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Tan Q, Ruan Y, Wu S, Jiang Y, Fu R, Gu X, Yu J, Wu Q, Li M, Jiang S. Vagus nerve stimulation (VNS) inhibits cardiac mast cells activation and improves myocardial atrophy after ischemic stroke. Int Immunopharmacol 2024; 139:112714. [PMID: 39068751 DOI: 10.1016/j.intimp.2024.112714] [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: 05/09/2024] [Revised: 06/30/2024] [Accepted: 07/15/2024] [Indexed: 07/30/2024]
Abstract
BACKGROUND Ischemic stroke is one of the leading causes of chronic disability worldwide, and stroke-induced heart damage can lead to death. According to research, patients with a variety of brain disease have good clinical results after vagus nerve stimulation (VNS). After ischemic stroke, mast cells (MCs) degranulate and release a large number of mediators, which may cause systemic inflammation. Chymase secreted by MCs can increase the levels of pathological angiotensin II (AngⅡ), which plays a crucial role in the deterioration of heart disease. Our goal was to develop a minimally invasive, targeted, and convenient VNS approach to assess the impact of VNS and to clarify the relationship between VNS and MCs in the prognosis of patients with myocardial atrophy after acute ischemic stroke. METHODS In this study, we verified the role of VNS in the treatment of myocardial atrophy after stroke and its molecular mechanism using a rat model of middle cerebral artery occlusion (MCAO/r). Behavioral studies were assessed using neurobehavioral deficit scores. Enzyme-linked immunosorbent assays, immunofluorescence staining, Western blotting and qRT-PCR were used to analyze the expression levels of myocardial atrophy, MC and inflammatory markers in rat hearts. RESULTS VNS improved myocardial atrophy in MCAO/r rats, inhibited MC activation, reduced the expression of chymase and AngⅡ, and inhibited the expression of proinflammatory factors. The chymase activator C48/80 reversed these effects of VNS. Chymase activation inhibited the effect of VNS on myocardial atrophy in MCAO/r rats, increased AngⅡ expression and aggravated inflammation and autophagy. The myocardial atrophy of MCAO/r rats was improved after chymase inhibition, and AngⅡ expression, inflammation and autophagy were reduced. Our results suggest that VNS may reduce the expression of chymase and AngⅡ by inhibiting MC activation, thereby improving myocardial atrophy and reducing inflammation and autophagy in MCAO/r rats. Inhibition of MC activation may be an effective strategy for treating myocardial atrophy after stroke. CONCLUSIONS VNS inhibits MC activation and reduces the expression of chymase and AngII, thereby alleviating myocardial atrophy, inflammation and autophagy after stroke.
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Affiliation(s)
- Qianqian Tan
- Rehabilitation Medicine Center, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Intelligent Rehabilitation Research Center, International Institute for Acupuncture and Rehabilitation, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; The Provincial Key Laboratory for Acupuncture and Rehabilitation in Zhejiang Province, The Wenzhou Key Laboratory for Rehabilitation Research, China
| | - Yu Ruan
- Rehabilitation Medicine Center, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Shaoqi Wu
- Rehabilitation Medicine Center, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Intelligent Rehabilitation Research Center, International Institute for Acupuncture and Rehabilitation, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; The Provincial Key Laboratory for Acupuncture and Rehabilitation in Zhejiang Province, The Wenzhou Key Laboratory for Rehabilitation Research, China
| | - Yong Jiang
- Rehabilitation Medicine Center, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Intelligent Rehabilitation Research Center, International Institute for Acupuncture and Rehabilitation, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; The Provincial Key Laboratory for Acupuncture and Rehabilitation in Zhejiang Province, The Wenzhou Key Laboratory for Rehabilitation Research, China
| | - Rongrong Fu
- Rehabilitation Medicine Center, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Intelligent Rehabilitation Research Center, International Institute for Acupuncture and Rehabilitation, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; The Provincial Key Laboratory for Acupuncture and Rehabilitation in Zhejiang Province, The Wenzhou Key Laboratory for Rehabilitation Research, China
| | - Xiaoxue Gu
- Rehabilitation Medicine Center, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Intelligent Rehabilitation Research Center, International Institute for Acupuncture and Rehabilitation, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; The Provincial Key Laboratory for Acupuncture and Rehabilitation in Zhejiang Province, The Wenzhou Key Laboratory for Rehabilitation Research, China
| | - Jiaying Yu
- Rehabilitation Medicine Center, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Intelligent Rehabilitation Research Center, International Institute for Acupuncture and Rehabilitation, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; The Provincial Key Laboratory for Acupuncture and Rehabilitation in Zhejiang Province, The Wenzhou Key Laboratory for Rehabilitation Research, China
| | - Qiaoyun Wu
- Rehabilitation Medicine Center, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Intelligent Rehabilitation Research Center, International Institute for Acupuncture and Rehabilitation, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; The Provincial Key Laboratory for Acupuncture and Rehabilitation in Zhejiang Province, The Wenzhou Key Laboratory for Rehabilitation Research, China
| | - Ming Li
- School of Basic Medical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
| | - Songhe Jiang
- Rehabilitation Medicine Center, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Intelligent Rehabilitation Research Center, International Institute for Acupuncture and Rehabilitation, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; The Provincial Key Laboratory for Acupuncture and Rehabilitation in Zhejiang Province, The Wenzhou Key Laboratory for Rehabilitation Research, China.
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Zhang X, Li K, Wang C, Rao Y, Tuan RS, Wang DM, Ker DFE. Facile and rapid fabrication of a novel 3D-printable, visible light-crosslinkable and bioactive polythiourethane for large-to-massive rotator cuff tendon repair. Bioact Mater 2024; 37:439-458. [PMID: 38698918 PMCID: PMC11063952 DOI: 10.1016/j.bioactmat.2024.03.036] [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: 03/08/2024] [Revised: 03/29/2024] [Accepted: 03/29/2024] [Indexed: 05/05/2024] Open
Abstract
Facile and rapid 3D fabrication of strong, bioactive materials can address challenges that impede repair of large-to-massive rotator cuff tears including personalized grafts, limited mechanical support, and inadequate tissue regeneration. Herein, we developed a facile and rapid methodology that generates visible light-crosslinkable polythiourethane (PHT) pre-polymer resin (∼30 min at room temperature), yielding 3D-printable scaffolds with tendon-like mechanical attributes capable of delivering tenogenic bioactive factors. Ex vivo characterization confirmed successful fabrication, robust human supraspinatus tendon (SST)-like tensile properties (strength: 23 MPa, modulus: 459 MPa, at least 10,000 physiological loading cycles without failure), excellent suture retention (8.62-fold lower than acellular dermal matrix (ADM)-based clinical graft), slow degradation, and controlled release of fibroblast growth factor-2 (FGF-2) and transforming growth factor-β3 (TGF-β3). In vitro studies showed cytocompatibility and growth factor-mediated tenogenic-like differentiation of mesenchymal stem cells. In vivo studies demonstrated biocompatibility (3-week mouse subcutaneous implantation) and ability of growth factor-containing scaffolds to notably regenerate at least 1-cm of tendon with native-like biomechanical attributes as uninjured shoulder (8-week, large-to-massive 1-cm gap rabbit rotator cuff injury). This study demonstrates use of a 3D-printable, strong, and bioactive material to provide mechanical support and pro-regenerative cues for challenging injuries such as large-to-massive rotator cuff tears.
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Affiliation(s)
- Xu Zhang
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, New Territories, Hong Kong SAR, Hong Kong
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, New Territories, Hong Kong SAR, Hong Kong
- Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, Hong Kong SAR, Hong Kong
| | - Ke Li
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, New Territories, Hong Kong SAR, Hong Kong
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, New Territories, Hong Kong SAR, Hong Kong
- Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, Hong Kong SAR, Hong Kong
| | - Chenyang Wang
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, New Territories, Hong Kong SAR, Hong Kong
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, New Territories, Hong Kong SAR, Hong Kong
| | - Ying Rao
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, New Territories, Hong Kong SAR, Hong Kong
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, New Territories, Hong Kong SAR, Hong Kong
| | - Rocky S. Tuan
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, New Territories, Hong Kong SAR, Hong Kong
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, New Territories, Hong Kong SAR, Hong Kong
- Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, Hong Kong SAR, Hong Kong
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, New Territories, Hong Kong SAR, Hong Kong
| | - Dan Michelle Wang
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, New Territories, Hong Kong SAR, Hong Kong
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, New Territories, Hong Kong SAR, Hong Kong
- Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, Hong Kong SAR, Hong Kong
- Ministry of Education Key Laboratory for Regenerative Medicine, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, New Territories, Hong Kong SAR, Hong Kong
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, New Territories, Hong Kong SAR, Hong Kong
| | - Dai Fei Elmer Ker
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, New Territories, Hong Kong SAR, Hong Kong
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, New Territories, Hong Kong SAR, Hong Kong
- Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, Hong Kong SAR, Hong Kong
- Ministry of Education Key Laboratory for Regenerative Medicine, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, New Territories, Hong Kong SAR, Hong Kong
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, New Territories, Hong Kong SAR, Hong Kong
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Pampanella L, Petrocelli G, Abruzzo PM, Zucchini C, Canaider S, Ventura C, Facchin F. Cytochalasins as Modulators of Stem Cell Differentiation. Cells 2024; 13:400. [PMID: 38474364 PMCID: PMC10931372 DOI: 10.3390/cells13050400] [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: 01/22/2024] [Revised: 02/16/2024] [Accepted: 02/22/2024] [Indexed: 03/14/2024] Open
Abstract
Regenerative medicine aims to identify new research strategies for the repair and restoration of tissues damaged by pathological or accidental events. Mesenchymal stem cells (MSCs) play a key role in regenerative medicine approaches due to their specific properties, such as the high rate of proliferation, the ability to differentiate into several cell lineages, the immunomodulatory potential, and their easy isolation with minimal ethical issues. One of the main goals of regenerative medicine is to modulate, both in vitro and in vivo, the differentiation potential of MSCs to improve their use in the repair of damaged tissues. Over the years, much evidence has been collected about the ability of cytochalasins, a large family of 60 metabolites isolated mainly from fungi, to modulate multiple properties of stem cells (SCs), such as proliferation, migration, and differentiation, by altering the organization of the cyto- and the nucleo-skeleton. In this review, we discussed the ability of two different cytochalasins, cytochalasins D and B, to influence specific SC differentiation programs modulated by several agents (chemical or physical) or intra- and extra-cellular factors, with particular attention to human MSCs (hMSCs).
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Affiliation(s)
- Luca Pampanella
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (L.P.); (G.P.); (P.M.A.); (C.Z.); (F.F.)
| | - Giovannamaria Petrocelli
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (L.P.); (G.P.); (P.M.A.); (C.Z.); (F.F.)
| | - Provvidenza Maria Abruzzo
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (L.P.); (G.P.); (P.M.A.); (C.Z.); (F.F.)
| | - Cinzia Zucchini
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (L.P.); (G.P.); (P.M.A.); (C.Z.); (F.F.)
| | - Silvia Canaider
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (L.P.); (G.P.); (P.M.A.); (C.Z.); (F.F.)
| | - Carlo Ventura
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (L.P.); (G.P.); (P.M.A.); (C.Z.); (F.F.)
- National Laboratory of Molecular Biology and Stem Cell Bioengineering of the National Institute of Biostructures and Biosystems (NIBB) c/o Eldor Lab, Via Corticella 183, 40129 Bologna, Italy
| | - Federica Facchin
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (L.P.); (G.P.); (P.M.A.); (C.Z.); (F.F.)
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Dhanjal DS, Singh R, Sharma V, Nepovimova E, Adam V, Kuca K, Chopra C. Advances in Genetic Reprogramming: Prospects from Developmental Biology to Regenerative Medicine. Curr Med Chem 2024; 31:1646-1690. [PMID: 37138422 DOI: 10.2174/0929867330666230503144619] [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: 11/12/2022] [Revised: 03/13/2023] [Accepted: 03/16/2023] [Indexed: 05/05/2023]
Abstract
The foundations of cell reprogramming were laid by Yamanaka and co-workers, who showed that somatic cells can be reprogrammed into pluripotent cells (induced pluripotency). Since this discovery, the field of regenerative medicine has seen advancements. For example, because they can differentiate into multiple cell types, pluripotent stem cells are considered vital components in regenerative medicine aimed at the functional restoration of damaged tissue. Despite years of research, both replacement and restoration of failed organs/ tissues have remained elusive scientific feats. However, with the inception of cell engineering and nuclear reprogramming, useful solutions have been identified to counter the need for compatible and sustainable organs. By combining the science underlying genetic engineering and nuclear reprogramming with regenerative medicine, scientists have engineered cells to make gene and stem cell therapies applicable and effective. These approaches have enabled the targeting of various pathways to reprogramme cells, i.e., make them behave in beneficial ways in a patient-specific manner. Technological advancements have clearly supported the concept and realization of regenerative medicine. Genetic engineering is used for tissue engineering and nuclear reprogramming and has led to advances in regenerative medicine. Targeted therapies and replacement of traumatized , damaged, or aged organs can be realized through genetic engineering. Furthermore, the success of these therapies has been validated through thousands of clinical trials. Scientists are currently evaluating induced tissue-specific stem cells (iTSCs), which may lead to tumour-free applications of pluripotency induction. In this review, we present state-of-the-art genetic engineering that has been used in regenerative medicine. We also focus on ways that genetic engineering and nuclear reprogramming have transformed regenerative medicine and have become unique therapeutic niches.
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Affiliation(s)
- Daljeet Singh Dhanjal
- School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab, India
| | - Reena Singh
- School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab, India
| | - Varun Sharma
- Head of Bioinformatic Division, NMC Genetics India Pvt. Ltd., Gurugram, India
| | - Eugenie Nepovimova
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, 50003, Czech Republic
| | - Vojtech Adam
- Department of Chemistry and Biochemistry, Mendel University in Brno, Zemedelska 1, Brno, CZ 613 00, Czech Republic
- Central European Institute of Technology, Brno University of Technology, Purkynova 123, Brno, CZ-612 00, Czech Republic
| | - Kamil Kuca
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, 50003, Czech Republic
- Biomedical Research Center, University Hospital Hradec Kralove, Hradec Kralove, 50005, Czech Republic
| | - Chirag Chopra
- School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab, India
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Lin M, Li W, Ni X, Sui Y, Li H, Chen X, Lu Y, Jiang M, Wang C. Growth factors in the treatment of Achilles tendon injury. Front Bioeng Biotechnol 2023; 11:1250533. [PMID: 37781529 PMCID: PMC10539943 DOI: 10.3389/fbioe.2023.1250533] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 09/04/2023] [Indexed: 10/03/2023] Open
Abstract
Achilles tendon (AT) injury is one of the most common tendon injuries, especially in athletes, the elderly, and working-age people. In AT injury, the biomechanical properties of the tendon are severely affected, leading to abnormal function. In recent years, many efforts have been underway to develop effective treatments for AT injuries to enable patients to return to sports faster. For instance, several new techniques for tissue-engineered biological augmentation for tendon healing, growth factors (GFs), gene therapy, and mesenchymal stem cells were introduced. Increasing evidence has suggested that GFs can reduce inflammation, promote extracellular matrix production, and accelerate AT repair. In this review, we highlighted some recent investigations regarding the role of GFs, such as transforming GF-β(TGF-β), bone morphogenetic proteins (BMP), fibroblast GF (FGF), vascular endothelial GF (VEGF), platelet-derived GF (PDGF), and insulin-like GF (IGF), in tendon healing. In addition, we summarized the clinical trials and animal experiments on the efficacy of GFs in AT repair. We also highlighted the advantages and disadvantages of the different isoforms of TGF-β and BMPs, including GFs combined with stem cells, scaffolds, or other GFs. The strategies discussed in this review are currently in the early stages of development. It is noteworthy that although these emerging technologies may potentially develop into substantial clinical treatment options for AT injury, definitive conclusions on the use of these techniques for routine management of tendon ailments could not be drawn due to the lack of data.
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Affiliation(s)
- Meina Lin
- Liaoning Research Institute of Family Planning, China Medical University, Shenyang, China
| | - Wei Li
- Liaoning Research Institute of Family Planning, China Medical University, Shenyang, China
- Medical School, Shandong Modern University, Jinan, China
| | - Xiang Ni
- Liaoning Research Institute of Family Planning, China Medical University, Shenyang, China
| | - Yu Sui
- Liaoning Research Institute of Family Planning, China Medical University, Shenyang, China
| | - Huan Li
- Liaoning Research Institute of Family Planning, China Medical University, Shenyang, China
| | - Xinren Chen
- Liaoning Research Institute of Family Planning, China Medical University, Shenyang, China
| | - Yongping Lu
- Liaoning Research Institute of Family Planning, China Medical University, Shenyang, China
| | - Miao Jiang
- Liaoning Research Institute of Family Planning, China Medical University, Shenyang, China
| | - Chenchao Wang
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, China
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Jeannerat A, Meuli J, Peneveyre C, Jaccoud S, Chemali M, Thomas A, Liao Z, Abdel-Sayed P, Scaletta C, Hirt-Burri N, Applegate LA, Raffoul W, Laurent A. Bio-Enhanced Neoligaments Graft Bearing FE002 Primary Progenitor Tenocytes: Allogeneic Tissue Engineering & Surgical Proofs-of-Concept for Hand Ligament Regenerative Medicine. Pharmaceutics 2023; 15:1873. [PMID: 37514060 PMCID: PMC10385025 DOI: 10.3390/pharmaceutics15071873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 06/27/2023] [Accepted: 06/30/2023] [Indexed: 07/30/2023] Open
Abstract
Hand tendon/ligament structural ruptures (tears, lacerations) often require surgical reconstruction and grafting, for the restauration of finger mechanical functions. Clinical-grade human primary progenitor tenocytes (FE002 cryopreserved progenitor cell source) have been previously proposed for diversified therapeutic uses within allogeneic tissue engineering and regenerative medicine applications. The aim of this study was to establish bioengineering and surgical proofs-of-concept for an artificial graft (Neoligaments Infinity-Lock 3 device) bearing cultured and viable FE002 primary progenitor tenocytes. Technical optimization and in vitro validation work showed that the combined preparations could be rapidly obtained (dynamic cell seeding of 105 cells/cm of scaffold, 7 days of co-culture). The studied standardized transplants presented homogeneous cellular colonization in vitro (cellular alignment/coating along the scaffold fibers) and other critical functional attributes (tendon extracellular matrix component such as collagen I and aggrecan synthesis/deposition along the scaffold fibers). Notably, major safety- and functionality-related parameters/attributes of the FE002 cells/finished combination products were compiled and set forth (telomerase activity, adhesion and biological coating potentials). A two-part human cadaveric study enabled to establish clinical protocols for hand ligament cell-assisted surgery (ligamento-suspension plasty after trapeziectomy, thumb metacarpo-phalangeal ulnar collateral ligamentoplasty). Importantly, the aggregated experimental results clearly confirmed that functional and clinically usable allogeneic cell-scaffold combination products could be rapidly and robustly prepared for bio-enhanced hand ligament reconstruction. Major advantages of the considered bioengineered graft were discussed in light of existing clinical protocols based on autologous tenocyte transplantation. Overall, this study established proofs-of-concept for the translational development of a functional tissue engineering protocol in allogeneic musculoskeletal regenerative medicine, in view of a pilot clinical trial.
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Affiliation(s)
- Annick Jeannerat
- Preclinical Research Department, LAM Biotechnologies SA, CH-1066 Epalinges, Switzerland
| | - Joachim Meuli
- Plastic and Hand Surgery Service, Lausanne University Hospital, University of Lausanne, CH-1011 Lausanne, Switzerland
| | - Cédric Peneveyre
- Preclinical Research Department, LAM Biotechnologies SA, CH-1066 Epalinges, Switzerland
| | - Sandra Jaccoud
- Plastic and Hand Surgery Service, Lausanne University Hospital, University of Lausanne, CH-1011 Lausanne, Switzerland
- Laboratory of Biomechanical Orthopedics, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
| | - Michèle Chemali
- Plastic and Hand Surgery Service, Lausanne University Hospital, University of Lausanne, CH-1011 Lausanne, Switzerland
| | - Axelle Thomas
- Plastic and Hand Surgery Service, Lausanne University Hospital, University of Lausanne, CH-1011 Lausanne, Switzerland
| | - Zhifeng Liao
- Plastic and Hand Surgery Service, Lausanne University Hospital, University of Lausanne, CH-1011 Lausanne, Switzerland
| | - Philippe Abdel-Sayed
- Plastic and Hand Surgery Service, Lausanne University Hospital, University of Lausanne, CH-1011 Lausanne, Switzerland
- DLL Bioengineering, STI School of Engineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
| | - Corinne Scaletta
- Plastic and Hand Surgery Service, Lausanne University Hospital, University of Lausanne, CH-1011 Lausanne, Switzerland
| | - Nathalie Hirt-Burri
- Plastic and Hand Surgery Service, Lausanne University Hospital, University of Lausanne, CH-1011 Lausanne, Switzerland
| | - Lee Ann Applegate
- Plastic and Hand Surgery Service, Lausanne University Hospital, University of Lausanne, CH-1011 Lausanne, Switzerland
- Center for Applied Biotechnology and Molecular Medicine, University of Zurich, CH-8057 Zurich, Switzerland
- Oxford OSCAR Suzhou Center, Oxford University, Suzhou 215123, China
| | - Wassim Raffoul
- Plastic and Hand Surgery Service, Lausanne University Hospital, University of Lausanne, CH-1011 Lausanne, Switzerland
| | - Alexis Laurent
- Preclinical Research Department, LAM Biotechnologies SA, CH-1066 Epalinges, Switzerland
- Plastic and Hand Surgery Service, Lausanne University Hospital, University of Lausanne, CH-1011 Lausanne, Switzerland
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Watson-Levings RS, Palmer GD, Levings PP, Dacanay EA, Evans CH, Ghivizzani SC. Gene Therapy in Orthopaedics: Progress and Challenges in Pre-Clinical Development and Translation. Front Bioeng Biotechnol 2022; 10:901317. [PMID: 35837555 PMCID: PMC9274665 DOI: 10.3389/fbioe.2022.901317] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 05/27/2022] [Indexed: 11/25/2022] Open
Abstract
In orthopaedics, gene-based treatment approaches are being investigated for an array of common -yet medically challenging- pathologic conditions of the skeletal connective tissues and structures (bone, cartilage, ligament, tendon, joints, intervertebral discs etc.). As the skeletal system protects the vital organs and provides weight-bearing structural support, the various tissues are principally composed of dense extracellular matrix (ECM), often with minimal cellularity and vasculature. Due to their functional roles, composition, and distribution throughout the body the skeletal tissues are prone to traumatic injury, and/or structural failure from chronic inflammation and matrix degradation. Due to a mixture of environment and endogenous factors repair processes are often slow and fail to restore the native quality of the ECM and its function. In other cases, large-scale lesions from severe trauma or tumor surgery, exceed the body’s healing and regenerative capacity. Although a wide range of exogenous gene products (proteins and RNAs) have the potential to enhance tissue repair/regeneration and inhibit degenerative disease their clinical use is hindered by the absence of practical methods for safe, effective delivery. Cumulatively, a large body of evidence demonstrates the capacity to transfer coding sequences for biologic agents to cells in the skeletal tissues to achieve prolonged delivery at functional levels to augment local repair or inhibit pathologic processes. With an eye toward clinical translation, we discuss the research progress in the primary injury and disease targets in orthopaedic gene therapy. Technical considerations important to the exploration and pre-clinical development are presented, with an emphasis on vector technologies and delivery strategies whose capacity to generate and sustain functional transgene expression in vivo is well-established.
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Affiliation(s)
- Rachael S. Watson-Levings
- Department of Orthopaedic Surgery and Sports Medicine, University of Florida College of Medicine, Gainesville, FL, United States
| | - Glyn D. Palmer
- Department of Orthopaedic Surgery and Sports Medicine, University of Florida College of Medicine, Gainesville, FL, United States
| | - Padraic P. Levings
- Department of Orthopaedic Surgery and Sports Medicine, University of Florida College of Medicine, Gainesville, FL, United States
| | - E. Anthony Dacanay
- Department of Orthopaedic Surgery and Sports Medicine, University of Florida College of Medicine, Gainesville, FL, United States
| | - Christopher H. Evans
- Rehabilitation Medicine Research Center, Mayo Clinic, Rochester, MI, United States
| | - Steven C. Ghivizzani
- Department of Orthopaedic Surgery and Sports Medicine, University of Florida College of Medicine, Gainesville, FL, United States
- *Correspondence: Steven C. Ghivizzani,
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Russo V, Mauro A, Peserico A, Di Giacinto O, Khatib ME, Citeroni MR, Rossi E, Canciello A, Mazzotti E, Barboni B. Tendon Healing Response Is Dependent on Epithelial-Mesenchymal-Tendon Transition State of Amniotic Epithelial Stem Cells. Biomedicines 2022; 10:biomedicines10051177. [PMID: 35625913 PMCID: PMC9138831 DOI: 10.3390/biomedicines10051177] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 05/05/2022] [Accepted: 05/17/2022] [Indexed: 11/24/2022] Open
Abstract
Tendinopathies are at the frontier of advanced responses to health challenges and sectoral policy targets. Cell-based therapy holds great promise for tendon disorder resolution. To verify the role of stepwise trans-differentiation of amniotic epithelial stem cells (AECs) in tendon regeneration, in the present research three different AEC subsets displaying an epithelial (eAECs), mesenchymal (mAECs), and tendon-like (tdAECs) phenotype were allotransplanted in a validated experimental sheep Achilles tendon injury model. Tissue healing was analyzed adopting a comparative approach at two early healing endpoints (14 and 28 days). All three subsets of transplanted cells were able to accelerate regeneration: mAECs with a lesser extent than eAECs and tdAECs as indicated in the summary of the total histological scores (TSH), where at day 28 eAECs and tdAECs had better significant scores with respect to mAEC-treated tendons (p < 0.0001). In addition, the immunomodulatory response at day 14 showed in eAEC-transplanted tendons an upregulation of pro-regenerative M2 macrophages with respect to mAECs and tdAECs (p < 0.0001). In addition, in all allotransplanted tendons there was a favorable IL10/IL12 compared to CTR (p < 0.001). The eAECs and tdAECs displayed two different underlying regenerative mechanisms in the tendon. The eAECs positively influenced regeneration mainly through their greater ability to convey in the host tissue the shift from pro-inflammatory to pro-regenerative responses, leading to an ordered extracellular matrix (ECM) deposition and blood vessel remodeling. On the other hand, the transplantation of tdAECs acted mainly on the proliferative phase by impacting the density of ECM and by supporting a prompt recovery, inducing a low cellularity and angle alignment of the host cell compartment. These results support the idea that AECs lay the groundwork for production of different cell phenotypes that can orient tendon regeneration through a crosstalk with the host tissue. In particular, the obtained evidence suggests that eAECs are a practicable and efficient strategy for the treatment of acute tendinopathies, thus reinforcing the grounds to move their use towards clinical practice.
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Affiliation(s)
- Valentina Russo
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (A.M.); (A.P.); (O.D.G.); (M.E.K.); (M.R.C.); (A.C.); (E.M.); (B.B.)
- Correspondence:
| | - Annunziata Mauro
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (A.M.); (A.P.); (O.D.G.); (M.E.K.); (M.R.C.); (A.C.); (E.M.); (B.B.)
| | - Alessia Peserico
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (A.M.); (A.P.); (O.D.G.); (M.E.K.); (M.R.C.); (A.C.); (E.M.); (B.B.)
| | - Oriana Di Giacinto
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (A.M.); (A.P.); (O.D.G.); (M.E.K.); (M.R.C.); (A.C.); (E.M.); (B.B.)
| | - Mohammad El Khatib
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (A.M.); (A.P.); (O.D.G.); (M.E.K.); (M.R.C.); (A.C.); (E.M.); (B.B.)
| | - Maria Rita Citeroni
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (A.M.); (A.P.); (O.D.G.); (M.E.K.); (M.R.C.); (A.C.); (E.M.); (B.B.)
| | - Emanuela Rossi
- Istituto Zooprofilattico Sperimentale dell’Abruzzo e del Molise “Giuseppe Caporale”, 64100 Teramo, Italy;
| | - Angelo Canciello
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (A.M.); (A.P.); (O.D.G.); (M.E.K.); (M.R.C.); (A.C.); (E.M.); (B.B.)
| | - Eleonora Mazzotti
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (A.M.); (A.P.); (O.D.G.); (M.E.K.); (M.R.C.); (A.C.); (E.M.); (B.B.)
| | - Barbara Barboni
- Unit of Basic and Applied Sciences, Faculty of Biosciences and Agro-Food and Environmental Technologies, University of Teramo, 64100 Teramo, Italy; (A.M.); (A.P.); (O.D.G.); (M.E.K.); (M.R.C.); (A.C.); (E.M.); (B.B.)
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9
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Roberts JH, Halper J. Growth Factor Roles in Soft Tissue Physiology and Pathophysiology. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1348:139-159. [PMID: 34807418 DOI: 10.1007/978-3-030-80614-9_6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Repair and healing of injured and diseased tendons has been traditionally fraught with apprehension and difficulties, and often led to rather unsatisfactory results. The burgeoning research field of growth factors has opened new venues for treatment of tendon disorders and injuries, and possibly for treatment of disorders of the aorta and major arteries as well. Several chapters in this volume elucidate the role of transforming growth factor β (TGFß) in pathogenesis of several heritable disorders affecting soft tissues, such as aorta, cardiac valves, and tendons and ligaments. Several members of the bone morphogenetic group either have been approved by the FDA for treatment of non-healing fractures or have been undergoing intensive clinical and experimental testing for use of healing bone fractures and tendon injuries. Because fibroblast growth factors (FGFs) are involved in embryonic development of tendons and muscles among other tissues and organs, the hope is that applied research on FGF biological effects will lead to the development of some new treatment strategies providing that we can control angiogenicity of these growth factors. The problem, or rather question, regarding practical use of imsulin-like growth factor I (IGF-I) in tendon repair is whether IGF-I acts independently or under the guidance of growth hormone. FGF2 or platelet-derived growth factor (PDGF) alone or in combination with IGF-I stimulates regeneration of periodontal ligament: a matter of importance in Marfan patients with periodontitis. In contrast, vascular endothelial growth factor (VEGF) appears to have rather deleterious effects on experimental tendon healing, perhaps because of its angiogenic activity and stimulation of matrix metalloproteinases-proteases whose increased expression has been documented in a variety of ruptured tendons. Other modalities, such as local administration of platelet-rich plasma (PRP) and/or of mesenchymal stem cells have been explored extensively in tendon healing. Though treatment with PRP and mesenchymal stem cells has met with some success in horses (who experience a lot of tendon injuries and other tendon problems), the use of PRP and mesenchymal stem cells in people has been more problematic and requires more studies before PRP and mesenchymal stem cells can become reliable tools in management of soft tissue injuries and disorders.
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Affiliation(s)
- Jennifer H Roberts
- Department of Pathology, College of Veterinary Medicine, The University of Georgia, Athens, GA, USA
| | - Jaroslava Halper
- Department of Pathology, College of Veterinary Medicine, and Department of Basic Sciences, AU/UGA Medical Partnership, The University of Georgia, Athens, GA, USA.
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10
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Foo JB, Looi QH, Chong PP, Hassan NH, Yeo GEC, Ng CY, Koh B, How CW, Lee SH, Law JX. Comparing the Therapeutic Potential of Stem Cells and their Secretory Products in Regenerative Medicine. Stem Cells Int 2021; 2021:2616807. [PMID: 34422061 PMCID: PMC8378970 DOI: 10.1155/2021/2616807] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 07/28/2021] [Indexed: 12/12/2022] Open
Abstract
Cell therapy involves the transplantation of human cells to replace or repair the damaged tissues and modulate the mechanisms underlying disease initiation and progression in the body. Nowadays, many different types of cell-based therapy are developed and used to treat a variety of diseases. In the past decade, cell-free therapy has emerged as a novel approach in regenerative medicine after the discovery that the transplanted cells exerted their therapeutic effect mainly through the secretion of paracrine factors. More and more evidence showed that stem cell-derived secretome, i.e., growth factors, cytokines, and extracellular vesicles, can repair the injured tissues as effectively as the cells. This finding has spurred a new idea to employ secretome in regenerative medicine. Despite that, will cell-free therapy slowly replace cell therapy in the future? Or are these two modes of treatment still needed to address different diseases and conditions? This review provides an indepth discussion about the values of stem cells and secretome in regenerative medicine. In addition, the safety, efficacy, advantages, and disadvantages of using these two modes of treatment in regenerative medicine are also critically reviewed.
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Affiliation(s)
- Jhi Biau Foo
- School of Pharmacy, Faculty of Health and Medical Sciences, Taylor's University, 47500 Subang Jaya, Selangor, Malaysia
- Centre for Drug Discovery and Molecular Pharmacology (CDDMP), Faculty of Health and Medical Sciences, Taylor's University, 47500 Subang Jaya, Selangor, Malaysia
| | - Qi Hao Looi
- My Cytohealth Sdn Bhd, Bandar Seri Petaling, 57000 Kuala Lumpur, Malaysia
| | - Pan Pan Chong
- National Orthopaedic Centre of Excellence for Research and Learning (NOCERAL), Department of Orthopaedic Surgery, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | - Nur Hidayah Hassan
- National Orthopaedic Centre of Excellence for Research and Learning (NOCERAL), Department of Orthopaedic Surgery, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
- Institute of Medical Science Technology, Universiti Kuala Lumpur, 43000 Kajang, Selangor, Malaysia
| | - Genieve Ee Chia Yeo
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, 56000 Kuala Lumpur, Malaysia
| | - Chiew Yong Ng
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, 56000 Kuala Lumpur, Malaysia
| | - Benson Koh
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, 56000 Kuala Lumpur, Malaysia
| | - Chee Wun How
- School of Pharmacy, Monash University Malaysia, 47500 Bandar Sunway, Selangor, Malaysia
| | - Sau Har Lee
- Centre for Drug Discovery and Molecular Pharmacology (CDDMP), Faculty of Health and Medical Sciences, Taylor's University, 47500 Subang Jaya, Selangor, Malaysia
- School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, 47500 Subang Jaya, Malaysia
| | - Jia Xian Law
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, 56000 Kuala Lumpur, Malaysia
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11
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Lakhani A, Sharma E, Kapila A, Khatri K. Known data on applied regenerative medicine in tendon healing. Bioinformation 2021; 17:514-527. [PMID: 34602779 PMCID: PMC8450149 DOI: 10.6026/97320630017514] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/31/2021] [Accepted: 04/29/2021] [Indexed: 12/03/2022] Open
Abstract
Tendons and ligaments are important structures in the musculoskeletal system. Ligaments connect various bones and provide stability in complex movements of joints in the knee. Tendon is made of dense connective tissue and transmits the force of contraction from muscle to bone. They are injured due to direct trauma in sports or roadside accidents. Tendon healing after repair is often poor due to the formation of fibro vascular scar tissues with low mechanical property. Regenerative techniques such as PRP (platelet-rich plasma), stem cells, scaffolds, gene therapy, cell sheets, and scaffolds help augment repair and regenerate tissue in this context. Therefore, it is of interest to document known data (repair process, tissue regeneration, mechanical strength, and clinical outcome) on applied regenerative medicine in tendon healing.
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Affiliation(s)
- Amit Lakhani
- Dr Br Ambedkar State Institute of Medical Sciences, Mohali Punjab, India
| | - Ena Sharma
- Maharishi Markandeshwar College of Dental Sciences and Hospital Mullana, Ambala, Haryana, India
| | | | - Kavin Khatri
- All India Institute of Medical Sciences, Bathinda, Punjab, India
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12
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Refolding, purification, and characterization of constitutive-active human-Smad8 produced as inclusion bodies in ClearColi® BL21 (DE3). Protein Expr Purif 2021; 184:105878. [PMID: 33812004 DOI: 10.1016/j.pep.2021.105878] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/24/2021] [Accepted: 03/27/2021] [Indexed: 11/21/2022]
Abstract
Smad8 is a transcriptional regulator that participates in the intracellular signaling pathway of the transforming growth factor-β (TGF-β) family. Full-length Smad8 is an inactive protein in the absence of ligand stimulation. The expression of a truncated version of the protein lacking the MH1 domain (cSmad8) revealed constitutive activity in genetically engineered mesenchymal stem cells and, in combination with BMP-2, exhibited a tendon cell-inducing potential. To further explore function and applicability of Smad8 in regenerative medicine recombinant production is required. Herein, we further engineered cSmad8 to include the transactivation signal (TAT) of the human immunodeficiency virus (HIV) to allow internalization into cells. TAT-hcSmad8 was produced in endotoxin-free ClearColi® BL21 (DE3), refolded from inclusion bodies (IBs) and purified by Heparin chromatography. Analysis of TAT-hcSmad8 by thermal shift assay revealed the formation of a hydrophobic core. The presence of mixed α-helixes and β-sheets, in line with theoretical models, was proven by circular dichroism. TAT-hcSmad8 was successfully internalized by C3H10T1/2 cells, where it was mainly found in the cytoplasm and partially in the nucleus. Finally, it was shown that TAT-hcSmad8 exhibited biological activity in C3H10T1/2 cells after co-stimulation with BMP-2.
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13
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Wang D, Zhang X, Huang S, Liu Y, Fu BSC, Mak KKL, Blocki AM, Yung PSH, Tuan RS, Ker DFE. Engineering multi-tissue units for regenerative Medicine: Bone-tendon-muscle units of the rotator cuff. Biomaterials 2021; 272:120789. [PMID: 33845368 DOI: 10.1016/j.biomaterials.2021.120789] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 03/25/2021] [Accepted: 03/26/2021] [Indexed: 12/13/2022]
Abstract
Our body systems are comprised of numerous multi-tissue units. For the musculoskeletal system, one of the predominant functional units is comprised of bone, tendon/ligament, and muscle tissues working in tandem to facilitate locomotion. To successfully treat musculoskeletal injuries and diseases, critical consideration and thoughtful integration of clinical, biological, and engineering aspects are necessary to achieve translational bench-to-bedside research. In particular, identifying ideal biomaterial design specifications, understanding prior and recent tissue engineering advances, and judicious application of biomaterial and fabrication technologies will be crucial for addressing current clinical challenges in engineering multi-tissue units. Using rotator cuff tears as an example, insights relevant for engineering a bone-tendon-muscle multi-tissue unit are presented. This review highlights the tissue engineering strategies for musculoskeletal repair and regeneration with implications for other bone-tendon-muscle units, their derivatives, and analogous non-musculoskeletal tissue structures.
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Affiliation(s)
- Dan Wang
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR; Ministry of Education Key Laboratory for Regenerative Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR; Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR
| | - Xu Zhang
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR
| | - Shuting Huang
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR
| | - Yang Liu
- Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR
| | - Bruma Sai-Chuen Fu
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR; Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR
| | | | - Anna Maria Blocki
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR; Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR
| | - Patrick Shu-Hang Yung
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR; Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR
| | - Rocky S Tuan
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR
| | - Dai Fei Elmer Ker
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR; Ministry of Education Key Laboratory for Regenerative Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR; Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR.
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14
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Theodossiou SK, Murray JB, Hold LA, Courtright JM, Carper AM, Schiele NR. Akt signaling is activated by TGFβ2 and impacts tenogenic induction of mesenchymal stem cells. Stem Cell Res Ther 2021; 12:88. [PMID: 33499914 PMCID: PMC7836508 DOI: 10.1186/s13287-021-02167-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 01/14/2021] [Indexed: 12/12/2022] Open
Abstract
Background Tissue engineered and regenerative approaches for treating tendon injuries are challenged by the limited information on the cellular signaling pathways driving tenogenic differentiation of stem cells. Members of the transforming growth factor (TGF) β family, particularly TGFβ2, play a role in tenogenesis, which may proceed via Smad-mediated signaling. However, recent evidence suggests some aspects of tenogenesis may be independent of Smad signaling, and other pathways potentially involved in tenogenesis are understudied. Here, we examined the role of Akt/mTORC1/P70S6K signaling in early TGFβ2-induced tenogenesis of mesenchymal stem cells (MSCs) and evaluated TGFβ2-induced tenogenic differentiation when Smad3 is inhibited. Methods Mouse MSCs were treated with TGFβ2 to induce tenogenesis, and Akt or Smad3 signaling was chemically inhibited using the Akt inhibitor, MK-2206, or the Smad3 inhibitor, SIS3. Effects of TGFβ2 alone and in combination with these inhibitors on the activation of Akt signaling and its downstream targets mTOR and P70S6K were quantified using western blot analysis, and cell morphology was assessed using confocal microscopy. Levels of the tendon marker protein, tenomodulin, were also assessed. Results TGFβ2 alone activated Akt signaling during early tenogenic induction. Chemically inhibiting Akt prevented increases in tenomodulin and attenuated tenogenic morphology of the MSCs in response to TGFβ2. Chemically inhibiting Smad3 did not prevent tenogenesis, but appeared to accelerate it. MSCs treated with both TGFβ2 and SIS3 produced significantly higher levels of tenomodulin at 7 days and morphology appeared tenogenic, with localized cell alignment and elongation. Finally, inhibiting Smad3 did not appear to impact Akt signaling, suggesting that Akt may allow TGFβ2-induced tenogenesis to proceed during disruption of Smad3 signaling. Conclusions These findings show that Akt signaling plays a role in TGFβ2-induced tenogenesis and that tenogenesis of MSCs can be initiated by TGFβ2 during disruption of Smad3 signaling. These findings provide new insights into the signaling pathways that regulate tenogenic induction in stem cells. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02167-2.
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Affiliation(s)
- Sophia K Theodossiou
- Chemical and Biological Engineering, University of Idaho, 875 Perimeter Dr. MS 0904, ID, 83844, Moscow, USA
| | - Jett B Murray
- Chemical and Biological Engineering, University of Idaho, 875 Perimeter Dr. MS 0904, ID, 83844, Moscow, USA
| | - LeeAnn A Hold
- Chemical and Biological Engineering, University of Idaho, 875 Perimeter Dr. MS 0904, ID, 83844, Moscow, USA
| | - Jeff M Courtright
- Chemical and Biological Engineering, University of Idaho, 875 Perimeter Dr. MS 0904, ID, 83844, Moscow, USA
| | - Anne M Carper
- Chemical and Biological Engineering, University of Idaho, 875 Perimeter Dr. MS 0904, ID, 83844, Moscow, USA
| | - Nathan R Schiele
- Chemical and Biological Engineering, University of Idaho, 875 Perimeter Dr. MS 0904, ID, 83844, Moscow, USA.
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15
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Hogan MV, Scott DM, Canton SP, LaBaze D, Yan AY, Wang JHC. Biologic therapies for foot and ankle injuries. Expert Opin Biol Ther 2020; 21:717-730. [PMID: 33382002 DOI: 10.1080/14712598.2021.1866534] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Introduction: The use of orthobiologics as supplemental treatment for foot and ankle pathologies have increased in the past decades. They have been used to improve the healing of bone and soft tissue injuries. There have been several studies that examined the use of biologics for knee and hip pathologies but the foot and ankle construct has unique features that must be considered.Areas covered: The biologics for foot and ankle injuries that are covered in this review are platelet-rich plasma (PRP), stem cells, growth factors, hyaluronic acid, bone grafts, bone substitutes, and scaffolds. These modalities are used in the treatment of pathologies related to tendon and soft tissue as well as cartilage.Expert opinion: The utilization of biological adjuncts for improved repair and regeneration of ankle injuries represents a promising future in our efforts to address difficult clinical problems. The application of concentrated bone marrow and PRP each represents the most widely studied and commonly used injection therapies with early clinical studies demonstrating promising results, research is also being done using other potential therapies such as stem cells and growth factors; further investigation and outcome data are still needed.
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Affiliation(s)
- MaCalus V Hogan
- Departments of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.,Foot and Ankle Injury Research Center, University of Pittsburgh, Pittsburgh, PA, USA.,Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Devon M Scott
- Departments of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Stephen P Canton
- Departments of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Dukens LaBaze
- Departments of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Alan Y Yan
- Departments of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.,Foot and Ankle Injury Research Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - James H-C Wang
- Departments of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.,Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.,Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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16
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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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17
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Citeroni MR, Ciardulli MC, Russo V, Della Porta G, Mauro A, El Khatib M, Di Mattia M, Galesso D, Barbera C, Forsyth NR, Maffulli N, Barboni B. In Vitro Innovation of Tendon Tissue Engineering Strategies. Int J Mol Sci 2020; 21:E6726. [PMID: 32937830 PMCID: PMC7555358 DOI: 10.3390/ijms21186726] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 09/06/2020] [Accepted: 09/07/2020] [Indexed: 12/12/2022] Open
Abstract
Tendinopathy is the term used to refer to tendon disorders. Spontaneous adult tendon healing results in scar tissue formation and fibrosis with suboptimal biomechanical properties, often resulting in poor and painful mobility. The biomechanical properties of the tissue are negatively affected. Adult tendons have a limited natural healing capacity, and often respond poorly to current treatments that frequently are focused on exercise, drug delivery, and surgical procedures. Therefore, it is of great importance to identify key molecular and cellular processes involved in the progression of tendinopathies to develop effective therapeutic strategies and drive the tissue toward regeneration. To treat tendon diseases and support tendon regeneration, cell-based therapy as well as tissue engineering approaches are considered options, though none can yet be considered conclusive in their reproduction of a safe and successful long-term solution for full microarchitecture and biomechanical tissue recovery. In vitro differentiation techniques are not yet fully validated. This review aims to compare different available tendon in vitro differentiation strategies to clarify the state of art regarding the differentiation process.
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Affiliation(s)
- Maria Rita Citeroni
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (V.R.); (A.M.); (M.E.K.); (M.D.M.); (B.B.)
| | - Maria Camilla Ciardulli
- Department of Medicine, Surgery and Dentistry, University of Salerno, Via S. Allende, 84081 Baronissi (SA), Italy; (M.C.C.); (G.D.P.); (N.M.)
| | - Valentina Russo
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (V.R.); (A.M.); (M.E.K.); (M.D.M.); (B.B.)
| | - Giovanna Della Porta
- Department of Medicine, Surgery and Dentistry, University of Salerno, Via S. Allende, 84081 Baronissi (SA), Italy; (M.C.C.); (G.D.P.); (N.M.)
- Interdepartment Centre BIONAM, Università di Salerno, via Giovanni Paolo I, 84084 Fisciano (SA), Italy
| | - Annunziata Mauro
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (V.R.); (A.M.); (M.E.K.); (M.D.M.); (B.B.)
| | - Mohammad El Khatib
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (V.R.); (A.M.); (M.E.K.); (M.D.M.); (B.B.)
| | - Miriam Di Mattia
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (V.R.); (A.M.); (M.E.K.); (M.D.M.); (B.B.)
| | - Devis Galesso
- Fidia Farmaceutici S.p.A., via Ponte della Fabbrica 3/A, 35031 Abano Terme (PD), Italy; (D.G.); (C.B.)
| | - Carlo Barbera
- Fidia Farmaceutici S.p.A., via Ponte della Fabbrica 3/A, 35031 Abano Terme (PD), Italy; (D.G.); (C.B.)
| | - Nicholas R. Forsyth
- Guy Hilton Research Centre, School of Pharmacy and Bioengineering, Keele University, Thornburrow Drive, Stoke on Trent ST4 7QB, UK;
| | - Nicola Maffulli
- Department of Medicine, Surgery and Dentistry, University of Salerno, Via S. Allende, 84081 Baronissi (SA), Italy; (M.C.C.); (G.D.P.); (N.M.)
- Department of Musculoskeletal Disorders, Faculty of Medicine and Surgery, University of Salerno, Via San Leonardo 1, 84131 Salerno, Italy
- Centre for Sports and Exercise Medicine, Barts and The London School of Medicine and Dentistry, Mile End Hospital, Queen Mary University of London, 275 Bancroft Road, London E1 4DG, UK
- School of Pharmacy and Bioengineering, Keele University School of Medicine, Thornburrow Drive, Stoke on Trent ST5 5BG, UK
| | - Barbara Barboni
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (V.R.); (A.M.); (M.E.K.); (M.D.M.); (B.B.)
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18
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Chen S, Wang J, Chen Y, Mo X, Fan C. Tenogenic adipose-derived stem cell sheets with nanoyarn scaffolds for tendon regeneration. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2020; 119:111506. [PMID: 33321604 DOI: 10.1016/j.msec.2020.111506] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 07/17/2020] [Accepted: 09/09/2020] [Indexed: 12/20/2022]
Abstract
Tissue engineering, especially cell sheets-based engineering, offers a promising approach to tendon regeneration; however, obtaining a sufficient source of cells for tissue engineering applications is challenging. Adipose-derived stem cells (ASCs) are essential sources for tissue regeneration and have been shown to have the potential for tenogenic differentiation in vitro via induction by growth differentiation factor 5 (GDF-5). In this study, we explored the feasibility of ASCs cell sheets stimulated by GDF-5 for engineered tendon repair. As shown by quantitative polymerase chain reaction and western blotting, tenogenesis-related markers (Col I&III, TNMD, biglycan, and tenascin C) were significantly increased in GDF-5-induced ASCs cell sheets compared with the uninduced. Moreover, the levels of SMAD2/3 proteins and phospho-SMAD1/5/9 were significantly enhanced, demonstrating that GDF-5 may exert its functions through phosphorylation of SMAD1/5/9. Furthermore, the cell sheets were combined with P(LLA-CL)/Silk fibroin nanoyarn scaffolds to form constructs for tendon tissue engineering. Terminal deoxynucleotidyl transferase dUTP nick end labeling and immunofluorescence assays demonstrated favorable cell viability and tenogenesis-related marker expression in GDF-5-induced constructs. In addition, the constructs showed the potential for tendon repair in rabbit models, as demonstrated by histological, immunohistochemical, and biomechanical analyses. In our study, we successfully produced a new tissue-engineered tendon by the combination of GDF-5-induced ASCs cell sheets and nanoyarn scaffold which is valuable for tendon regeneration.
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Affiliation(s)
- Shuai Chen
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, PR China
| | - Juan Wang
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, PR China; Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, PR China
| | - Yini Chen
- Department of Ultrasound in Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, PR China
| | - Xiumei Mo
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, PR China.
| | - Cunyi Fan
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, PR China.
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19
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Migliorini F, Tingart M, Maffulli N. Progress with stem cell therapies for tendon tissue regeneration. Expert Opin Biol Ther 2020; 20:1373-1379. [DOI: 10.1080/14712598.2020.1786532] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Filippo Migliorini
- Department of Orthopaedics, University Clinic Aachen, RWTH Aachen University Clinic, Aachen, Germany
| | - Markus Tingart
- Department of Orthopaedics, University Clinic Aachen, RWTH Aachen University Clinic, Aachen, Germany
| | - Nicola Maffulli
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy
- School of Pharmacy and Bioengineering, Keele University School of Medicine, Stoke on Trent, UK
- Queen Mary University of London, Barts and the London School of Medicine and Dentistry, Centre for Sports and Exercise Medicine, Mile End Hospital, London, UK
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20
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Muraoka K, Le W, Behn AW, Yao J. The Effect of Growth Differentiation Factor 8 (Myostatin) on Bone Marrow-Derived Stem Cell-Coated Bioactive Sutures in a Rabbit Tendon Repair Model. Hand (N Y) 2020; 15:264-270. [PMID: 30079783 PMCID: PMC7076613 DOI: 10.1177/1558944718792708] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Background: We have reported that bioactive sutures coated with bone marrow-derived mesenchymal stem cells (BMSCs) enhance tendon repair strength in an in vivo rat model. We have additionally shown that growth differentiation factor 8 (GDF-8, also known as myostatin) simulates tenogenesis in BMSCs in vitro. The purpose of this study was to determine the possibility of BMSC-coated bioactive sutures treated with GDF-8 to increase tendon repair strength in an in vivo rabbit tendon repair model. Methods: Rabbit BMSCs were grown and seeded on to 4-0 Ethibond sutures and treated with GDF-8. New Zealand white rabbits' bilateral Achilles tendons were transected and randomized to experimental (BMSC-coated bioactive sutures treated with GDF-8) or plain suture repaired control groups. Tendons were harvested at 4 and 7 days after the surgery and subjected to tensile mechanical testing and quantitative polymerase chain reaction. Results: There were distinguishing differences of collagen and matrix metalloproteinase RNA level between the control and experimental groups in the early repair periods (day 4 and day 7). However, there were no significant differences between the experimental and control groups in force to 1-mm or 2-mm gap formation or stiffness at 4 or 7 days following surgery. Conclusions: BMSC-coated bioactive sutures with GDF-8 do not appear to affect in vivo rabbit tendon healing within the first week following repair despite an increased presence of quantifiable RNA level of collagen. GDF-8's treatment efficacy of the early tendon repair remains to be defined.
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Affiliation(s)
- Kunihide Muraoka
- Robert A. Chase Hand & Upper Limb Center, Department of Orthopaedic Surgery, Stanford University School of Medicine, Redwood City, CA, USA,Fukuoka University Faculty of Medicine, Japan
| | - Wei Le
- Robert A. Chase Hand & Upper Limb Center, Department of Orthopaedic Surgery, Stanford University School of Medicine, Redwood City, CA, USA
| | - Anthony W. Behn
- Robert A. Chase Hand & Upper Limb Center, Department of Orthopaedic Surgery, Stanford University School of Medicine, Redwood City, CA, USA
| | - Jeffrey Yao
- Robert A. Chase Hand & Upper Limb Center, Department of Orthopaedic Surgery, Stanford University School of Medicine, Redwood City, CA, USA,Jeffrey Yao, Robert A. Chase Hand & Upper Limb Center, Department of Orthopaedic Surgery, Stanford University Medical Center, 450 Broadway Street C-442, Redwood City, CA 94063, USA.
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21
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Russo V, El Khatib M, di Marcantonio L, Ancora M, Wyrwa R, Mauro A, Walter T, Weisser J, Citeroni MR, Lazzaro F, Di Federico M, Berardinelli P, Cammà C, Schnabelrauch M, Barboni B. Tendon Biomimetic Electrospun PLGA Fleeces Induce an Early Epithelial-Mesenchymal Transition and Tenogenic Differentiation on Amniotic Epithelial Stem Cells. Cells 2020; 9:E303. [PMID: 32012741 PMCID: PMC7072418 DOI: 10.3390/cells9020303] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 01/24/2020] [Accepted: 01/25/2020] [Indexed: 01/08/2023] Open
Abstract
Background. The design of tendon biomimetic electrospun fleece with Amniotic Epithelial Stem Cells (AECs) that have shown a high tenogenic attitude may represent an alternative strategy to overcome the unsatisfactory results of conventional treatments in tendon regeneration. Methods. In this study, we evaluated AEC-engineered electrospun poly(lactide-co-glycolide) (PLGA) fleeces with highly aligned fibers (ha-PLGA) that mimic tendon extracellular matrix, their biocompatibility, and differentiation towards the tenogenic lineage. PLGA fleeces with randomly distributed fibers (rd-PLGA) were generated as control. Results. Optimal cell infiltration and biocompatibility with both PLGA fleeces were shown. However, only ha-PLGA fleeces committed AECs towards an Epithelial-Mesenchymal Transition (EMT) after 48 h culture, inducing their cellular elongation along the fibers' axis and the upregulation of mesenchymal markers. AECs further differentiated towards tenogenic lineage as confirmed by the up-regulation of tendon-related genes and Collagen Type 1 (COL1) protein expression that, after 28 days culture, appeared extracellularly distributed along the direction of ha-PLGA fibers. Moreover, long-term co-cultures of AEC-ha-PLGA bio-hybrids with fetal tendon explants significantly accelerated of half time AEC tenogenic differentiation compared to ha-PLGA fleeces cultured only with AECs. Conclusions. The fabricated tendon biomimetic ha-PLGA fleeces induce AEC tenogenesis through an early EMT, providing a potential tendon substitute for tendon engineering research.
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Affiliation(s)
- Valentina Russo
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (V.R.); (A.M.); (M.R.C.); (M.D.F.); (P.B.); (B.B.)
| | - Mohammad El Khatib
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (V.R.); (A.M.); (M.R.C.); (M.D.F.); (P.B.); (B.B.)
| | - Lisa di Marcantonio
- Laboratory of Bacteriology, Istituto Zooprofilattico Sperimentale dell’Abruzzo e del Molise “Giuseppe Caporale”, 64100 Teramo, Italy;
| | - Massimo Ancora
- Laboratory of Molecular Biology and Genomic, Istituto Zooprofilattico Sperimentale dell’Abruzzo e del Molise “Giuseppe Caporale, 64100 Teramo, Italy; (M.A.); (C.C.)
| | - Ralf Wyrwa
- Department of Biomaterials, INNOVENT e. V, J-07749 Jena, Germany; (R.W.); (T.W.); (J.W.); (M.S.)
| | - Annunziata Mauro
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (V.R.); (A.M.); (M.R.C.); (M.D.F.); (P.B.); (B.B.)
| | - Torsten Walter
- Department of Biomaterials, INNOVENT e. V, J-07749 Jena, Germany; (R.W.); (T.W.); (J.W.); (M.S.)
| | - Jürgen Weisser
- Department of Biomaterials, INNOVENT e. V, J-07749 Jena, Germany; (R.W.); (T.W.); (J.W.); (M.S.)
| | - Maria Rita Citeroni
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (V.R.); (A.M.); (M.R.C.); (M.D.F.); (P.B.); (B.B.)
| | - Francesco Lazzaro
- Research & Development Department, Assut Europe S.p.A., Magliano dei Marsi, 67062 L’Aquila, Italy;
| | - Marta Di Federico
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (V.R.); (A.M.); (M.R.C.); (M.D.F.); (P.B.); (B.B.)
- Laboratory of Molecular Biology and Genomic, Istituto Zooprofilattico Sperimentale dell’Abruzzo e del Molise “Giuseppe Caporale, 64100 Teramo, Italy; (M.A.); (C.C.)
| | - Paolo Berardinelli
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (V.R.); (A.M.); (M.R.C.); (M.D.F.); (P.B.); (B.B.)
| | - Cesare Cammà
- Laboratory of Molecular Biology and Genomic, Istituto Zooprofilattico Sperimentale dell’Abruzzo e del Molise “Giuseppe Caporale, 64100 Teramo, Italy; (M.A.); (C.C.)
| | - Matthias Schnabelrauch
- Department of Biomaterials, INNOVENT e. V, J-07749 Jena, Germany; (R.W.); (T.W.); (J.W.); (M.S.)
| | - Barbara Barboni
- Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy; (V.R.); (A.M.); (M.R.C.); (M.D.F.); (P.B.); (B.B.)
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22
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Transforming Growth Factor Beta 3-Loaded Decellularized Equine Tendon Matrix for Orthopedic Tissue Engineering. Int J Mol Sci 2019; 20:ijms20215474. [PMID: 31684150 PMCID: PMC6862173 DOI: 10.3390/ijms20215474] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 10/25/2019] [Accepted: 11/01/2019] [Indexed: 12/19/2022] Open
Abstract
Transforming growth factor beta 3 (TGFβ3) promotes tenogenic differentiation and may enhance tendon regeneration in vivo. This study aimed to apply TGFβ3 absorbed in decellularized equine superficial digital flexor tendon scaffolds, and to investigate the bioactivity of scaffold-associated TGFβ3 in an in vitro model. TGFβ3 could effectively be loaded onto tendon scaffolds so that at least 88% of the applied TGFβ3 were not detected in the rinsing fluid of the TGFβ3-loaded scaffolds. Equine adipose tissue-derived multipotent mesenchymal stromal cells (MSC) were then seeded on scaffolds loaded with 300 ng TGFβ3 to assess its bioactivity. Both scaffold-associated TGFβ3 and TGFβ3 dissolved in the cell culture medium, the latter serving as control group, promoted elongation of cell shapes and scaffold contraction (p < 0.05). Furthermore, scaffold-associated and dissolved TGFβ3 affected MSC musculoskeletal gene expression in a similar manner, with an upregulation of tenascin c and downregulation of other matrix molecules, most markedly decorin (p < 0.05). These results demonstrate that the bioactivity of scaffold-associated TGFβ3 is preserved, thus TGFβ3 application via absorption in decellularized tendon scaffolds is a feasible approach.
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23
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Kremen TJ, Bez M, Sheyn D, Ben-David S, Da X, Tawackoli W, Wagner S, Gazit D, Pelled G. In Vivo Imaging of Exogenous Progenitor Cells in Tendon Regeneration via Superparamagnetic Iron Oxide Particles. Am J Sports Med 2019; 47:2737-2744. [PMID: 31336056 DOI: 10.1177/0363546519861080] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Although tendon injuries and repairs are common, treatment of these injuries has limitations. The application of mesenchymal progenitor cells (MPCs) is increasingly used to optimize the biological process of tendon repair healing. However, clinically relevant technologies that effectively assess the localization of exogenous MPCs in vivo are lacking. HYPOTHESIS Exogenous MPCs labeled with superparamagnetic iron oxide (SPIO) particles would allow monitoring of the localization and retention of cells within the site of implantation via magnetic resonance imaging (MRI) without negatively affecting cell survival or differentiation. STUDY DESIGN Descriptive laboratory study. METHODS Genetically modified C3H10T1/2 MPCs engineered to express luciferase (Luc+) reporter gene were implanted into surgically created Achilles tendon defects of 10 athymic nude rats (Hsd:RH-Foxn1rnu). Of these animals, 5 animals received Luc+ C3H10T1/2 MPCs colabeled with SPIO nanoparticles (+SPIO). These 2 groups of animals then underwent optical imaging with quantification of bioluminescence and MRI at 7, 14, and 28 days after surgery. Statistical analysis was conducted by use of 2-way analysis of variance. At 28 days after surgery, animals were euthanized and the treated limbs underwent histologic analysis. RESULTS Optical imaging demonstrated that the implanted cells not only survived but also proliferated in vivo, and these cells remained viable for at least 4 weeks after implantation. In addition, SPIO labeling did not appear to affect MPC survival or proliferation, as assessed by quantitative bioluminescence imaging (P > .05, n = 5). MRI demonstrated that SPIO labeling was an effective method to monitor cell localization, retention, and viability for at least 4 weeks after implantation. Histologic and immunofluorescence analyses of the repaired tendon defect sites demonstrated tenocyte-like labeled cells, suggesting that cell differentiation was not affected by labeling the cells with the SPIO nanoparticles. CONCLUSION MRI of exogenous MPCs labeled with SPIO particles allows for effective in vivo assessments of cell localization and retention in the setting of tendon regeneration for at least 4 weeks after implantation. This SPIO labeling does not appear to impair cell survival, transgene expression, or differentiation. CLINICAL RELEVANCE SPIO labeling of MPCs appears to be safe for in vivo assessments of MPCs in tendon regeneration therapies and may be used for future clinical investigations of musculoskeletal regenerative medicine.
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Affiliation(s)
- Thomas J Kremen
- Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Maxim Bez
- Skeletal Biotech Laboratory, Faculty of Dental Medicine, The Hebrew University of Jerusalem, Ein Kerem, Jerusalem, Israel.,Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Dmitriy Sheyn
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.,Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.,Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.,Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Shiran Ben-David
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.,Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Xiaoyu Da
- Biomedical Imaging Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Wafa Tawackoli
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.,Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.,Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Shawn Wagner
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.,Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Dan Gazit
- Skeletal Biotech Laboratory, Faculty of Dental Medicine, The Hebrew University of Jerusalem, Ein Kerem, Jerusalem, Israel.,Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.,Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.,Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.,Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, California, USA.,Biomedical Imaging Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Gadi Pelled
- Skeletal Biotech Laboratory, Faculty of Dental Medicine, The Hebrew University of Jerusalem, Ein Kerem, Jerusalem, Israel.,Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.,Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.,Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.,Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, California, USA
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24
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Zhang YJ, Qing Q, Zhang YJ, Ning LJ, Cui J, Yao X, Luo JC, Ding W, Qin TW. Enhancement of tenogenic differentiation of rat tendon-derived stem cells by biglycan. J Cell Physiol 2019; 234:15898-15910. [PMID: 30714152 DOI: 10.1002/jcp.28247] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 01/12/2019] [Accepted: 01/15/2019] [Indexed: 02/05/2023]
Abstract
Biglycan (BGN) has been identified as one of the critical components of the tendon-derived stem cells (TDSCs) niche and may be related to tendon formation. However, so far, no study has demonstrated whether the soluble BGN could induce the tenogenic differentiation of TDSCs in vitro. The aim of this study was to investigate the effect of BGN on the tenogenic differentiation of TDSCs. The proliferation and tenogenic differentiation of TDSCs exposed to different concentrations of BGN (0, 50, 100, and 500 ng/ml) were determined by the live/dead cell staining assay, CCK-8 assay, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot analysis. The BGN signaling pathway of TDSCs (with and without 50 ng/ml of BGN) was determined by western blot analysis and qRT-PCR analysis. At a concentration of 50 ng/ml, BGN increased the expression of the tenogenic markers THBS-4 and TNMD at both the messenger RNA (mRNA) and protein levels. Meanwhile, 50 ng/ml of BGN inhibited the expression of the chondrogenic and osteogenic markers SOX9, ACN, and RUNX2 at both the mRNA and protein levels. Moreover, BGN (50 ng/ml) affected the expression of the components of the extracellular matrix of TDSCs. Additionally, BGN activated the Smad1/5/8 pathway as indicated by an increase in phosphorylation and demonstrated by inhibition experiments. Upregulation in the gene expression of BMP-associated receptors (BMPRII, ActR-IIa, and BMPR-Ib) and Smad pathway components (Smad4 and 8) was observed. Taken together, BGN regulates tenogenic differentiation of TDSCs via BMP7/Smad1/5/8 pathway and this regulation may provide a basic insight into treating tendon injury.
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Affiliation(s)
- Yan-Jing Zhang
- Laboratory of Stem Cell and Tissue Engineering, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Quan Qing
- Division of Tissue Engineering, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, People's Republic of China.,Faculty of Basic Medicine, Sichuan College of Traditional Chinese Medicine, Mianyang, People's Republic of China
| | - Ya-Jing Zhang
- Laboratory of Stem Cell and Tissue Engineering, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Liang-Ju Ning
- Laboratory of Stem Cell and Tissue Engineering, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Jing Cui
- Laboratory of Stem Cell and Tissue Engineering, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Xuan Yao
- Laboratory of Stem Cell and Tissue Engineering, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Jing-Cong Luo
- Laboratory of Stem Cell and Tissue Engineering, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Wei Ding
- Laboratory of Stem Cell and Tissue Engineering, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Ting-Wu Qin
- Laboratory of Stem Cell and Tissue Engineering, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China
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25
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Intraarticular Ligament Degeneration Is Interrelated with Cartilage and Bone Destruction in Osteoarthritis. Cells 2019; 8:cells8090990. [PMID: 31462003 PMCID: PMC6769780 DOI: 10.3390/cells8090990] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 08/18/2019] [Accepted: 08/20/2019] [Indexed: 12/16/2022] Open
Abstract
Osteoarthritis (OA) induces inflammation and degeneration of all joint components including cartilage, joint capsule, bone and bone marrow, and ligaments. Particularly intraarticular ligaments, which connect the articulating bones such as the anterior cruciate ligament (ACL) and meniscotibial ligaments, fixing the fibrocartilaginous menisci to the tibial bone, are prone to the inflamed joint milieu in OA. However, the pathogenesis of ligament degeneration on the cellular level, most likely triggered by OA associated inflammation, remains poorly understood. Hence, this review sheds light into the intimate interrelation between ligament degeneration, synovitis, joint cartilage degradation, and dysbalanced subchondral bone remodeling. Various features of ligament degeneration accompanying joint cartilage degradation have been reported including chondroid metaplasia, cyst formation, heterotopic ossification, and mucoid and fatty degenerations. The entheses of ligaments, fixing ligaments to the subchondral bone, possibly influence the localization of subchondral bone lesions. The transforming growth factor (TGF)β/bone morphogenetic (BMP) pathway could present a link between degeneration of the osteochondral unit and ligaments with misrouted stem cell differentiation as one likely reason for ligament degeneration, but less studied pathways such as complement activation could also contribute to inflammation. Facilitation of OA progression by changed biomechanics of degenerated ligaments should be addressed in more detail in the future.
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26
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Barboni B, Russo V, Berardinelli P, Mauro A, Valbonetti L, Sanyal H, Canciello A, Greco L, Muttini A, Gatta V, Stuppia L, Mattioli M. Placental Stem Cells from Domestic Animals: Translational Potential and Clinical Relevance. Cell Transplant 2019; 27:93-116. [PMID: 29562773 PMCID: PMC6434480 DOI: 10.1177/0963689717724797] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The field of regenerative medicine is moving toward clinical practice in veterinary science. In this context, placenta-derived stem cells isolated from domestic animals have covered a dual role, acting both as therapies for patients and as a valuable cell source for translational models. The biological properties of placenta-derived cells, comparable among mammals, make them attractive candidates for therapeutic approaches. In particular, stemness features, low immunogenicity, immunomodulatory activity, multilineage plasticity, and their successful capacity for long-term engraftment in different host tissues after autotransplantation, allo-transplantation, or xenotransplantation have been demonstrated. Their beneficial regenerative effects in domestic animals have been proven using preclinical studies as well as clinical trials starting to define the mechanisms involved. This is, in particular, for amniotic-derived cells that have been thoroughly studied to date. The regenerative role arises from a mutual tissue-specific cell differentiation and from the paracrine secretion of bioactive molecules that ultimately drive crucial repair processes in host tissues (e.g., anti-inflammatory, antifibrotic, angiogenic, and neurogenic factors). The knowledge acquired so far on the mechanisms of placenta-derived stem cells in animal models represent the proof of concept of their successful use in some therapeutic treatments such as for musculoskeletal disorders. In the next future, legislation in veterinary regenerative medicine will be a key element in order to certify those placenta-derived cell-based protocols that have already demonstrated their safety and efficacy using rigorous approaches and to improve the degree of standardization of cell-based treatments among veterinary clinicians.
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Affiliation(s)
- B Barboni
- 1 Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy
| | - V Russo
- 1 Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy
| | - P Berardinelli
- 1 Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy
| | - A Mauro
- 1 Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy
| | - L Valbonetti
- 1 Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy
| | - H Sanyal
- 1 Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy
| | - A Canciello
- 1 Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy
| | - L Greco
- 1 Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy
| | - A Muttini
- 1 Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy
| | - V Gatta
- 1 Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy
| | - L Stuppia
- 2 Medical Genetics, University "G. d'Annunzio" of Chieti Pescara, Chieti, Italy
| | - M Mattioli
- 3 Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise "G. Caporale," Teramo, Italy
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27
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Liu F, Meng Q, Yin H, Yan Z. Stem Cells in Rotator Cuff Injuries and Reconstructions: A Systematic Review and Meta-Analysis. Curr Stem Cell Res Ther 2019; 14:683-697. [PMID: 31244430 DOI: 10.2174/1574888x14666190617143952] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 04/18/2019] [Accepted: 04/19/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Multiple studies have focused on stem cell-based treatments for rotator cuff disorders; however, the outcomes are not consistent. OBJECTIVES This systematic review and meta-analysis were performed to evaluate the effects of stem cells on rotator cuff healing. METHODS A detailed search of relevant studies was conducted in three databases including Pubmed/ Medline, Cochrane library, and Embase databases, using the following keywords: "rotator cuff" or "Tissue Engineering" AND "stem cell" from inception to January 01, 2019. The standard mean difference (SMD) and 95% confidence interval (CI) for each individual study were extracted from the original studies or calculated based on relevant data and pooled to obtain integrated estimates using random effects modeling. RESULTS A total of 22 studies were identified. The results demonstrated that the ultimate strain in the stem cell group was significantly higher than that in the control group at 4 and 8 weeks. Muscle weight in the stem cell group was higher than the control group at 8 weeks, while no significant differences were detected at 16 weeks. The stem cell group had lower visual analog scale scores (VAS) at 1, 3, and 6 months, and higher American shoulder and elbow surgeons score (ASES) at 3 months. In addition, the walking distance, time, and speed in the stem cell group were significantly superior to those in the control group. CONCLUSIONS This meta-analysis confirms that stem cells improved the rehabilitation of rotator cuff disorders. However, larger-scale studies are needed to further support these findings.
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Affiliation(s)
- Fanxiao Liu
- Department of Orthopaedics, Shandong Provincial Hospital Affiliated to Shandong University, No.324, Road Jing Wu Wei Qi, Jinan 250021, Shandong, China
| | - Qingqi Meng
- Department of Orthopaedics, Guangzhou Red Cross Hospital, Jinan University, Tongfu road 396, Haizhu district, Guangzhou, China
| | - Heyong Yin
- Department of Trauma Surgery, University of Regensburg, Am biopark 9, 93049 Regensburg, Germany
| | - Zexing Yan
- Department of Trauma Surgery, University of Regensburg, Am biopark 9, 93049 Regensburg, Germany
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28
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Ker DFE, Wang D, Behn AW, Wang ETH, Zhang X, Zhou BY, Mercado-Pagán ÁE, Kim S, Kleimeyer J, Gharaibeh B, Shanjani Y, Nelson D, Safran M, Cheung E, Campbell P, Yang YP. Functionally Graded, Bone- and Tendon-Like Polyurethane for Rotator Cuff Repair. ADVANCED FUNCTIONAL MATERIALS 2018; 28:1707107. [PMID: 29785178 PMCID: PMC5959293 DOI: 10.1002/adfm.201707107] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Indexed: 05/25/2023]
Abstract
Critical considerations in engineering biomaterials for rotator cuff repair include bone-tendon-like mechanical properties to support physiological loading and biophysicochemical attributes that stabilize the repair site over the long-term. In this study, UV-crosslinkable polyurethane based on quadrol (Q), hexamethylene diisocyante (H), and methacrylic anhydride (M; QHM polymers), which are free of solvent, catalyst, and photoinitiator, is developed. Mechanical characterization studies demonstrate that QHM polymers possesses phototunable bone- and tendon-like tensile and compressive properties (12-74 MPa tensile strength, 0.6-2.7 GPa tensile modulus, 58-121 MPa compressive strength, and 1.5-3.0 GPa compressive modulus), including the capability to withstand 10 000 cycles of physiological tensile loading and reduce stress concentrations via stiffness gradients. Biophysicochemical studies demonstrate that QHM polymers have clinically favorable attributes vital to rotator cuff repair stability, including slow degradation profiles (5-30% mass loss after 8 weeks) with little-to-no cytotoxicity in vitro, exceptional suture retention ex vivo (2.79-3.56-fold less suture migration relative to a clinically available graft), and competent tensile properties (similar ultimate load but higher normalized tensile stiffness relative to a clinically available graft) as well as good biocompatibility for augmenting rat supraspinatus tendon repair in vivo. This work demonstrates functionally graded, bone-tendon-like biomaterials for interfacial tissue engineering.
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Affiliation(s)
- Dai Fei Elmer Ker
- Department of Orthopaedic Surgery Stanford University 300 Pasteur Drive, Stanford, CA 94305, USA
| | - Dan Wang
- Department of Orthopaedic Surgery Stanford University 300 Pasteur Drive, Stanford, CA 94305, USA
| | - Anthony William Behn
- Department of Orthopaedic Surgery Stanford University 300 Pasteur Drive, Stanford, CA 94305, USA
| | - Evelyna Tsi Hsin Wang
- Department of Material Science and Engineering Stanford University 496 Lomita Mall, Stanford, CA 94305, USA
| | - Xu Zhang
- Institute for Tissue Engineering and Regenerative Medicine The Chinese University of Hong Kong New Territories, Hong Kong SAR
| | - Benjamin Yamin Zhou
- Department of Mathematics Stanford University Building 380, Sloan Mathematical Center, Stanford, CA 94305, USA
| | | | - Sungwoo Kim
- Department of Orthopaedic Surgery Stanford University 300 Pasteur Drive, Stanford, CA 94305, USA
| | - John Kleimeyer
- Department of Orthopaedic Surgery Stanford University 300 Pasteur Drive, Stanford, CA 94305, USA
| | - Burhan Gharaibeh
- Department of Biological Sciences University of Pittsburgh 4249 Fifth Avenue, Pittsburgh, PA 15260, USA
| | - Yaser Shanjani
- Department of Orthopaedic Surgery Stanford University 300 Pasteur Drive, Stanford, CA 94305, USA
| | - Drew Nelson
- Department of Mechanical Engineering Stanford University 440 Escondido Mall, Stanford, CA 94305, USA
| | - Marc Safran
- Department of Orthopaedic Surgery Stanford University 300 Pasteur Drive, Stanford, CA 94305, USA
| | - Emilie Cheung
- Department of Orthopaedic Surgery Stanford University 300 Pasteur Drive, Stanford, CA 94305, USA
| | - Phil Campbell
- Engineering Research Accelerator Carnegie Mellon University 5000 Forbes Avenue, Pittsburgh, PA 15213, USA
| | - Yunzhi Peter Yang
- Department of Orthopaedic Surgery Stanford University 300 Pasteur Drive, Stanford, CA 94305, USA
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Grafe I, Alexander S, Peterson JR, Snider TN, Levi B, Lee B, Mishina Y. TGF-β Family Signaling in Mesenchymal Differentiation. Cold Spring Harb Perspect Biol 2018; 10:a022202. [PMID: 28507020 PMCID: PMC5932590 DOI: 10.1101/cshperspect.a022202] [Citation(s) in RCA: 174] [Impact Index Per Article: 24.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Mesenchymal stem cells (MSCs) can differentiate into several lineages during development and also contribute to tissue homeostasis and regeneration, although the requirements for both may be distinct. MSC lineage commitment and progression in differentiation are regulated by members of the transforming growth factor-β (TGF-β) family. This review focuses on the roles of TGF-β family signaling in mesenchymal lineage commitment and differentiation into osteoblasts, chondrocytes, myoblasts, adipocytes, and tenocytes. We summarize the reported findings of cell culture studies, animal models, and interactions with other signaling pathways and highlight how aberrations in TGF-β family signaling can drive human disease by affecting mesenchymal differentiation.
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Affiliation(s)
- Ingo Grafe
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030
| | - Stefanie Alexander
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030
| | - Jonathan R Peterson
- Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan 48109
| | - Taylor Nicholas Snider
- Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48109
| | - Benjamin Levi
- Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan 48109
| | - Brendan Lee
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030
| | - Yuji Mishina
- Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48109
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30
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Schneider M, Angele P, Järvinen TA, Docheva D. Rescue plan for Achilles: Therapeutics steering the fate and functions of stem cells in tendon wound healing. Adv Drug Deliv Rev 2018; 129:352-375. [PMID: 29278683 DOI: 10.1016/j.addr.2017.12.016] [Citation(s) in RCA: 100] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2017] [Revised: 12/01/2017] [Accepted: 12/22/2017] [Indexed: 02/07/2023]
Abstract
Due to the increasing age of our society and a rise in engagement of young people in extreme and/or competitive sports, both tendinopathies and tendon ruptures present a clinical and financial challenge. Tendon has limited natural healing capacity and often responds poorly to treatments, hence it requires prolonged rehabilitation in most cases. Till today, none of the therapeutic options has provided successful long-term solutions, meaning that repaired tendons do not recover their complete strength and functionality. Our understanding of tendon biology and healing increases only slowly and the development of new treatment options is insufficient. In this review, following discussion on tendon structure, healing and the clinical relevance of tendon injury, we aim to elucidate the role of stem cells in tendon healing and discuss new possibilities to enhance stem cell treatment of injured tendon. To date, studies mainly apply stem cells, often in combination with scaffolds or growth factors, to surgically created tendon defects. Deeper understanding of how stem cells and vasculature in the healing tendon react to growth factors, common drugs used to treat injured tendons and promising cellular boosters could help to develop new and more efficient ways to manage tendon injuries.
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31
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Zhang C, Zhang E, Yang L, Tu W, Lin J, Yuan C, Bunpetch V, Chen X, Ouyang H. Histone deacetylase inhibitor treated cell sheet from mouse tendon stem/progenitor cells promotes tendon repair. Biomaterials 2018; 172:66-82. [PMID: 29723756 DOI: 10.1016/j.biomaterials.2018.03.043] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2017] [Revised: 03/17/2018] [Accepted: 03/25/2018] [Indexed: 12/13/2022]
Abstract
Tendon stem/progenitor cells (TSPCs) have been identified as a rare population in tendons. In vitro propagation is indispensable to obtain sufficient quantities of TSPCs for therapies. However, culture-expanded TSPCs are prone to lose their phenotype, resulting in an inferior repaired capability. And little is known about the underlying mechanism. Here, we found that altered gene expression was associated with increased histone deacetylase (HDAC) activity and expression of HDAC subtypes. Therefore, we exposed ScxGFP mice-derived TSPCs to HDAC inhibitor (HDACi) trichostatin A (TSA) or valproic acid (VPA), and observed significant expansion of ScxGFP+ cells without altering phenotypic properties. TSA upregulated Scx expression by inhibiting HDAC1 and -3, and increasing the H3K27Ac level of Tgfb1 and -2 genome region. Additionally, cell sheets formed from TSA-pretreated mTSPCs retained the ability to accelerate tendon repair in vivo. Thus, our results uncovered an unrecognized role of HDACi in phenotypic and functional mTSPCs expansion to enhance their therapeutic potential.
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Affiliation(s)
- Can Zhang
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Tissue Engineering, Zhejiang University, Hangzhou 310058, China; Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou 310058, China; Institute of Biomedical Engineering, College of Biology, Hunan University, Changsha 410082, China
| | - Erchen Zhang
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Tissue Engineering, Zhejiang University, Hangzhou 310058, China; Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou 310058, China
| | - Long Yang
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Tissue Engineering, Zhejiang University, Hangzhou 310058, China; Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou 310058, China
| | - Wenjing Tu
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Tissue Engineering, Zhejiang University, Hangzhou 310058, China; Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou 310058, China
| | - Junxin Lin
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Tissue Engineering, Zhejiang University, Hangzhou 310058, China; Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou 310058, China
| | - Chunhui Yuan
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Tissue Engineering, Zhejiang University, Hangzhou 310058, China; Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou 310058, China
| | - Varisara Bunpetch
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Tissue Engineering, Zhejiang University, Hangzhou 310058, China; Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou 310058, China
| | - Xiao Chen
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Tissue Engineering, Zhejiang University, Hangzhou 310058, China; Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou 310058, China.
| | - Hongwei Ouyang
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Tissue Engineering, Zhejiang University, Hangzhou 310058, China; Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou 310058, China; Department of Sports Medicine, School of Medicine, Zhejiang University, Hangzhou 310058, China; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China.
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Growth factor delivery strategies for rotator cuff repair and regeneration. Int J Pharm 2018; 544:358-371. [PMID: 29317260 DOI: 10.1016/j.ijpharm.2018.01.006] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 12/21/2017] [Accepted: 01/01/2018] [Indexed: 12/21/2022]
Abstract
The high incidence of degenerative tears and prevalence of retears (20-95%) after surgical repair makes rotator cuff injuries a significant health problem. This high retear rate is attributed to the failure of the repaired tissue to regenerate the native tendon-to-bone insertion (enthesis). Biological augmentation of surgical repair such as autografts, allografts, and xenografts are confounded by donor site morbidity, immunogenicity, and disease transmission, respectively. In contrast, these risks may be alleviated via growth factor therapy, which can actively influence the healing environment to promote functional repair. Several challenges have to be overcome before growth factor delivery can translate into clinical practice such as the selection of optimal growth factor(s) or combination, identification of the most efficient stage and duration of delivery, and the design considerations for the delivery device. Emerging insight into the injury-repair microenvironment and our understanding of growth factor mechanisms in healing are informing the design of advanced delivery scaffolds to effectively treat rotator cuff tears. Here, we review potential growth factor candidates, design parameters and material selection for growth factor delivery, innovative and dynamic delivery scaffolds, and novel therapeutic targets from tendon and developmental biology for the structural and functional healing of rotator cuff repair.
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Usuelli FG, D'Ambrosi R, Maccario C, Indino C, Manzi L, Maffulli N. Adipose-derived stem cells in orthopaedic pathologies. Br Med Bull 2017; 124:31-54. [PMID: 29253149 DOI: 10.1093/bmb/ldx030] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2017] [Accepted: 07/22/2017] [Indexed: 02/06/2023]
Abstract
INTRODUCTION To examine the current literature regarding the clinical application of adipose-derived stem cells (ADSCs) for the management of orthopaedic pathologies. SOURCES OF DATA MEDLINE,SCOPUS, CINAHL and EMBASE (1950 to April 14, 2017) were searched by two independent investigators for articles published in English. Reviews, meta-analyses, expert opinions, case reports, mini case series and editorials were excluded. Furthermore, we excluded animal studies, cadaveric studies and in vitro studies. AREAS OF AGREEMENT ADSCs seem to produce excellent clinical results. However, the length and modalities of follow-up in the different conditions are extremely variable. Nevertheless, it appears that the use of adipose-derived stem cells is associated with subjective and objective clinical improvements and minimal complication rates. AREAS OF CONTROVERSY None of the studies identified is a randomized double-blinded trial, and most of the selected studies present major limitations, and different methods, confounding the results of our review. GROWING POINTS It is necessary to conduct more and better studies to ascertain whether ADSCs really play a role in orthopaedic surgery with particular attention to ADSCs harvesting method, type of administration and the conditions treated. AREAS TIMELY FOR DEVELOPING RESEARCH The current literature regarding the use of ADSCs for orthopaedic pathologies is limited. At present, long-term safety is the biggest challenge of ADSCs based regenerative medicine. LEVEL OF EVIDENCE Level IV-Study of Level I, II, III, IV.
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Affiliation(s)
| | - Riccardo D'Ambrosi
- Foot and Ankle Unit, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Italy
| | - Camilla Maccario
- Foot and Ankle Unit, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Italy
| | - Cristian Indino
- Foot and Ankle Unit, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
| | - Luigi Manzi
- Foot and Ankle Unit, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
| | - Nicola Maffulli
- Department of Orthopaedics and Traumatology, Azienda Ospedaliera San Giovanni di Dio e Ruggi d'Aragona, University of Salerno, Italy
- Queen Mary University of London, Barts and the London School of Medicine and Dentistry, Centre for Sports and Exercise Medicine, Mile End Hospital, London, UK
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Barboni B, Russo V, Gatta V, Bernabò N, Berardinelli P, Mauro A, Martelli A, Valbonetti L, Muttini A, Di Giacinto O, Turriani M, Silini A, Calabrese G, Abate M, Parolini O, Stuppia L, Mattioli M. Therapeutic potential of hAECs for early Achilles tendon defect repair through regeneration. J Tissue Eng Regen Med 2017; 12:e1594-e1608. [PMID: 29024514 DOI: 10.1002/term.2584] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 09/26/2017] [Accepted: 09/29/2017] [Indexed: 12/26/2022]
Abstract
Cell-based therapy holds great promise for tendon disorders, a widespread debilitating musculoskeletal condition. Even if the cell line remains to be defined, preliminary evidences have proven that amniotic-derived cells possess in vitro and in vivo a great tenogenic potential. This study investigated the efficacy of transplanted human amniotic epithelial cells (hAECs) by testing their early regenerative properties and mechanisms involved on a validated ovine Achilles tendon partial defect performed on 29 animals. The injured tendons treated with hAECs recovered rapidly, in 28 days, structural and biomechanical properties undertaking a programmed tissue regeneration, differently from the spontaneous healing tissues. hAECs remained viable within the host tendons establishing with the endogenous progenitor cells an active dialogue. Through the secretion of modulatory factors, hAECs inhibited the inflammatory cells infiltration, activated the M2 macrophage subpopulation early recruitment, and accelerated blood vessel as well as extracellular matrix remodelling. In parallel, some in situ differentiated hAECs displayed a tenocytelike phenotype. Both paracrine and direct hAECs stimulatory effects were confirmed analysing their genome profile before and after transplantation. The 49 human up-regulated transcripts recorded in transplanted hAECs belonged to tendon lineage differentiation (epithelial-mesenchymal transition, connective specific matrix components, and skeleton or muscle system development-related transcripts), as well as the in situ activation of paracrine signalling involved in inflammatory and immunomodulatory response. Altogether, these evidences support the hypothesis that hAECs are a practicable and efficient strategy for the acute treatment of tendinopathy, reinforcing the idea of a concrete use of amniotic epithelial cells towards the clinical practice.
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Affiliation(s)
- Barbara Barboni
- Faculty of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, Teramo, Italy
| | - Valentina Russo
- Faculty of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, Teramo, Italy
| | - Valentina Gatta
- Medical Genetics, University "G. d'Annunzio" of Chieti Pescara, Chieti, Italy
| | - Nicola Bernabò
- Faculty of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, Teramo, Italy
| | - Paolo Berardinelli
- Faculty of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, Teramo, Italy
| | - Annunziata Mauro
- Faculty of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, Teramo, Italy
| | - Alessandra Martelli
- Faculty of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, Teramo, Italy
| | - Luca Valbonetti
- Faculty of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, Teramo, Italy
| | - Aurelio Muttini
- Faculty of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, Teramo, Italy
| | - Oriana Di Giacinto
- Faculty of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, Teramo, Italy
| | - Maura Turriani
- Faculty of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, Teramo, Italy
| | - Antonietta Silini
- Centro di Ricerca "E. Menni", Fondazione Poliambulanza-Istituto Ospedaliero, Brescia, Italy
| | - Giuseppe Calabrese
- Medical Genetics, University "G. d'Annunzio" of Chieti Pescara, Chieti, Italy
| | - Michele Abate
- Department of Medicine and Science of Aging, University "G. d'Annunzio" Chieti Pescara, Chieti, Italy
| | - Ornella Parolini
- Centro di Ricerca "E. Menni", Fondazione Poliambulanza-Istituto Ospedaliero, Brescia, Italy
| | - Liborio Stuppia
- Medical Genetics, University "G. d'Annunzio" of Chieti Pescara, Chieti, Italy
| | - Mauro Mattioli
- Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise "G. Caporale", Teramo, Italy
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Madrigal JL, Stilhano R, Silva EA. Biomaterial-Guided Gene Delivery for Musculoskeletal Tissue Repair. TISSUE ENGINEERING. PART B, REVIEWS 2017; 23:347-361. [PMID: 28166711 PMCID: PMC5749599 DOI: 10.1089/ten.teb.2016.0462] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 01/11/2017] [Indexed: 02/07/2023]
Abstract
Gene therapy is a promising strategy for musculoskeletal tissue repair and regeneration where local and sustained expression of proteins and/or therapeutic nucleic acids can be achieved. However, the musculoskeletal tissues present unique engineering and biological challenges as recipients of genetic vectors. Targeting specific cell populations, regulating expression in vivo, and overcoming the harsh environment of damaged tissue accompany the general concerns of safety and efficacy common to all applications of gene therapy. In this review, we will first summarize these challenges and then discuss how biomaterial carriers for genetic vectors can address these issues. Second, we will review how limitations specific to given vectors further motivate the utility of biomaterial carriers. Finally, we will discuss how these concepts have been combined with tissue engineering strategies and approaches to improve the delivery of these vectors for musculoskeletal tissue regeneration.
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Affiliation(s)
- Justin L Madrigal
- Department of Biomedical Engineering, University of California , Davis, Davis, California
| | - Roberta Stilhano
- Department of Biomedical Engineering, University of California , Davis, Davis, California
| | - Eduardo A Silva
- Department of Biomedical Engineering, University of California , Davis, Davis, California
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36
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Dale TP, Mazher S, Webb WR, Zhou J, Maffulli N, Chen GQ, El Haj AJ, Forsyth NR. Tenogenic Differentiation of Human Embryonic Stem Cells. Tissue Eng Part A 2017; 24:361-368. [PMID: 28548630 DOI: 10.1089/ten.tea.2017.0017] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Tendon healing is complex to manage because of the limited regeneration capacity of tendon tissue; stem cell-based tissue engineering approaches may provide alternative healing strategies. We sought to determine whether human embryonic stem cells (hESC) could be induced to differentiate into tendon-like cells by the addition of exogenous bone morphogenetic protein (BMP)12 (growth differentiation factor[GDF]7) and BMP13 (GDF6). hESC (SHEF-1) were maintained with or without BMP12/13 supplementation, or supplemented with BMP12/13 and the Smad signaling cascade blocking agent, dorsomorphin. Primary rat tenocytes were included as a positive control in immunocytochemistry analysis. A tenocyte-like elongated morphology was observed in hESC after 40-days continuous supplementation with BMP12/13 and ascorbic acid (AA). These cells displayed a tenomodulin expression pattern and morphology consistent with that of the primary tenocyte control. Analysis of tendon-linked gene transcription in BMP12/13 supplemented hESC demonstrated consistent expression of COL1A2, COL3A1, DCN, TNC, THBS4, and TNMD levels. Conversely, when hESCs were cultured in the presence of BMP12/13 and dorsomorphin COL3A1, DCN, and TNC gene expression and tendon matrix formation were inhibited. Taken together, we have demonstrated that hESCs are responsive to tenogenic induction via BMP12/13 in the presence of AA. The directed in vitro generation of tenocytes from pluripotent stem cells may facilitate the development of novel repair approaches for this difficult to heal tissue.
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Affiliation(s)
- Tina P Dale
- 1 Guy Hilton Research Centre, Institute for Science and Technology in Medicine, Faculty of Medicine and Health Sciences, Keele University , Thornburrow Drive, Stoke-on-Trent, Staffordshire, United Kingdom
| | - Shazia Mazher
- 1 Guy Hilton Research Centre, Institute for Science and Technology in Medicine, Faculty of Medicine and Health Sciences, Keele University , Thornburrow Drive, Stoke-on-Trent, Staffordshire, United Kingdom
| | - William R Webb
- 1 Guy Hilton Research Centre, Institute for Science and Technology in Medicine, Faculty of Medicine and Health Sciences, Keele University , Thornburrow Drive, Stoke-on-Trent, Staffordshire, United Kingdom
| | - Jing Zhou
- 2 School of Life Science, Tsinghua University , Beijing, China
| | - Nicola Maffulli
- 3 Centre for Sport and Exercise Medicine, Queen Mary University of London , United Kingdom
| | - Guo-Qiang Chen
- 2 School of Life Science, Tsinghua University , Beijing, China
| | - Alicia J El Haj
- 1 Guy Hilton Research Centre, Institute for Science and Technology in Medicine, Faculty of Medicine and Health Sciences, Keele University , Thornburrow Drive, Stoke-on-Trent, Staffordshire, United Kingdom
| | - Nicholas R Forsyth
- 1 Guy Hilton Research Centre, Institute for Science and Technology in Medicine, Faculty of Medicine and Health Sciences, Keele University , Thornburrow Drive, Stoke-on-Trent, Staffordshire, United Kingdom
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Han W, Chen L, Liu J, Guo A. Enhanced tenogenic differentiation and tendon-like tissue formation by CHIP overexpression in tendon-derived stem cells. Acta Biochim Biophys Sin (Shanghai) 2017; 49:311-317. [PMID: 28338815 DOI: 10.1093/abbs/gmx005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Indexed: 12/23/2022] Open
Abstract
The carboxyl terminus of Hsc70-interacting protein (CHIP, also known as STUB1) plays critical roles in the proliferation and differentiation of many types of cells. The potential function of CHIP in tendon-derived stem cells (TDSCs) remains largely unknown at present. Here, we investigated the effects of CHIP on tenogenic differentiation of TDSCs via lentivirus-mediated overexpression. Forced expression of CHIP induced morphological changes and significantly enhanced cell proliferation, as well as tendon differentiation in vitro. Upon stimulation with differentiation induction medium, CHIP-overexpressing TDSCs displayed significant inhibition of differentiation into osteogenic and adipogenic lineages. Subsequent implantation of TDSCs overexpressing CHIP with collagen sponges into nude mice induced a marked increase in ectopic tendon formation in vivo, compared with the control group. Our findings collectively suggest that CHIP is an important contributory factor to tenogenic tissue formation.
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Affiliation(s)
- Weifeng Han
- Department of Orthopaedics, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Lei Chen
- Institute of Orthopaedics, The First Affiliated Hospital of Chinese People's Liberation Army General Hospital, Beijing 100048, China
| | - Junpeng Liu
- Department of Orthopaedics, Air Force General Hospital, People's Liberation Army of China, Beijing 100142, China
| | - Ai Guo
- Department of Orthopaedics, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
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Chailakhyan RK, Shekhter AB, Ivannikov SV, Tel'pukhov VI, Suslin DS, Gerasimov YV, Tonenkov AM, Grosheva AG, Panyushkin PV, Moskvina IL, Vorob'eva NN, Bagratashvili VN. Reconstruction of Ligament and Tendon Defects Using Cell Technologies. Bull Exp Biol Med 2017; 162:563-568. [PMID: 28243921 DOI: 10.1007/s10517-017-3660-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Indexed: 12/14/2022]
Abstract
We studied the possibility of restoring the integrity of the Achilles tendon in rabbits using autologous multipotent stromal cells. Collagen or gelatin sponges populated with cells were placed in a resorbable Vicryl mesh tube and this tissue-engineered construct was introduced into a defect of the middle part of the Achilles tendon. In 4 months, histological analysis showed complete regeneration of the tendon with the formation of parallel collagen fibers, spindle-shaped tenocytes, and newly formed vessels.
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Affiliation(s)
- R K Chailakhyan
- N. F. Gamaleya Research Centre of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, Moscow, Russia.
| | - A B Shekhter
- I. M. Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow, Russia
| | - S V Ivannikov
- I. M. Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow, Russia
| | - V I Tel'pukhov
- I. M. Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow, Russia
| | - D S Suslin
- I. M. Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow, Russia
| | - Yu V Gerasimov
- N. F. Gamaleya Research Centre of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - A M Tonenkov
- I. M. Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow, Russia
| | - A G Grosheva
- N. F. Gamaleya Research Centre of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - P V Panyushkin
- I. M. Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow, Russia
| | - I L Moskvina
- N. F. Gamaleya Research Centre of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - N N Vorob'eva
- Institute of Photonics Technologies, Russian Academy of Sciences, Federal Research Center "Crystallography and Photonics", Russian Academy of Sciences, Moscow, Russia
| | - V N Bagratashvili
- Institute of Photonics Technologies, Russian Academy of Sciences, Federal Research Center "Crystallography and Photonics", Russian Academy of Sciences, Moscow, Russia
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Yin Z, Hu JJ, Yang L, Zheng ZF, An CR, Wu BB, Zhang C, Shen WL, Liu HH, Chen JL, Heng BC, Guo GJ, Chen X, Ouyang HW. Single-cell analysis reveals a nestin + tendon stem/progenitor cell population with strong tenogenic potentiality. SCIENCE ADVANCES 2016; 2:e1600874. [PMID: 28138519 PMCID: PMC5262457 DOI: 10.1126/sciadv.1600874] [Citation(s) in RCA: 104] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/23/2016] [Accepted: 10/20/2016] [Indexed: 05/12/2023]
Abstract
The repair of injured tendons remains a formidable clinical challenge because of our limited understanding of tendon stem cells and the regulation of tenogenesis. With single-cell analysis to characterize the gene expression profiles of individual cells isolated from tendon tissue, a subpopulation of nestin+ tendon stem/progenitor cells (TSPCs) was identified within the tendon cell population. Using Gene Expression Omnibus datasets and immunofluorescence assays, we found that nestin expression was activated at specific stages of tendon development. Moreover, isolated nestin+ TSPCs exhibited superior tenogenic capacity compared to nestin- TSPCs. Knockdown of nestin expression in TSPCs suppressed their clonogenic capacity and reduced their tenogenic potential significantly both in vitro and in vivo. Hence, these findings provide new insights into the identification of subpopulations of TSPCs and illustrate the crucial roles of nestin in TSPC fate decisions and phenotype maintenance, which may assist in future therapeutic strategies to treat tendon disease.
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Affiliation(s)
- Zi Yin
- Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, China
- China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, China
| | - Jia-jie Hu
- Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, China
| | - Long Yang
- Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, China
| | - Ze-Feng Zheng
- Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, China
| | - Cheng-rui An
- Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, China
| | - Bing-bing Wu
- Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, China
| | - Can Zhang
- Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, China
| | - Wei-Liang Shen
- China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, China
- Department of Orthopedic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Huan-huan Liu
- Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jia-lin Chen
- Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, China
| | - Boon Chin Heng
- Faculty of Dentistry, University of Hong Kong, Pokfulam, Hong Kong
| | - Guo-ji Guo
- Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiao Chen
- Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, China
- China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, China
- Corresponding author. (H.-W.O.); (X.C.)
| | - Hong-Wei Ouyang
- Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, China
- China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, China
- Department of Sports Medicine, School of Medicine, Zhejiang University, Hangzhou, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Corresponding author. (H.-W.O.); (X.C.)
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Ruschke K, Meier C, Ullah M, Krebs AC, Silberreis K, Kohl B, Knaus P, Jagielski M, Arens S, Schulze-Tanzil G. Bone morphogenetic protein 2/SMAD signalling in human ligamentocytes of degenerated and aged anterior cruciate ligaments. Osteoarthritis Cartilage 2016; 24:1816-1825. [PMID: 27208419 DOI: 10.1016/j.joca.2016.05.014] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Revised: 04/27/2016] [Accepted: 05/11/2016] [Indexed: 02/02/2023]
Abstract
OBJECTIVE Anterior cruciate ligament (ACL) degeneration leads to knee instability and favors osteoarthritis (OA) progression. During ageing the growth factor sensitivity of ligaments changes but nothing is known about BMP2-signalling and -sensitivity in degenerated ACLs. This study addressed the question whether a dysregulated BMP2 signalling might contribute to age- and OA-dependent ACL degeneration. METHOD ACL samples from patients with/without OA of different ages (<60 and ≥60 years, males, females) were graded histopathologically (n = 45). After stimulation of cultured ACL fibroblasts with 5 nM BMP2 for different time points, phosphorylation of SMAD1/5/8 and gene expression of crucial BMP2 signalling proteins, ligamentogenic and chondrogenic transcription factors, scleraxis (SCX) and SOX9, were analyzed. RESULTS ACL samples displayed different grades of degeneration, often associated with synovitis and calcium deposits. Degeneration correlated significantly with synovitis. ACL fibroblasts expressed BMP type I receptors ALK3 and ALK6 and the BMP type II receptor BMPRII. Donors could be divided into "responders" and "non responders" since their BMP2 mediated SMAD1/5/8 phosphorylation level differed. Basal ID1 expression was lower in cells derived from OA compared with non-OA patients and BMP2 led to an ID1 induction in both. Irrespective of BMP2 stimulation, the donor age significantly influenced the expression profile of BMP6 and SCX but not BMP signalling. The BMP2-mediated SMAD6 expression differed between OA and healthy ACL fibroblasts. CONCLUSION Our data indicate that the expression level of BMP2/SMAD target genes such as ID1 and SMAD6 was reduced in ACL fibroblasts derived from OA compared with non OA patients.
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Affiliation(s)
- K Ruschke
- Freie Universität Berlin, Institute of Chemistry and Biochemistry, Berlin, Germany
| | - C Meier
- Charité-Universitätsmedizin Berlin, Department of Orthopaedic, Trauma and Reconstructive Surgery, Campus Benjamin Franklin, Berlin, Germany
| | - M Ullah
- Charité-Universitätsmedizin Berlin, Department of Orthopaedic, Trauma and Reconstructive Surgery, Campus Benjamin Franklin, Berlin, Germany
| | - A-C Krebs
- Freie Universität Berlin, Institute of Chemistry and Biochemistry, Berlin, Germany; Charité-Universitätsmedizin Berlin, Department of Orthopaedic, Trauma and Reconstructive Surgery, Campus Benjamin Franklin, Berlin, Germany
| | - K Silberreis
- Charité-Universitätsmedizin Berlin, Department of Orthopaedic, Trauma and Reconstructive Surgery, Campus Benjamin Franklin, Berlin, Germany
| | - B Kohl
- Charité-Universitätsmedizin Berlin, Department of Orthopaedic, Trauma and Reconstructive Surgery, Campus Benjamin Franklin, Berlin, Germany
| | - P Knaus
- Freie Universität Berlin, Institute of Chemistry and Biochemistry, Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - M Jagielski
- Charité-Universitätsmedizin Berlin, Department of Orthopaedic, Trauma and Reconstructive Surgery, Campus Benjamin Franklin, Berlin, Germany
| | - S Arens
- Charité-Universitätsmedizin Berlin, Department of Orthopaedic, Trauma and Reconstructive Surgery, Campus Benjamin Franklin, Berlin, Germany
| | - G Schulze-Tanzil
- Charité-Universitätsmedizin Berlin, Department of Orthopaedic, Trauma and Reconstructive Surgery, Campus Benjamin Franklin, Berlin, Germany; Institute of Anatomy, Paracelsus Medical University, Salzburg and Nuremberg, Nuremberg, Germany.
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Walden G, Liao X, Donell S, Raxworthy MJ, Riley GP, Saeed A. A Clinical, Biological, and Biomaterials Perspective into Tendon Injuries and Regeneration. TISSUE ENGINEERING PART B-REVIEWS 2016; 23:44-58. [PMID: 27596929 PMCID: PMC5312458 DOI: 10.1089/ten.teb.2016.0181] [Citation(s) in RCA: 104] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Tendon injury is common and debilitating, and it is associated with long-term pain and ineffective healing. It is estimated to afflict 25% of the adult population and is often a career-ending disease in athletes and racehorses. Tendon injury is associated with high morbidity, pain, and long-term suffering for the patient. Due to the low cellularity and vascularity of tendon tissue, once damage has occurred, the repair process is slow and inefficient, resulting in mechanically, structurally, and functionally inferior tissue. Current treatment options focus on pain management, often being palliative and temporary and ending in reduced function. Most treatments available do not address the underlying cause of the disease and, as such, are often ineffective with variable results. The need for an advanced therapeutic that addresses the underlying pathology is evident. Tissue engineering and regenerative medicine is an emerging field that is aimed at stimulating the body's own repair system to produce de novo tissue through the use of factors such as cells, proteins, and genes that are delivered by a biomaterial scaffold. Successful tissue engineering strategies for tendon regeneration should be built on a foundation of understanding of the molecular and cellular composition of healthy compared with damaged tendon, and the inherent differences seen in the tissue after disease. This article presents a comprehensive clinical, biological, and biomaterials insight into tendon tissue engineering and regeneration toward more advanced therapeutics.
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Affiliation(s)
- Grace Walden
- 1 School of Pharmacy, University of East Anglia, Norwich, United Kingdom
| | - Xin Liao
- 1 School of Pharmacy, University of East Anglia, Norwich, United Kingdom
| | - Simon Donell
- 2 Norfolk and Norwich University Hospital, Norwich, United Kingdom .,3 Norwich Medical School, University of East Anglia, Norwich, United Kingdom
| | - Mike J Raxworthy
- 4 Neotherix Limited, York, United Kingdom .,5 University of Leeds, Leeds, United Kingdom
| | - Graham P Riley
- 6 School of Biological Sciences, University of East Anglia, Norwich, United Kingdom
| | - Aram Saeed
- 1 School of Pharmacy, University of East Anglia, Norwich, United Kingdom
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Veronesi F, Salamanna F, Tschon M, Maglio M, Nicoli Aldini N, Fini M. Mesenchymal stem cells for tendon healing: what is on the horizon? J Tissue Eng Regen Med 2016; 11:3202-3219. [PMID: 27597421 DOI: 10.1002/term.2209] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Revised: 10/28/2015] [Accepted: 04/05/2016] [Indexed: 02/06/2023]
Abstract
Tendon injuries are a noteworthy morbidity but at present there are few effective scientifically proven treatments. In recent decades, a number of new strategies including tissue engineering with mesenchymal stem cells (MSCs) have been proposed to enhance tendon healing. Although MSCs are an interesting and promising approach, many questions regarding their use in tendon repair remain unanswered. This descriptive overview of the literature of the last decade explores the in vivo studies on tendon healing, in small and large animal models, which used MSCs harvested from different tissues, and the state of the art in clinical applications. It was observed that there are still doubts about the optimum amount of MSCs to use and their source and the type of scaffolds to deliver the cells. Thus, further studies are needed to determine the best protocol for MSC use in tendon healing. Copyright © 2016 John Wiley & Sons, Ltd.
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Affiliation(s)
- Francesca Veronesi
- Laboratory of Preclinical and Surgical Studies, Rizzoli Orthopaedic Institute, Bologna, Italy
| | - Francesca Salamanna
- Laboratory of Preclinical and Surgical Studies, Rizzoli Orthopaedic Institute, Bologna, Italy
| | - Matilde Tschon
- Laboratory of Preclinical and Surgical Studies, Rizzoli Orthopaedic Institute, Bologna, Italy
| | - Melania Maglio
- Laboratory of Preclinical and Surgical Studies, Rizzoli Orthopaedic Institute, Bologna, Italy
| | - Nicolo Nicoli Aldini
- Laboratory of Preclinical and Surgical Studies, Rizzoli Orthopaedic Institute, Bologna, Italy
| | - Milena Fini
- Laboratory of Preclinical and Surgical Studies, Rizzoli Orthopaedic Institute, Bologna, Italy
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Linderman SW, Gelberman RH, Thomopoulos S, Shen H. Cell and Biologic-Based Treatment of Flexor Tendon Injuries. ACTA ACUST UNITED AC 2016; 26:206-215. [PMID: 28042226 DOI: 10.1053/j.oto.2016.06.011] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The two primary factors leading to poor clinical results after intrasynovial tendon repair are adhesion formation within the digital sheath and repair-site elongation and rupture. As the outcomes following modern tendon multi-strand repair and controlled rehabilitation techniques are often unsatisfactory, alternative approaches, such as the application of growth factors and mesenchymal stem cells (MSCs), have become increasingly attractive treatment options. Successful biological therapies require carefully controlled spatiotemporal delivery of cells, growth factors, and biocompatible scaffold matrices in order to simultaneously (1) promote matrix synthesis at the tendon repair site leading to increased biomechanical strength and stiffness and (2) suppress matrix synthesis along the tendon surface and synovial sheath preventing adhesion formation. This review summarizes recent cell and biologic-based experimental treatments for flexor tendon injury, with an emphasis on large animal translational studies.
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Affiliation(s)
- Stephen W Linderman
- Department of Orthopaedic Surgery, Washington University, St. Louis, MO, United States; Department of Biomedical Engineering, Washington University, St. Louis, MO, United States
| | - Richard H Gelberman
- Department of Orthopaedic Surgery, Washington University, St. Louis, MO, United States
| | - Stavros Thomopoulos
- Department of Orthopaedic Surgery, Columbia University, New York, NY, United States; Department of Biomedical Engineering, Columbia University, New York, NY, United States
| | - Hua Shen
- Department of Orthopaedic Surgery, Washington University, St. Louis, MO, United States
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An investigation of BMP-7 mediated alterations to BMP signalling components in human tenocyte-like cells. Sci Rep 2016; 6:29703. [PMID: 27406972 PMCID: PMC4942578 DOI: 10.1038/srep29703] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 06/21/2016] [Indexed: 12/12/2022] Open
Abstract
The incidence of tendon re-tears post-surgery is an ever present complication. It is suggested that the application of biological factors, such as bone morphogenetic protein 7 (BMP-7), can reduce complication rates by promoting tenogenic characteristics in in vitro studies. However, there remains a dearth of information in regards to the mechanisms of BMP-7 signalling in tenocytes. Using primary human tenocyte-like cells (hTLCs) from the supraspinatus tendon the BMP-7 signalling pathway was investigated: induction of the BMP associated Smad pathway and non-Smad pathways (AKT, p38, ERK1/2 and JNK); alterations in gene expression of BMP-7 associated receptors, Smad pathway components, Smad target gene (ID1) and tenogenic marker scleraxis. BMP-7 increases the expression of specific BMP associated receptors, BMPR-Ib and BMPR-II, and Smad8. Additionally, BMP-7 activates significantly Smad1/5/8 and slightly p38 pathways as indicated by an increase in phosphorylation and proven by inhibition experiments, where p-ERK1/2 and p-JNK pathways remain mainly unresponsive. Furthermore, BMP-7 increases the expression of the Smad target gene ID1, and the tendon specific transcription factor scleraxis. The study shows that tenocyte-like cells undergo primarily Smad8 and p38 signalling after BMP-7 stimulation. The up-regulation of tendon related marker genes and matrix proteins such as Smad8/9, scleraxis and collagen I might lead to positive effects of BMP-7 treatment for rotator cuff repair, without significant induction of osteogenic and chondrogenic markers.
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Buttler K, Lohrberg M, Gross G, Weich HA, Wilting J. Integration of CD45-positive leukocytes into newly forming lymphatics of adult mice. Histochem Cell Biol 2016; 145:629-36. [PMID: 26748643 PMCID: PMC4848334 DOI: 10.1007/s00418-015-1399-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/21/2015] [Indexed: 10/28/2022]
Abstract
The embryonic origin of lymphatic endothelial cells (LECs) has been a matter of controversy since more than a century. However, recent studies in mice have supported the concept that embryonic lymphangiogenesis is a complex process consisting of growth of lymphatics from specific venous segments as well as the integration of lymphangioblasts into the lymphatic networks. Similarly, the mechanisms of adult lymphangiogenesis are poorly understood and have rarely been studied. We have recently shown that endothelial progenitor cells isolated from the lung of adult mice have the capacity to form both blood vessels and lymphatics when grafted with Matrigel plugs into the skin of syngeneic mice. Here, we followed up on these experiments and studied the behavior of host leukocytes during lymphangiogenesis in the Matrigel plugs. We observed a striking co-localization of CD45(+) leukocytes with the developing lymphatics. Numerous CD45(+) cells expressed the LEC marker podoplanin and were obviously integrated into the lining of lymphatic capillaries. This indicates that, similar to inflammation-induced lymphangiogenesis in man, circulating CD45(+) cells of adult mice are capable of initiating lymphangiogenesis and of adopting a lymphvasculogenic cellular differentiation program. The data are discussed in the context of embryonic and inflammation-induced lymphangiogenesis.
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Affiliation(s)
- K Buttler
- Department of Anatomy and Cell Biology, University Medical School Göttingen, Göttingen, Germany
| | - M Lohrberg
- Department of Anatomy and Cell Biology, University Medical School Göttingen, Göttingen, Germany
| | - G Gross
- Department of Gene Regulation, Helmholtz Centre for Infection Research, Brunswick, Germany
| | - H A Weich
- Department of Chemical Biology, Helmholtz Centre for Infection Research, Brunswick, Germany
| | - J Wilting
- Department of Anatomy and Cell Biology, University Medical School Göttingen, Göttingen, Germany.
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Hsieh CF, Alberton P, Loffredo-Verde E, Volkmer E, Pietschmann M, Müller P, Schieker M, Docheva D. Scaffold-free Scleraxis-programmed tendon progenitors aid in significantly enhanced repair of full-size Achilles tendon rupture. Nanomedicine (Lond) 2016; 11:1153-67. [DOI: 10.2217/nnm.16.34] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Aim: Currently there is no effective approach to enhance tendon repair, hence we aimed to identify a suitable cell source for tendon engineering utilizing an established clinically relevant animal model for tendon injury. Materials & methods: We compared, by in-depth histomorphometric evaluation, the regenerative potential of uncommitted human mesenchymal stem cells (hMSC) and Scleraxis (Scx)-programmed tendon progenitors (hMSC-Scx) in the healing of a full-size of rat Achilles tendon defect. Results: Our analyses clearly demonstrated that implantation of hMSC-Scx, in contrast to hMSC and empty defect, results in smaller diameters, negligible ectopic calcification and advanced cellular organization and matrix maturation in the injured tendons. Conclusion: Scaffold-free delivery of hMSC-Scx aids in enhanced repair in a clinically translatable Achilles tendon injury model.
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Affiliation(s)
- Chi-Fen Hsieh
- Experimental Surgery & Regenerative Medicine, Department of Surgery, Ludwig-Maximilians-University (LMU), Nussbaumstr. 20, 80336 Munich, Germany
| | - Paolo Alberton
- Experimental Surgery & Regenerative Medicine, Department of Surgery, Ludwig-Maximilians-University (LMU), Nussbaumstr. 20, 80336 Munich, Germany
| | - Eva Loffredo-Verde
- Experimental Surgery & Regenerative Medicine, Department of Surgery, Ludwig-Maximilians-University (LMU), Nussbaumstr. 20, 80336 Munich, Germany
| | - Elias Volkmer
- Experimental Surgery & Regenerative Medicine, Department of Surgery, Ludwig-Maximilians-University (LMU), Nussbaumstr. 20, 80336 Munich, Germany
| | - Matthias Pietschmann
- Department of Orthopaedic Surgery, Physical Medicine & Rehabilitation, University Hospital Grosshadern, LMU, Marchioninistr. 15, 81377 Munich, Germany
| | - Peter Müller
- Department of Orthopaedic Surgery, Physical Medicine & Rehabilitation, University Hospital Grosshadern, LMU, Marchioninistr. 15, 81377 Munich, Germany
| | - Matthias Schieker
- Experimental Surgery & Regenerative Medicine, Department of Surgery, Ludwig-Maximilians-University (LMU), Nussbaumstr. 20, 80336 Munich, Germany
| | - Denitsa Docheva
- Experimental Surgery & Regenerative Medicine, Department of Surgery, Ludwig-Maximilians-University (LMU), Nussbaumstr. 20, 80336 Munich, Germany
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Jiang Y, Shi Y, He J, Zhang Z, Zhou G, Zhang W, Cao Y, Liu W. Enhanced tenogenic differentiation and tendon-like tissue formation by tenomodulin overexpression in murine mesenchymal stem cells. J Tissue Eng Regen Med 2016; 11:2525-2536. [PMID: 27098985 DOI: 10.1002/term.2150] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Revised: 11/12/2015] [Accepted: 12/22/2015] [Indexed: 01/22/2023]
Affiliation(s)
- Yongkang Jiang
- Department of Plastic and Reconstructive Surgery shanghai 9th People's Hospital; People's Republic of China
| | - Yuan Shi
- Department of Plastic and Reconstructive Surgery shanghai 9th People's Hospital; People's Republic of China
| | - Jing He
- Department of Anatomy and Neurobiology; Tongji University School of Medicine; Shanghai People's Republic of China
| | - Zhiyong Zhang
- Department of Plastic and Reconstructive Surgery shanghai 9th People's Hospital; People's Republic of China
- National Tissue Engineering Centre of China; Shanghai People's Republic of China
| | - Guangdong Zhou
- Department of Plastic and Reconstructive Surgery shanghai 9th People's Hospital; People's Republic of China
- National Tissue Engineering Centre of China; Shanghai People's Republic of China
| | - Wenjie Zhang
- Department of Plastic and Reconstructive Surgery shanghai 9th People's Hospital; People's Republic of China
- National Tissue Engineering Centre of China; Shanghai People's Republic of China
| | - Yilin Cao
- Department of Plastic and Reconstructive Surgery shanghai 9th People's Hospital; People's Republic of China
- National Tissue Engineering Centre of China; Shanghai People's Republic of China
| | - Wei Liu
- Department of Plastic and Reconstructive Surgery shanghai 9th People's Hospital; People's Republic of China
- National Tissue Engineering Centre of China; Shanghai People's Republic of China
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Mauro A, Russo V, Di Marcantonio L, Berardinelli P, Martelli A, Muttini A, Mattioli M, Barboni B. M1 and M2 macrophage recruitment during tendon regeneration induced by amniotic epithelial cell allotransplantation in ovine. Res Vet Sci 2016; 105:92-102. [PMID: 27033915 DOI: 10.1016/j.rvsc.2016.01.014] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Revised: 11/25/2015] [Accepted: 01/19/2016] [Indexed: 12/31/2022]
Abstract
Recently, we have demonstrated that ovine amniotic epithelial cells (oAECs) allotransplanted into experimentally induced tendon lesions are able to stimulate tissue regeneration also by reducing leukocyte infiltration. Amongst leukocytes, macrophages (Mφ) M1 and M2 phenotype cells are known to mediate inflammatory and repairing processes, respectively. In this research it was investigated if, during tendon regeneration induced by AECs allotransplantation, M1Mφ and M2Mφ phenotype cells are recruited and differently distributed within the lesion site. Ovine AECs treated and untreated (Ctr) tendons were explanted at 7, 14, and 28 days and tissue microarchitecture was analyzed together with the distribution and quantification of leukocytes (CD45 positive), Mφ (CD68 pan positive), and M1Mφ (CD86, and IL12b) and M2Mφ (CD206, YM1 and IL10) phenotype related markers. In oAEC transplanted tendons CD45 and CD68 positive cells were always reduced in the lesion site. At day 14, oAEC treated tendons began to recover their microarchitecture, contextually a reduction of M1Mφ markers, mainly distributed close to oAECs, and an increase of M2Mφ markers was evidenced. CD206 positive cells were distributed near the regenerating areas. At day 28 oAECs treated tendons acquired a healthy-like structure with a reduction of M2Mφ. Differently, Ctr tendons maintained a disorganized morphology throughout the experimental time and constantly showed high values of M1Mφ markers. These findings indicate that M2Mφ recruitment could be correlated to tendon regeneration induced by oAECs allotransplantation. Moreover, these results demonstrate oAECs immunomodulatory role also in vivo and support novel insights into their allogeneic use underlying the resolution of tendon fibrosis.
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Affiliation(s)
- Annunziata Mauro
- Faculty of Veterinary Medicine, University of Teramo, Campus Universitario Coste S. Agostino Via R. Balzarini 1, 64100 Teramo, Italy; StemTeCh Group, Italy
| | - Valentina Russo
- Faculty of Veterinary Medicine, University of Teramo, Campus Universitario Coste S. Agostino Via R. Balzarini 1, 64100 Teramo, Italy; StemTeCh Group, Italy.
| | - Lisa Di Marcantonio
- Faculty of Veterinary Medicine, University of Teramo, Campus Universitario Coste S. Agostino Via R. Balzarini 1, 64100 Teramo, Italy
| | - Paolo Berardinelli
- Faculty of Veterinary Medicine, University of Teramo, Campus Universitario Coste S. Agostino Via R. Balzarini 1, 64100 Teramo, Italy
| | - Alessandra Martelli
- Faculty of Veterinary Medicine, University of Teramo, Campus Universitario Coste S. Agostino Via R. Balzarini 1, 64100 Teramo, Italy
| | - Aurelio Muttini
- Faculty of Veterinary Medicine, University of Teramo, Campus Universitario Coste S. Agostino Via R. Balzarini 1, 64100 Teramo, Italy; StemTeCh Group, Italy
| | - Mauro Mattioli
- Faculty of Veterinary Medicine, University of Teramo, Campus Universitario Coste S. Agostino Via R. Balzarini 1, 64100 Teramo, Italy
| | - Barbara Barboni
- Faculty of Veterinary Medicine, University of Teramo, Campus Universitario Coste S. Agostino Via R. Balzarini 1, 64100 Teramo, Italy; StemTeCh Group, Italy
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Grognuz A, Scaletta C, Farron A, Pioletti DP, Raffoul W, Applegate LA. Stability Enhancement Using Hyaluronic Acid Gels for Delivery of Human Fetal Progenitor Tenocytes. CELL MEDICINE 2016; 8:87-97. [PMID: 28003934 DOI: 10.3727/215517916x690486] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Tendon afflictions are very common, and their negative impact is high both at the workplace and in leisure activities. Tendinopathies are increasing in prevalence and can lead to tendon ruptures, where healing is a long process with outcomes that are often disappointing. Human fetal progenitor tenocytes (hFPTs) have been recently tested in vitro as a potential cell source to stimulate tendon regeneration. The aim of the present study was to compare different commercial hyaluronic acid (HA) gels, which could be used to resuspend hFPTs in a formulation that would allow for good delivery of the cells. No medium or growth supplement was used in the formulation in order to make it therapeutically dispensable. These conditions are stringent for cells, but surprisingly, we found that different formulations could allow a good survival for up to 3 days when stored at 4°C (refrigerator stable). The gels must allow a good survival of the cells in parallel with a good stability of the preparation over time and sufficient viscosity to remain in place if deposited on a wounded location. Moreover, the cells must conserve their ability to attach and to proliferate. hFPTs were able to survive and to recover from all of the tested gels, but some products showed some advantages over others in terms of survival and viscosity. Finally, the Ostenil Tendon HA gel fulfilled all of the requirements and presented the best compromise between a good survival and sufficient rheological characteristics to create an interesting cell delivery system.
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Affiliation(s)
- A Grognuz
- Unit of Regenerative Therapy, Service of Plastic, Reconstructive and Hand Surgery, Department of Musculoskeletal Medicine, University Hospital of Lausanne , Lausanne , Switzerland
| | - C Scaletta
- Unit of Regenerative Therapy, Service of Plastic, Reconstructive and Hand Surgery, Department of Musculoskeletal Medicine, University Hospital of Lausanne , Lausanne , Switzerland
| | - A Farron
- † Service of Orthopaedics and Traumatology, Department of Musculoskeletal Medicine, University Hospital of Lausanne , Lausanne , Switzerland
| | - D P Pioletti
- ‡ Laboratory of Biomechanical Orthopedics, Institute of Bioengineering, EPFL , Lausanne , Switzerland
| | - W Raffoul
- Unit of Regenerative Therapy, Service of Plastic, Reconstructive and Hand Surgery, Department of Musculoskeletal Medicine, University Hospital of Lausanne , Lausanne , Switzerland
| | - L A Applegate
- Unit of Regenerative Therapy, Service of Plastic, Reconstructive and Hand Surgery, Department of Musculoskeletal Medicine, University Hospital of Lausanne , Lausanne , Switzerland
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Tenogenic differentiation of mesenchymal stem cells and noncoding RNA: From bench to bedside. Exp Cell Res 2015; 341:237-42. [PMID: 26724570 DOI: 10.1016/j.yexcr.2015.12.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Revised: 12/21/2015] [Accepted: 12/23/2015] [Indexed: 11/21/2022]
Abstract
Tendon is a critical unit of musculoskeletal system that connects muscle to bone to control bone movement. More population participate in physical activities, tendon injuries, such as acute tendon rupture and tendinopathy due to overuse, are common causing unbearable pain and disability. However, the process of tendon development and the pathogenesis of tendinopathy are not well defined, limiting the development of clinical therapy for tendon injuries. Studying the tendon differentiation control pathways may help to develop novel therapeutic strategies. This review summarized the novel molecular and cellular events in tendon development and highlighted the clinical application potential of non-coding RNAs and tendon-derived stem cells in gene and cell therapy for tendon injuries, which may bring insights into research and new therapy for tendon disorders.
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