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Liu H, Liang X, Li H, Wang L. Pathogenesis of fibrosis in patella-patellar tendon junction induced by jumping load in a rabbit model. J Appl Physiol (1985) 2025; 138:378-388. [PMID: 39772986 DOI: 10.1152/japplphysiol.00515.2024] [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: 07/03/2024] [Revised: 12/16/2024] [Accepted: 12/20/2024] [Indexed: 01/11/2025] Open
Abstract
The mechanism of fibrosis at the patella-patellar tendon junction (PPTJ) was investigated using a rabbit overuse jumping model. Thirty-two female New Zealand White rabbits were randomly divided into control and jumping groups, and each group was further divided into four groups at 2, 4, 6, and 8 wk. The rabbit in the jumping group jumped 150 times/day, 5 days/wk. The PPTJ was removed at the corresponding time point and subjected to hematoxylin and eosin, safranin O, and immunohistochemical staining. Significant differences were observed in histological changes and fibrosis-related factors between the jumping and control groups (P < 0.01). Comparison within the jumping group indicated that the changes in the fibrocartilage zone thickness and proteoglycan area were pronounced at week 6; the expressions of transforming growth factor β (TGF-β1), Smad3, CTGF, α-SMA, COL-I, and COL-III peaked at week 6 (P < 0.05). The jumping load can lead to morphological and fibrotic changes in the patella-patellar tendon junction, with peak changes occurring at week 6. The fibrosis in the patella-patellar tendon junction may be associated with increased secretion of TGF-β1 and Smad3 due to jump loading, which upregulates CTGF expression and thus promotes the synthesis of α-SMA, COL-I, and COL-III.NEW & NOTEWORTHY The temporal pattern of fibrosis in the patella-patellar tendon junction (PPTJ) was determined by observing changes in histology and fibrosis-related factors at different time points in an overused jumping rabbit model. The results revealed that 1) the peak fibrotic changes in the PPTJ occurred at week 6 of jump training; 2) fibrosis in PPTJ may be associated with the changes in TGF-β1/Smad3. This study contributes to the development of targeted early interventions.
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Affiliation(s)
- Haitao Liu
- College of Physical Education, Henan University, Kaifeng, People's Republic of China
| | - Xiaotian Liang
- Zhejiang Police College, Hangzhou, People's Republic of China
| | - Haiwei Li
- College of Physical Education, Shanxi Normal University, Taiyuan, People's Republic of China
| | - Lin Wang
- School of Sports Medicine and Rehabilitation, Beijing Sport University, Beijing, People's Republic of China
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An H, Jang Y, Choi J, Hur J, Kim S, Kwon Y. New Insights into AMPK, as a Potential Therapeutic Target in Metabolic Dysfunction-Associated Steatotic Liver Disease and Hepatic Fibrosis. Biomol Ther (Seoul) 2025; 33:18-38. [PMID: 39702310 PMCID: PMC11704404 DOI: 10.4062/biomolther.2024.188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 12/08/2024] [Accepted: 12/10/2024] [Indexed: 12/21/2024] Open
Abstract
AMP-activated protein kinase (AMPK) activators have garnered significant attention for their potential to prevent the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) into liver fibrosis and to fundamentally improve liver function. The broad spectrum of pathways regulated by AMPK activators makes them promising alternatives to conventional liver replacement therapies and the limited pharmacological treatments currently available. In this study, we aim to illustrate the newly detailed multiple mechanisms of MASLD progression based on the multiple-hit hypothesis. This model posits that impaired lipid metabolism, combined with insulin resistance and metabolic imbalance, initiates inflammatory cascades, gut dysbiosis, and the accumulation of toxic metabolites, ultimately promoting fibrosis and accelerating MASLD progression to irreversible hepatocellular carcinoma (HCC). AMPK plays a multifaceted protective role against these pathological conditions by regulating several key downstream signaling pathways. It regulates biological effectors critical to metabolic and inflammatory responses, such as SIRT1, Nrf2, mTOR, and TGF-β, through complex and interrelated mechanisms. Due to these intricate connections, AMPK's role is pivotal in managing metabolic and inflammatory disorders. In this review, we demonstrate the specific roles of AMPK and its related pathways. Several agents directly activate AMPK by binding as agonists, while some others indirectly activate AMPK by modulating upstream molecules, including adiponectin, LKB1, and the AMP: ATP ratio. As AMPK activators can target each stage of MASLD progression, the development of AMPK activators offers immense potential to expand therapeutic strategies for liver diseases such as MASH, MASLD, and liver fibrosis.
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Affiliation(s)
- Haeun An
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Yerin Jang
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Jungin Choi
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Juhee Hur
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Seojeong Kim
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Youngjoo Kwon
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
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Wang S, Sha P, Zhao X, Tao Z, Liu S. Peritendinous adhesion: Therapeutic targets and progress of drug therapy. Comput Struct Biotechnol J 2024; 23:251-263. [PMID: 38173878 PMCID: PMC10762322 DOI: 10.1016/j.csbj.2023.11.059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 11/28/2023] [Accepted: 11/28/2023] [Indexed: 01/05/2024] Open
Abstract
Peritendinous adhesion (PA) is one of the most common complications following hand surgery and characterized with abnormal hyperplasia of connective tissue and excessive deposition of extracellular matrix. Subsequently, various clinical symptoms such as chronic pain, limb dyskinesia and even joint stiffness occur and patients are always involved in the vicious cycle of "adhesion - release - re-adhesion", which seriously compromise the quality of life. Until present, the underlying mechanism remains controversial and lack of specific treatment, with symptomatic treatment being the only option to relieve symptoms, but not contributing no more to the fundamentally rehabilitation of basic structure and function. Recently, novel strategies have been proposed to inhibit the formation of adhesion tissues including implantation of anti-adhesion barriers, anti-inflammation, restraint of myofibroblast transformation and regulation of collagen overproduction. Furthermore, gene therapy has also been considered as a promising anti-adhesion treatment. In this review, we provide an overview of anti-adhesion targets and relevant drugs to summarize the potential pharmacological roles and present subsequent challenges and prospects of anti-adhesion drugs.
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Affiliation(s)
| | | | | | - Zaijin Tao
- Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Hanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Shen Liu
- Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Hanghai Jiao Tong University School of Medicine, Shanghai 200233, China
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López-Cerdá S, Molinaro G, Tello RP, Correia A, Künig S, Steinberger P, Jeltsch M, Hirvonen JT, Barreto G, Stöckl J, Santos HA. Study of the Synergistic Immunomodulatory and Antifibrotic Effects of Dual-Loaded Budesonide and Serpine1 siRNA Lipid-Polymer Nanoparticles Targeting Macrophage Dysregulation in Tendinopathy. ACS APPLIED MATERIALS & INTERFACES 2024; 16:18643-18657. [PMID: 38564504 DOI: 10.1021/acsami.4c02363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Musculoskeletal diseases involving tissue injury comprise tendon, ligament, and muscle injury. Recently, macrophages have been identified as key players in the tendon repair process, but no therapeutic strategy involving dual drug delivery and gene delivery to macrophages has been developed for targeting the two main dysregulated aspects of macrophages in tendinopathy, i.e., inflammation and fibrosis. Herein, the anti-inflammatory and antifibrotic effects of dual-loaded budesonide and serpine1 siRNA lipid-polymer hybrid nanoparticles (LPNs) are evaluated in murine and human macrophage cells. The modulation of the gene and protein expression of factors associated with inflammation and fibrosis in tendinopathy is demonstrated by real time polymerase chain reaction and Western blot. Macrophage polarization to the M2 phenotype and a decrease in the production of pro-inflammatory cytokines are confirmed in macrophage cell lines and primary cells. The increase in the activity of a matrix metalloproteinase involved in tissue remodelling is proven, and studies evaluating the interactions of LPNs with T cells proved that dual-loaded LPNs act specifically on macrophages and do not induce any collateral effects on T cells. Overall, these dual-loaded LPNs are a promising combinatorial therapeutic strategy with immunomodulatory and antifibrotic effects in dysregulated macrophages in the context of tendinopathy.
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Affiliation(s)
- Sandra López-Cerdá
- Drug Research Program, Division of Pharmaceutical Chemistry and Technology, University of Helsinki, Helsinki FI-00014, Finland
| | - Giuseppina Molinaro
- Drug Research Program, Division of Pharmaceutical Chemistry and Technology, University of Helsinki, Helsinki FI-00014, Finland
| | - Rubén Pareja Tello
- Drug Research Program, Division of Pharmaceutical Chemistry and Technology, University of Helsinki, Helsinki FI-00014, Finland
| | - Alexandra Correia
- Drug Research Program, Division of Pharmaceutical Chemistry and Technology, University of Helsinki, Helsinki FI-00014, Finland
| | - Sarojinidevi Künig
- Centre for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Medical University of Vienna, 1090 Vienna, Austria
| | - Peter Steinberger
- Centre for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Medical University of Vienna, 1090 Vienna, Austria
| | - Michael Jeltsch
- Drug Research Program, Division of Pharmaceutical Chemistry and Technology, University of Helsinki, Helsinki FI-00014, Finland
- Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki FI-00014, Finland
- Wihuri Research Institute, Helsinki FI-00014, Finland
- Helsinki One Health, University of Helsinki, Helsinki FI-00014, Finland
| | - Jouni T Hirvonen
- Drug Research Program, Division of Pharmaceutical Chemistry and Technology, University of Helsinki, Helsinki FI-00014, Finland
| | - Goncalo Barreto
- Translational Immunology Research Program, Faculty of Medicine, University of Helsinki, Helsinki FI-00014, Finland
- Orton Orthopedic Hospital, Tenholantie 10, Helsinki 00280, Finland
- Medical Ultrasonics Laboratory (MEDUSA), Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo 02150, Finland
| | - Johannes Stöckl
- Centre for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Medical University of Vienna, 1090 Vienna, Austria
| | - Hélder A Santos
- Drug Research Program, Division of Pharmaceutical Chemistry and Technology, University of Helsinki, Helsinki FI-00014, Finland
- Department of Biomaterials and Biomedical Technology, University Medical Center Groningen, University of Groningen, Ant. Deusinglaan 1, 9713 AV Groningen, The Netherlands
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Medina Pizaño MY, Loera Arias MDJ, Montes de Oca Luna R, Saucedo Cárdenas O, Ventura Juárez J, Muñoz Ortega MH. Neuroimmunomodulation of adrenoblockers during liver cirrhosis: modulation of hepatic stellate cell activity. Ann Med 2023; 55:543-557. [PMID: 36826975 PMCID: PMC9970206 DOI: 10.1080/07853890.2022.2164047] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/25/2023] Open
Abstract
The sympathetic nervous system and the immune system are responsible for producing neurotransmitters and cytokines that interact by binding to receptors; due to this, there is communication between these systems. Liver immune cells and nerve fibres are systematically distributed in the liver, and the partial overlap of both patterns may favour interactions between certain elements. Dendritic cells are attached to fibroblasts, and nerve fibres are connected via the dendritic cell-fibroblast complex. Receptors for most neuroactive substances, such as catecholamines, have been discovered on dendritic cells. The sympathetic nervous system regulates hepatic fibrosis through sympathetic fibres and adrenaline from the adrenal glands through the blood. When there is liver damage, the sympathetic nervous system is activated locally and systemically through proinflammatory cytokines that induce the production of epinephrine and norepinephrine. These neurotransmitters bind to cells through α-adrenergic receptors, triggering a cellular response that secretes inflammatory factors that stimulate and activate hepatic stellate cells. Hepatic stellate cells are key in the fibrotic process. They initiate the overproduction of extracellular matrix components in an active state that progresses from fibrosis to liver cirrhosis. It has also been shown that they can be directly activated by norepinephrine. Alpha and beta adrenoblockers, such as carvedilol, prazosin, and doxazosin, have recently been used to reverse CCl4-induced liver cirrhosis in rodent and murine models.KEY MESSAGESNeurotransmitters from the sympathetic nervous system activate and increase the proliferation of hepatic stellate cells.Hepatic fibrosis and cirrhosis treatment might depend on neurotransmitter and hepatic nervous system regulation.Strategies to reduce hepatic stellate cell activation and fibrosis are based on experimentation with α-adrenoblockers.
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Affiliation(s)
| | | | | | - Odila Saucedo Cárdenas
- Histology Department, Faculty of Medicine, Autonomous University of Nuevo León, Monterrey, México
| | - Javier Ventura Juárez
- Department of Morphology, Autonomous University of Aguascalientes, Aguascalientes, México
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Li H, Luo S, Wang H, Chen Y, Ding M, Lu J, Jiang L, Lyu K, Huang S, Shi H, Chen H, Li S. The mechanisms and functions of TGF-β1 in tendon healing. Injury 2023; 54:111052. [PMID: 37738787 DOI: 10.1016/j.injury.2023.111052] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 09/11/2023] [Indexed: 09/24/2023]
Abstract
Tendon injury accounts for 30% of musculoskeletal diseases and often leads to disability, pain, healthcare cost, and lost productivity. Following injury to tendon, tendon healing proceeds via three overlapping healing processes. However, due to the structural defects of the tendon itself, the tendon healing process is characterized by the formation of excessive fibrotic scar tissue, and injured tendons rarely return to native tendons, which can easily contribute to tendon reinjury. Moreover, the resulting fibrous scar is considered to be a precipitating factor for subsequent degenerative tendinopathy. Despite this, therapies are almost limited because underlying molecular mechanisms during tendon healing are still unknown. Transforming Growth Factor-β1 (TGF-β1) is known as one of most potent profibrogenic factors during tendon healing process. However, blockage TGF-β1 fails to effectively enhance tendon healing. A detailed understanding of real abilities of TGF-β1 involved in tendon healing can bring promising perspectives for therapeutic value that improve the tendon healing process. Thus, in this review, we describe recent efforts to identify and characterize the roles and mechanisms of TGF-β1 involved at each stage of the tendon healing and highlight potential roles of TGF-β1 leading to the fibrotic response to tendon injury.
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Affiliation(s)
- Hanyue Li
- School of Physical Education, Southwest Medical University, Luzhou, China
| | - Shengyu Luo
- School of Physical Education, Southwest Medical University, Luzhou, China
| | - Hao Wang
- Spinal Surgery Department, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Yixuan Chen
- School of Physical Education, Southwest Medical University, Luzhou, China
| | - MingZhe Ding
- School of Public Health, Southwest Medical University, Luzhou, China
| | - Jingwei Lu
- School of Physical Education, Southwest Medical University, Luzhou, China
| | - Li Jiang
- School of Physical Education, Southwest Medical University, Luzhou, China
| | - Kexin Lyu
- School of Physical Education, Southwest Medical University, Luzhou, China
| | - Shilin Huang
- School of Physical Education, Southwest Medical University, Luzhou, China
| | - Houyin Shi
- School of Public Health, Southwest Medical University, Luzhou, China
| | - Hui Chen
- Spinal Surgery Department, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Sen Li
- School of Physical Education, Southwest Medical University, Luzhou, China.
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Ali FE, Abd El-Aziz MK, Sharab EI, Bakr AG. Therapeutic interventions of acute and chronic liver disorders: A comprehensive review. World J Hepatol 2023; 15:19-40. [PMID: 36744165 PMCID: PMC9896501 DOI: 10.4254/wjh.v15.i1.19] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 11/17/2022] [Accepted: 12/21/2022] [Indexed: 01/16/2023] Open
Abstract
Liver disorders are one of the most common pathological problems worldwide. It affects more than 1.5 billion worldwide. Many types of hepatic cells have been reported to be involved in the initiation and propagation of both acute and chronic liver diseases, including hepatocytes, Kupffer cells, sinusoidal endothelial cells, and hepatic stellate cells (HSCs). In addition, oxidative stress, cytokines, fibrogenic factors, microRNAs, and autophagy are also involved. Understanding the molecular mechanisms of liver diseases leads to discovering new therapeutic interventions that can be used in clinics. Recently, antioxidant, anti-inflammatory, anti-HSCs therapy, gene therapy, cell therapy, gut microbiota, and nanoparticles have great potential for preventing and treating liver diseases. Here, we explored the recent possible molecular mechanisms involved in the pathogenesis of acute and chronic liver diseases. Besides, we overviewed the recent therapeutic interventions that targeted liver diseases and summarized the recent studies concerning liver disorders therapy.
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Affiliation(s)
- Fares Em Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt.
| | | | - Elham I Sharab
- Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt
| | - Adel G Bakr
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt
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Koch DW, Schnabel LV, Ellis IM, Bates RE, Berglund AK. TGF-β2 enhances expression of equine bone marrow-derived mesenchymal stem cell paracrine factors with known associations to tendon healing. Stem Cell Res Ther 2022; 13:477. [PMID: 36114555 PMCID: PMC9482193 DOI: 10.1186/s13287-022-03172-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 09/07/2022] [Indexed: 12/01/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) secrete paracrine factors and extracellular matrix proteins that contribute to their ability to support tissue healing and regeneration. Both the transcriptome and the secretome of MSCs can be altered by treating the cells with cytokines, but neither have been thoroughly investigated following treatment with the specific cytokine transforming growth factor (TGF)-β2. Methods RNA-sequencing and western blotting were used to compare gene and protein expression between untreated and TGF-β2-treated equine bone marrow-derived MSCs (BM-MSCs). A co-culture system was utilized to compare equine tenocyte migration during co-culture with untreated and TGF-β2-treated BM-MSCs. Results TGF-β2 treatment significantly upregulated gene expression of collagens, extracellular matrix molecules, and growth factors. Protein expression of collagen type I and tenascin-C was also confirmed to be upregulated in TGF-β2-treated BM-MSCs compared to untreated BM-MSCs. Both untreated and TGF-β2-treated BM-MSCs increased tenocyte migration in vitro. Conclusions Treating equine BM-MSCs with TGF-β2 significantly increases production of paracrine factors and extracellular matrix molecules important for tendon healing and promotes the migration of tenocytes in vitro. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-03172-9.
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Wilson SE, Sampaio LP, Shiju TM, Hilgert GSL, de Oliveira RC. Corneal Opacity: Cell Biological Determinants of the Transition From Transparency to Transient Haze to Scarring Fibrosis, and Resolution, After Injury. Invest Ophthalmol Vis Sci 2022; 63:22. [PMID: 35044454 PMCID: PMC8787546 DOI: 10.1167/iovs.63.1.22] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 12/22/2021] [Indexed: 12/18/2022] Open
Abstract
Purpose To highlight the cellular, matrix, and hydration changes associated with opacity that occurs in the corneal stroma after injury. Methods Review of the literature. Results The regulated transition of keratocytes to corneal fibroblasts and myofibroblasts, and of bone marrow-derived fibrocytes to myofibroblasts, is in large part modulated by transforming growth factor beta (TGFβ) entry into the stroma after injury to the epithelial basement membrane (EBM) and/or Descemet's membrane. The composition, stoichiometry, and organization of the stromal extracellular matrix components and water is altered by corneal fibroblast and myofibroblast production of large amounts of collagen type I and other extracellular matrix components-resulting in varying levels of stromal opacity, depending on the intensity of the healing response. Regeneration of EBM and/or Descemet's membrane, and stromal cell production of non-EBM collagen type IV, reestablishes control of TGFβ entry and activity, and triggers TGFβ-dependent myofibroblast apoptosis. Eventually, corneal fibroblasts also disappear, and repopulating keratocytes reorganize the disordered extracellular matrix to reestablish transparency. Conclusions Injuries to the cornea produce varying amounts of corneal opacity depending on the magnitude of cellular and molecular responses to injury. The EBM and Descemet's membrane are key regulators of stromal cellularity through their modulation of TGFβ. After injury to the cornea, depending on the severity of the insult, and possibly genetic factors, trace opacity to severe scarring fibrosis develops. Stromal cellularity, and the functions of different cell types, are the major determinants of the level of the stromal opacity.
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Affiliation(s)
- Steven E. Wilson
- Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States
| | - Lycia Pedral Sampaio
- Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States
- Department of Ophthalmology, University of Sao Paulo, Sao Paulo, Brazil
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Sanjay K, Vishwakarma S, Zope BR, Mane VS, Mohire S, Dhakshinamoorthy S. ATP citrate lyase inhibitor Bempedoic Acid alleviate long term HFD induced NASH through improvement in glycemic control, reduction of hepatic triglycerides & total cholesterol, modulation of inflammatory & fibrotic genes and improvement in NAS score. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2021; 2:100051. [PMID: 34909677 PMCID: PMC8663992 DOI: 10.1016/j.crphar.2021.100051] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 08/20/2021] [Accepted: 08/31/2021] [Indexed: 12/20/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and Non-alcoholic steatohepatitis (NASH) are chronic liver disorders, the prevalence of which is increasing worldwide. Long term High Fat Diet (HFD) induced NASH animal models closely mimic the characteristics of human NASH and hence used by investigators as a model system for studying the mechanism of action of new drugs. Bempedoic acid (ETC-1002), a ATP citrate lyase (ACLY) inhibitor that lowers the LDL cholesterol was recently approved by US FDA for the treatment of heterozygous familial hypercholesterolemia (HeFH) and established atherosclerotic cardiovascular disease (ASCVD). ACLY is one of the genes modulated in NASH patients and hence we studied the effect of ACLY inhibitor Bempedoic acid in long term HFD induced NASH animal model to understand the pharmacological benefits and the associated mechanism of action of this newly approved drug in NASH. Mice fed with 60% Kcal High Fat Diet for 32 weeks were used for the study and the animals were given Bempedoic acid for 5 weeks at doses of 10 mg kg−1, po, qd, and 30 mg kg−1, po, qd. Bempedoic acid treatment resulted in inhibition of body weight gain and improved the glycemic control. Bempedoic acid treated group showed statistically significant reduction in plasma ALT, AST, hepatic triglycerides (TG) and total cholesterol (TC), along with statistically significant reduction in steatosis score by histological analysis. Hepatic gene expression analysis showed significant reduction in inflammatory and fibrotic genes such as Mcp-1/Ccl2, Timp-1 & Col1α1. Histological analysis showed significant improvement in NAS score. Overall, Bempedoic acid alleviated HFD induced Non-Alcoholic Steatohepatitis through inhibition of body weight gain, improvement in glycemic control, reduction of hepatic triglycerides & total cholesterol, modulation of inflammatory & fibrotic genes, and improvement in NAS score. Hence, Bempedoic acid can be a potential therapeutic option for metabolic syndrome and NASH.
Bempedoic acid alleviated HFD induced Non-Alcoholic Steatohepatitis in a long term HFD induced NASH animal model. Mechanism of action includes modulation of lipid profile, inflammatory & fibrotic genes and inhibition of body weight gain. Overall improvement in NAS score was observed with Bempedoic acid treatment. Our study shows a promising role for Bempedoic acid in amelioration of metabolic disorders and NASH.
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11
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Song M, Cui Y, Wang Q, Zhang X, Zhang J, Liu M, Li Y. Ginsenoside Rg3 Alleviates Aluminum Chloride-Induced Bone Impairment in Rats by Activating the TGF-β1/Smad Signaling Pathway. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:12634-12644. [PMID: 34694773 DOI: 10.1021/acs.jafc.1c04695] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Aluminum (Al)-induced bone formation and metabolism disorder through inhibition of the TGF-β1/Smad signaling pathway is one of the important mechanisms of bone impairment. Ginsenoside Rg3 (Rg3), a specific biological effector molecule, can provide protection to bones. Previously, we demonstrated that Rg3 can reverse aluminum chloride (AlCl3)-induced oxidative stress and metabolic disorder of bones; however, whether the TGF-β1/Smad signaling pathway is involved in it remains unclear. First, we found that Rg3 attenuated Al-induced bone impairment in vivo and in vitro by relieving structural damage to the femur, increasing MC3T3-E1 cell activity, differentiation, mineralization, inhibition of cell apoptosis, and upregulating the extracellular matrix (ECM) synthesis and the expression of TGF-β1/Smad signaling pathway key factors. Subsequently, in the signal pathway intervention experiment, the protective effect of Rg3 on bone impairment induced by Al was weakened; these results indicate that activating the TGF-β1/Smad signaling pathway is one of the mechanisms of Rg3-attenuated Al-induced bone impairment.
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Affiliation(s)
- Miao Song
- Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, No. 600, Changjiang Road, Harbin 150030, China
| | - Yilong Cui
- Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, No. 600, Changjiang Road, Harbin 150030, China
| | - Qi Wang
- Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, No. 600, Changjiang Road, Harbin 150030, China
| | - Xuliang Zhang
- Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, No. 600, Changjiang Road, Harbin 150030, China
| | - Jian Zhang
- Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, No. 600, Changjiang Road, Harbin 150030, China
| | - Menglin Liu
- Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, No. 600, Changjiang Road, Harbin 150030, China
| | - Yanfei Li
- Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, No. 600, Changjiang Road, Harbin 150030, China
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Padilla S, Nurden AT, Prado R, Nurden P, Anitua E. Healing through the lens of immunothrombosis: Biology-inspired, evolution-tailored, and human-engineered biomimetic therapies. Biomaterials 2021; 279:121205. [PMID: 34710794 DOI: 10.1016/j.biomaterials.2021.121205] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 09/30/2021] [Accepted: 10/20/2021] [Indexed: 12/14/2022]
Abstract
Evolution, from invertebrates to mammals, has yielded and shaped immunoclotting as a defense and repair response against trauma and infection. This mosaic of immediate and local wound-sealing and pathogen-killing mechanisms results in survival, restoration of homeostasis, and tissue repair. In mammals, immunoclotting has been complemented with the neuroendocrine system, platelets, and contact system among other embellishments, adding layers of complexity through interconnecting blood-born proteolytic cascades, blood cells, and the neuroendocrine system. In doing so, immunothrombosis endows humans with survival advantages, but entails vulnerabilities in the current unprecedented and increasingly challenging environment. Immunothrombosis and tissue repair appear to go hand in hand with common mechanisms mediating both processes, a fact that is underlined by recent advances that are deciphering the mechanisms of the repair process and of the biochemical pathways that underpins coagulation, hemostasis and thrombosis. This review is intended to frame both the universal aspects of tissue repair and the therapeutic use of autologous fibrin matrix as a biology-as-a-drug approach in the context of the evolutionary changes in coagulation and hemostasis. In addition, we will try to shed some light on the molecular mechanisms underlying the use of the autologous fibrin matrix as a biology-inspired, evolution-tailored, and human-engineered biomimetic therapy.
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Affiliation(s)
- Sabino Padilla
- Eduardo Anitua Foundation for Biomedical Research, Vitoria, Spain; BTI-Biotechnology Institute ImasD, Vitoria, Spain; University Institute for Regenerative Medicine & Oral Implantology - UIRMI (UPV/EHU-Fundación Eduardo Anitua), Vitoria, Spain.
| | - Alan T Nurden
- Institut Hospitalo-Universitaire LIRYC, Hôpital Xavier Arnozan, Pessac, France
| | - Roberto Prado
- Eduardo Anitua Foundation for Biomedical Research, Vitoria, Spain; BTI-Biotechnology Institute ImasD, Vitoria, Spain; University Institute for Regenerative Medicine & Oral Implantology - UIRMI (UPV/EHU-Fundación Eduardo Anitua), Vitoria, Spain
| | - Paquita Nurden
- Institut Hospitalo-Universitaire LIRYC, Hôpital Xavier Arnozan, Pessac, France
| | - Eduardo Anitua
- Eduardo Anitua Foundation for Biomedical Research, Vitoria, Spain; BTI-Biotechnology Institute ImasD, Vitoria, Spain; University Institute for Regenerative Medicine & Oral Implantology - UIRMI (UPV/EHU-Fundación Eduardo Anitua), Vitoria, Spain.
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Myofibroblasts: Function, Formation, and Scope of Molecular Therapies for Skin Fibrosis. Biomolecules 2021; 11:biom11081095. [PMID: 34439762 PMCID: PMC8391320 DOI: 10.3390/biom11081095] [Citation(s) in RCA: 123] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Revised: 07/16/2021] [Accepted: 07/20/2021] [Indexed: 12/11/2022] Open
Abstract
Myofibroblasts are contractile, α-smooth muscle actin-positive cells with multiple roles in pathophysiological processes. Myofibroblasts mediate wound contractions, but their persistent presence in tissues is central to driving fibrosis, making them attractive cell targets for the development of therapeutic treatments. However, due to shared cellular markers with several other phenotypes, the specific targeting of myofibroblasts has long presented a scientific and clinical challenge. In recent years, myofibroblasts have drawn much attention among scientific research communities from multiple disciplines and specialisations. As further research uncovers the characterisations of myofibroblast formation, function, and regulation, the realisation of novel interventional routes for myofibroblasts within pathologies has emerged. The research community is approaching the means to finally target these cells, to prevent fibrosis, accelerate scarless wound healing, and attenuate associated disease-processes in clinical settings. This comprehensive review article describes the myofibroblast cell phenotype, their origins, and their diverse physiological and pathological functionality. Special attention has been given to mechanisms and molecular pathways governing myofibroblast differentiation, and updates in molecular interventions.
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Zhang M, Liu H, Shi M, Zhang T, Lu W, Yang S, Cui Q, Li Z. Potential Mechanisms of the Impact of Hepatocyte Growth Factor Gene-Modified Tendon Stem Cells on Tendon Healing. Front Cell Dev Biol 2021; 9:659389. [PMID: 34222233 PMCID: PMC8250428 DOI: 10.3389/fcell.2021.659389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 05/10/2021] [Indexed: 11/13/2022] Open
Abstract
The therapeutic impact of stem cells is potentially largely attributable to secretion of exosomes and soluble factors. The present study evaluates the impact of hepatocyte growth factor (HGF)-expressing tendon stem cells (TSCs) on tendon healing in a rat model. Patellar tendon TSCs were isolated and underwent transfection with lentiviral vectors containing HGF or green fluorescent protein (GFP) genes. In vivo, immunohistochemistry of tendons sampled 1 week postsurgery demonstrated that all stem cell-treated groups exhibited higher numbers of CD163+ M2 monocytes and IL-10+ cells (anti-inflammatory), and lower numbers of CCR7+ M1 monocytes and IL-6+ as well as COX-2+ cells (pro-inflammatory). Effects were most pronounced in the HGF-expressing TSCs (TSCs + HGF) treated group. Histology ± immunohistochemistry of tendons sampled 4 and 8 weeks postsurgery demonstrated that all stem cell-treated groups exhibited more ordered collagen fiber arrangement and lower levels of COLIII, α-SMA, TGF-β1, and fibronectin (proteins relevant to fibroscarring). Effects were most pronounced in the TSCs + HGF-treated group. For the in vitro study, isolated tendon fibroblasts pretreated with TGF-β1 to mimic the in vivo microenvironment of tendon injury were indirectly cocultured with TSCs, TSCs + GFP, or TSCs + HGF using a transwell system. Western blotting demonstrated that all stem cell types decreased TGF-β1-induced increases in fibroblast levels of COX-2, COLIII, and α-SMA, concomitant with decreased activation of major TGF-β1 signaling pathways (p38 MAPK, ERK1/2, but not Smad2/3). This effect was most pronounced for TSCs + HGF, which also decreased the TGF-β1-induced increase in activation of the Smad2/3 signaling pathway. The presence of specific inhibitors of these pathways during fibroblast TGF-β1 stimulation also attenuated increases in levels of COX-2, COLIII, and α-SMA. In conclusion, TSCs + HGF, which exhibit HGF overexpression, may promoting tendon healing via decreasing inflammation and fibrosis, perhaps partly via inhibiting TGF-β1-induced signaling. These findings identify a novel potential therapeutic strategy for tendon injuries, warranting additional research.
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Affiliation(s)
- Mingzhao Zhang
- Department of Pediatric Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hengchen Liu
- Department of Pediatric Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Manyu Shi
- Department of Pediatric Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Tingting Zhang
- Department of Pediatric Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wenjun Lu
- Department of Pediatric Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shulong Yang
- Department of Pediatric Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Qingbo Cui
- Department of Pediatric Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhaozhu Li
- Department of Pediatric Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
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Abstract
Hepatic fibrosis is a complex mechanism defined by the net deposition of the extracellular matrix (ECM) owing to liver injury caused by multiple etiologies such as viral hepatitis and nonalcoholic fatty liver disease. Many cell types are implicated in liver fibrosis development and progression. In general, liver fibrosis starts with the recruitment of inflammatory immune cells to generate cytokines, growth factors, and other activator molecules. Such chemical mediators drive the hepatic stellate cells (HSCs) to activate the production of the ECM component. The activation of HSC is thus a crucial event in the fibrosis initiation, and a significant contributor to collagen deposition (specifically type I). This review explores the causes and mechanisms of hepatic fibrosis and focuses on the roles of key molecules involved in liver fibro genesis, some of which are potential targets for therapeutics to hamper liver fibro genesis.
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Affiliation(s)
- Reham M Dawood
- Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre, Giza, Egypt
| | - Mai A El-Meguid
- Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre, Giza, Egypt
| | - Ghada Maher Salum
- Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre, Giza, Egypt
| | - Mostafa K El Awady
- Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre, Giza, Egypt
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Zhang M, Liu H, Cui Q, Han P, Yang S, Shi M, Zhang T, Zhang Z, Li Z. Tendon stem cell-derived exosomes regulate inflammation and promote the high-quality healing of injured tendon. Stem Cell Res Ther 2020; 11:402. [PMID: 32943109 PMCID: PMC7499865 DOI: 10.1186/s13287-020-01918-x] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 07/30/2020] [Accepted: 09/01/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Tendon stem cells (TSCs) have been reported to hold promises for tendon repair and regeneration. However, less is known about the effects of exosomes derived from TSCs. Therefore, we aimed to clarify the healing effects of TSC-derived exosomes (TSC-Exos) on tendon injury. METHODS The Achilles tendons of Sprague-Dawley male rats were used for primary culture of TSCs and tenocytes, and exosomes were isolated from TSCs. The proliferation of tenocytes induced by TSC-Exos was analyzed using an EdU assay; cell migration was measured by cell scratch and transwell assays. We used western blot to analyze the role of the PI3K/AKT and MAPK/ERK1/2 signaling pathways. In vivo, Achilles tendon injury models were created in Sprague-Dawley rats. Rats (n = 54) were then randomly assigned to three groups: the TSC-Exos group, the GelMA group, and the control group. We used immunofluorescence to detect changes in the expression of inflammatory and apoptotic markers at 1 week after surgery. Histology and changes in expression of extracellular matrix (ECM)-related indices were assessed by hematoxylin-eosin (H&E) staining and immunohistochemistry at 2 and 8 weeks. The collagen fiber diameter of the healing tendon was analyzed at 8 weeks by transmission electron microscopy (TEM). RESULTS TSC-Exos were taken up by tenocytes, which promoted the proliferation and migration of cells in a dose-dependent manner; this process may depend on the activation of the PI3K/AKT and MAPK/ERK1/2 signaling pathways. At 1 week after surgery, we found that inflammation and apoptosis were significantly suppressed by TSC-Exos. At 2 and 8 weeks, tendons treated with TSC-Exos showed more continuous and regular arrangement in contrast to disorganized tendons in the GelMA and control groups, and TSC-Exos may help regulate ECM balance and inhibited scar formation. Further, at 8 weeks, the TSC-Exos group had a larger diameter of collagen compared to the control group. CONCLUSIONS Our data suggest that TSC-Exos could promote high-quality healing of injured tendon, which may be a promising therapeutic approach for tendon injury.
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Affiliation(s)
- Mingzhao Zhang
- Department of Pediatric Surgery, The Second Affiliated Hospital of Harbin Medical University, No. 246, Xuefu Road, Nangang District, Harbin, 150001, China
| | - Hengchen Liu
- Department of Pediatric Surgery, The Second Affiliated Hospital of Harbin Medical University, No. 246, Xuefu Road, Nangang District, Harbin, 150001, China
| | - Qingbo Cui
- Department of Pediatric Surgery, The Second Affiliated Hospital of Harbin Medical University, No. 246, Xuefu Road, Nangang District, Harbin, 150001, China
| | - Peilin Han
- Department of Pediatric Surgery, The Second Affiliated Hospital of Harbin Medical University, No. 246, Xuefu Road, Nangang District, Harbin, 150001, China
| | - Shulong Yang
- Department of Pediatric Surgery, The Second Affiliated Hospital of Harbin Medical University, No. 246, Xuefu Road, Nangang District, Harbin, 150001, China
| | - Manyu Shi
- Department of Pediatric Surgery, The Second Affiliated Hospital of Harbin Medical University, No. 246, Xuefu Road, Nangang District, Harbin, 150001, China
| | - Tingting Zhang
- Department of Pediatric Surgery, The Second Affiliated Hospital of Harbin Medical University, No. 246, Xuefu Road, Nangang District, Harbin, 150001, China
| | - Zenan Zhang
- Department of Pediatric Surgery, The Second Affiliated Hospital of Harbin Medical University, No. 246, Xuefu Road, Nangang District, Harbin, 150001, China
| | - Zhaozhu Li
- Department of Pediatric Surgery, The Second Affiliated Hospital of Harbin Medical University, No. 246, Xuefu Road, Nangang District, Harbin, 150001, China.
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Quinet MT, Raghavan M, Morris E, Smith T, Cook H, Walter N, Shuler M. Effectiveness of Amniotic Fluid Injection in the Treatment of Trigger Finger: A Pilot Study. JOURNAL OF HAND SURGERY GLOBAL ONLINE 2020; 2:301-305. [PMID: 35415511 PMCID: PMC8991634 DOI: 10.1016/j.jhsg.2020.06.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 06/25/2020] [Indexed: 11/28/2022] Open
Abstract
Purpose To assess the efficacy and safety of amniotic fluid therapy injections in patients with mild to moderate trigger finger. Methods All participants received 1 mL of amniotic fluid injected into the tendon sheath of the affected tendon. Pretreatment and posttreatment data were collected for triggering frequency, Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire scores, and numerical pain rating scale scores. Results Of 111 digits from 96 patients, 51% experienced clinically notable improvement and did not receive an alternative treatment. Average length of follow-up was 11 months. From baseline to end of follow-up, average pain score (0–10) decreased from 5.19 to 1.19 (P < .001), median triggering per day decreased from 5 to 0 (P < .001), and median DASH score (1–100) decreased from 20 to 6.03 (P < .001). There was a 50% success rate in patients with diabetes and a 52.6% success rate in digits diagnosed with concomitant Dupuytren contracture in the same hand. Conclusions Amniotic fluid therapy injections may offer a biologic alternative for conservative treatment of trigger finger, particularly for patients with diabetes. Decreased pain, decreased triggering, and improved DASH scores offer preliminary evidence supporting the use of amniotic injections for stenosing tenosynovitis. Type of study/level of evidence Therapeutic IV.
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Affiliation(s)
- Michael T. Quinet
- Department of Medicine, Augusta University/Medical College of George Partnership, Athens, GA
| | | | - Emily Morris
- Department of Medicine, Augusta University/Medical College of George Partnership, Athens, GA
| | | | - Haley Cook
- Department of Medicine, Augusta University/Medical College of George Partnership, Athens, GA
| | - Nathan Walter
- Department of Medicine, Augusta University/Medical College of George Partnership, Athens, GA
| | - Michael Shuler
- Athens Orthopedic Clinic, Athens, GA
- Corresponding author: Michael Shuler, MD, Athens Orthopedic Clinic, 1765 Old West Broad Street, Building 2, Suite 200, Athens, GA 30606.
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de Oliveira RC, Murillo S, Saikia P, Wilson SE. The Efficacy of Topical HGF on Corneal Fibrosis and Epithelial Healing after Scar-Producing PRK Injury in Rabbits. Transl Vis Sci Technol 2020; 9:29. [PMID: 32818116 PMCID: PMC7396189 DOI: 10.1167/tvst.9.4.29] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Accepted: 01/14/2020] [Indexed: 01/18/2023] Open
Abstract
Purpose To determine the effect of topical hepatocyte growth factor (HGF) on myofibroblast development and corneal opacity after fibrosis-producing photorefractive keratectomy (PRK). Methods Twelve New Zealand rabbits had transepithelial PRK. Six rabbits received topical recombinant human HGF (rhHGF) (50 µL of 0.1 mg/mL) 3 times a day for 1 week beginning 6 hours prior surgery and until full closure of the epithelium, and 6 control rabbits received vehicle by the same schedule. Slit lamp photos were taken immediately and at 43 to 45 hours after surgery to determine the rate of epithelial healing. Slit lamp photographs and immunohistochemistry for α-smooth muscle actin were analyzed at 1 month in masked fashion. Results The rhHGF group tended to have slower re-epithelization when compared with the controls, but no statistically significant difference was noted (P = 0.62). There was no significant difference in the density of myofibroblasts in the central stroma (P = 0.49) or corneal opacity (P = 0.84) between the HGF and control groups at 1 month after PRK. Conclusions Topical rhHGF applied three times a day during the early postoperative period prior to epithelial closure did not significantly change the corneal epithelial healing rate, myofibroblast density, or opacity compared with vehicle after transepithelial -9.0 D PRK injury of the central cornea in rabbits. Translational Relevance HGF has been reported to decrease myofibroblast generation and fibrosis in many organs, but topical HGF applied to the cornea until epithelial healing had no effect on scarring fibrosis in rabbit corneas.
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Affiliation(s)
| | - Sofia Murillo
- The Cole Eye Institute, The Cleveland Clinic, Cleveland, OH, USA
| | | | - Steven E. Wilson
- The Cole Eye Institute, The Cleveland Clinic, Cleveland, OH, USA
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Han P, Cui Q, Lu W, Yang S, Shi M, Li Z, Gao P, Xu B, Li Z. Hepatocyte growth factor plays a dual role in tendon-derived stem cell proliferation, migration, and differentiation. J Cell Physiol 2019; 234:17382-17391. [PMID: 30807656 DOI: 10.1002/jcp.28360] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 01/28/2019] [Accepted: 01/30/2019] [Indexed: 12/18/2022]
Abstract
Heterotopic ossification is common in tendon healing after trauma, but the detailed mechanisms remain unknown. Tendon-derived stem cells (TDSCs) are a type of progenitor cell found in the tendon niche, and their incorrect differentiation after trauma may lead to tendon calcification. The expression of hepatocyte growth factor (HGF) presents drastic fluctuations in serum/tissue after trauma and was found to activate quiescent stellate cells and contribute to wound healing; however, its potential role in TDSCs remains elusive. In this study, TDSCs isolated from rats were cultured in media containing HGF with or without a signaling inhibitor, and the proliferation, migration, and differentiation ability of TDSCs were measured to determine the role and mechanism of HGF in TDSCs. We showed that HGF promotes TDSC proliferation and migration but inhibits TDSC osteogenic differentiation ability. HGF activated-HGF/c-Met, mitogen-activated protein kinase (MAPK)/extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling, which was positively correlated with TDSCs proliferation and migration but negatively related to TDSC osteogenic differentiation ability. The phosphorylation of Smad1/5/8 was also negatively related to HGF/c-Met, MAPK/ERK1/2, and PI3K/AKT signaling, which demonstrated that the inhibition of osteogenic differentiation was dependent on BMP/Smad1/5/8 signaling. Overall, we showed that HGF could promote TDSCs proliferation and migration and inhibit osteogenic differentiation in vitro, suggesting a potential role for HGF as a cytokine treatment of tendon trauma.
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Affiliation(s)
- Peilin Han
- Department of Pediatric Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Qingbo Cui
- Department of Pediatric Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wenjun Lu
- Department of Pediatric Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shulong Yang
- Department of Pediatric Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Manyu Shi
- Department of Pediatric Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhou Li
- Department of Pediatric Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Peng Gao
- Department of Pediatric Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Bo Xu
- Department of Pediatric Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhaozhu Li
- Department of Pediatric Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
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Ding X, Zhang R, Zhang S, Zhuang H, Xu G. Differential expression of connective tissue growth factor and hepatocyte growth factor in the vitreous of patients with high myopia versus vitreomacular interface disease. BMC Ophthalmol 2019; 19:25. [PMID: 30665391 PMCID: PMC6341692 DOI: 10.1186/s12886-019-1041-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 01/15/2019] [Indexed: 11/18/2022] Open
Abstract
Background To determine the levels of connective tissue growth factor (CTGF) and hepatocyte growth factor (HGF) in the vitreous of patients with high myopia, in comparison with those with a vitreomacular interface disease (VMID). Methods Patients with either high myopia (high myopia group) or a VMID (VMID group) were included in this study. Each of the two groups were further subdivided into two subgroups: group A (high myopia with macular hole), group B (high myopia with macular retinoschisis), group C (idiopathic macular hole), and group D (idiopathic epiretinal membrane). Vitreal specimens were collected during vitrectomy, and enzyme-linked immunosorbent assay was used to quantitatively measure the CTGF and HGF levels in the vitreous. Results The average axial length was markedly longer in the high myopia group than in the VMID group. The vitreal CTGF level was significantly higher in the high myopia group than in the VMID group. Subgroup analysis revealed significantly higher vitreal CTGF in group A than in the other three subgroups. The vitreal HGF level was not significantly different between the high myopia and VMID groups, but was significantly higher in group D than in group C in the subgroup analysis. Correlation analysis showed that the vitreal CTGF level was positively correlated with the axial length. Conclusions The vitreal CTGF level is elevated in highly myopic eyes and may be related to the pathogenesis of high myopia, whereas increased expression of HGF may be involved in the development of idiopathic epiretinal membrane.
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Affiliation(s)
- Xinyi Ding
- Department of Ophthalmology, Eye and ENT Hospital of Fudan University, 83 Fenyang Road, Shanghai, 200031, China.,Key Laboratory of Visual Impairment and Restoration of Shanghai and Key Laboratory of Myopia of State Health Ministry, Fudan University, Shanghai, China
| | - Rong Zhang
- Eye Institute, Eye and ENT Hospital of Fudan University, Shanghai, China.,Key Laboratory of Visual Impairment and Restoration of Shanghai and Key Laboratory of Myopia of State Health Ministry, Fudan University, Shanghai, China
| | - Shujie Zhang
- Eye Institute, Eye and ENT Hospital of Fudan University, Shanghai, China.,Key Laboratory of Visual Impairment and Restoration of Shanghai and Key Laboratory of Myopia of State Health Ministry, Fudan University, Shanghai, China
| | - Hong Zhuang
- Department of Ophthalmology, Eye and ENT Hospital of Fudan University, 83 Fenyang Road, Shanghai, 200031, China. .,Key Laboratory of Visual Impairment and Restoration of Shanghai and Key Laboratory of Myopia of State Health Ministry, Fudan University, Shanghai, China.
| | - Gezhi Xu
- Department of Ophthalmology, Eye and ENT Hospital of Fudan University, 83 Fenyang Road, Shanghai, 200031, China.,Key Laboratory of Visual Impairment and Restoration of Shanghai and Key Laboratory of Myopia of State Health Ministry, Fudan University, Shanghai, China
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Autologous fibrin scaffolds: When platelet- and plasma-derived biomolecules meet fibrin. Biomaterials 2018; 192:440-460. [PMID: 30500725 DOI: 10.1016/j.biomaterials.2018.11.029] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 11/08/2018] [Accepted: 11/20/2018] [Indexed: 02/06/2023]
Abstract
The healing of vascularized mammalian tissue injuries initiate with hemostasis and clotting as part of biological defense system leading to the formation of a fibrin clot in which activated platelets are trapped to quickly stop bleeding and destroy microbials. In order to harness the therapeutic potential of biomolecules secreted by platelets and stemmed from plasma, blood deconstruction has allowed to yield autologous platelet-and plasma-derived protein fibrin scaffold. The autologous growth factors and microparticles stemmed from platelets and plasma, interact with fibrin, extracellular matrix, and tissue cells in a combinatorial, synergistic, and multidirectional way on mechanisms governing tissue repair. This interplay will induce a wide range of cell specifications during inflammation and repair process including but not limited to fibrogenesis, angiogenesis, and immunomodulation. As biology-as-a-drug approach, autologous platelet-and plasma-derived protein fibrin scaffold is emerging as a safe and efficacious natural human-engineered growth factor delivery system to repair musculoskeletal tissues, and skin and corneal ulcers and burns. In doing so, it acts as therapeutic agent not perfect but close to biological precision. However, this autologous, biocompatible, biodegradable, and long in vivo lasting strategy faces several challenges, including its non-conventional single dose-response effect, the lack of standardization in its preparation and application, and the patient's biological features. In this review, we give an account of the main events of tissue repair. Then, we describe the procedure to prepare autologous platelet-and plasma-derived protein fibrin scaffolds, and the rationale behind these biomaterials, and finally, we highlight the significance of strategic accuracy in their application.
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Gao J, Ye J, Ying Y, Lin H, Luo Z. Negative regulation of TGF-β by AMPK and implications in the treatment of associated disorders. Acta Biochim Biophys Sin (Shanghai) 2018; 50:523-531. [PMID: 29873702 DOI: 10.1093/abbs/gmy028] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Indexed: 01/18/2023] Open
Abstract
Transforming growth factor beta (TGF-β) regulates a large number of biological processes, including proliferation, differentiation, immune response, and development. In addition, TGF-β plays important roles in some pathological processes, for instance, it is upregulated and activated in fibrosis and advanced cancer. Adenosine monophosphate-activated protein kinase (AMPK) acts as a fuel gauge that is activated when cells sense shortage of ATP and increase in AMP or AMP:ATP ratio. Activation of AMPK slows down anabolic processes and stimulates catabolic processes, leading to increased production of ATP. Furthermore, the functions of AMPK have been extended beyond energy homeostasis. In fact, AMPK has been shown to exert a tumor suppressive effect. Recent studies have demonstrated negative impacts of AMPK on TGF-β function. Therefore, in this review, we will discuss the differences in the biological functions of TGF-β and AMPK, and some pathological processes such as fibrosis, epithelial-mesenchymal transition (EMT) and cancer metastasis, as well as angiogenesis and heterotopic ossifications where TGF-β and AMPK exert opposite effects.
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Affiliation(s)
- Jiayu Gao
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology, Nanchang University Jiangxi Medical College, Nanchang 330000, China
- Department of Pathology, Schools of Basic Sciences, Nanchang University Jiangxi Medical College, Nanchang 330000, China
| | - Jinhui Ye
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology, Nanchang University Jiangxi Medical College, Nanchang 330000, China
| | - Ying Ying
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology, Nanchang University Jiangxi Medical College, Nanchang 330000, China
| | - Hui Lin
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology, Nanchang University Jiangxi Medical College, Nanchang 330000, China
| | - Zhijun Luo
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology, Nanchang University Jiangxi Medical College, Nanchang 330000, China
- Department of Pathology, Schools of Basic Sciences, Nanchang University Jiangxi Medical College, Nanchang 330000, China
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Zou Y, Xiong JB, Ma K, Wang AZ, Qian KJ. Rac2 deficiency attenuates CCl 4-induced liver injury through suppressing inflammation and oxidative stress. Biomed Pharmacother 2017; 94:140-149. [PMID: 28759751 DOI: 10.1016/j.biopha.2017.07.074] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2017] [Revised: 06/25/2017] [Accepted: 07/17/2017] [Indexed: 12/19/2022] Open
Abstract
Oxidative stress is a leading cause to liver injury. Rac2 is a Ras-associated guanosine triphosphatase, an important molecule modulating a large number of cells and involved in the regulation of reactive oxygen species (ROS). For the study described here, we supposed that Rac2 knockout protects mice against CCl4-induced acute liver injury. We found that Rac2 expressed highly in CCl4-induced liver tissues. CCl4-treated Rac2 knockout (Rac2-/-) mice had reduced CD24 levels and steatosis. In addition, CCl4-induced high expression of pro-inflammatory cytokines and chemokine were reversed by Rac2 deficiency compared to CCl4-treated wild type (WT) mice. We also found that fibrosis-related signals of MMP-9, MMP-2 and TGF-β1 were also down-regulated in Rac2 knockout mice induced by CCl4. Significantly, oxidative stress induced by CCl4 was also suppressed owing to the lack of Rac2, evidenced by enhanced superoxide dismutase (SOD) activity, and reduced malondialdehyde (MDA) levels, superoxide radical, H2O2, xanthine oxidase (XO), xanthine dehydrogenase (XDH) and XO/XDH ratio. Moreover, c-Jun N-terminal protein kinase mitogen-activated protein kinases (JNK MAPK) was activated by CCl4, which was reversed in the liver of Rac2-/- mice through western blot and immunohistochemical analysis. In vitro, endotoxin (LPS) was treated to hepatocytes isolated from WT mice and Rac2-/- mice. The data further confirmed the role of Rac2 deficiency suppressed pro-inflammatory cytokines and chemokine, as well as fibrosis-related signals. Of note, production of ROS induced by LPS was reduced in Rac2-/- cells, accompanied with enhanced SOD1, SOD2 and reduced XO and phosphorylated-JNK expressions. Our results indicated that Rac2 played an essential role in acute liver injury induced by CCl4, providing the compelling information of the effects of Rac2 on liver injury, and revealing a novel regulatory mechanism for acute liver injury.
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Affiliation(s)
- Yan Zou
- Department of Intensive Care Medicine, Shanghai Jiaotong University Affiliated Sixth People's Hospital, No. 222 Huanhuxisan Road, Pudong, Shanghai 201306, China
| | - Ji-Bin Xiong
- Department of Hyperbaric Oxygen Therapy, Shanghai Jiaotong University Affiliated Sixth People's Hospital, No. 222 Huanhuxisan Road, Pudong, Shanghai 201306, China
| | - Ke Ma
- Department of Emergency Medicine, Shanghai Jiaotong University Affiliated Sixth People's Hospital, No. 222 Huanhuxisan Road, Pudong, Shanghai 201306, China
| | - Ai-Zhong Wang
- Department of Anesthesiology, Shanghai Jiaotong University Affiliated Sixth People's Hospital, No. 222 Huanhuxisan Road, Pudong, Shanghai 201306, China
| | - Ke-Jian Qian
- Department of Intensive Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China.
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Namgung S, Yoon JJ, Yoon CS, Han BH, Choi ES, Oh H, Kim YC, Lee YJ, Kang DG, Lee HS. Prunella vulgaris Attenuates Diabetic Renal Injury by Suppressing Glomerular Fibrosis and Inflammation. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2017; 45:475-495. [PMID: 28359196 DOI: 10.1142/s0192415x1750029x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Diabetic nephropathy is both the most common complication and the leading cause of mortality associated with diabetes. Prunella vulgaris, a well-known traditional medicinal plant, is used for the cure of abscess, scrofula, hypertension and urinary diseases. This study confirmed whether an aqueous extract of Prunella vulgaris (APV) suppresses renal inflammation and fibrosis. In human mesangial cell (HMC), pretreatment of APV attenuated 25[Formula: see text]mM HG-induced suppressed TGF-[Formula: see text] and Smad-2/4 expression; it increased the expression level of Smad-7. Connective tissue growth factor (CTGF) and collagen IV, fibrosis biomarkers, were significantly decreased by APV. APV suppressed inflammatory factors such as intracellular cell adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1). APV inhibited activation and translocation of nuclear factor kappa-B (NF-[Formula: see text]B) in HG-stimulated HMCs. Moreover, APV significantly improved HG-induced ROS in a dose-dependent manner. In diabetic rat models, APV significantly decreased blood glucose, blood urea nitrogen (BUN) and ameliorated plasma creatinine (PCr). APV reduced the PAS positivity staining intensity and basement membrane thickening in glomeruli of diabetic rats. Fibrosis related proteins such as collagen IV and TGF-[Formula: see text]1 were also inhibited by APV. These results suggest that APV has a significant protective effect against diabetic renal dysfunction including inflammation and fibrosis through disruption of the TGF-[Formula: see text]/Smad signaling. Therefore, APV may be useful in potential therapies that target glomerulonephritis and glomerulosclerosis, which lead to diabetic nephropathy.
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Affiliation(s)
- Seung Namgung
- * College of Oriental Medicine and Professional, Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea.,† Hanbang Body-fluid Research Center, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
| | - Jung Joo Yoon
- * College of Oriental Medicine and Professional, Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea.,† Hanbang Body-fluid Research Center, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
| | - Chi-Su Yoon
- † Hanbang Body-fluid Research Center, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea.,‡ College of Pharmacy, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
| | - Byung Hyuk Han
- * College of Oriental Medicine and Professional, Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea.,† Hanbang Body-fluid Research Center, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
| | - Eun Sik Choi
- * College of Oriental Medicine and Professional, Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea.,† Hanbang Body-fluid Research Center, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
| | - Hyuncheol Oh
- † Hanbang Body-fluid Research Center, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea.,‡ College of Pharmacy, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
| | - Youn-Chul Kim
- † Hanbang Body-fluid Research Center, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea.,‡ College of Pharmacy, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
| | - Yun Jung Lee
- * College of Oriental Medicine and Professional, Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea.,† Hanbang Body-fluid Research Center, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
| | - Dae Gill Kang
- * College of Oriental Medicine and Professional, Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea.,† Hanbang Body-fluid Research Center, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
| | - Ho Sub Lee
- * College of Oriental Medicine and Professional, Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea.,† Hanbang Body-fluid Research Center, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
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Li X, Wang Y, An G, Liang D, Zhu Z, Lian X, Niu P, Guo C, Tian L. Bone marrow mesenchymal stem cells attenuate silica-induced pulmonary fibrosis via paracrine mechanisms. Toxicol Lett 2017; 270:96-107. [DOI: 10.1016/j.toxlet.2017.02.016] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2016] [Revised: 02/16/2017] [Accepted: 02/18/2017] [Indexed: 12/21/2022]
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Han P, Cui Q, Yang S, Wang H, Gao P, Li Z. Tumor necrosis factor-α and transforming growth factor-β1 facilitate differentiation and proliferation of tendon-derived stem cells in vitro. Biotechnol Lett 2017; 39:711-719. [PMID: 28155178 DOI: 10.1007/s10529-017-2296-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 01/24/2017] [Indexed: 12/19/2022]
Abstract
OBJECTIVES To investigate the effects of tumor necrosis factor-α (TNF-α) and transforming growth factor-β1 (TGF-β1) on the proliferation and differentiation of tendon-derived stem cells (TDSC). RESULTS TNF-α inhibits the proliferation and tenogenic/osteogenic differentiation of TDSC but, after simultaneous or sequential treatment with TGF-β1 and TNF-α, the expression of tenogenic/osteogenic-related marker and proliferation of TDSC was significantly increased. During these processes, Smad2/3 and Smad1/5/8 were highly phosphorylated, meaning that the TGF-β and BMP signaling pathways were highly activated. Further study revealed that the expression of Inhibitor-Smad appeared to be negatively correlated to the proliferation and differentiation of TDSC. CONCLUSIONS Combining the use of TNF-α and TGF-β1 could improve the proliferation and differentiation of TDSC in vitro, and the expression of I-Smad is negatively correlated with TDSC proliferation and differentiation.
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Affiliation(s)
- Peilin Han
- Pediatric Surgery Department, the Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Qingbo Cui
- Pediatric Surgery Department, the Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shulong Yang
- Pediatric Surgery Department, the Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hao Wang
- Pediatric Surgery Department, the Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Peng Gao
- Pediatric Surgery Department, the Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhaozhu Li
- Pediatric Surgery Department, the Second Affiliated Hospital of Harbin Medical University, Harbin, China.
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Sardone F, Santi S, Tagliavini F, Traina F, Merlini L, Squarzoni S, Cescon M, Wagener R, Maraldi NM, Bonaldo P, Faldini C, Sabatelli P. Collagen VI–NG2 axis in human tendon fibroblasts under conditions mimicking injury response. Matrix Biol 2016; 55:90-105. [DOI: 10.1016/j.matbio.2016.02.012] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Revised: 02/18/2016] [Accepted: 02/27/2016] [Indexed: 01/07/2023]
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Peterová E, Mrkvicová A, Podmolíková L, Řezáčová M, Kanta J. The role of cytokines TGF-beta1 and FGF-1 in the expression of characteristic markers of rat liver myofibroblasts cultured in three-dimensional collagen gel. Physiol Res 2016; 65:661-672. [PMID: 27429124 DOI: 10.33549/physiolres.933092] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Rat liver myofibroblasts (MFB) are the key cells involved in the deposition of extracellular matrix in fibrotic liver. They were isolated by repeated passaging of non-parenchymal cell fraction and cultured in 3-dimensional (3D) collagen gel mimicking tissue. The transfer of MFB from plastic dishes to collagen resulted in the change in their shape from large and spread to slender with long extensions. The expression of transforming growth factor-beta1 (TGF-beta1) and of MFB markers, alpha-smooth muscle actin (alpha-SMA) and cellular fibronectin (EDA-FN), on protein level was significantly decreased in collagen gel. The gel did not change the expression of metalloproteinase MMP-2 but activated the proenzyme. The experiments with inhibitors of metabolic pathways showed that EDA-FN and alpha-SMA were differently regulated. The expression of EDA-FN required functional TGF-beta1 receptors and was also dependent on the activity of protein kinases MEK1 and MEK2. alpha-SMA expression was primarily determined by the 3D environment. Fibroblast growth factor-1 (FGF-1) in combination with heparin decreased the expression of alpha-SMA and increased the expression of EDA-FN in the cells on plastic. The cellular environment may influence the cells per se and may modify the action of other agents.
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Affiliation(s)
- E Peterová
- Faculty of Medicine in Hradec Králové, Hradec Králové, Czech Republic.
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Robert S, Gicquel T, Bodin A, Lagente V, Boichot E. Characterization of the MMP/TIMP Imbalance and Collagen Production Induced by IL-1β or TNF-α Release from Human Hepatic Stellate Cells. PLoS One 2016; 11:e0153118. [PMID: 27046197 PMCID: PMC4821480 DOI: 10.1371/journal.pone.0153118] [Citation(s) in RCA: 114] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 03/23/2016] [Indexed: 12/19/2022] Open
Abstract
Inflammation has an important role in the development of liver fibrosis in general and the activation of hepatic stellate cells (HSCs) in particular. It is known that HSCs are themselves able to produce cytokines and chemokines, and that this production may be a key event in the initiation of fibrogenesis. However, the direct involvement of cytokines and chemokines in HSC (self-)activation remains uncertain. In this study, the effects of pro-inflammatory cytokines IL-1α and β, TNF-α, and IL-8 on the activation state of HSCs were examined, in comparison to the pro-fibrogenic mediator TGF-β1. LX-2 cells were stimulated for 24 or 48 hours with recombinant human form of the pro-inflammatory cytokines IL-1α and β, TNF-α, and IL-8, and also the pro-fibrogenic mediator TGF-β1. Two drugs were also evaluated, the anti-TNF-α monoclonal antibody infliximab and the IL-1 receptor antagonist anakinra, regarding their inhibitory effects. In LX-2 human HSC, treatment with TGF-β1 are associated with downregulation of the metalloproteinase (MMP)-1 and MMP-3, with upregulation of tissue inhibitor of metalloproteinase (TIMP)-1, collagen type I α1, collagen type IV α1, α-SMA, endothelin-1 and PDGF-BB. Cytokines and chemokines expression were found to be downregulated, excepting IL-6. In contrast, we observed that LX-2 exposure to IL-1, TNF-α and IL-8 can reverse the phenotype of pro-fibrogenic activated cells. Indeed, MMP-1, MMP-3 and MMP-9 were found elevated, associated with downregulation of α-SMA and/or PDGF-BB, and a greater expression of IL-1β, IL-6, IL-8, CXCL1 and CCL2. Lastly, we found that infliximab and anakinra successfully inhibits effects of TNF-α and IL-1 respectively in LX-2 cells. Infliximab and anakinra may be of value in preclinical trials in chronic liver disease. Overall, our results suggest that (i) pro-inflammatory mediators exert complex effects in HSCs via an MMP/TIMP imbalance, and (ii) targeting IL-1 signaling may be a potentially valuable therapeutic strategy in chronic liver diseases.
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Affiliation(s)
- Sacha Robert
- UMR991 INSERM, Université de Rennes 1, Rennes, France
| | | | - Aude Bodin
- UMR991 INSERM, Université de Rennes 1, Rennes, France
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Mao S, Zhang J. The emerging role of hepatocyte growth factor in renal diseases. J Recept Signal Transduct Res 2015; 36:303-9. [DOI: 10.3109/10799893.2015.1080275] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Jeon YR, Ahn HM, Choi IK, Yun CO, Rah DK, Lew DH, Lee WJ. Hepatocyte growth factor-expressing adenovirus upregulates matrix metalloproteinase-1 expression in keloid fibroblasts. Int J Dermatol 2015; 55:356-61. [PMID: 26234705 DOI: 10.1111/ijd.12965] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Revised: 11/12/2014] [Accepted: 12/29/2014] [Indexed: 11/28/2022]
Abstract
BACKGROUND Keloids are marked by an overabundance of extracellular matrix. The antifibrotic effect of hepatocyte growth factor (HGF) is achieved by increasing the expression of matrix metalloproteinases (MMPs) that drive extracellular matrix catabolism. As such, we cultivated an RGD-modified HGF-expressing adenovirus (dE1-RGD/lacZ/HGF) for introduction into keloid fibroblasts (KFs), looking at the subsequent impact on MMP-1 expression. METHODS KFs infected with either test virus as experimental group (dE1-RGD/lacZ/HGF) or its counterpart (dE1-RGD/lacZ) as control group were examined for HGF protein expression using an enzyme-linked immunosorbent assay (ELISA). Collagen (types I and III) and MMP-1 mRNA levels were also determined by reverse transcriptase-polymerase chain reaction, and ELISA was used to monitor MMP-1 protein expression. RESULTS In KFs harboring the test virus, high levels of HGF were induced at a multiplicity of infection ratio of 50 (3260.6 ± 162.7 pg/ml) after 72 hours of incubation. Furthermore, reverse transcriptase-polymerase chain reaction and ELISA confirmed that MMP-1 mRNA and protein expression rose significantly in KFs after transduction by the test virus (P < 0.05). However, mRNA levels of collagen were unaffected by the experimental group. CONCLUSION These results suggest that an HGF-expressing adenovirus may be therapeutic for keloids by increasing MMP-1 expression.
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Affiliation(s)
- Yeo Reum Jeon
- Institute for Human Tissue Restoration, Department of Plastic & Reconstructive Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hyo Min Ahn
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Korea
| | - Il Kyu Choi
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Korea
| | - Chae Ok Yun
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Korea
| | - Dong Kyun Rah
- Institute for Human Tissue Restoration, Department of Plastic & Reconstructive Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Dae Hyun Lew
- Institute for Human Tissue Restoration, Department of Plastic & Reconstructive Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Won Jai Lee
- Institute for Human Tissue Restoration, Department of Plastic & Reconstructive Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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Lan YW, Choo KB, Chen CM, Hung TH, Chen YB, Hsieh CH, Kuo HP, Chong KY. Hypoxia-preconditioned mesenchymal stem cells attenuate bleomycin-induced pulmonary fibrosis. Stem Cell Res Ther 2015; 6:97. [PMID: 25986930 PMCID: PMC4487587 DOI: 10.1186/s13287-015-0081-6] [Citation(s) in RCA: 164] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Revised: 03/19/2015] [Accepted: 04/21/2015] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION Idiopathic pulmonary fibrosis is a progressive diffuse parenchymal lung disorder of unknown etiology. Mesenchymal stem cell (MSC)-based therapy is a novel approach with great therapeutic potential for the treatment of lung diseases. Despite demonstration of MSC grafting, the populations of engrafted MSCs have been shown to decrease dramatically 24 hours post-transplantation due to exposure to harsh microenvironments. Hypoxia is known to induce expression of cytoprotective genes and also secretion of anti-inflammatory, anti-apoptotic and anti-fibrotic factors. Hypoxic preconditioning is thought to enhance the therapeutic potency and duration of survival of engrafted MSCs. In this work, we aimed to prolong the duration of survival of engrafted MSCs and to enhance the effectiveness of idiopathic pulmonary fibrosis transplantation therapy by the use of hypoxia-preconditioned MSCs. METHODS Hypoxic preconditioning was achieved in MSCs under an optimal hypoxic environment. The expression levels of cytoprotective factors and their biological effects on damaged alveolar epithelial cells or transforming growth factor-beta 1-treated fibroblast cells were studied in co-culture experiments in vitro. Furthermore, hypoxia-preconditioned MSCs (HP-MSCs) were intratracheally instilled into bleomycin-induced pulmonary fibrosis mice at day 3, and lung functions, cellular, molecular and pathological changes were assessed at 7 and 21 days after bleomycin administration. RESULTS The expression of genes for pro-survival, anti-apoptotic, anti-oxidant and growth factors was upregulated in MSCs under hypoxic conditions. In transforming growth factor-beta 1-treated MRC-5 fibroblast cells, hypoxia-preconditioned MSCs attenuated extracellular matrix production through paracrine effects. The pulmonary respiratory functions significantly improved for up to 18 days of hypoxia-preconditioned MSC treatment. Expression of inflammatory factors and fibrotic factor were all downregulated in the lung tissues of the hypoxia-preconditioned MSC-treated mice. Histopathologic examination observed a significant amelioration of the lung fibrosis. Several LacZ-labeled MSCs were observed within the lungs in the hypoxia-preconditioned MSC treatment groups at day 21, but no signals were detected in the normoxic MSC group. Our data further demonstrated that upregulation of hepatocyte growth factor possibly played an important role in mediating the therapeutic effects of transplanted hypoxia-preconditioned MSCs. CONCLUSION Transplantation of hypoxia-preconditioned MSCs exerted better therapeutic effects in bleomycin-induced pulmonary fibrotic mice and enhanced the survival rate of engrafted MSCs, partially due to the upregulation of hepatocyte growth factor.
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Affiliation(s)
- Ying-Wei Lan
- Division of Biotechnology, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China.
| | - Kong-Bung Choo
- Department of Preclinical Sciences, Faculty of Medicine and Health Sciences and Centre for Stem Cell Research, Universiti Tunku Abdul Rahman, Selangor, Malaysia.
| | - Chuan-Mu Chen
- Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan, Republic of China.
- Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan, Republic of China.
- Rong-Hsing Translational Medicine Center, National Chung Hsing University, Taichung, Taiwan, Republic of China.
| | - Tsai-Hsien Hung
- Division of Biotechnology, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China.
| | - Young-Bin Chen
- Institute of Biotechnology, National Taiwan University, Taichung, Taiwan, Republic of China.
| | - Chung-Hsing Hsieh
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China.
- Department of Thoracic Medicine, St Paul's Hospital, Taoyuan, Taiwan, Republic of China.
- Department of Thoracic Medicine, Ton-Yen General Hospital, Hsinchu, Taiwan, Republic of China.
| | - Han-Pin Kuo
- Department of Thoracic Medicine, Pulmonary Disease Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan, Republic of China.
- Department of Medicine, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China.
| | - Kowit-Yu Chong
- Division of Biotechnology, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China.
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China.
- Molecular Medicine Research Center, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China.
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Comparison of Combination Therapy (Steroid, Calcium Channel Blocker, and Interferon) With Steroid Monotherapy for Treating Human Hypertrophic Scars in an Animal Model. Ann Plast Surg 2015; 74 Suppl 2:S162-7. [DOI: 10.1097/sap.0000000000000470] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Zhao Z, Sun Y, Yang S, Cui Q, Li Z. FAK activity is required for HGF to suppress TGF-β1-induced cellular proliferation. In Vitro Cell Dev Biol Anim 2015; 51:941-9. [PMID: 25898827 DOI: 10.1007/s11626-015-9914-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Accepted: 04/08/2015] [Indexed: 12/11/2022]
Abstract
Due to the complex nature of the tendon architecture, the regeneration of these tissues results in the formation of scars. As a direct result of scar formation, the ability of the tendon tissues to function is impaired and often results in further damage that has been afflicted to the tendon architecture. The growth and proliferation of tendon fibroblasts involve a complex network of signalling molecules. To understand and aid in the proper repair of this complex tissue network, a more in-depth understanding is required in the events that induce the growth of tendon cells. Several studies have shown the apoptotic mechanisms induced by the mitogen, hepatocyte growth factor, in multiple biological and pathological systems. In our recent research, we have described a mechanism where hepatocyte growth factor (HGF) is able to inhibit the proliferative effects of transforming growth factor-β1 (TGF-β1) and induce apoptosis in rat tendon fibroblasts. Transforming growth factor-β1 is able to induce the proliferation of fibroblast cells by increasing both the gene expression and protein levels of α-smooth muscle actin (α-SMA) and c-MET. We have also shown that inhibition of extracellular signal-regulated kinase 1/2 does not block hepatocyte growth factor-induced growth arrest. However, we have shown that blocking the activity of focal adhesion kinase can prevent the growth inhibition ability of hepatocyte growth factor in tendon fibroblasts. Collectively, our studies show growth inhibitory pathway in tendon fibroblasts induced by hepatocyte growth factor and mediated focal adhesion kinase.
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Affiliation(s)
- Zheng Zhao
- Pediatric Orthopedics Unit, First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin, 150001, China
| | - Yu Sun
- Pediatric Orthopedics Unit, Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, 150086, China
| | - Sulong Yang
- Pediatric Orthopedics Unit, Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, 150086, China
| | - Qingbo Cui
- Pediatric Orthopedics Unit, Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, 150086, China
| | - Zhaozhu Li
- Pediatric Orthopedics Unit, Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, 150086, China.
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Gaspar D, Spanoudes K, Holladay C, Pandit A, Zeugolis D. Progress in cell-based therapies for tendon repair. Adv Drug Deliv Rev 2015; 84:240-56. [PMID: 25543005 DOI: 10.1016/j.addr.2014.11.023] [Citation(s) in RCA: 127] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Revised: 11/08/2014] [Accepted: 11/12/2014] [Indexed: 02/07/2023]
Abstract
The last decade has seen significant developments in cell therapies, based on permanently differentiated, reprogrammed or engineered stem cells, for tendon injuries and degenerative conditions. In vitro studies assess the influence of biophysical, biochemical and biological signals on tenogenic phenotype maintenance and/or differentiation towards tenogenic lineage. However, the ideal culture environment has yet to be identified due to the lack of standardised experimental setup and readout system. Bone marrow mesenchymal stem cells and tenocytes/dermal fibroblasts appear to be the cell populations of choice for clinical translation in equine and human patients respectively based on circumstantial, rather than on hard evidence. Collaborative, inter- and multi-disciplinary efforts are expected to provide clinically relevant and commercially viable cell-based therapies for tendon repair and regeneration in the years to come.
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Affiliation(s)
- Diana Gaspar
- Network of Excellence for Functional Biomaterials (NFB), National University of Ireland, Galway (NUI Galway), Galway, Ireland
| | - Kyriakos Spanoudes
- Network of Excellence for Functional Biomaterials (NFB), National University of Ireland, Galway (NUI Galway), Galway, Ireland
| | - Carolyn Holladay
- Network of Excellence for Functional Biomaterials (NFB), National University of Ireland, Galway (NUI Galway), Galway, Ireland
| | - Abhay Pandit
- Network of Excellence for Functional Biomaterials (NFB), National University of Ireland, Galway (NUI Galway), Galway, Ireland
| | - Dimitrios Zeugolis
- Network of Excellence for Functional Biomaterials (NFB), National University of Ireland, Galway (NUI Galway), Galway, Ireland.
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Abstract
Injuries of the Achilles tendon are relatively common with potentially devastating outcomes. Healing Achilles tendons form a fibrovascular scar resulting in a tendon which may be mechanically weaker than the native tendon. The resulting strength deficit causes a high risk for reinjury and other complications. Treatments using biologics aim to restore the normal properties of the native tendon and reduce the risk of rerupture and maximize tendon function. The purpose of this review was to summarize the current findings of various therapies using biologics in an attempt to improve the prognosis of Achilles tendon ruptures and tendinopathies. A PubMed search was performed using specific search terms. The search was open for original manuscripts and review papers limited to publication within the last 10 years. From these searches, papers were included in the review if they investigated the effects of biological augmentation on Achilles tendon repair or healing. Platelet-rich plasma may assist in the healing process of Achilles tendon ruptures, while the evidence to support its use in the treatment of chronic Achilles tendinopathies remains insufficient. The use of growth factors such as hepatocyte growth factor, recombinant human platelet-derived growth factor-BB, interleukin-6, and transforming growth factor beta as well as several bone morphogenetic proteins have shown promising results for Achilles tendon repair. In vitro and preclinical studies have indicated the potential effectiveness of bone marrow aspirate as well. Stem cells also have positive effects on Achilles tendon healing, particularly during the early phases. Polyhydroxyalkanoates (PHA), decellularized tendon tissue, and porcine small intestinal submucosa (SIS) are biomaterials which have shown promising results as scaffolds used in Achilles tendon repair. The application of biological augmentation techniques in Achilles tendon repair appears promising; however, several techniques require further investigation to evaluate their clinical application.
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Affiliation(s)
- Evan Shapiro
- Orthopedics Department, Feinstein Institute for Medical Research, 350 Community Dr, Manhasset, NY, 11030, USA
| | - Daniel Grande
- Orthopedics Department, Feinstein Institute for Medical Research, 350 Community Dr, Manhasset, NY, 11030, USA.
| | - Mark Drakos
- Orthopedics Department, Feinstein Institute for Medical Research, 350 Community Dr, Manhasset, NY, 11030, USA
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Lücker PB, Javaherian S, Soleas JP, Halverson D, Zandstra PW, McGuigan AP. A microgroove patterned multiwell cell culture plate for high-throughput studies of cell alignment. Biotechnol Bioeng 2014; 111:2537-48. [DOI: 10.1002/bit.25298] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2014] [Revised: 05/21/2014] [Accepted: 05/21/2014] [Indexed: 11/11/2022]
Affiliation(s)
- Petra B. Lücker
- Department of Chemical Engineering and Applied Chemistry; University of Toronto; 200 College St. Toronto Ontario M5T 3J9 Canada
- Institute of Biomaterials and Biomedical Engineering; University of Toronto; Toronto Ontario Canada
| | - Sahar Javaherian
- Department of Chemical Engineering and Applied Chemistry; University of Toronto; 200 College St. Toronto Ontario M5T 3J9 Canada
| | - John P. Soleas
- Institute of Medical Science; University of Toronto; Toronto Ontario Canada
| | - Duncan Halverson
- Department of Chemistry; University of Toronto; Toronto Ontario Canada
| | - Peter W. Zandstra
- Institute of Biomaterials and Biomedical Engineering; University of Toronto; Toronto Ontario Canada
| | - Alison P. McGuigan
- Department of Chemical Engineering and Applied Chemistry; University of Toronto; 200 College St. Toronto Ontario M5T 3J9 Canada
- Institute of Biomaterials and Biomedical Engineering; University of Toronto; Toronto Ontario Canada
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Zhou WC, Zhang QB, Qiao L. Pathogenesis of liver cirrhosis. World J Gastroenterol 2014; 20:7312-7324. [PMID: 24966602 PMCID: PMC4064077 DOI: 10.3748/wjg.v20.i23.7312] [Citation(s) in RCA: 380] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Revised: 03/16/2014] [Accepted: 04/29/2014] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis is the final pathological result of various chronic liver diseases, and fibrosis is the precursor of cirrhosis. Many types of cells, cytokines and miRNAs are involved in the initiation and progression of liver fibrosis and cirrhosis. Activation of hepatic stellate cells (HSCs) is a pivotal event in fibrosis. Defenestration and capillarization of liver sinusoidal endothelial cells are major contributing factors to hepatic dysfunction in liver cirrhosis. Activated Kupffer cells destroy hepatocytes and stimulate the activation of HSCs. Repeated cycles of apoptosis and regeneration of hepatocytes contribute to pathogenesis of cirrhosis. At the molecular level, many cytokines are involved in mediation of signaling pathways that regulate activation of HSCs and fibrogenesis. Recently, miRNAs as a post-transcriptional regulator have been found to play a key role in fibrosis and cirrhosis. Robust animal models of liver fibrosis and cirrhosis, as well as the recently identified critical cellular and molecular factors involved in the development of liver fibrosis and cirrhosis will facilitate the development of more effective therapeutic approaches for these conditions.
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Li XJ, Yang XP, Wan GM, Wang YY, Zhang JS. Effects of hepatocyte growth factor on MMP-2 expression in scleral fibroblasts from a guinea pig myopia model. Int J Ophthalmol 2014; 7:239-44. [PMID: 24790864 DOI: 10.3980/j.issn.2222-3959.2014.02.09] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2013] [Accepted: 03/01/2014] [Indexed: 02/02/2023] Open
Abstract
AIM To investigate the effects of hepatocyte growth factor (HGF) on MMP-2 expression in scleral fibroblasts from guinea pig with LIM. METHODS Sixty 1-week-old guinea pigs were chosen for the study. The right eyes were treated with -10.0 D lenses as the LIM group; the left eyes remained untreated as the control group. The refraction and axial length were measured by streak retinoscopy and A-scan ultrasonography respectively prior to and 4 weeks after the experiment. Four weeks later, the guinea pigs were sacrificed and primary scleral fibroblasts were taken for tissue culture. The 3rd-5th generation scleral fibroblasts were chosen for the experiments. The expression levels of HGF and MMP-2 protein in the scleral fibroblasts were analyzed by Western blotting. After HGF with different doses acted on the scleral fibroblasts of the control group, MMP-2 protein expression in the scleral fibroblasts was analyzed by Western blotting. HGF siRNA was transfected into the scleral fibroblasts of the LIM group and the protein expressions of HGF and MMP-2 were analyzed by Western blotting. RESULTS The LIM group became myopic with a significant increase in axial length (7.97±0.29 mm vs 7.01±0.26 mm, P<0.05), and a significant decrease in refraction (-5.06±0.31 D vs 0.55±0.25 D, P<0.05) compared with the control group. The protein expression of HGF in the scleral fibroblasts of the LIM group was significantly higher compared with the control group ( 1.26±0.04 vs 0.32 ±0.04, P<0.05). The protein expression of MMP-2 in the scleral fibroblasts of the LIM group was significantly higher compared with the control group (0.89±0.06 vs 0.42±0.05, P<0.05). In the scleral fibroblasts of the control group, HGF(0, 0.1, 1, 10 ng/mL) upregulated MMP-2 protein expression in a dose-dependent manner (0.35±0.03, 0.44±0.02, 0.91±0.03, 1.33±0.04, all P<0.05). In the scleral fibroblasts of the LIM group transfected with HGF siRNA, MMP-2 protein expressions were significantly decreased compared with the negative control group (0.29±0.03 vs 0.81±0.05, P<0.05). CONCLUSION HGF is a upstream mediator of MMP-2 in scleral fibroblasts from guinea pig.
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Affiliation(s)
- Xiu-Juan Li
- Department of Ophthalmology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Xiao-Peng Yang
- Department of Medical Equipment, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Guang-Ming Wan
- Department of Ophthalmology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Yu-Ying Wang
- Department of Ophthalmology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Jin-Song Zhang
- Department of Ophthalmology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
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Cadby JA, Buehler E, Godbout C, van Weeren PR, Snedeker JG. Differences between the cell populations from the peritenon and the tendon core with regard to their potential implication in tendon repair. PLoS One 2014; 9:e92474. [PMID: 24651449 PMCID: PMC3961373 DOI: 10.1371/journal.pone.0092474] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Accepted: 02/24/2014] [Indexed: 11/22/2022] Open
Abstract
The role of intrinsic and extrinsic healing in injured tendons is still debated. In this study, we characterized cell plasticity, proliferative capacity, and migration characteristics as proxy measures of healing potential in cells derived from the peritenon (extrinsic healing) and compared these to cells from the tendon core (intrinsic healing). Both cell populations were extracted from horse superficial digital flexor tendon and characterized for tenogenic and matrix remodeling markers as well as for rates of migration and replication. Furthermore, colony-forming unit assays, multipotency assays, and real-time quantitative polymerase chain reaction analyses of markers of osteogenic and adipogenic differentiation after culture in induction media were performed. Finally, cellular capacity for differentiation towards a myofibroblastic phenotype was assessed. Our results demonstrate that both tendon- and peritenon-derived cell populations are capable of adipogenic and osteogenic differentiation, with higher expression of progenitor cell markers in peritenon cells. Cells from the peritenon also migrated faster, replicate more quickly, and show higher differentiation potential toward a myofibroblastic phenotype when compared to cells from the tendon core. Based on these data, we suggest that cells from the peritenon have substantial potential to influence tendon-healing outcome, warranting further scrutiny of their role.
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Affiliation(s)
- Jennifer A. Cadby
- Department of Orthopaedics, Balgrist Hospital, University of Zurich, Zurich, Switzerland
- Department Health Sciences and Technology, Swiss Federal Institute of Technology, Zurich, Switzerland
- Department of Equine Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Evelyne Buehler
- Department of Orthopaedics, Balgrist Hospital, University of Zurich, Zurich, Switzerland
- Department Health Sciences and Technology, Swiss Federal Institute of Technology, Zurich, Switzerland
| | - Charles Godbout
- Osteoarthritis Research Unit, University of Montreal Hospital Research Centre (CRCHUM), Montreal, Quebec, Canada
| | - P. René van Weeren
- Department of Equine Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Jess G. Snedeker
- Department of Orthopaedics, Balgrist Hospital, University of Zurich, Zurich, Switzerland
- Department Health Sciences and Technology, Swiss Federal Institute of Technology, Zurich, Switzerland
- * E-mail:
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Sassoli C, Nosi D, Tani A, Chellini F, Mazzanti B, Quercioli F, Zecchi-Orlandini S, Formigli L. Defining the role of mesenchymal stromal cells on the regulation of matrix metalloproteinases in skeletal muscle cells. Exp Cell Res 2014; 323:297-313. [PMID: 24631289 DOI: 10.1016/j.yexcr.2014.03.003] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2013] [Revised: 03/01/2014] [Accepted: 03/03/2014] [Indexed: 12/11/2022]
Abstract
Recent studies indicate that mesenchymal stromal cell (MSC) transplantation improves healing of injured and diseased skeletal muscle, although the mechanisms of benefit are poorly understood. In the present study, we investigated whether MSCs and/or their trophic factors were able to regulate matrix metalloproteinase (MMP) expression and activity in different cells of the muscle tissue. MSCs in co-culture with C2C12 cells or their conditioned medium (MSC-CM) up-regulated MMP-2 and MMP-9 expression and function in the myoblastic cells; these effects were concomitant with the down-regulation of the tissue inhibitor of metalloproteinases (TIMP)-1 and -2 and with increased cell motility. In the single muscle fiber experiments, MSC-CM administration increased MMP-2/9 expression in Pax-7(+) satellite cells and stimulated their mobilization, differentiation and fusion. The anti-fibrotic properties of MSC-CM involved also the regulation of MMPs by skeletal fibroblasts and the inhibition of their differentiation into myofibroblasts. The treatment with SB-3CT, a potent MMP inhibitor, prevented in these cells, the decrease of α-smooth actin and type-I collagen expression induced by MSC-CM, suggesting that MSC-CM could attenuate the fibrogenic response through mechanisms mediated by MMPs. Our results indicate that growth factors and cytokines released by these cells may modulate the fibrotic response and improve the endogenous mechanisms of muscle repair/regeneration.
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Affiliation(s)
- Chiara Sassoli
- Dept. of Experimental and Clinical Medicine-Section of Anatomy and Histology, University of Florence, Largo Brambilla, 3, 50134, Florence, Italy
| | - Daniele Nosi
- Dept. of Experimental and Clinical Medicine-Section of Anatomy and Histology, University of Florence, Largo Brambilla, 3, 50134, Florence, Italy
| | - Alessia Tani
- Dept. of Experimental and Clinical Medicine-Section of Anatomy and Histology, University of Florence, Largo Brambilla, 3, 50134, Florence, Italy
| | - Flaminia Chellini
- Dept. of Experimental and Clinical Medicine-Section of Anatomy and Histology, University of Florence, Largo Brambilla, 3, 50134, Florence, Italy
| | - Benedetta Mazzanti
- Dept. of Experimental and Clinical Medicine-Section of Haematology, University of Florence, Largo Brambilla, 3, 50134, Florence, Italy
| | - Franco Quercioli
- CNR-National Institute of Optics (INO), Largo Enrico Fermi 6, 50125 Arcetri-Florence, Italy
| | - Sandra Zecchi-Orlandini
- Dept. of Experimental and Clinical Medicine-Section of Anatomy and Histology, University of Florence, Largo Brambilla, 3, 50134, Florence, Italy
| | - Lucia Formigli
- Dept. of Experimental and Clinical Medicine-Section of Anatomy and Histology, University of Florence, Largo Brambilla, 3, 50134, Florence, Italy.
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Branford OA, Klass BR, Grobbelaar AO, Rolfe KJ. The growth factors involved in flexor tendon repair and adhesion formation. J Hand Surg Eur Vol 2014; 39:60-70. [PMID: 24162452 DOI: 10.1177/1753193413509231] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Flexor tendon injuries remain a significant clinical problem, owing to the formation of adhesions or tendon rupture. A number of strategies have been tried to improve outcomes, but as yet none are routinely used in clinical practice. Understanding the role that growth factors play in tendon repair should enable a more targeted approach to be developed to improve the results of flexor tendon repair. This review describes the main growth factors in tendon wound healing, and the role they play in both repair and adhesion formation.
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Affiliation(s)
- O A Branford
- Institute for Plastic Surgery Research and Education, The Royal Free Hospital, London, UK
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Cui Q, Fu S, Li Z. Hepatocyte growth factor inhibits TGF-β1-induced myofibroblast differentiation in tendon fibroblasts: role of AMPK signaling pathway. J Physiol Sci 2013; 63:163-70. [PMID: 23371911 PMCID: PMC10718008 DOI: 10.1007/s12576-013-0251-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2012] [Accepted: 01/13/2013] [Indexed: 11/29/2022]
Abstract
The transforming growth factor-β1 (TGF-β1)-induced myofibroblastic differentiation in tendon fibroblasts was thought to be one of the most important features of scar fibrosis formation, which is associated with occurrence of re-rupture. Previously, we reported that hepatocyte growth factor (HGF) inhibited TGF-β1-induced myofibroblast differentiation and extracellular matrix deposition in the Achilles tendon of rats. Here, we investigated the potential molecular mechanisms underlying the inhibitory effect of HGF on TGF-β1-induced myofibroblast differentiation. We found that treatment with HGF (10, 20, and 40 ng/ml) increased phosphorylation of adenosine monophosphate kinase (AMPK) and acetyl-CoA carboxylase (ACC) in tendon fibroblasts. Pharmacological inhibition of the AMPK signaling pathway using compound C, a specific blocker of AMPK signaling, remarkably attenuated the inhibitory effect of HGF on TGF-β1-induced myofibroblastic differentiation in tendon fibroblasts. Moreover, small interfering RNA (siRNA)-mediated knockdown of AMPKα1 subunit decreased the inhibitory effect of HGF on TGF-β1-induced myofibroblastic differentiation in tendon fibroblasts. Finally, overexpression of constitutively active AMPKα1, which led to constitutive activation of the AMPK signaling pathway in tendon fibroblasts, mimicked the inhibitory effect of HGF on the TGF-β1-induced myofibroblastic differentiation. Our study therefore suggests that HGF inhibits TGF-β1-induced myofibroblastic differentiation via an AMPK signaling pathway-dependent manner in tendon fibroblasts.
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Affiliation(s)
- Qingbo Cui
- Pediatric Orthopedics Unit, Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, 150081 China
| | - Songbin Fu
- Laboratory of Medical Genetics, Harbin Medical University, Harbin, China
| | - Zhaozhu Li
- Pediatric Orthopedics Unit, Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, 150081 China
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