoting syncytiotrophoblast differentiation in the absence of FGF4. Moreover, the impaired trophoblast giant cell and spongiotrophoblast differentiation upon Bcor knockdown also resembled the function of activin. Reporter analysis showed that BCOR inhibited the expression of the key trophoblast regulator genes Eomes and Cebpa by binding to their promoter regions. Our findings provide us with a better understanding of placental development and placenta-related diseases.
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Affiliation(s)
- Gaoyang Zhu
- From the The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Teng Fei
- From the The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Zhongwei Li
- From the The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Xiaohua Yan
- From the The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Ye-Guang Chen
- From the The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
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Kubanov AA, Gallyamova YUA, Selezneva OA. Role of peptide growth factors in the rhythm of change hair. VESTNIK DERMATOLOGII I VENEROLOGII 2015. [DOI: 10.25208/0042-4609-2015-91-3-54-61] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
Abstract
The article presents current data on the role growth factors play in hair physiology. Based on a review of literature, the authors described the role growth factors play for initiating, suppressing the growth and differentiating hair follicles. According to them, each morphologic development stage of hair follicles is characterized by its own factor expression pattern. Referring to experimental and clinical studies, the authors describe the role some growth factors play for mechanisms promoting the development of androgynous and focal alopecia.
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Li J, Yang Z, Li Z, Gu L, Wang Y, Sung C. Exogenous IGF-1 promotes hair growth by stimulating cell proliferation and down regulating TGF-β1 in C57BL/6 mice in vivo. Growth Horm IGF Res 2014; 24:89-94. [PMID: 24797500 DOI: 10.1016/j.ghir.2014.03.004] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2013] [Revised: 03/07/2014] [Accepted: 03/23/2014] [Indexed: 01/02/2023]
Abstract
OBJECTIVE Insulin-like growth factor 1 (IGF-1) increases the growth of cultured hair follicles and plays a role in regulating hair migration during the development of hair follicles in transgenic mice. However, the exogenous effect of IGF-1 on hair growth in wild-type mice has not been reported. In the present study, we examined whether IGF-1 was an important regulator of hair follicle growth in wide-type mice in vivo. DESIGN C57BL/6 mice were injected with different concentrations of IGF-1 on dorsal skin. The treated tissues were analyzed by immunoassay methods for TGF-β1 and BrdU. RESULTS Local injection of IGF-1 increased hair follicle number and prolonged the growing phase during the transition from anagen to telogen. Meanwhile, immunology analyses revealed that IGF-1 also stimulated the proliferation of follicle cells in anagen of the matrix and down regulated TGF-β1 expression in hair follicles. CONCLUSIONS These observations suggest that IGF-1 is an effective stimulator of hair follicle development in wide-type mice in vivo and may be a promising drug candidate for baldness therapy.
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Affiliation(s)
- Jingjie Li
- Department of Food Science and Technology, Chungnam National University, Daejeon 305-764, Republic of Korea
| | - Zhihong Yang
- College of Life Science, Huzhou University, Huzhou, Zhejiang 31300, PR China
| | - Zheng Li
- Department of Food Science and Technology, Chungnam National University, Daejeon 305-764, Republic of Korea
| | - Lijuan Gu
- Department of Food Science and Technology, Chungnam National University, Daejeon 305-764, Republic of Korea
| | - Yunbo Wang
- Department of Food Science and Technology, Chungnam National University, Daejeon 305-764, Republic of Korea
| | - Changkeun Sung
- Department of Food Science and Technology, Chungnam National University, Daejeon 305-764, Republic of Korea.
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Li Y, Zhang Y, Zhang X, Sun J, Hao J. BMP4/Smad Signaling Pathway Induces the Differentiation of Mouse Spermatogonial Stem Cells via Upregulation of Sohlh2. Anat Rec (Hoboken) 2014; 297:749-57. [DOI: 10.1002/ar.22891] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2013] [Accepted: 01/10/2014] [Indexed: 01/17/2023]
Affiliation(s)
- Yi Li
- Department of Histology and Embryology; School of Medicine, Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University; Jinan 250012 People's Republic of China
- Obstetric Genetic Disease Laboratory; Maternal and Child Health Hospital of Zibo City; Zibo 255029 People's Republic of China
| | - Yuecun Zhang
- Department of Gynaecology and Obstetrics; Qilu Hospital, Shandong University; Jinan 250012 People's Republic of China
| | - Xiaoli Zhang
- Department of Histology and Embryology; School of Medicine, Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University; Jinan 250012 People's Republic of China
| | - Jinhao Sun
- Department of Human Anatomy; School of Medicine; Shandong University; Jinan 250012 People's Republic of China
| | - Jing Hao
- Department of Histology and Embryology; School of Medicine, Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University; Jinan 250012 People's Republic of China
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Hu P, Shen Z, Tu H, Zhang L, Shi T. Integrating multiple resources to identify specific transcriptional cooperativity with a Bayesian approach. ACTA ACUST UNITED AC 2013; 30:823-30. [PMID: 24192543 DOI: 10.1093/bioinformatics/btt596] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
MOTIVATION Limited cohort of transcription factors is capable to structure various gene-expression patterns. Transcriptional cooperativity (TC) is deemed to be the main mechanism of complexity and precision in regulatory programs. Although many data types generated from numerous experimental technologies are utilized in an attempt to understand combinational transcriptional regulation, complementary computational approach that can integrate diverse data resources and assimilate them into biological model is still under development. RESULTS We developed a novel Bayesian approach for integrative analysis of proteomic, transcriptomic and genomic data to identify specific TC. The model evaluation demonstrated distinguishable power of features derived from distinct data sources and their essentiality to model performance. Our model outperformed other classifiers and alternative methods. The application that contextualized TC within hepatocarcinogenesis revealed carcinoma associated alterations. Derived TC networks were highly significant in capturing validated cooperativity as well as revealing novel ones. Our methodology is the first multiple data integration approach to predict dynamic nature of TC. It is promising in identifying tissue- or disease-specific TC and can further facilitate the interpretation of underlying mechanisms for various physiological conditions. CONTACT tieliushi01@gmail.com SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
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Affiliation(s)
- Pengzhan Hu
- Center for Bioinformatics and Computational Biology, Shanghai Key Laboratory of Regulatory Biology, the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
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14
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Li P, Chen Y, Meng X, Kwok KY, Huang X, Choy KW, Wang CC, Lan H, Yuan P. Suppression of malignancy by Smad3 in mouse embryonic stem cell formed teratoma. Stem Cell Rev Rep 2013; 9:709-720. [PMID: 23794057 DOI: 10.1007/s12015-013-9452-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Disease associated gene deficient embryonic stem cells can serve as valuable in vitro models to study disease mechanisms and screen drugs. Smad3 mediated TGF-β/Activin/Nodal signaling plays important roles in many biological processes. Despite numerous studies regarding Smad3 function, the role of Smad3 in mouse ES cells is not well studied. To understand the function of Smad3 in mouse ES cells, we derived Smad3-/- ES cells and wild type ES cells. Smad3-/- ES cells display no defect on self-renewal. They express similar level of pluripotent genes and lineage genes compared to wild type ES cells. However, Smad3 ablation results in transient difference in germ layer marker expression during embryoid body formation. Mesoderm lineage marker expression is significantly reduced in the embryoid body formed by Smad3-/- ES cells compared to wild type ES cells. Intriguingly, subcutaneous injection of Smad3-/- ES cells into nude mice leads to formation of malignant immature teratomas, whilst wild type ES cells tend to form mature teratomas. Smad3-/- ES cell formed teratomas can therefore provide a new model for the study of the mechanism of malignant teratomas.
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Affiliation(s)
- Peng Li
- Department of Chemical Pathology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China
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15
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Shaw L, Sneddon SF, Zeef L, Kimber SJ, Brison DR. Global gene expression profiling of individual human oocytes and embryos demonstrates heterogeneity in early development. PLoS One 2013; 8:e64192. [PMID: 23717564 PMCID: PMC3661520 DOI: 10.1371/journal.pone.0064192] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2013] [Accepted: 04/10/2013] [Indexed: 11/19/2022] Open
Abstract
Early development in humans is characterised by low and variable embryonic viability, reflected in low fecundity and high rates of miscarriage, relative to other mammals. Data from assisted reproduction programmes provides additional evidence that this is largely mediated at the level of embryonic competence and is highly heterogeneous among embryos. Understanding the basis of this heterogeneity has important implications in a number of areas including: the regulation of early human development, disorders of pregnancy, assisted reproduction programmes, the long term health of children which may be programmed in early development, and the molecular basis of pluripotency in human stem cell populations. We have therefore investigated global gene expression profiles using polyAPCR amplification and microarray technology applied to individual human oocytes and 4-cell and blastocyst stage embryos. In order to explore the basis of any variability in detail, each developmental stage is replicated in triplicate. Our data show that although transcript profiles are highly stage-specific, within each stage they are relatively variable. We describe expression of a number of gene families and pathways including apoptosis, cell cycle and amino acid metabolism, which are variably expressed and may be reflective of embryonic developmental competence. Overall, our data suggest that heterogeneity in human embryo developmental competence is reflected in global transcript profiles, and that the vast majority of existing human embryo gene expression data based on pooled oocytes and embryos need to be reinterpreted.
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Affiliation(s)
- Lisa Shaw
- Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom
- Department of Reproductive Medicine, Old St Mary’s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, United Kingdom
- Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom
| | - Sharon F. Sneddon
- Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom
- Department of Reproductive Medicine, Old St Mary’s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, United Kingdom
- Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom
| | - Leo Zeef
- Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom
| | - Susan J. Kimber
- Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom
| | - Daniel R. Brison
- Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom
- Department of Reproductive Medicine, Old St Mary’s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, United Kingdom
- * E-mail:
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16
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Zhang J, Fei T, Li Z, Zhu G, Wang L, Chen YG. BMP induces cochlin expression to facilitate self-renewal and suppress neural differentiation of mouse embryonic stem cells. J Biol Chem 2013; 288:8053-8060. [PMID: 23344953 DOI: 10.1074/jbc.m112.433995] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
BMP4 maintains self-renewal of mouse embryonic stem cells (ESCs) in collaboration with LIF. Here, we report the identification of a novel key BMP target gene, cochlin (Coch) in mouse ESCs. Coch can be significantly up-regulated by BMP4 specifically in ESCs but not in somatic differentiated cells, and this up-regulation is dependent on the BMP signaling mediators Smad1/5 and Smad4. Overexpression of Coch can partially substitute BMP4 to promote self-renewal of mouse ESCs together with LIF, whereas knockdown of Coch impairs self-renewal marker gene expression even in the presence of both BMP4 and LIF. Further studies showed that COCH could mimic BMP4 in repressing neural differentiation of mouse ESCs upon LIF withdrawal and the inhibitory effect of BMP4 on neural differentiation is compromised by Coch knockdown. Taken together, our data suggest that COCH is a part of the downstream target network of BMP signaling and serves as another important effector to fine-tune mouse ESC fates.
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Affiliation(s)
- Jianping Zhang
- State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Teng Fei
- State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Zhongwei Li
- State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Gaoyang Zhu
- State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Lu Wang
- State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Ye-Guang Chen
- State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
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17
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Pereira PNG, Dobreva MP, Maas E, Cornelis FM, Moya IM, Umans L, Verfaillie CM, Camus A, de Sousa Lopes SMC, Huylebroeck D, Zwijsen A. Antagonism of Nodal signaling by BMP/Smad5 prevents ectopic primitive streak formation in the mouse amnion. Development 2012; 139:3343-54. [PMID: 22912414 DOI: 10.1242/dev.075465] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The strength and spatiotemporal activity of Nodal signaling is tightly controlled in early implantation mouse embryos, including by autoregulation and feedback loops, and involves secreted and intracellular antagonists. These control mechanisms, which are established at the extra-embryonic/embryonic interfaces, are essential for anterior-posterior patterning of the epiblast and correct positioning of the primitive streak. Formation of an ectopic primitive streak, or streak expansion, has previously been reported in mutants lacking antagonists that target Nodal signaling. Here, we demonstrate that loss-of-function of a major bone morphogenetic protein (BMP) effector, Smad5, results in formation of an ectopic primitive streak-like structure in mutant amnion accompanied by ectopic Nodal expression. This suggests that BMP/Smad5 signaling contributes to negative regulation of Nodal. In cultured cells, we find that BMP-activated Smad5 antagonizes Nodal signaling by interfering with the Nodal-Smad2/4-Foxh1 autoregulatory pathway through the formation of an unusual BMP4-induced Smad complex containing Smad2 and Smad5. Quantitative expression analysis supports that ectopic Nodal expression in the Smad5 mutant amnion is induced by the Nodal autoregulatory loop and a slow positive-feedback loop. The latter involves BMP4 signaling and also induction of ectopic Wnt3. Ectopic activation of these Nodal feedback loops in the Smad5 mutant amnion results in the eventual formation of an ectopic primitive streak-like structure. We conclude that antagonism of Nodal signaling by BMP/Smad5 signaling prevents primitive streak formation in the amnion of normal mouse embryos.
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Affiliation(s)
- Paulo N G Pereira
- Laboratory of Developmental Signaling of the VIB11 Center for the Biology of Disease, VIB, and Center for Human Genetics, KU Leuven, B-3000 Leuven, Belgium
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18
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Zhao M, Gao J, Zhu S, Qian L, Wang X, Gao J, Zhang Y, Yu Y, Han W, Wu M. Characterization of activin A in the culture of primitive human umbilical cord blood hematopoietic cells. Biomed Pharmacother 2012; 66:603-6. [PMID: 23089481 DOI: 10.1016/j.biopha.2012.08.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2012] [Accepted: 08/13/2012] [Indexed: 11/28/2022] Open
Abstract
Transforming growth factor-β (TGF-β) superfamily controls many physiological processes such as cell proliferation and differentiation, immune responses, wound repair and various endocrine activities. As a member of TGF-β, activin A can maintain the pluripotency of embryonic stem cells. We report here that activin A exhibited cell type-dependent function of expanding the human primitive hematopoietic cells isolated from umbilical cord blood (UCB). However, the multipotency of the cells pretreated with activin A was exhausted in the sequential dilution culture. In conclusion, activin A may not be a key factor, but a regulator, in the multipotency maintenance of primitive hematopoietic cells and the application of activin A in the hematopoietic stem/progenitor cells (HS/PCs) culture expansion remains a significant challenge.
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Affiliation(s)
- Mei Zhao
- Laboratory of Regeneromics, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
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19
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Li Z, Fei T, Zhang J, Zhu G, Wang L, Lu D, Chi X, Teng Y, Hou N, Yang X, Zhang H, Han JDJ, Chen YG. BMP4 Signaling Acts via dual-specificity phosphatase 9 to control ERK activity in mouse embryonic stem cells. Cell Stem Cell 2012; 10:171-82. [PMID: 22305567 DOI: 10.1016/j.stem.2011.12.016] [Citation(s) in RCA: 116] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2011] [Revised: 11/14/2011] [Accepted: 12/09/2011] [Indexed: 12/26/2022]
Abstract
Extrinsic BMP and LIF signaling collaboratively maintain mouse embryonic stem cell (ESC) pluripotency, whereas appropriate ERK activity is essential for ESC fate commitment. However, how the extrinsic signals restrain appropriate ERK activity remains elusive. Here, we show that, whereas LIF sustains relatively high ERK activity, BMP4 can steadily attenuate ERK activity by upregulating ERK-specific dual-specificity phosphatase 9 (DUSP9). This upregulation requires Smad1/5 and Smad4 and specifically occurs to DUSP9, but not other DUSPs, and only in ESCs. Through DUSP9-mediated inhibition of ERK activity, BMP signaling reinforces the self-renewal status of mouse ESCs together with LIF. Upon LIF withdrawal, ESCs spontaneously undergo neural differentiation, during which process DUSP9 can partially mediate BMP inhibition on neural commitment. Collectively, our findings identify DUSP9 as a critical mediator of BMP signaling to control appropriate ERK activity critical for ESC fate determination.
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Affiliation(s)
- Zhongwei Li
- The State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
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20
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Guo X, Chen SY. Transforming growth factor-β and smooth muscle differentiation. World J Biol Chem 2012; 3:41-52. [PMID: 22451850 PMCID: PMC3312200 DOI: 10.4331/wjbc.v3.i3.41] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2011] [Revised: 01/19/2012] [Accepted: 01/26/2012] [Indexed: 02/05/2023] Open
Abstract
Transforming growth factor (TGF)-β family members are multifunctional cytokines regulating diverse cellular functions such as growth, adhesion, migration, apoptosis, and differentiation. TGF-βs elicit their effects via specific type I and type II serine/threonine kinase receptors and intracellular Smad transcription factors. Knockout mouse models for the different components of the TGF-β signaling pathway have revealed their critical roles in smooth muscle cell (SMC) differentiation. Genetic studies in humans have linked mutations in these signaling components to specific cardiovascular disorders such as aorta aneurysm and congenital heart diseases due to SMC defects. In this review, the current understanding of TGF-β function in SMC differentiation is highlighted, and the role of TGF-β signaling in SMC-related diseases is discussed.
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Affiliation(s)
- Xia Guo
- Xia Guo, Shi-You Chen, Department of Physiology and Pharmacology, University of Georgia, Athens, GA 30602, United States
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21
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A Glimpse of Stem Cell Research in China. PROG BIOCHEM BIOPHYS 2011. [DOI: 10.3724/sp.j.1206.2011.00489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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22
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Zeng-Yi CHANG. Science China Life Sciences in 2010: a New Name Marking a New Start. PROG BIOCHEM BIOPHYS 2011. [DOI: 10.3724/sp.j.1206.2011.00416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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23
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Wu J, Mukherjee A, Lebman DA, Fang X. Lysophosphatidic acid-induced p21Waf1 expression mediates the cytostatic response of breast and ovarian cancer cells to TGFβ. Mol Cancer Res 2011; 9:1562-70. [PMID: 21890597 DOI: 10.1158/1541-7786.mcr-11-0340] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Lysophosphatidic acid (LPA) is a multifunctional intercellular phospholipid mediator present in blood and other biological fluids. In cancer cells, LPA stimulates expression or activity of inflammatory cytokines, angiogenic factors, matrix metalloproteinases, and other oncogenic proteins. In this study, we showed that LPA upregulated expression of the cyclin-dependent kinase inhibitor p21(Waf1) in TGFβ-sensitive breast and ovarian cancer cells, but not in TGFβ-resistant ones. We examined the possibility that LPA-induced p21 might contribute to the cytostatic response to TGFβ. In serum-free conditions, TGFβ alone induced p21 expression weakly in TGFβ-sensitive cells. Serum or serum-borne LPA cooperated with TGFβ to elicit the maximal p21 induction. LPA stimulated p21 via LPA(1) and LPA(2) receptors and Erk-dependent activation of the CCAAT/enhancer binding protein beta transcription factor independent of p53. Loss or gain of p21 expression led to a shift between TGFβ-sensitive and -resistant phenotypes in breast and ovarian cancer cells, indicating that p21 is a key determinant of the growth inhibitory activity of TGFβ. Our results reveal a novel cross-talk between LPA and TGFβ that underlies TGFβ-sensitive and -resistant phenotypes of breast and ovarian cancer cells.
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Affiliation(s)
- Jinhua Wu
- Virginia Commonwealth University School of Medicine, Department of Biochemistry and Molecular Biology, Richmond, VA 23298, USA
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Smad2 mediates Activin/Nodal signaling in mesendoderm differentiation of mouse embryonic stem cells. Cell Res 2010; 20:1306-18. [PMID: 21079647 DOI: 10.1038/cr.2010.158] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Although Activin/Nodal signaling regulates pluripotency of human embryonic stem (ES) cells, how this signaling acts in mouse ES cells remains largely unclear. To investigate this, we confirmed that mouse ES cells possess active Smad2-mediated Activin/Nodal signaling and found that Smad2-mediated Activin/Nodal signaling is dispensable for self-renewal maintenance but is required for proper differentiation toward the mesendoderm lineage. To gain insights into the underlying mechanisms, Smad2-associated genes were identified by genome-wide chromatin immunoprecipitation-chip analysis. The results showed that there is a transcriptional correlation between Smad2 binding and Activin/Nodal signaling modulation, and that the development-related genes were enriched among the Smad2-bound targets. We further identified Tapbp as a key player in mesendoderm differentiation of mouse ES cells acting downstream of the Activin/Nodal-Smad2 pathway. Taken together, our findings suggest that Smad2-mediated Activin/Nodal signaling orchestrates mesendoderm lineage commitment of mouse ES cells through direct modulation of corresponding developmental regulator expression.
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