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Tiwari S, Chaturvedi S, Kaul A, Choudhary V, Barthélémy P, Mishra AK. Development of amphiphilic self-assembled nucleolipid as BBB targeting probe based on SPECT. DISCOVER NANO 2024; 19:210. [PMID: 39690348 DOI: 10.1186/s11671-024-04129-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 10/14/2024] [Indexed: 12/19/2024]
Abstract
Several approaches have been utilised to deliver therapeutic nanoparticles inside the brain but rendered by certain limitation such as active efflux, non-stability, toxicity of the nanocarrier, transport, physicochemical properties and many more. In this context use of biocompatible nano carriers is currently investigated. We herein present the hypothesis that the nucleoside-lipid based conjugates (nucleolipids) which are biocompatible in nature and have molecular recognition can be tuned for improved permeation across blood-brain barrier (BBB). In this work, a di-C15-palmitoyl-ketal nucleolipid nanoparticle bearing an acyclic chelator has been formulated, radiolabeled with 99mTc and evaluated for in vivo fate using SPECT imaging. The mean particle size of particles was 113 nm and found to be nontoxic as depticted through haemolytic assay (2.33% erythrocyte destruction) and 75 ± 0.3% HEK(Human Embryonic Kidney) cells survived at 72 h as depicted in SRB (Sulforhodamine B) toxicity assay. The encapsulation efficiency (68 ± 2.75%) and drug loading capacity (22 ± 1.8%.) was calculated for nanoparticles using Methotrexate as model anti-cancer drug. The mathematical models indicate fickian release with a release constant KH = 20.70. With 98 ± 0.75% radiolabelling efficiency and established in vitro stability, nanoparticles showed brain uptake in normal mice as 0.91 times in comparison to BBB compromised mice (1.6% ± 0.03 ID/g)indicating higher brain uptake with rapid clearance as depicted through blood kinetics.
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Affiliation(s)
- Swastika Tiwari
- Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, 110054, India.
- NOMATEN Center of Excellence, National Center for Nuclear Research, Ul. Andrzeja Soltana 7, 05-400, Otwock, Poland.
| | - Shubhra Chaturvedi
- Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, 110054, India.
| | - Ankur Kaul
- Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, 110054, India
| | - Vishakha Choudhary
- Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, 110054, India
| | - Philippe Barthélémy
- Université de Bordeaux, INSERM, U1212, CNRS UMR 5320, ARNA, ARN: Régulations Naturelle Et Artificielle, ChemBioPharm, 146 Rue Léo Saignat, 33076, Bordeaux Cedex, France
| | - A K Mishra
- Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, 110054, India.
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Ebrahim T, Ebrahim AS, Kandouz M. Diversity of Intercellular Communication Modes: A Cancer Biology Perspective. Cells 2024; 13:495. [PMID: 38534339 PMCID: PMC10969453 DOI: 10.3390/cells13060495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 02/27/2024] [Accepted: 03/10/2024] [Indexed: 03/28/2024] Open
Abstract
From the moment a cell is on the path to malignant transformation, its interaction with other cells from the microenvironment becomes altered. The flow of molecular information is at the heart of the cellular and systemic fate in tumors, and various processes participate in conveying key molecular information from or to certain cancer cells. For instance, the loss of tight junction molecules is part of the signal sent to cancer cells so that they are no longer bound to the primary tumors and are thus free to travel and metastasize. Upon the targeting of a single cell by a therapeutic drug, gap junctions are able to communicate death information to by-standing cells. The discovery of the importance of novel modes of cell-cell communication such as different types of extracellular vesicles or tunneling nanotubes is changing the way scientists look at these processes. However, are they all actively involved in different contexts at the same time or are they recruited to fulfill specific tasks? What does the multiplicity of modes mean for the overall progression of the disease? Here, we extend an open invitation to think about the overall significance of these questions, rather than engage in an elusive attempt at a systematic repertory of the mechanisms at play.
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Affiliation(s)
- Thanzeela Ebrahim
- Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48202, USA
| | - Abdul Shukkur Ebrahim
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI 48202, USA
| | - Mustapha Kandouz
- Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48202, USA
- Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48202, USA
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Picotti S, Forte L, Serrentino J. A pre-market interventional, single-arm clinical investigation of a new topical lotion based on hyaluronic acid and peptides, EGYFIL TM, for the treatment of pain and stiffness in soft tissues. BMC Musculoskelet Disord 2023; 24:777. [PMID: 37784053 PMCID: PMC10544473 DOI: 10.1186/s12891-023-06903-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 09/21/2023] [Indexed: 10/04/2023] Open
Abstract
BACKGROUND Muscle pain and stiffness are strictly interconnected. Injuries frequently occur during sport activities, causing muscle pain, with or without stiffness, and require effective as well as fast-acting treatments. Topical products can be ideal for the treatment of such physical alterations as they are convenient and simple to use. In this study, it was investigated the application of a novel topical formulation, EGYFIL™, for the treatment of pain and stiffness due to muscle contracture, trauma, and/or overtraining. The lotion is composed of hyaluronic acid, a well-known ingredient for the pain alleviation, mixed with skin conditioning SH-Polypeptide-6 and SH-Oligopeptide-1, embedded in it. METHODS Twenty-six patients with pain and/or stiffness were enrolled. After a screening visit (Time 0, t0), patients were treated for the first time with the IP. The treatment consisted of topical application of the pain lotion. Level of pain and stiffness were measured with Numerical Rating Scale (NRS). Patients' pain and/or stiffness were evaluated at t0 (prior to using the product), after three hours (t1), and after three days (t2) of treatment. Participants were free to apply and re-apply the product ad libitum over the course of the study period (3 days). Potential adverse events (AE) and tolerance were evaluated during each visit. RESULTS There was a 22% decrease in pain in the first three hours (p < 0.001), followed by an additional 20% decrease after three days (p=0.0873). Overall, there was a 42% decrease in pain over the three days of the study (p =0.001). Furthermore, a 24% reduction in stiffness in the first three hours (p=0.025) and a 38% decrease in stiffness over three days (p < 0.001) were observed. Reduction in pain and stiffness were neither age, nor sex dependent. No adverse effects were reported during the study. CONCLUSION EGYFIL™ is safe and seems to reduce pain and stiffness in patients during the 3 days of treatment, already after 3 h from the first application. TRIAL REGISTRATION ClinicalTrials.gov ID: NCT05711953. This trial was registered on 03/02/2023.
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Affiliation(s)
| | - Luca Forte
- Contrad Swiss SA, Via Ferruccio Pelli 2, Lugano, 6900, Switzerland.
| | - Jo Serrentino
- International Institute of Clinical Ecology (IICE), Quebec, Canada
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Vinhas A, Almeida AF, Rodrigues MT, Gomes ME. Prospects of magnetically based approaches addressing inflammation in tendon tissues. Adv Drug Deliv Rev 2023; 196:114815. [PMID: 37001644 DOI: 10.1016/j.addr.2023.114815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 03/24/2023] [Accepted: 03/25/2023] [Indexed: 03/31/2023]
Abstract
Tendon afflictions constitute a significant share of musculoskeletal diseases and represent a primary cause of incapacity worldwide. Unresolved/chronic inflammatory states have been associated with the onset and progression of tendon disorders, contributing to undesirable immune stimulation and detrimental tissue effects. Thus, targeting persistent inflammatory events could assist important developments to solve pathophysiological processes and innovative therapeutics to address impaired healing and accomplish complete tendon regeneration. This review overviews the impact of inflammation and inflammatory mediators in tendon niches, unveiling the importance of tendon cell populations and their signature features, and the influence of microenvironmental factors on inflamed and injured tendons. The demand for non-invasive instructive strategies to manage persistent inflammatory mediators, guide inflammatory pathways, and modulate cellular responses will also be approached by exploring the role of pulsed electromagnetic field (PEMF). PEMF alone or combined with more sophisticated systems triggered by magnetic fields will be considered in the design of successful therapies to control inflammation in tendinopathic conditions.
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Rampin A, Skoufos I, Raghunath M, Tzora A, Diakakis N, Prassinos N, Zeugolis DI. Allogeneic Serum and Macromolecular Crowding Maintain Native Equine Tenocyte Function in Culture. Cells 2022; 11:1562. [PMID: 35563866 PMCID: PMC9103545 DOI: 10.3390/cells11091562] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/22/2022] [Accepted: 05/04/2022] [Indexed: 02/06/2023] Open
Abstract
The absence of a native extracellular matrix and the use of xenogeneic sera are often associated with rapid tenocyte function losses during in vitro culture. Herein, we assessed the influence of different sera (equine serum and foetal bovine serum) on equine tenocyte morphology, viability, metabolic activity, proliferation and protein synthesis as a function of tissue-specific extracellular matrix deposition (induced via macromolecular crowding), aging (passages 3, 6, 9) and time in culture (days 3, 5, 7). In comparison to cells at passage 3, at day 3, in foetal bovine serum and without macromolecular crowding (traditional equine tenocyte culture), the highest number of significantly decreased readouts were observed for cells in foetal bovine serum, at passage 3, at day 5 and day 7 and without macromolecular crowding. Again, in comparison to traditional equine tenocyte culture, the highest number of significantly increased readouts were observed for cells in equine serum, at passage 3 and passage 6, at day 7 and with macromolecular crowding. Our data advocate the use of an allogeneic serum and tissue-specific extracellular matrix for effective expansion of equine tenocytes.
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Affiliation(s)
- Andrea Rampin
- Laboratory of Animal Science, Nutrition and Biotechnology, School of Agriculture, University of Ioannina, 47100 Arta, Greece; (A.R.); (I.S.); (A.T.)
- School of Veterinary Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (N.D.); (N.P.)
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Charles Institute of Dermatology, Conway Institute of Biomolecular & Biomedical Research, School of Mechanical & Materials Engineering, University College Dublin (UCD), D04 V1W8 Dublin, Ireland
| | - Ioannis Skoufos
- Laboratory of Animal Science, Nutrition and Biotechnology, School of Agriculture, University of Ioannina, 47100 Arta, Greece; (A.R.); (I.S.); (A.T.)
| | - Michael Raghunath
- Center for Cell Biology and Tissue Engineering, Institute for Chemistry and Biotechnology, Zurich University of Applied Sciences, 8820 Wädenswil, Switzerland;
| | - Athina Tzora
- Laboratory of Animal Science, Nutrition and Biotechnology, School of Agriculture, University of Ioannina, 47100 Arta, Greece; (A.R.); (I.S.); (A.T.)
| | - Nikolaos Diakakis
- School of Veterinary Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (N.D.); (N.P.)
| | - Nikitas Prassinos
- School of Veterinary Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (N.D.); (N.P.)
| | - Dimitrios I. Zeugolis
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Charles Institute of Dermatology, Conway Institute of Biomolecular & Biomedical Research, School of Mechanical & Materials Engineering, University College Dublin (UCD), D04 V1W8 Dublin, Ireland
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Egerbacher M, Gardner K, Caballero O, Hlavaty J, Schlosser S, Arnoczky SP, Lavagnino M. Stress-deprivation induces an up-regulation of versican and connexin-43 mRNA and protein synthesis and increased ADAMTS-1 production in tendon cells in situ. Connect Tissue Res 2022; 63:43-52. [PMID: 33467936 DOI: 10.1080/03008207.2021.1873302] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Purpose: The proper function of the tenocyte network depends on cell-matrix as well as intercellular communication that is mechanosensitive. Building on the concept that the etiopathogenic stimulus for tendon degeneration is the catabolic response of tendon cells to mechanobiologic under-stimulation, we studied the pericellular matrix rich in versican and its predominant proteolytic enzyme ADAMTS-1, as well as Connexin-43 (Cx43), a major gap junction forming protein in tendons, in stress-deprived rat tail tendon fascicles (RTTfs).Materials and Methods: RTTfs were stress-deprived for up to 7 days under tissue culture conditions. RT-qPCR was used to measure mRNA expression of versican, ADAMTS-1, and Cx43. Protein synthesis was determined using Western blotting and immunohistochemistry.Results: Stress-deprivation (SD) caused a statistically significant up-regulation of versican, ADAMTS-1, and Cx43 mRNA expression that was persistent over the 7-day test period. Western blot analysis and immunohistochemical assessment of protein synthesis revealed a marked increase of the respective proteins with SD. Inhibition of proteolytic enzyme activity with ilomastat prevented the increased versican degradation and Cx43 synthesis in 3 days stress-deprived tendons when compared with non-treated, stress-deprived tendons.Conclusion: In the absence of mechanobiological signaling the immediate pericellular matrix is modulated as tendon cells up-regulate their production of ADAMTS-1, and versican with subsequent proteoglycan degradation potentially leading to cell signaling cues increasing Cx43 gap junctional protein. The results also provide further support for the hypothesis that the cellular changes associated with tendinopathy are a result of decreased mechanobiological signaling and a loss of homeostatic cytoskeletal tension.
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Affiliation(s)
- Monika Egerbacher
- Histology & Embryology, Department of Pathobiology, University of Veterinary Medicine, Vienna, Austria
| | - Keri Gardner
- Laboratory for Comparative Orthopaedic Research, Michigan State University, East Lansing, MI, USA
| | - Oscar Caballero
- Laboratory for Comparative Orthopaedic Research, Michigan State University, East Lansing, MI, USA
| | - Juraj Hlavaty
- Histology & Embryology, Department of Pathobiology, University of Veterinary Medicine, Vienna, Austria
| | - Sarah Schlosser
- VetCORE Facility for Research, University of Veterinary Medicine, Vienna, Austria
| | - Steven P Arnoczky
- Laboratory for Comparative Orthopaedic Research, Michigan State University, East Lansing, MI, USA
| | - Michael Lavagnino
- Laboratory for Comparative Orthopaedic Research, Michigan State University, East Lansing, MI, USA.,Department of Mechanical Engineering, Michigan State University, East Lansing, MI, USA
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Wang Q, Duan M, Liao J, Xie J, Zhou C. Are Osteoclasts Mechanosensitive Cells? J Biomed Nanotechnol 2021; 17:1917-1938. [PMID: 34706793 DOI: 10.1166/jbn.2021.3171] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Skeleton metabolism is a process in which osteoclasts constantly remove old bone and osteoblasts form new osteoid and induce mineralization; disruption of this balance may cause diseases. Osteoclasts play a key role in bone metabolism, as osteoclastogenesis marks the beginning of each bone remodeling cycle. As the only cell capable of bone resorption, osteoclasts are derived from the monocyte/macrophage hematopoietic precursors that terminally adhere to mineralized extracellular matrix, and they subsequently break down the extracellular compartment. Bone is generally considered the load-burdening tissue, bone homeostasis is critically affected by mechanical conductions, and the bone cells are mechanosensitive. The functions of various bone cells under mechanical forces such as chondrocytes and osteoblasts have been reported; however, the unique bone-resorbing osteoclasts are less studied. The oversuppression of osteoclasts in mechanical studies may be because of its complicated differentiation progress and flexible structure, which increases difficulty in targeting mechanical structures. This paper will focus on recent findings regarding osteoclasts and attempt to uncover proposed candidate mechanosensing structures in osteoclasts including podosome-associated complexes, gap junctions and transient receptor potential family (ion channels). We will additionally describe possible mechanotransduction signaling pathways including GTPase ras homologue family member A (RhoA), Yes-associated protein/transcriptional co-activator with PDZ-binding motif (TAZ), Ca2+ signaling and non-canonical Wnt signaling. According to numerous studies, evaluating the possible influence of various physical environments on osteoclastogenesis is conducive to the study of bone homeostasis.
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Affiliation(s)
- Qingxuan Wang
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610064, China
| | - Mengmeng Duan
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610064, China
| | - Jingfeng Liao
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610064, China
| | - Jing Xie
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610064, China
| | - Chenchen Zhou
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610064, China
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Maintenance of Ligament Homeostasis of Spheroid-Colonized Embroidered and Functionalized Scaffolds after 3D Stretch. Int J Mol Sci 2021; 22:ijms22158204. [PMID: 34360970 PMCID: PMC8348491 DOI: 10.3390/ijms22158204] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 07/18/2021] [Accepted: 07/23/2021] [Indexed: 01/12/2023] Open
Abstract
Anterior cruciate ligament (ACL) ruptures are usually treated with autograft implantation to prevent knee instability. Tissue engineered ACL reconstruction is becoming promising to circumvent autograft limitations. The aim was to evaluate the influence of cyclic stretch on lapine (L) ACL fibroblasts on embroidered scaffolds with respect to adhesion, DNA and sulphated glycosaminoglycan (sGAG) contents, gene expression of ligament-associated extracellular matrix genes, such as type I collagen, decorin, tenascin C, tenomodulin, gap junctional connexin 43 and the transcription factor Mohawk. Control scaffolds and those functionalized by gas phase fluorination and cross-linked collagen foam were either pre-cultured with a suspension or with spheroids of LACL cells before being subjected to cyclic stretch (4%, 0.11 Hz, 3 days). Stretch increased significantly the scaffold area colonized with cells but impaired sGAGs and decorin gene expression (functionalized scaffolds seeded with cell suspension). Stretching increased tenascin C, connexin 43 and Mohawk but decreased decorin gene expression (control scaffolds seeded with cell suspension). Pre-cultivation of functionalized scaffolds with spheroids might be the more suitable method for maintaining ligamentogenesis in 3D scaffolds compared to using a cell suspension due to a significantly higher sGAG content in response to stretching and type I collagen gene expression in functionalized scaffolds.
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Bramson MTK, Van Houten SK, Corr DT. Mechanobiology in Tendon, Ligament, and Skeletal Muscle Tissue Engineering. J Biomech Eng 2021; 143:070801. [PMID: 33537704 DOI: 10.1115/1.4050035] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Indexed: 12/28/2022]
Abstract
Tendon, ligament, and skeletal muscle are highly organized tissues that largely rely on a hierarchical collagenous matrix to withstand high tensile loads experienced in activities of daily life. This critical biomechanical role predisposes these tissues to injury, and current treatments fail to recapitulate the biomechanical function of native tissue. This has prompted researchers to pursue engineering functional tissue replacements, or dysfunction/disease/development models, by emulating in vivo stimuli within in vitro tissue engineering platforms-specifically mechanical stimulation, as well as active contraction in skeletal muscle. Mechanical loading is critical for matrix production and organization in the development, maturation, and maintenance of native tendon, ligament, and skeletal muscle, as well as their interfaces. Tissue engineers seek to harness these mechanobiological benefits using bioreactors to apply both static and dynamic mechanical stimulation to tissue constructs, and induce active contraction in engineered skeletal muscle. The vast majority of engineering approaches in these tissues are scaffold-based, providing interim structure and support to engineered constructs, and sufficient integrity to withstand mechanical loading. Alternatively, some recent studies have employed developmentally inspired scaffold-free techniques, relying on cellular self-assembly and matrix production to form tissue constructs. Whether utilizing a scaffold or not, incorporation of mechanobiological stimuli has been shown to improve the composition, structure, and biomechanical function of engineered tendon, ligament, and skeletal muscle. Together, these findings highlight the importance of mechanobiology and suggest how it can be leveraged to engineer these tissues and their interfaces, and to create functional multitissue constructs.
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Affiliation(s)
- Michael T K Bramson
- Department of Biomedical Engineering, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180
| | - Sarah K Van Houten
- Department of Biomedical Engineering, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180
| | - David T Corr
- Department of Biomedical Engineering, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180
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Wang HN, Huang YC, Ni GX. Mechanotransduction of stem cells for tendon repair. World J Stem Cells 2020; 12:952-965. [PMID: 33033557 PMCID: PMC7524696 DOI: 10.4252/wjsc.v12.i9.952] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 05/06/2020] [Accepted: 07/19/2020] [Indexed: 02/06/2023] Open
Abstract
Tendon is a mechanosensitive tissue that transmits force from muscle to bone. Physiological loading contributes to maintaining the homeostasis and adaptation of tendon, but aberrant loading may lead to injury or failed repair. It is shown that stem cells respond to mechanical loading and play an essential role in both acute and chronic injuries, as well as in tendon repair. In the process of mechanotransduction, mechanical loading is detected by mechanosensors that regulate cell differentiation and proliferation via several signaling pathways. In order to better understand the stem-cell response to mechanical stimulation and the potential mechanism of the tendon repair process, in this review, we summarize the source and role of endogenous and exogenous stem cells active in tendon repair, describe the mechanical response of stem cells, and finally, highlight the mechanotransduction process and underlying signaling pathways.
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Affiliation(s)
- Hao-Nan Wang
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Yong-Can Huang
- Shenzhen Engineering Laboratory of Orthopaedic Regenerative Technologies, Department of Spine Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong Province, China
| | - Guo-Xin Ni
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China.
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11
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Tendon and ligament mechanical loading in the pathogenesis of inflammatory arthritis. Nat Rev Rheumatol 2020; 16:193-207. [PMID: 32080619 DOI: 10.1038/s41584-019-0364-x] [Citation(s) in RCA: 132] [Impact Index Per Article: 26.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/20/2019] [Indexed: 12/18/2022]
Abstract
Mechanical loading is an important factor in musculoskeletal health and disease. Tendons and ligaments require physiological levels of mechanical loading to develop and maintain their tissue architecture, a process that is achieved at the cellular level through mechanotransduction-mediated fine tuning of the extracellular matrix by tendon and ligament stromal cells. Pathological levels of force represent a biological (mechanical) stress that elicits an immune system-mediated tissue repair pathway in tendons and ligaments. The biomechanics and mechanobiology of tendons and ligaments form the basis for understanding how such tissues sense and respond to mechanical force, and the anatomical extent of several mechanical stress-related disorders in tendons and ligaments overlaps with that of chronic inflammatory arthritis in joints. The role of mechanical stress in 'overuse' injuries, such as tendinopathy, has long been known, but mechanical stress is now also emerging as a possible trigger for some forms of chronic inflammatory arthritis, including spondyloarthritis and rheumatoid arthritis. Thus, seemingly diverse diseases of the musculoskeletal system might have similar mechanisms of immunopathogenesis owing to conserved responses to mechanical stress.
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12
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Abstract
Tendons connect muscles to bones to transfer the forces necessary for movement. Cell-cell junction proteins, cadherins and connexins, may play a role in tendon development and injury. In this review, we begin by highlighting current understanding of how cell-cell junctions may regulate embryonic tendon development and differentiation. We then examine cell-cell junctions in postnatal tendon, before summarizing the role of cadherins and connexins in adult tendons. More information exists regarding the role of cell-cell junctions in the formation and homeostasis of other musculoskeletal tissues, namely cartilage and bone. Therefore, to inform future tendon studies, we include a brief survey of cadherins and connexins in chondrogenesis and osteogenesis, and summarize how cell-cell junctions are involved in some musculoskeletal tissue pathologies. An enhanced understanding of how cell-cell junctions participate in tendon development, maintenance, and disease will benefit future regenerative strategies.
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Affiliation(s)
| | - Jett B Murray
- Biological Engineering, University of Idaho, Moscow, ID
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13
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Theodossiou SK, Tokle J, Schiele NR. TGFβ2-induced tenogenesis impacts cadherin and connexin cell-cell junction proteins in mesenchymal stem cells. Biochem Biophys Res Commun 2018; 508:889-893. [PMID: 30538046 DOI: 10.1016/j.bbrc.2018.12.023] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 12/04/2018] [Indexed: 12/22/2022]
Abstract
Tenogenic differentiation of stem cells is needed for tendon tissue engineering approaches. A current challenge is the limited information on the cellular-level changes during tenogenic induction. Tendon cells in embryonic and adult tendons possess an array of cell-cell junction proteins that include cadherins and connexins, but how these proteins are impacted by tenogenic differentiation is unknown. Our objective was to explore how tenogenic induction of mesenchymal stem cells (MSCs) using the transforming growth factor (TGF)β2 impacted protein markers of tendon differentiation and protein levels of N-cadherin, cadherin-11 and connexin-43. MSCs were treated with TGFβ2 for 21 days. At 3 days, TGFβ2-treated MSCs developed a fibroblastic morphology and significantly decreased levels of N-cadherin protein, which were maintained through 21 days. Similar decreases in protein levels were found for cadherin-11. Connexin-43 protein levels significantly increased at 3 days, but then decreased below control levels, though not significantly. Protein levels of scleraxis and tenomodulin were significantly increased at day 14 and 21, respectively. Taken together, our results indicate that TGFβ2 is an inducer of tendon marker proteins (scleraxis and tenomodulin) in MSCs and that tenogenesis alters the protein levels of N-cadherin, cadherin-11 and connexin-43. These findings suggest a role for connexin-43 early in tenogenesis, and show that early-onset and sustained decreases in N-cadherin and cadherin-11 may be novel markers of tenogenesis in MSCs.
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Affiliation(s)
- Sophia K Theodossiou
- Biological Engineering, 875 Perimeter Dr. MS 0904, University of Idaho, Moscow, ID, 83844, USA.
| | - John Tokle
- Biological Sciences, 875 Perimeter Dr. MS 3051, University of Idaho, Moscow, ID, 83844, USA.
| | - Nathan R Schiele
- Biological Engineering, 875 Perimeter Dr. MS 0904, University of Idaho, Moscow, ID, 83844, USA.
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Wall M, Butler D, El Haj A, Bodle JC, Loboa EG, Banes AJ. Key developments that impacted the field of mechanobiology and mechanotransduction. J Orthop Res 2018; 36:605-619. [PMID: 28817244 DOI: 10.1002/jor.23707] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Accepted: 08/10/2017] [Indexed: 02/04/2023]
Abstract
Advances in mechanobiology have evolved through insights from multiple disciplines including structural engineering, biomechanics, vascular biology, and orthopaedics. In this paper, we reviewed the impact of key reports related to the study of applied loads on tissues and cells and the resulting signal transduction pathways. We addressed how technology has helped advance the burgeoning field of mechanobiology (over 33,600 publications from 1970 to 2016). We analyzed the impact of critical ideas and then determined how these concepts influenced the mechanobiology field by looking at the citation frequency of these reports as well as tracking how the overall number of citations within the field changed over time. These data allowed us to understand how a key publication, idea, or technology guided or enabled the field. Initial observations of how forces acted on bone and soft tissues stimulated the development of computational solutions defining how forces affect tissue modeling and remodeling. Enabling technologies, such as cell and tissue stretching, compression, and shear stress devices, allowed more researchers to explore how deformation and fluid flow affect cells. Observation of the cell as a tensegrity structure and advanced methods to study genetic regulation in cells further advanced knowledge of specific mechanisms of mechanotransduction. The future of the field will involve developing gene and drug therapies to simulate or augment beneficial load regimens in patients and in mechanically conditioning organs for implantation. Here, we addressed a history of the field, but we limited our discussions to advances in musculoskeletal mechanobiology, primarily in bone, tendon, and ligament tissues. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:605-619, 2018.
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Affiliation(s)
- Michelle Wall
- Flexcell International Corp., 2730 Tucker St., Suite 200, Burlington, 27215, North Carolina
| | - David Butler
- Department of Biomedical, Chemical, and Environmental Engineering, University of Cincinnati, Cincinnati, Ohio
| | - Alicia El Haj
- Institute for Science & Technology in Medicine, Keele University, Staffordshire, UK
| | | | | | - Albert J Banes
- Flexcell International Corp., 2730 Tucker St., Suite 200, Burlington, 27215, North Carolina.,Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, North Carolina
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Enhanced gap junction intercellular communication inhibits catabolic and pro-inflammatory responses in tenocytes against heat stress. J Cell Commun Signal 2017; 11:369-380. [PMID: 28601938 DOI: 10.1007/s12079-017-0397-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 05/28/2017] [Indexed: 12/17/2022] Open
Abstract
Elevation of tendon core temperature during severe activity is well known. However, its effects on tenocyte function have not been studied in detail. The present study tested a hypothesis that heat stimulation upregulates tenocyte catabolism, which can be modulated by the inhibition or the enhancement of gap junction intercellular communication (GJIC). Tenocytes isolated from rabbit Achilles tendons were subjected to heat stimulation at 37 °C, 41 °C or 43 °C for 30 min, and changes in cell viability, gene expressions and GJIC were examined. It was found that GJIC exhibited no changes by the stimulation even at 43 °C, but cell viability was decreased and catabolic and proinflammatory gene expressions were upregulated. Inhibition of GJIC demonstrated further upregulated catabolic and proinflammatory gene expressions. In contrast, enhanced GJIC, resulting from forced upregulation of connexin 43 gene, counteracted the heat-induced upregulation of catabolic and proinflammatory genes. These findings suggest that the temperature rise in tendon core could upregulate catabolic and proinflammatory activities, potentially leading to the onset of tendinopathy, and such upregulations could be suppressed by the enhancement of GJIC. Therefore, to prevent tendon injury at an early stage from becoming chronic injury, tendon core temperature and GJIC could be targets for post-activity treatments.
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Maeda E, Pian H, Ohashi T. Temporal regulation of gap junctional communication between tenocytes subjected to static tensile strain with physiological and non-physiological amplitudes. Biochem Biophys Res Commun 2017; 482:1170-1175. [DOI: 10.1016/j.bbrc.2016.12.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Accepted: 12/02/2016] [Indexed: 01/28/2023]
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Frizziero A, Salamanna F, Della Bella E, Vittadini F, Gasparre G, Nicoli Aldini N, Masiero S, Fini M. The Role of Detraining in Tendon Mechanobiology. Front Aging Neurosci 2016; 8:43. [PMID: 26973517 PMCID: PMC4770795 DOI: 10.3389/fnagi.2016.00043] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Accepted: 02/15/2016] [Indexed: 12/18/2022] Open
Abstract
Introduction: Several conditions such as training, aging, estrogen deficiency and drugs could affect the biological and anatomo-physiological characteristics of the tendon. Additionally, recent preclinical and clinical studies examined the effect of detraining on tendon, showing alterations in its structure and morphology and in tenocyte mechanobiology. However, few data evaluated the importance that cessation of training might have on tendon. Basically, we do not fully understand how tendons react to a phase of training followed by sudden detraining. Therefore, within this review, we summarize the studies where tendon detraining was examined. Materials and Methods: A descriptive systematic literature review was carried out by searching three databases (PubMed, Scopus and Web of Knowledge) on tendon detraining. Original articles in English from 2000 to 2015 were included. In addition, the search was extended to the reference lists of the selected articles. A public reference manager (www.mendeley.com) was adopted to remove duplicate articles. Results: An initial literature search yielded 134 references (www.pubmed.org: 53; www.scopus.com: 11; www.webofknowledge.com: 70). Fifteen publications were extracted based on the title for further analysis by two independent reviewers. Abstracts and complete articles were after that reviewed to evaluate if they met inclusion criteria. Conclusions: The revised literature comprised four clinical studies and an in vitro and three in vivo reports. Overall, the results showed that tendon structure and properties after detraining are compromised, with an alteration in the tissue structural organization and mechanical properties. Clinical studies usually showed a lesser extent of tendon alterations, probably because preclinical studies permit an in-depth evaluation of tendon modifications, which is hard to perform in human subjects. In conclusion, after a period of sudden detraining (e.g., after an injury), physical activity should be taken with caution, following a targeted rehabilitation program. However, further research should be performed to fully understand the effect of sudden detraining on tendons.
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Affiliation(s)
- Antonio Frizziero
- Department of Physical and Rehabilitation Medicine, University of Padua Padua, Italy
| | - Francesca Salamanna
- Laboratory of Biocompatibility, Technological Innovations and Advanced Therapies, RIT Department, Rizzoli Orthopedic Institute Bologna, Italy
| | - Elena Della Bella
- Laboratory of Preclinical and Surgical Studies, Rizzoli Orthopedic InstituteBologna, Italy; Department of Experimental, Diagnostic and Specialty Medicine, University of BolognaBologna, Italy
| | - Filippo Vittadini
- Department of Physical and Rehabilitation Medicine, University of Padua Padua, Italy
| | - Giuseppe Gasparre
- Department of Physical and Rehabilitation Medicine, University of Padua Padua, Italy
| | - Nicolò Nicoli Aldini
- Laboratory of Biocompatibility, Technological Innovations and Advanced Therapies, RIT Department, Rizzoli Orthopedic InstituteBologna, Italy; Laboratory of Preclinical and Surgical Studies, Rizzoli Orthopedic InstituteBologna, Italy
| | - Stefano Masiero
- Department of Physical and Rehabilitation Medicine, University of Padua Padua, Italy
| | - Milena Fini
- Laboratory of Biocompatibility, Technological Innovations and Advanced Therapies, RIT Department, Rizzoli Orthopedic InstituteBologna, Italy; Laboratory of Preclinical and Surgical Studies, Rizzoli Orthopedic InstituteBologna, Italy
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Cell Signaling in Tenocytes: Response to Load and Ligands in Health and Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 920:79-95. [DOI: 10.1007/978-3-319-33943-6_7] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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