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Walker NM, Ibuki Y, McLinden AP, Misumi K, Mitchell DC, Kleer GG, Lock AM, Vittal R, Sonenberg N, Garner AL, Lama VN. MNK-driven eIF4E phosphorylation regulates the fibrogenic transformation of mesenchymal cells and chronic lung allograft dysfunction. J Clin Invest 2024; 134:e168393. [PMID: 39145446 PMCID: PMC11324311 DOI: 10.1172/jci168393] [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] [Academic Contribution Register] [Received: 01/09/2023] [Accepted: 06/25/2024] [Indexed: 08/16/2024] Open
Abstract
Tissue fibrosis remains unamenable to meaningful therapeutic interventions and is the primary cause of chronic graft failure after organ transplantation. Eukaryotic translation initiation factor (eIF4E), a key translational regulator, serves as convergent target of multiple upstream profibrotic signaling pathways that contribute to mesenchymal cell (MC) activation. Here, we investigate the role of MAP kinase-interacting serine/threonine kinase-induced (MNK-induced) direct phosphorylation of eIF4E at serine 209 (Ser209) in maintaining fibrotic transformation of MCs and determine the contribution of the MNK/eIF4E pathway to the pathogenesis of chronic lung allograft dysfunction (CLAD). MCs from patients with CLAD demonstrated constitutively higher eIF4E phosphorylation at Ser209, and eIF4E phospho-Ser209 was found to be critical in regulating key fibrogenic protein autotaxin, leading to sustained β-catenin activation and profibrotic functions of CLAD MCs. MNK1 signaling was upregulated in CLAD MCs, and genetic or pharmacologic targeting of MNK1 activity inhibited eIF4E phospho-Ser209 and profibrotic functions of CLAD MCs in vitro. Treatment with an MNK1/2 inhibitor (eFT-508) abrogated allograft fibrosis in an orthotopic murine lung-transplant model. Together these studies identify what we believe is a previously unrecognized MNK/eIF4E/ATX/β-catenin signaling pathway of fibrotic transformation of MCs and present the first evidence, to our knowledge, for the utility of MNK inhibitors in fibrosis.
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Affiliation(s)
- Natalie M. Walker
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Yuta Ibuki
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - A. Patrick McLinden
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Keizo Misumi
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Dylan C. Mitchell
- Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan, USA
| | - Gabriel G. Kleer
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Alison M. Lock
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Ragini Vittal
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Nahum Sonenberg
- Department of Biochemistry and McGill Cancer Center, McGill University, Montreal, Quebec, Canada
| | - Amanda L. Garner
- Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan, USA
| | - Vibha N. Lama
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
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2
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Aoki Y, Walker NM, Misumi K, Mimura T, Vittal R, McLinden AP, Fitzgerald L, Combs MP, Lyu D, Osterholzer JJ, Pinsky DJ, Lama VN. The mitigating effect of exogenous carbon monoxide on chronic allograft rejection and fibrosis post-lung transplantation. J Heart Lung Transplant 2023; 42:317-326. [PMID: 36522238 DOI: 10.1016/j.healun.2022.11.005] [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] [Academic Contribution Register] [Received: 02/04/2022] [Revised: 10/22/2022] [Accepted: 11/15/2022] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Small airway inflammation and fibrosis or bronchiolitis obliterans (BO) is the predominant presentation of chronic lung allograft dysfunction (CLAD) post-lung transplantation. Carbon monoxide (CO) is a critical endogenous signaling transducer with known anti-inflammatory and anti-fibrotic effects but its therapeutic potential in CLAD remains to be fully elucidated. METHODS Here we investigate the effect of inhaled CO in modulating chronic lung allograft rejection pathology in a murine orthotopic lung transplant model of BO (B6D2F1/J→DBA/2J). Additionally, the effects of CO on the activated phenotype of mesenchymal cells isolated from human lung transplant recipients with CLAD were studied. RESULTS Murine lung allografts treated with CO (250 ppm × 30 minutes twice daily from days 7 to 40 post-transplantation) demonstrated decreased immune cell infiltration, fibrosis, and airway obliteration by flow cytometry, trichrome staining, and morphometric analysis, respectively. Decreased total collagen, with levels comparable to isografts, was noted in CO-treated allografts by quantitative hydroxyproline assay. In vitro, CO (250 ppm × 16h) was effective in reversing the fibrotic phenotype of human CLAD mesenchymal cells with decreased collagen I and β-catenin expression as well as an inhibitory effect on ERK1/2 MAPK, and mTORC1/2 signaling. Sildenafil, a phosphodiesterase 5 inhibitor, partially mimicked the effects of CO on CLAD mesenchymal cells and was partially effective in decreasing collagen deposition in murine allografts, suggesting the contribution of cGMP-dependent and -independent mechanisms in mediating the effect of CO. CONCLUSION These results suggest a potential role for CO in alleviating allograft fibrosis and mitigating chronic rejection pathology post-lung transplant.
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Affiliation(s)
- Yoshiro Aoki
- Divisions of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan
| | - Natalie M Walker
- Divisions of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan
| | - Keizo Misumi
- Divisions of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan
| | - Takeshi Mimura
- Divisions of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan
| | - Ragini Vittal
- Divisions of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan
| | - Aidan P McLinden
- Divisions of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan
| | - Linda Fitzgerald
- Department of Pharmacy Services, University of Michigan Health System, Ann Arbor, Michigan
| | - Michael P Combs
- Divisions of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan
| | - Dennis Lyu
- Divisions of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan
| | - John J Osterholzer
- Divisions of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan; Pulmonary Section, VA Ann Arbor Health System, Ann Arbor, Michigan
| | - David J Pinsky
- Cardiology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan
| | - Vibha N Lama
- Divisions of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan.
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3
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Odontogenic Differentiation-Induced Tooth Regeneration by Psoralea corylifolia L. Curr Issues Mol Biol 2022; 44:2300-2308. [PMID: 35678685 PMCID: PMC9164060 DOI: 10.3390/cimb44050156] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/15/2022] [Revised: 05/13/2022] [Accepted: 05/18/2022] [Indexed: 01/22/2023] Open
Abstract
Psoralea corylifolia L. (P. corylifolia) has been used as an oriental phytomedicine to treat coldness of hands and feet in bone marrow injury. Hydroxyapatite is usually used for tooth regeneration. In this study, the role of P. corylifolia and bakuchiol, a compound originated from P. corylifolia as differentiation-inducing substances for tooth regeneration, was determined by monitoring odontogenic differentiation in human dental pulp stem cells (hDPSCs). We confirmed that P. corylifolia extracts and bakuchiol increased the odontogenic differentiation of hDPSCs. In addition, the expression of the odontogenic differentiation marker genes alkaline phosphatase (APL), Runt-related transcription factor 2 (RUNX-2), osteocalcin (OC), and dentin matrix acidic phosphoprotein-1 (DMP-1) was proved by real-time polymerase chain reaction, and protein expression of dentin matrix acidic phosphoprotein-1 (DMP-1) and dentin sialophosphoprotein (DSPP) was proved by western blotting. Further, by confirming the increase in small mothers against decapentaplegia (SMAD) 1/5/8 phosphorylation, the SMAD signaling pathway was found to increase the differentiation of odontoblasts. This study confirmed that P. corylifolia L. extracts and bakuchiol alone promote odontogenic differentiation in hDPSCs. These results suggest that bakuchiol from P. corylifolia is responsible for odontogenic differentiation, and they encourage future in vivo studies on dentin regeneration.
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4
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Alioli C, Demesmay L, Peyruchaud O, Machuca-Gayet I. Autotaxin/Lysophosphatidic Acid Axis: From Bone Biology to Bone Disorders. Int J Mol Sci 2022; 23:ijms23073427. [PMID: 35408784 PMCID: PMC8998661 DOI: 10.3390/ijms23073427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/04/2022] [Revised: 03/18/2022] [Accepted: 03/19/2022] [Indexed: 02/01/2023] Open
Abstract
Lysophosphatidic acid (LPA) is a natural bioactive phospholipid with pleiotropic activities affecting multiple tissues, including bone. LPA exerts its biological functions by binding to G-protein coupled LPA receptors (LPA1-6) to stimulate cell migration, proliferation, and survival. It is largely produced by autotaxin (ATX), a secreted enzyme with lysophospholipase D activity that converts lysophosphatidylcholine (LPC) into active LPA. Beyond its enzymatic activity, ATX serves as a docking molecule facilitating the efficient delivery of LPA to its specific cell surface receptors. Thus, LPA effects are the result of local production by ATX in a given tissue or cell type. As a consequence, the ATX/LPA axis should be considered as an entity to better understand their roles in physiology and pathophysiology and to propose novel therapeutic strategies. Herein, we provide not only an extensive overview of the relevance of the ATX/LPA axis in bone cell commitment and differentiation, skeletal development, and bone disorders, but also discuss new working hypotheses emerging from the interplay of ATX/LPA with well-established signaling pathways regulating bone mass.
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5
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Tigyi G, Lin KH, Jang IH, Lee SC. Revisiting the role of lysophosphatidic acid in stem cell biology. Exp Biol Med (Maywood) 2021; 246:1802-1809. [PMID: 34038224 DOI: 10.1177/15353702211019283] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/25/2023] Open
Abstract
Stem cells possess unique biological characteristics such as the ability to self-renew and to undergo multilineage differentiation into specialized cells. Whereas embryonic stem cells (ESC) can differentiate into all cell types of the body, somatic stem cells (SSC) are a population of stem cells located in distinct niches throughout the body that differentiate into the specific cell types of the tissue in which they reside in. SSC function mainly to restore cells as part of normal tissue homeostasis or to replenish cells that are damaged due to injury. Cancer stem-like cells (CSC) are said to be analogous to SSC in this manner where tumor growth and progression as well as metastasis are fueled by a small population of CSC that reside within the corresponding tumor. Moreover, emerging evidence indicates that CSC are inherently resistant to chemo- and radiotherapy that are often the cause of cancer relapse. Hence, major research efforts have been directed at identifying CSC populations in different cancer types and understanding their biology. Many factors are thought to regulate and maintain cell stemness, including bioactive lysophospholipids such as lysophosphatidic acid (LPA). In this review, we discuss some of the newly discovered functions of LPA not only in the regulation of CSC but also normal SSC, the similarities in these regulatory functions, and how these discoveries can pave way to the development of novel therapies in cancer and regenerative medicine.
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Affiliation(s)
- Gábor Tigyi
- Department of Physiology, University of Tennessee Health Science Center Memphis, Memphis, TN 38163, USA
| | - Kuan-Hung Lin
- Department of Physiology, University of Tennessee Health Science Center Memphis, Memphis, TN 38163, USA
| | - Il Ho Jang
- Department of Oral Biochemistry, Pusan National University School of Dentistry, Yangsan 50612, Republic of Korea.,Dental and Life Science Institute, Pusan National University School of Dentistry, Yangsan 50612, Republic of Korea
| | - Sue Chin Lee
- Department of Physiology, University of Tennessee Health Science Center Memphis, Memphis, TN 38163, USA
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6
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Zhu Y, Chang J, Tan K, Huang SK, Liu X, Wang X, Cao M, Zhang H, Li S, Duan X, Chang Y, Fan Y, Cao P. Clioquinol Attenuates Pulmonary Fibrosis through Inactivation of Fibroblasts via Iron Chelation. Am J Respir Cell Mol Biol 2021; 65:189-200. [PMID: 33861690 DOI: 10.1165/rcmb.2020-0279oc] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/24/2022] Open
Abstract
Strict control of iron homeostasis is critical for the maintenance of normal lung function. Iron accumulates in the lungs of patients with idiopathic pulmonary fibrosis (PF), but the characteristics of iron metabolism in the pathogenesis of PF and related targeting therapeutics are not well studied. In this study, we investigated the cellular and molecular characteristics of iron metabolism in fibrotic lungs and further explored the efficacy of clioquinol (CQ) for the treatment of PF as well as its functional mechanism. Iron aggregates accumulated in the lungs of patients with idiopathic PF, and FTL (ferritin light chain) transcripts were increased in their pulmonary fibroblasts. In the bleomycin (BLM)-induced PF (BLM-PF) mouse model, pulmonary iron accumulation is a very early and concomitant event of PF. Labile iron pool levels in both fibroblasts and macrophages from the BLM-PF model were elevated, and iron metabolism was dysregulated. CQ attenuated PF induced by BLM and FITC, and iron-saturated CQ did not alleviate BLM-PF. Furthermore, CQ inhibited the activation of fibroblasts, including proliferation, fibrotic differentiation, proinflammatory cytokine secretion, and migration. In conclusion, our study demonstrated that CQ, acting as an iron chelator, attenuates experimental PF through inactivation of fibroblasts, providing support for targeting iron metabolism as a basis for PF treatment.
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Affiliation(s)
- Yumeng Zhu
- Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, China
| | - Jing Chang
- Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, China
| | - Ke Tan
- Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, China
| | - Steven K Huang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, University of Michigan, Ann Arbor, Michigan; and
| | - Xin Liu
- Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, China
| | - Xiaofan Wang
- Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, China
| | - Mengshu Cao
- Department of Respiratory and Critical Care Medicine, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, Jiangsu, China
| | - Hongmin Zhang
- Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, China
| | - Shuxin Li
- Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, China
| | - Xianglin Duan
- Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, China
| | - Yanzhong Chang
- Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, China
| | - Yumei Fan
- Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, China
| | - Pengxiu Cao
- Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, China
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7
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Shi W, Zhang C, Ning Z, Hua Y, Li Y, Chen L, Liu L, Chen Z, Meng Z. CMTM8 as an LPA1-associated partner mediates lysophosphatidic acid-induced pancreatic cancer metastasis. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:42. [PMID: 33553335 PMCID: PMC7859753 DOI: 10.21037/atm-20-1013] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Indexed: 12/13/2022]
Abstract
Background Lysophosphatidic acid (LPA) is known to promote cancer cell invasiveness through LPA1, but the downstream signaling cascades are still not fully clarified. The CKLF-like MARVEL transmembrane domain-containing (CMTM) family regulates aggressive phenotype in many cancers. Methods We performed LPA1 co-immunoprecipitation combined with mass spectrometry to search for LPA1-associated proteins. The role of CMTM8 in mediating the pro-invasive activity of LPA was investigated in pancreatic cancer. Results We identified CMTM8 as an LPA1-interacting protein. LPA1 and CMTM8 were co-localized in pancreatic cancer cells. LPA treatment led to stabilization of CMTM8 protein, which was impaired by knockdown of LPA1. Depletion of CMTM8 significantly suppressed the migration and invasion of pancreatic cancer cells. Conversely, ectopic expression of CMTM8 enhanced the migratory and invasive capacity of pancreatic cancer cells. CMTM8 depletion blocked the formation of metastatic lesions in the lung. Knockdown of CMTM8 attenuated LPA-induced migration and invasion in pancreatic cancer cells. CMTM8 overexpression stimulated β-catenin activation through reduction of GSK3β. In addition, knockdown of β-catenin dramatically antagonized CMTM8-mediated migration and invasion in pancreatic cancer cells. Conclusions CMTM8 serves as a key mediator of LPA-induced invasiveness in pancreatic cancer. The interaction between CMTM8 and LPA1 leads to activation of oncogenic β-catenin signaling. CMTM8 represents a potential therapeutic target for pancreatic cancer.
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Affiliation(s)
- Weidong Shi
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Chenyue Zhang
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Zhouyu Ning
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yongqiang Hua
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Ye Li
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Lianyu Chen
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Luming Liu
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Zhen Chen
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Zhiqiang Meng
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
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8
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Cao P, Walker NM, Braeuer RR, Mazzoni-Putman S, Aoki Y, Misumi K, Wheeler DS, Vittal R, Lama VN. Loss of FOXF1 expression promotes human lung-resident mesenchymal stromal cell migration via ATX/LPA/LPA1 signaling axis. Sci Rep 2020; 10:21231. [PMID: 33277571 PMCID: PMC7718269 DOI: 10.1038/s41598-020-77601-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/25/2020] [Accepted: 11/09/2020] [Indexed: 02/08/2023] Open
Abstract
Forkhead box F1 (FOXF1) is a lung embryonic mesenchyme-associated transcription factor that demonstrates persistent expression into adulthood in mesenchymal stromal cells. However, its biologic function in human adult lung-resident mesenchymal stromal cells (LR-MSCs) remain to be elucidated. Here, we demonstrate that FOXF1 expression acts as a restraint on the migratory function of LR-MSCs via its role as a novel transcriptional repressor of autocrine motility-stimulating factor Autotaxin (ATX). Fibrotic human LR-MSCs demonstrated lower expression of FOXF1 mRNA and protein, compared to non-fibrotic controls. RNAi-mediated FOXF1 silencing in LR-MSCs was associated with upregulation of key genes regulating proliferation, migration, and inflammatory responses and significantly higher migration were confirmed in FOXF1-silenced LR-MSCs by Boyden chamber. ATX is a secreted lysophospholipase D largely responsible for extracellular lysophosphatidic acid (LPA) production, and was among the top ten upregulated genes upon Affymetrix analysis. FOXF1-silenced LR-MSCs demonstrated increased ATX activity, while mFoxf1 overexpression diminished ATX expression and activity. The FOXF1 silencing-induced increase in LR-MSC migration was abrogated by genetic and pharmacologic targeting of ATX and LPA1 receptor. Chromatin immunoprecipitation analyses identified three putative FOXF1 binding sites in the 1.5 kb ATX promoter which demonstrated transcriptional repression of ATX expression. Together these findings identify FOXF1 as a novel transcriptional repressor of ATX and demonstrate that loss of FOXF1 promotes LR-MSC migration via the ATX/LPA/LPA1 signaling axis.
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Affiliation(s)
- Pengxiu Cao
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, 1500 W Medical Center Drive, 3916 Taubman Center, Ann Arbor, MI, 48109-0360, USA
| | - Natalie M Walker
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, 1500 W Medical Center Drive, 3916 Taubman Center, Ann Arbor, MI, 48109-0360, USA
| | - Russell R Braeuer
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, 1500 W Medical Center Drive, 3916 Taubman Center, Ann Arbor, MI, 48109-0360, USA
| | - Serina Mazzoni-Putman
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, 1500 W Medical Center Drive, 3916 Taubman Center, Ann Arbor, MI, 48109-0360, USA
| | - Yoshiro Aoki
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, 1500 W Medical Center Drive, 3916 Taubman Center, Ann Arbor, MI, 48109-0360, USA
| | - Keizo Misumi
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, 1500 W Medical Center Drive, 3916 Taubman Center, Ann Arbor, MI, 48109-0360, USA
| | - David S Wheeler
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, 1500 W Medical Center Drive, 3916 Taubman Center, Ann Arbor, MI, 48109-0360, USA
| | - Ragini Vittal
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, 1500 W Medical Center Drive, 3916 Taubman Center, Ann Arbor, MI, 48109-0360, USA
| | - Vibha N Lama
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, 1500 W Medical Center Drive, 3916 Taubman Center, Ann Arbor, MI, 48109-0360, USA.
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9
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Fang Y, Tian J, Fan Y, Cao P. Latest progress on the molecular mechanisms of idiopathic pulmonary fibrosis. Mol Biol Rep 2020; 47:9811-9820. [PMID: 33230784 DOI: 10.1007/s11033-020-06000-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/26/2020] [Accepted: 11/11/2020] [Indexed: 01/11/2023]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a serious life-threatening lung disease, and the median survival period of PF patients after diagnosis is only 2.5-3.5 years. At present, there are no effective drugs or therapeutics to reverse or even inhibit IPF. The main pathological characteristics of pulmonary fibrosis (PF) include damage to alveolar epithelial cells, fibroblast activation and extracellular matrix accumulation, which gradually lead to damage to the lung structure and decreased lung function. It is important to understand the cellular and molecular mechanisms of PF comprehensively and clearly. In this paper, critical signaling pathways related to PF were reviewed to present updates on the molecular mechanisms of PF.
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Affiliation(s)
- Yue Fang
- Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, 20 East Road of 2nd South Ring, Yuhua District, Shijiazhuang, 050024, China.,Key Laboratory of Brain Functional Genomics of Ministry of Education, School of Life Sciences, East China Normal University, Shanghai, 200062, China
| | - Jingya Tian
- Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, 20 East Road of 2nd South Ring, Yuhua District, Shijiazhuang, 050024, China.,College of Chemistry and Environmental Sciences, Hebei University, Baoding, China
| | - Yumei Fan
- Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, 20 East Road of 2nd South Ring, Yuhua District, Shijiazhuang, 050024, China.
| | - Pengxiu Cao
- Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University, 20 East Road of 2nd South Ring, Yuhua District, Shijiazhuang, 050024, China.
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10
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Sah JP, Hao NTT, Han X, Tran TTT, McCarthy S, Oh Y, Yoon JK. Ectonucleotide pyrophosphatase 2 (ENPP2) plays a crucial role in myogenic differentiation through the regulation by WNT/β-Catenin signaling. Int J Biochem Cell Biol 2019; 118:105661. [PMID: 31805399 DOI: 10.1016/j.biocel.2019.105661] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/12/2019] [Revised: 11/28/2019] [Accepted: 11/30/2019] [Indexed: 12/23/2022]
Abstract
Ectonucleotide pyrophosphate phosphodiesterase type II (ENPP2), also known as Autotaxin (ATX), is an enzyme present in blood circulation that converts lysophosphatidyl choline (LPC) to lysophosphatidic acid (LPA). While LPA has been demonstrated to play diverse roles in skeletal myogenesis, mainly through in vitro studies, the role of ENPP2 in skeletal myogenesis has not been determined. We previously found that Enpp2 is induced by a positive WNT/β-Catenin signaling regulator, R-spondin2 (RSPO2), in C2C12 myoblast cells. As RSPO2 promotes myogenic differentiation via the WNT/β-Catenin signaling pathway, we hypothesized that ENPP2 may act as a key mediator for the crosstalk between WNT and LPA signaling during myogenic differentiation. Herein, we found that ENPP2 function is essential for myogenic differentiation in C2C12 cells. Pharmacological ENPP2 inhibitors or RNAi-mediated Enpp2 gene knockdown severely impaired the myogenic differentiation, including the cell fusion process, whereas administration of the recombinant ENPP2 protein enhanced myogenic differentiation. Consistent with the in vitro results, mice lacking the Enpp2 gene showed a disrupted muscle regeneration after acute muscle injury. The size of newly regenerated myofibers in Enpp2 mutant muscle was significantly reduced compared with wild-type regenerated muscle. Modified expression patterns of myogenic markers in Enpp2 mutant muscle further emphasized the impaired muscle regeneration process. Finally, we convincingly demonstrate that the Enpp2 gene is a direct transcriptional target for WNT/β-Catenin signaling. Functional TCF/LEF1 binding sites within the upstream region of Enpp2 gene were identified by chromatin immunoprecipitation using anti-β-Catenin antibodies and reporter assay. Our study reveals that ENPP2 is regulated by WNT/β-Catenin signaling and plays a key positive role in myogenic differentiation.
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Affiliation(s)
- Jay Prakash Sah
- Soonchunhyang Institute of Medi-Bio Science, Soonchunhyang University, 25 Bongjeong-ro, Dongnam-gu, Cheonan-si, 31151, South Korea; Department of Integrated Biomedical Science, Soonchunhyang University, 25 Bongjeong-ro, Dongnam-gu, Cheonan-si, 31151, South Korea
| | - Nguyen Thi Thu Hao
- Soonchunhyang Institute of Medi-Bio Science, Soonchunhyang University, 25 Bongjeong-ro, Dongnam-gu, Cheonan-si, 31151, South Korea; Department of Integrated Biomedical Science, Soonchunhyang University, 25 Bongjeong-ro, Dongnam-gu, Cheonan-si, 31151, South Korea
| | - Xianghua Han
- Center for Molecular Medicine, Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME, 04074, USA
| | - Trinh Thi Tuyet Tran
- Soonchunhyang Institute of Medi-Bio Science, Soonchunhyang University, 25 Bongjeong-ro, Dongnam-gu, Cheonan-si, 31151, South Korea; Department of Integrated Biomedical Science, Soonchunhyang University, 25 Bongjeong-ro, Dongnam-gu, Cheonan-si, 31151, South Korea
| | - Sarah McCarthy
- Center for Molecular Medicine, Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME, 04074, USA
| | - Younjeong Oh
- Soonchunhyang Institute of Medi-Bio Science, Soonchunhyang University, 25 Bongjeong-ro, Dongnam-gu, Cheonan-si, 31151, South Korea
| | - Jeong Kyo Yoon
- Soonchunhyang Institute of Medi-Bio Science, Soonchunhyang University, 25 Bongjeong-ro, Dongnam-gu, Cheonan-si, 31151, South Korea; Department of Integrated Biomedical Science, Soonchunhyang University, 25 Bongjeong-ro, Dongnam-gu, Cheonan-si, 31151, South Korea.
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11
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Chen L, Zhang J, Yang X, Liu Y, Deng X, Yu C. Lysophosphatidic acid decreased macrophage foam cell migration correlated with downregulation of fucosyltransferase 8 via HNF1α. Atherosclerosis 2019; 290:19-30. [PMID: 31557675 DOI: 10.1016/j.atherosclerosis.2019.09.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 05/09/2019] [Revised: 08/19/2019] [Accepted: 09/10/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS Aberrant fucosylation, such as α-1,6 fucosylation catalyzed by fucosyltransferase 8 (Fut8), is associated with reduced cell migration and is responsible for cholesterol-enriched foam cell accumulation in the intima in the early stage of atherosclerosis. The current study evaluated the impact of glycosyltransferases on foam cell migration induced by lysophosphatidic acid (LPA) and its potential mechanism. METHODS The mobility of foam cells was evaluated via transwell and scratch assays. The expression of Fut8 and α-1,6 fucosylation of proteins were assessed by RT-PCR, Western blotting, etc. Overexpression of Fut8 was used to explore the direct relationship between Fut8 and foam cell migration. Dual luciferase reporter assay was performed to determine whether the regulation of Fut8 by LPA occurred at the transcriptional level. Binding of hepatocyte nuclear factor 1-alpha (HNF1α) to the Fut8 promoter was assessed by electrophoretic mobility shift assay and chromatin immunoprecipitation assay. RESULTS We found that the migration capacity of foam cells induced by LPA was significantly decreased. Fut8 and α-1,6 fucosylation showed the most obvious decline after treatment with 200 μM LPA for 24 h. Overexpression of Fut8 was able to restore the foam cell migration capacity. Another important finding was that the LPA1 and LPA3 (LPA1,3) receptors were involved in the regulation of Fut8. It is interesting to note that LPA led to a decrease in Fut8 gene transcription activity, and HNF1α transcription factor played a positive role in downregulation of Fut8 promoter activity. CONCLUSIONS Our results strongly indicated that the LPA-LPA1, 3 receptor-HNF1α pathway is involved in the downregulation of Fut8, leading to diminished foam cell migration.
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Affiliation(s)
- Linmu Chen
- Institute of Life Science, Chongqing Medical University, Chongqing, 400016, PR China
| | - Jun Zhang
- Institute of Life Science, Chongqing Medical University, Chongqing, 400016, PR China
| | - Xi Yang
- Institute of Life Science, Chongqing Medical University, Chongqing, 400016, PR China; College of Basic Medicine, Inner Mongolia Medical University, Hohhot, 010110, China
| | - Yan Liu
- Institute of Life Science, Chongqing Medical University, Chongqing, 400016, PR China
| | - Xiao Deng
- Institute of Life Science, Chongqing Medical University, Chongqing, 400016, PR China
| | - Chao Yu
- College of Pharmacy, Chongqing Medical University, Chongqing, 400016, PR China.
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12
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Fu X, Halim A, Tian B, Luo Q, Song G. MT1-MMP downregulation via the PI3K/Akt signaling pathway is required for the mechanical stretching-inhibited invasion of bone-marrow-derived mesenchymal stem cells. J Cell Physiol 2019; 234:14133-14144. [PMID: 30659604 DOI: 10.1002/jcp.28105] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/03/2018] [Accepted: 12/07/2018] [Indexed: 12/21/2022]
Abstract
Mobilization from the bone marrow and the migration of bone-marrow-derived mesenchymal stem cells (BMSCs) through the peripheral circulation to injured tissue sites are regulated by multiple mechanical and chemical factors. We previously demonstrated that mechanical stretching promotes the migration but inhibits the invasion of BMSCs. However, the involved mechanisms, especially the mechanism of stretching-inhibited BMSC invasion, have not been thoroughly elucidated to date. In this study, we found that mechanical stretching with a 10% amplitude at a 1-Hz frequency for 8 hr significantly reduces BMSC invasion and downregulates the expression of membrane type-1 matrix metalloproteinases (MT1-MMP) at both the messenger RNA and protein levels. The overexpression of MT1-MMP restores mechanical stretching-reduced BMSC invasion. Moreover, phosphatidylinositol 3-kinase (PI3K)-dependent Akt phosphorylation in BMSCs was found to be inactivated by mechanical stretching. Pharmacological inhibitors of PI3K/Akt signaling (LY294002 or A443654) reduced the expression of MT1-MMP and impaired BMSC invasion. In addition, the upregulation of Akt phosphorylation by a pharmacological activator (SC79) increased MT1-MMP expression and suppressed mechanical stretching-reduced BMSC invasion. Taken together, our results suggest that mechanical stretching inhibits BMSC invasion by downregulating MT1-MMP expression by suppressing the PI3K/Akt signaling pathway.
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Affiliation(s)
- Xiaorong Fu
- Department of Bioengineering, College of Bioengineering, Chongqing University, Key Laboratory of Biorheological Science and Technology, Ministry of Education, Chongqing, China
| | - Alexander Halim
- Department of Bioengineering, College of Bioengineering, Chongqing University, Key Laboratory of Biorheological Science and Technology, Ministry of Education, Chongqing, China
| | - Boren Tian
- Department of Bioengineering, College of Bioengineering, Chongqing University, Key Laboratory of Biorheological Science and Technology, Ministry of Education, Chongqing, China
| | - Qing Luo
- Department of Bioengineering, College of Bioengineering, Chongqing University, Key Laboratory of Biorheological Science and Technology, Ministry of Education, Chongqing, China
| | - Guanbin Song
- Department of Bioengineering, College of Bioengineering, Chongqing University, Key Laboratory of Biorheological Science and Technology, Ministry of Education, Chongqing, China
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13
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Walker NM, Mazzoni SM, Vittal R, Fingar DC, Lama VN. c-Jun N-terminal kinase (JNK)-mediated induction of mSin1 expression and mTORC2 activation in mesenchymal cells during fibrosis. J Biol Chem 2018; 293:17229-17239. [PMID: 30217824 DOI: 10.1074/jbc.ra118.003926] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/15/2018] [Revised: 09/06/2018] [Indexed: 02/03/2023] Open
Abstract
Mammalian target of rapamycin complex 2 (mTORC2) has been shown to regulate mTORC1/4E-BP1/eIF4E signaling and collagen I expression in mesenchymal cells (MCs) during fibrotic activation. Here we investigated the regulation of the mTORC2 binding partner mammalian stress-activated protein kinase-interacting protein 1 (mSin1) in MCs derived from human lung allografts and identified a novel role for mSin1 during fibrosis. mSin1 was identified as a common downstream target of key fibrotic pathways, and its expression was increased in MCs in response to pro-fibrotic mediators: lysophosphatidic acid (LPA), transforming growth factor β, and interleukin 13. Fibrotic MCs had higher mSin1 protein levels than nonfibrotic MCs, and siRNA-mediated silencing of mSIN1 inhibited collagen I expression and mTORC1/2 activity in these cells. Autocrine LPA signaling contributed to constitutive up-regulation of mSin1 in fibrotic MCs, and mSin1 was decreased because of LPA receptor 1 siRNA treatment. We identified c-Jun N-terminal kinase (JNK) as a key intermediary in mSin1 up-regulation by the pro-fibrotic mediators, as pharmacological and siRNA-mediated inhibition of JNK prevented the LPA-induced mSin1 increase. Proteasomal inhibition rescued mSin1 levels after JNK inhibition in LPA-treated MCs, and the decrease in mSin1 ubiquitination in response to LPA was counteracted by JNK inhibitors. Constitutive JNK1 overexpression induced mSin1 expression and could drive mTORC2 and mTORC1 activation and collagen I expression in nonfibrotic MCs, effects that were reversed by siRNA-mediated mSIN1 silencing. These results indicate that LPA stabilizes mSin1 protein expression via JNK signaling by blocking its proteasomal degradation and identify the LPA/JNK/mSin1/mTORC/collagen I pathway as critical for fibrotic activation of MCs.
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Affiliation(s)
- Natalie M Walker
- From the Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and
| | - Serina M Mazzoni
- From the Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and
| | - Ragini Vittal
- From the Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and
| | - Diane C Fingar
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109-0360
| | - Vibha N Lama
- From the Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and
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14
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Lidgerwood GE, Pitson SM, Bonder C, Pébay A. Roles of lysophosphatidic acid and sphingosine-1-phosphate in stem cell biology. Prog Lipid Res 2018; 72:42-54. [PMID: 30196008 DOI: 10.1016/j.plipres.2018.09.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/05/2018] [Revised: 08/15/2018] [Accepted: 09/05/2018] [Indexed: 02/06/2023]
Abstract
Stem cells are unique in their ability to self-renew and differentiate into various cell types. Because of these features, stem cells are key to the formation of organisms and play fundamental roles in tissue regeneration and repair. Mechanisms controlling their fate are thus fundamental to the development and homeostasis of tissues and organs. Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are bioactive phospholipids that play a wide range of roles in multiple cell types, during developmental and pathophysiological events. Considerable evidence now demonstrates the potent roles of LPA and S1P in the biology of pluripotent and adult stem cells, from maintenance to repair. Here we review their roles for each main category of stem cells and explore how those effects impact development and physiopathology.
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Affiliation(s)
- Grace E Lidgerwood
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia; Ophthalmology, Department of Surgery, the University of Melbourne, Melbourne, Australia
| | - Stuart M Pitson
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia
| | - Claudine Bonder
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia
| | - Alice Pébay
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia; Ophthalmology, Department of Surgery, the University of Melbourne, Melbourne, Australia.
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15
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Li N, Yan YL, Fu S, Li RJ, Zhao PF, Xu XY, Yang JP, Damirin A. Lysophosphatidic acid enhances human umbilical cord mesenchymal stem cell viability without differentiation via LPA receptor mediating manner. Apoptosis 2018; 22:1296-1309. [PMID: 28766061 PMCID: PMC5630659 DOI: 10.1007/s10495-017-1399-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 02/06/2023]
Abstract
Human umbilical cord mesenchymal stem cells (hUC-MSCs) are potential stromal cells which are regarded as the most feasible stem cell group in cell therapy. The maintenance of cell survival without differentiation is important in cell transplantation and stem cell therapy. However, negative factors exist in cell transplantation. Lysophosphatidic acid (LPA) is a non-antigenic small molecule phospholipid which induced several fundamental cellular responses, such as cell proliferation, apoptosis and migration. In this study we aimed to explore the effects of LPA on the survival and differentiation of MSCs and its availability in cell therapy. We found that LPA stimulated hUC-MSC proliferation and protected hUC-MSCs from lipopolysaccharide (LPS) induced apoptosis. We also observed that CD29, CD44, CD73, CD90 and CD105 were expressed, whereas CD34 and CD45 were not expressed in hUC-MSCs, and these makers have no change in LPA containing medium, which indicated that LPA accelerated the survival of hUC-MSCs in an undifferentiating status. We also demonstrated that higher expressed LPAR1 involved in LPA stimulated cell survival action. LPA stimulated cell proliferation was associated with LPAR1 mediated Gi/o-proteins/ERK1/2 pathway. On the other hand, LPA protected hUC-MSCs from LPS-induced apoptosis through suppressing caspase-3 activation by LPAR1 coupled with a G protein, but not Gi/o or Gq/11 in hUC-MSC. Collectively, this study demonstrated that LPA increased the proliferation and survival of hUC-MSCs without differentiation through LPAR1 mediated manner. Our findings provide that LPA as a anti-apoptotic agent having potential application prospect in cell transplantation and stem cell therapy.
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Affiliation(s)
- Narengerile Li
- Department of Biology, College of Life Sciences, Inner Mongolia University, Hohhot, 010021, Inner Mongolia, China
- Department of Respiratory and Critical Medicine, The Third Affiliated Hospital, Inner Mongolia Medical University, Baotou, 014010, Inner Mongolia, China
| | - Ya-Li Yan
- Department of Biology, College of Life Sciences, Inner Mongolia University, Hohhot, 010021, Inner Mongolia, China
| | - Sachaofu Fu
- Department of Biology, College of Life Sciences, Inner Mongolia University, Hohhot, 010021, Inner Mongolia, China
| | - Rui-Juan Li
- Department of Biology, College of Life Sciences, Inner Mongolia University, Hohhot, 010021, Inner Mongolia, China
| | - Peng-Fei Zhao
- Department of Biology, College of Life Sciences, Inner Mongolia University, Hohhot, 010021, Inner Mongolia, China
| | - Xi-Yuan Xu
- Department of Respiratory and Critical Medicine, The Third Affiliated Hospital, Inner Mongolia Medical University, Baotou, 014010, Inner Mongolia, China
| | - Jing-Ping Yang
- Department of Respiratory and Critical Medicine, The Third Affiliated Hospital, Inner Mongolia Medical University, Baotou, 014010, Inner Mongolia, China.
| | - Alatangaole Damirin
- Department of Biology, College of Life Sciences, Inner Mongolia University, Hohhot, 010021, Inner Mongolia, China.
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16
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Nelson DL, Zhao Y, Fabiilli ML, Cook KE. In vitro evaluation of lysophosphatidic acid delivery via reverse perfluorocarbon emulsions to enhance alveolar epithelial repair. Colloids Surf B Biointerfaces 2018; 169:411-417. [PMID: 29807339 DOI: 10.1016/j.colsurfb.2018.05.037] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/29/2017] [Revised: 05/15/2018] [Accepted: 05/16/2018] [Indexed: 02/05/2023]
Abstract
BACKGROUND Alveolar drug delivery is needed to enhance alveolar repair during acute respiratory distress syndrome. However, delivery of inhaled drugs is poor in this setting. Drug delivery via liquid perfluorocarbon emulsions could address this problem through better alveolar penetration and improved spatial distribution. Therefore, this study investigated the efficacy of the delivery of lysophosphatidic acid (LPA) growth factor to cultured alveolar epithelial cells via a perfluorocarbon emulsion. METHODS Murine alveolar epithelial cells were treated for 2 h with varying concentrations (0-10 μM) of LPA delivered via aqueous solution or PFC emulsion. Cell migration was evaluated 18 h post-treatment using a scratch assay. Barrier function was evaluated 1 h post-treatment using a permeability assay. Proliferation was evaluated 72 h post-treatment using a viability assay. RESULTS Partially due to emulsion creaming and stability, the effects of LPA were either diminished or completely hindered when delivered via emulsion versus aqueous. Migration increased significantly following treatment with the 10 μM emulsion (p < 10-3), but required twice the concentration to achieve an increase similar to aqueous LPA. Both barrier function and proliferation increased following aqueous treatment, but neither were significantly affected by the emulsion. CONCLUSIONS The availability and thus the biological effect of LPA is significantly blunted during emulsified delivery in vitro, and this attenuation depends on the specific cellular function examined. Thus, the cellular level effects of drug delivery to the lungs via PFC emulsion are likely to vary based on the drug and the effect it is intended to create.
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Affiliation(s)
- Diane L Nelson
- Department of Biomedical Engineering, Carnegie Mellon University, 5000 Forbes Avenue, Scott Hall 4th Floor, Pittsburgh, PA, 15213, USA.
| | - Yutong Zhao
- Department of Medicine, University of Pittsburgh, Division of Pulmonary, Allergy and Critical Care Medicine, East 1200A Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA, 15213, USA.
| | - Mario L Fabiilli
- Department of Radiology, University of Michigan, 3226A Medical Sciences Building I, 1301 Catherine Street, Ann Arbor, MI, 48109, USA.
| | - Keith E Cook
- Department of Biomedical Engineering, Carnegie Mellon University, 5000 Forbes Avenue, Scott Hall 4th Floor, Pittsburgh, PA, 15213, USA.
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17
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Stuelten CH, Lee RM, Losert W, Parent CA. Lysophosphatidic acid regulates the motility of MCF10CA1a breast cancer cell sheets via two opposing signaling pathways. Cell Signal 2018; 45:1-11. [PMID: 29337044 PMCID: PMC5845779 DOI: 10.1016/j.cellsig.2018.01.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/02/2017] [Revised: 12/22/2017] [Accepted: 01/07/2018] [Indexed: 01/31/2023]
Abstract
Aberrant cell migration leads to the dispersal of malignant cells. The ubiquitous lipid mediator lysophosphatidic acid (LPA) modulates cell migration and is implicated in tumor progression. Yet, the signaling cascades that regulate LPA's effect on cell motility remain unclear. Using time-lapse imaging and quantitative analyses, we studied the role of signaling cascades that act downstream of LPA on the motility of MCF10CA1a breast cancer cells. We found that LPA alters cell motility via two major signaling pathways. The Rho/ROCK signaling cascade is the predominant pathway that increases E-Cadherin containing cell-cell adhesions and cortical arrangement of actomyosin to promote slow, directional, spatially coherent and temporally consistent movement. In contrast, Gαi/o- and Gαq/11-dependent signaling cascades lessen directionality and support the independent movement of cells. The net effect of LPA on breast cancer cell migration therefore results from the integrated signaling activity of the Rho/ROCK and Gαi/o- and Gαq/11-dependent pathways, thus allowing for a dynamic migratory response to changes in the cellular or microenvironmental context.
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Affiliation(s)
- Christina H Stuelten
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States.
| | - Rachel M Lee
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States; Department of Physics, Physical Sciences Complex, University of Maryland, College Park, MD, United States
| | - Wolfgang Losert
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States; Department of Physics, Physical Sciences Complex, University of Maryland, College Park, MD, United States
| | - Carole A Parent
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States; Department of Pharmacology, Michigan Medicine, Life Sciences Institute, University of Michigan, Ann Arbor, MI..
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18
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El Agha E, Kramann R, Schneider RK, Li X, Seeger W, Humphreys BD, Bellusci S. Mesenchymal Stem Cells in Fibrotic Disease. Cell Stem Cell 2018; 21:166-177. [PMID: 28777943 DOI: 10.1016/j.stem.2017.07.011] [Citation(s) in RCA: 305] [Impact Index Per Article: 43.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/13/2022]
Abstract
Fibrosis is associated with organ failure and high mortality and is commonly characterized by aberrant myofibroblast accumulation. Investigating the cellular origin of myofibroblasts in various diseases is thus a promising strategy for developing targeted anti-fibrotic treatments. Recent studies using genetic lineage tracing technology have implicated diverse organ-resident perivascular mesenchymal stem cell (MSC)-like cells and bone marrow-MSCs in myofibroblast generation during fibrosis development. In this Review, we give an overview of the emerging role of MSCs and MSC-like cells in myofibroblast-mediated fibrotic disease in the kidney, lung, heart, liver, skin, and bone marrow.
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Affiliation(s)
- Elie El Agha
- Institute of Life Sciences, Wenzhou University, Wenzhou University-Wenzhou Medical University Collaborative Innovation Center of Biomedicine, Wenzhou, Zhejiang, China; Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities of Giessen and Marburg Lung Center (UGMLC), Justus-Liebig-University Giessen, German Center for Lung Research (DZL), Giessen, Germany.
| | - Rafael Kramann
- Division of Nephrology and Clinical Immunology, Medical Faculty RWTH Aachen University, RWTH Aachen University, Aachen, Germany
| | - Rebekka K Schneider
- Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, RWTH Aachen University, Aachen, Germany
| | - Xiaokun Li
- Institute of Life Sciences, Wenzhou University, Wenzhou University-Wenzhou Medical University Collaborative Innovation Center of Biomedicine, Wenzhou, Zhejiang, China
| | - Werner Seeger
- Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities of Giessen and Marburg Lung Center (UGMLC), Justus-Liebig-University Giessen, German Center for Lung Research (DZL), Giessen, Germany; Max Planck Institute for Heart and Lung Research, W.G. Kerckhoff Institute, Bad Nauheim, Germany
| | - Benjamin D Humphreys
- Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, USA
| | - Saverio Bellusci
- Institute of Life Sciences, Wenzhou University, Wenzhou University-Wenzhou Medical University Collaborative Innovation Center of Biomedicine, Wenzhou, Zhejiang, China; Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities of Giessen and Marburg Lung Center (UGMLC), Justus-Liebig-University Giessen, German Center for Lung Research (DZL), Giessen, Germany.
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Mo WM, Kwon YW, Jang IH, Choi EJ, Kwon SM, Kim JH. Role of TAZ in Lysophosphatidic Acid-Induced Migration and Proliferation of Human Adipose-Derived Mesenchymal Stem Cells. Biomol Ther (Seoul) 2017; 25:354-361. [PMID: 28554198 PMCID: PMC5499612 DOI: 10.4062/biomolther.2016.263] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/29/2016] [Revised: 02/28/2017] [Accepted: 02/28/2017] [Indexed: 12/15/2022] Open
Abstract
Transcriptional co-activator with a PDZ-binding motif (TAZ) is an important factor in lysophosphatidic acid (LPA)-induced promotion of migration and proliferation of human mesenchymal stem cells (MSCs). The expression of TAZ significantly increased at 6 h after LPA treatment, and TAZ knockdown inhibited the LPA-induced migration and proliferation of MSCs. In addition, embryonic fibroblasts from TAZ knockout mice exhibited the reduction in LPA-induced migration and proliferation. The LPA1 receptor inhibitor Ki16425 blocked LPA responses in MSCs. Although TAZ knockdown or knockout did not reduce LPA-induced phosphorylation of ERK and AKT, the MEK inhibitor U0126 or the ROCK inhibitor Y27632 blocked LPA-induced TAZ expression along with the reduction in the proliferation and migration of MSCs. Our data suggest that TAZ is an important mediator of LPA signaling in MSCs in the downstream of MEK and ROCK signaling.
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Affiliation(s)
- Won Min Mo
- Department of Physiology, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
| | - Yang Woo Kwon
- Department of Physiology, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
| | - Il Ho Jang
- Department of Oral Biochemistry and Molecular Biology, Pusan National University School of Dentistry, Yangsan 50612, Republic of Korea.,BK21 PLUS Project, Pusan National University School of Dentistry, Yangsan 50612, Republic of Korea
| | - Eun Jung Choi
- Department of Physiology, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
| | - Sang Mo Kwon
- Department of Physiology, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
| | - Jae Ho Kim
- Department of Physiology, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea.,Research Institute of Convergence Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea
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20
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Cao P, Aoki Y, Badri L, Walker NM, Manning CM, Lagstein A, Fearon ER, Lama VN. Autocrine lysophosphatidic acid signaling activates β-catenin and promotes lung allograft fibrosis. J Clin Invest 2017; 127:1517-1530. [PMID: 28240604 DOI: 10.1172/jci88896] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/01/2016] [Accepted: 01/05/2017] [Indexed: 12/21/2022] Open
Abstract
Tissue fibrosis is the primary cause of long-term graft failure after organ transplantation. In lung allografts, progressive terminal airway fibrosis leads to an irreversible decline in lung function termed bronchiolitis obliterans syndrome (BOS). Here, we have identified an autocrine pathway linking nuclear factor of activated T cells 2 (NFAT1), autotaxin (ATX), lysophosphatidic acid (LPA), and β-catenin that contributes to progression of fibrosis in lung allografts. Mesenchymal cells (MCs) derived from fibrotic lung allografts (BOS MCs) demonstrated constitutive nuclear β-catenin expression that was dependent on autocrine ATX secretion and LPA signaling. We found that NFAT1 upstream of ATX regulated expression of ATX as well as β-catenin. Silencing NFAT1 in BOS MCs suppressed ATX expression, and sustained overexpression of NFAT1 increased ATX expression and activity in non-fibrotic MCs. LPA signaling induced NFAT1 nuclear translocation, suggesting that autocrine LPA synthesis promotes NFAT1 transcriptional activation and ATX secretion in a positive feedback loop. In an in vivo mouse orthotopic lung transplant model of BOS, antagonism of the LPA receptor (LPA1) or ATX inhibition decreased allograft fibrosis and was associated with lower active β-catenin and dephosphorylated NFAT1 expression. Lung allografts from β-catenin reporter mice demonstrated reduced β-catenin transcriptional activation in the presence of LPA1 antagonist, confirming an in vivo role for LPA signaling in β-catenin activation.
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Li HY, Oh YS, Choi JW, Jung JY, Jun HS. Blocking lysophosphatidic acid receptor 1 signaling inhibits diabetic nephropathy in db/db mice. Kidney Int 2017; 91:1362-1373. [PMID: 28111010 DOI: 10.1016/j.kint.2016.11.010] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/19/2016] [Revised: 11/07/2016] [Accepted: 11/10/2016] [Indexed: 01/03/2023]
Abstract
Lysophosphatidic acid (LPA) is known to regulate various biological responses by binding to LPA receptors. The serum level of LPA is elevated in diabetes, but the involvement of LPA in the development of diabetes and its complications remains unknown. Therefore, we studied LPA signaling in diabetic nephropathy and the molecular mechanisms involved. The expression of autotaxin, an LPA synthesis enzyme, and LPA receptor 1 was significantly increased in both mesangial cells (SV40 MES13) maintained in high-glucose media and the kidney cortex of diabetic db/db mice. Increased urinary albumin excretion, increased glomerular tuft area and volume, and mesangial matrix expansion were observed in db/db mice and reduced by treatment with ki16425, a LPA receptor 1/3 antagonist. Transforming growth factor (TGF)β expression and Smad-2/3 phosphorylation were upregulated in SV40 MES13 cells by LPA stimulation or in the kidney cortex of db/db mice, and this was blocked by ki16425 treatment. LPA receptor 1 siRNA treatment inhibited LPA-induced TGFβ expression, whereas cells overexpressing LPA receptor 1 showed enhanced LPA-induced TGFβ expression. LPA treatment of SV40 MES13 cells increased phosphorylated glycogen synthase kinase (GSK)3β at Ser9 and induced translocation of sterol regulatory element-binding protein (SREBP)1 into the nucleus. Blocking GSK3β phosphorylation inhibited SREBP1 activation and consequently blocked LPA-induced TGFβ expression in SV40 MES13 cells. Phosphorylated GSK3β and nuclear SREBP1 accumulation were increased in the kidney cortex of db/db mice and ki16425 treatment blocked these pathways. Thus, LPA receptor 1 signaling increased TGFβ expression via GSK3β phosphorylation and SREBP1 activation, contributing to the development of diabetic nephropathy.
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Affiliation(s)
- Hui Ying Li
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea; Department of Internal Medicine, Yanbian University Hospital, Yanji, Jilin Province, China
| | - Yoon Sin Oh
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea; Gachon Medical Research Institute, Gil Hospital, Incheon, Korea.
| | - Ji-Woong Choi
- College of Pharmacy, Gachon University, Incheon, Korea
| | - Ji Yong Jung
- Gachon Medical Research Institute, Gil Hospital, Incheon, Korea; Division of Nephrology, Department of Internal Medicine, Gachon University School of Medicine, Incheon, Korea
| | - Hee-Sook Jun
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea; Gachon Medical Research Institute, Gil Hospital, Incheon, Korea; College of Pharmacy, Gachon University, Incheon, Korea.
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LPA receptor activity is basal specific and coincident with early pregnancy and involution during mammary gland postnatal development. Sci Rep 2016; 6:35810. [PMID: 27808166 PMCID: PMC5093903 DOI: 10.1038/srep35810] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/02/2016] [Accepted: 10/06/2016] [Indexed: 01/08/2023] Open
Abstract
During pregnancy, luminal and basal epithelial cells of the adult mammary gland proliferate and differentiate resulting in remodeling of the adult gland. While pathways that control this process have been characterized in the gland as a whole, the contribution of specific cell subtypes, in particular the basal compartment, remains largely unknown. Basal cells provide structural and contractile support, however they also orchestrate the communication between the stroma and the luminal compartment at all developmental stages. Using RNA-seq, we show that basal cells are extraordinarily transcriptionally dynamic throughout pregnancy when compared to luminal cells. We identified gene expression changes that define specific basal functions acquired during development that led to the identification of novel markers. Enrichment analysis of gene sets from 24 mouse models for breast cancer pinpoint to a potential new function for insulin-like growth factor 1 (Igf1r) in the basal epithelium during lactogenesis. We establish that β-catenin signaling is activated in basal cells during early pregnancy, and demonstrate that this activity is mediated by lysophosphatidic acid receptor 3 (Lpar3). These findings identify novel pathways active during functional maturation of the adult mammary gland.
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Yao D, Lin Z, Wu J. Near-Infrared Fluorogenic Probes with Polarity-Sensitive Emission for in Vivo Imaging of an Ovarian Cancer Biomarker. ACS APPLIED MATERIALS & INTERFACES 2016; 8:5847-5856. [PMID: 26910257 DOI: 10.1021/acsami.5b11826] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 06/05/2023]
Abstract
Lysophosphatidic acid (LPA, cutoff values ≥ 1.5 μM) is an effective biomarker for early stage ovarian cancer. The development of selective probes for LPA detection is therefore critical for early clinical diagnosis. Although current methods have been developed for the detection of LPA in solution, they cannot be used for tracking LPA in vivo. Here, we report a near-infrared (NIR) fluorescent probe that can selectively respond to LPA based on polarity-sensitive emission at a very low detection limit of 0.5 μM in situ. This probe exhibits a marked increase of fluorescence at 720 nm upon binding to LPA, allowing the direct visualization of LPA in vitro and in vivo without interference from other biomolecules. Moreover, the probe containing two arginine-glycine-aspartic acid units can be efficiently taken up by cancer cells based on an αvβ3 integrin receptor targeting mechanism. It also exhibits excellent biocompatibility and high pH stability in live cells and in vivo. Confocal laser scanning microscopy and flow cytometric imaging of SKOV-3 cells have confirmed that our probe can be used to image LPA in live cells. In particular, its NIR turn-on fluorescence can be used to effectively monitor LPA imaging in a SKOV-3 tumor-bearing mouse model. Our probe may pave the way for the detection of cancer-related biomarkers and even for early stage cancer diagnosis.
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Affiliation(s)
- Defan Yao
- Key Laboratory for Advanced Materials & Institute of Fine Chemicals, East China University of Science and Technology , Shanghai 200237, China
| | - Zhi Lin
- College of Chemistry and Molecular Engineering, Peking University , Beijing 100871, China
| | - Junchen Wu
- Key Laboratory for Advanced Materials & Institute of Fine Chemicals, East China University of Science and Technology , Shanghai 200237, China
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Ryu JM, Han HJ. Autotaxin-LPA axis regulates hMSC migration by adherent junction disruption and cytoskeletal rearrangement via LPAR1/3-dependent PKC/GSK3β/β-catenin and PKC/Rho GTPase pathways. Stem Cells 2015; 33:819-32. [PMID: 25376707 DOI: 10.1002/stem.1882] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/08/2014] [Revised: 09/30/2014] [Accepted: 10/15/2014] [Indexed: 12/29/2022]
Abstract
Bioactive molecules and stem cell-based regenerative engineering is emerging a promising approach for regenerating tissues. Autotaxin (ATX) is a key enzyme that regulates lysophosphatidic acid (LPA) levels in biological fluids, which exerts a wide range of cellular functions. However, the biological role of ATX in human umbilical cord blood-derived mesenchymal stem cells (hMSCs) migration remains to be fully elucidated. In this study, we observed that hMSCs, which were stimulated with LPA, accelerated wound healing, and LPA increased the migration of hMSCs into a wound site in a mouse skin wound healing model. In an experiment to investigate the effect of LPA on hMSC migration, ATX and LPA increased hMSC migration in a dose-dependent manner, and LPA receptor 1/3 siRNA transfections inhibited the ATX-induced cell migration. Furthermore, LPA increased Ca(2+) influx and PKC phosphorylation, which were blocked by Gαi and Gαq knockdown as well as by Ptx pretreatment. LPA increased GSK3β phosphorylation and β-catenin activation. LPA induced the cytosol to nuclear translocation of β-catenin, which was inhibited by PKC inhibitors. LPA stimulated the binding of β-catenin on the E-box located in the promoter of the CDH-1 gene and decreased CDH-1 promoter activity. In addition, the ATX and LPA-induced increase in hMSC migration was blocked by β-catenin siRNA transfection. LPA-induced PKC phosphorylation is also involved in Rac1 and CDC42 activation, and Rac1 and CDC42 knockdown abolished LPA-induced F-actin reorganization. In conclusion, ATX/LPA stimulates the migration of hMSCs through LPAR1/3-dependent E-cadherin reduction and cytoskeletal rearrangement via PKC/GSK3β/β-catenin and PKC/Rho GTPase pathways.
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Affiliation(s)
- Jung Min Ryu
- Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, Seoul National University, Seoul, South Korea; BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul, South Korea
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The Role of Lysophosphatidic Acid on Airway Epithelial Cell Denudation in a Murine Heterotopic Tracheal Transplant Model. Transplant Direct 2015; 1:e35. [PMID: 27500235 PMCID: PMC4946481 DOI: 10.1097/txd.0000000000000542] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/30/2015] [Accepted: 07/15/2015] [Indexed: 01/06/2023] Open
Abstract
Supplemental digital content is available in the text. Background Chronic rejection is the major leading cause of morbidity and mortality after lung transplantation. Obliterative bronchiolitis (OB), a fibroproliferative disorder of the small airways, is the main manifestation of chronic lung allograft rejection. However, there is currently no treatment for the disease. We hypothesized that lysophosphatidic acid (LPA) participates in the progression of OB. The aim of this study was to reveal the involvement of LPA on the lesion of OB. Methods Ki16198, an antagonist specifically for LPA1 and LPA3, was daily administered into the heterotopic tracheal transplant model mice at the day of transplantation. At days 10 and 28, the allografts were isolated and evaluated histologically. The messenger RNA levels of LPAR in microdissected mouse airway regions were assessed to reveal localization of lysophosphatidic acid receptors. The human airway epithelial cell was used to evaluate the mechanism of LPA-induced suppression of cell adhesion to the extracellular matrix (ECM). Results The administration of Ki16198 attenuated airway epithelial cell loss in the allograft at day 10. Messenger RNAs of LPA1 and LPA3 were detected in the airway epithelial cells of the mice. Lysophosphatidic acid inhibited the attachment of human airway epithelial cells to the ECM and induced cell detachment from the ECM, which was mediated by LPA1 and Rho-kinase pathway. However, Ki16198 did not prevent obliteration of allograft at day 28. Conclusions The LPA signaling is involved in the status of epithelial cells by distinct contribution in 2 different phases of the OB lesion. This finding suggests a role of LPA in the pathogenesis of OB.
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KANG SANGJIN, HAN JUHEE, SONG SEUNGYONG, KIM WONSERK, SHIN SOYOUNG, KIM JIHYE, AHN HYOSUN, JEONG JINHYUN, HWANG SUNGJOO, SUNG JONGHYUK. Lysophosphatidic acid increases the proliferation and migration of adipose-derived stem cells via the generation of reactive oxygen species. Mol Med Rep 2015; 12:5203-10. [DOI: 10.3892/mmr.2015.4023] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/24/2014] [Accepted: 06/15/2015] [Indexed: 11/06/2022] Open
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Stem cells, cell therapies, and bioengineering in lung biology and diseases. Comprehensive review of the recent literature 2010-2012. Ann Am Thorac Soc 2014; 10:S45-97. [PMID: 23869446 DOI: 10.1513/annalsats.201304-090aw] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/18/2022] Open
Abstract
A conference, "Stem Cells and Cell Therapies in Lung Biology and Lung Diseases," was held July 25 to 28, 2011 at the University of Vermont to review the current understanding of the role of stem and progenitor cells in lung repair after injury and to review the current status of cell therapy and ex vivo bioengineering approaches for lung diseases. These are rapidly expanding areas of study that provide further insight into and challenge traditional views of mechanisms of lung repair after injury and pathogenesis of several lung diseases. The goals of the conference were to summarize the current state of the field, to discuss and debate current controversies, and to identify future research directions and opportunities for basic and translational research in cell-based therapies for lung diseases. The goal of this article, which accompanies the formal conference report, is to provide a comprehensive review of the published literature in lung regenerative medicine from the last conference report through December 2012.
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Foronjy RF, Majka SM. The potential for resident lung mesenchymal stem cells to promote functional tissue regeneration: understanding microenvironmental cues. Cells 2014; 1:874. [PMID: 23626909 PMCID: PMC3634590 DOI: 10.3390/cells1040874] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/14/2023] Open
Abstract
Tissue resident mesenchymal stem cells (MSCs) are important regulators of tissue repair or regeneration, fibrosis, inflammation, angiogenesis and tumor formation. Bone marrow derived mesenchymal stem cells (BM-MSCs) and endothelial progenitor cells (EPC) are currently being considered and tested in clinical trials as a potential therapy in patients with such inflammatory lung diseases including, but not limited to, chronic lung disease, pulmonary arterial hypertension (PAH), pulmonary fibrosis (PF), chronic obstructive pulmonary disease (COPD)/emphysema and asthma. However, our current understanding of tissue resident lung MSCs remains limited. This review addresses how environmental cues impact on the phenotype and function of this endogenous stem cell pool. In addition, it examines how these local factors influence the efficacy of cell-based treatments for lung diseases.
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Affiliation(s)
- Robert F. Foronjy
- Department of Medicine, St. Luke’s Roosevelt Health Sciences Center, Antenucci Building, 432 West 58th Street, Room 311, New York, NY 10019, USA; ; Tel.: +1-212-523-7265
| | - Susan M. Majka
- Department of Medicine, Vanderbilt University, 1161 21st. Ave S, T1218 MCN, Nashville, TN 37232, USA
- Author to whom correspondence should be addressed; ; Tel.: +1-303-883-8786
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Haak AJ, Tsou PS, Amin MA, Ruth JH, Campbell P, Fox DA, Khanna D, Larsen SD, Neubig RR. Targeting the myofibroblast genetic switch: inhibitors of myocardin-related transcription factor/serum response factor-regulated gene transcription prevent fibrosis in a murine model of skin injury. J Pharmacol Exp Ther 2014; 349:480-6. [PMID: 24706986 DOI: 10.1124/jpet.114.213520] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/09/2023] Open
Abstract
Systemic sclerosis (SSc), or scleroderma, similar to many fibrotic disorders, lacks effective therapies. Current trials focus on anti-inflammatory drugs or targeted approaches aimed at one of the many receptor mechanisms initiating fibrosis. In light of evidence that a myocardin-related transcription factor (MRTF)-and serum response factor (SRF)-regulated gene transcriptional program induced by Rho GTPases is essential for myofibroblast activation, we explored the hypothesis that inhibitors of this pathway may represent novel antifibrotics. MRTF/SRF-regulated genes show spontaneously increased expression in primary dermal fibroblasts from patients with diffuse cutaneous SSc. A novel small-molecule inhibitor of MRTF/SRF-regulated transcription (CCG-203971) inhibits expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and collagen 1 (COL1A2) in both SSc fibroblasts and in lysophosphatidic acid (LPA)-and transforming growth factor β (TGFβ)-stimulated fibroblasts. In vivo treatment with CCG-203971 also prevented bleomycin-induced skin thickening and collagen deposition. Thus, targeting the MRTF/SRF gene transcription pathway could provide an efficacious new approach to therapy for SSc and other fibrotic disorders.
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Affiliation(s)
- Andrew J Haak
- Department of Pharmacology (A.J.H.) and Department of Internal Medicine, Division of Rheumatology (P.T., M.A.A., J.H.R., P.C., D.A.F., D.K.), University of Michigan Medical Center, Ann Arbor, Michigan; Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (S.D.L.); and Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan (R.R.N.)
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Magkrioti C, Aidinis V. Autotaxin and lysophosphatidic acid signalling in lung pathophysiology. World J Respirol 2013; 3:77-103. [DOI: 10.5320/wjr.v3.i3.77] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 08/29/2013] [Revised: 10/03/2013] [Accepted: 11/19/2013] [Indexed: 02/06/2023] Open
Abstract
Autotaxin (ATX or ENPP2) is a secreted glycoprotein widely present in biological fluids. ATX primarily functions as a plasma lysophospholipase D and is largely responsible for the bulk of lysophosphatidic acid (LPA) production in the plasma and at inflamed and/or malignant sites. LPA is a phospholipid mediator produced in various conditions both in cells and in biological fluids, and it evokes growth-factor-like responses, including cell growth, survival, differentiation and motility, in almost all cell types. The large variety of LPA effector functions is attributed to at least six G-protein coupled LPA receptors (LPARs) with overlapping specificities and widespread distribution. Increased ATX/LPA/LPAR levels have been detected in a large variety of cancers and transformed cell lines, as well as in non-malignant inflamed tissues, suggesting a possible involvement of ATX in chronic inflammatory disorders and cancer. In this review, we focus exclusively on the role of the ATX/LPA axis in pulmonary pathophysiology, analysing the effects of ATX/LPA on pulmonary cells and leukocytes in vitro and in the context of pulmonary pathophysiological situations in vivo and in human diseases.
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Therapeutic potential of mesenchymal stem cells in regenerative medicine. Stem Cells Int 2013; 2013:496218. [PMID: 23577036 PMCID: PMC3615627 DOI: 10.1155/2013/496218] [Citation(s) in RCA: 143] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/21/2012] [Accepted: 02/25/2013] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are stromal cells that have the ability to self-renew and also exhibit multilineage differentiation into both mesenchymal and nonmesenchymal lineages. The intrinsic properties of these cells make them an attractive candidate for clinical applications. MSCs are of keen interest because they can be isolated from a small aspirate of bone marrow or adipose tissues and can be easily expanded in vitro. Moreover, their ability to modulate immune responses makes them an even more attractive candidate for regenerative medicine as allogeneic transplant of these cells is feasible without a substantial risk of immune rejection. MSCs secrete various immunomodulatory molecules which provide a regenerative microenvironment for a variety of injured tissues or organ to limit the damage and to increase self-regulated tissue regeneration. Autologous/allogeneic MSCs delivered via the bloodstream augment the titers of MSCs that are drawn to sites of tissue injury and can accelerate the tissue repair process. MSCs are currently being tested for their potential use in cell and gene therapy for a number of human debilitating diseases and genetic disorders. This paper summarizes the current clinical and nonclinical data for the use of MSCs in tissue repair and potential therapeutic role in various diseases.
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