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Goto A, Komura S, Kato K, Maki R, Hirakawa A, Aoki H, Tomita H, Taguchi J, Ozawa M, Matsushima T, Kishida A, Kimura T, Asahara H, Imai Y, Yamada Y, Akiyama H. PI3K-Akt signalling regulates Scx-lineage tenocytes and Tppp3-lineage paratenon sheath cells in neonatal tendon regeneration. Nat Commun 2025; 16:3734. [PMID: 40254618 PMCID: PMC12010001 DOI: 10.1038/s41467-025-59010-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 04/09/2025] [Indexed: 04/22/2025] Open
Abstract
Tendon injuries are frequently occurring disorders; it is clinically important to enhance tendon regeneration and prevent functional impairment post-injury. While tendon injuries in children heal quickly with minimal scarring, those in adults heal slowly and are accompanied by fibrotic scarring. Therefore, investigating the healing mechanisms after tendon injury, and identifying the factors that regulate the inherent regenerative capacity of tendons are promising approaches to promoting tendon regeneration. Here, we identify that the PI3K-Akt signalling pathway is preferentially upregulated in injured neonatal murine Achilles tendons. Inhibition of PI3K-Akt signalling in a neonatal murine Achilles tendon rupture model decreases cell proliferation and migration in both Scx-lineage intrinsic tenocytes and Tppp3-lineage extrinsic paratenon sheath cells. Moreover, the inhibition of PI3K-Akt signalling decreases stemness and promotes mature tenogenic differentiation in both Scx- and Tppp3-lineage cells. Collectively, these results suggest that PI3K-Akt signalling plays a pivotal role in neonatal tendon regeneration.
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Affiliation(s)
- Atsushi Goto
- Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Shingo Komura
- Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Gifu, Japan.
| | - Koki Kato
- Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Rie Maki
- Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Akihiro Hirakawa
- Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Hitomi Aoki
- Department of Stem Cell and Regenerative Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Hiroyuki Tomita
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan
- Center for One Medicine Innovative Translational Research (COMIT), Gifu University, Gifu, Japan
| | - Jumpei Taguchi
- Core Laboratory for Developing Advanced Animal Models, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Manabu Ozawa
- Core Laboratory for Developing Advanced Animal Models, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | | | - Akio Kishida
- Department of Material-Based Medical Engineering, Laboratory for Biomaterials and Bioengineering, Institute of Integrated Research, Institute of Science Tokyo, Tokyo, Japan
| | - Tsuyoshi Kimura
- Materials-based Medical Engineering Laboratory, Department of Biomedical Engineering, Faculty of Life Science, Toyo University, Tokyo, Japan
| | - Hiroshi Asahara
- Department of Systems BioMedicine, Institute of Science Tokyo, Tokyo, Japan
| | - Yuuki Imai
- Division of Integrative Pathophysiology, Proteo-Science Center, Ehime University, Toon, Ehime, Japan
| | - Yasuhiro Yamada
- Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Haruhiko Akiyama
- Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Gifu, Japan
- Center for One Medicine Innovative Translational Research (COMIT), Gifu University, Gifu, Japan
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2
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Ahn SY. Various Strategies of Tendon Stem/Progenitor Cell Reprogramming for Tendon Regeneration. Int J Mol Sci 2024; 25:11745. [PMID: 39519296 PMCID: PMC11547070 DOI: 10.3390/ijms252111745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 10/26/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024] Open
Abstract
Rotator cuff tears (RCT) are the most common cause of shoulder pain among adults. "Rotator cuff" refers to the four muscles that cover the shoulder joint: supraspinatus, infraspinatus, subscapularis, and teres minor. These muscles help maintain the rotational movement and stability of the shoulder joint. RCT is a condition in which one or more of these four muscles become ruptured or damaged, causing pain in the arms and shoulders. RCT results from degenerative changes caused by chronic inflammation of the tendons and consequent tendon tissue defects. This phenomenon occurs because of the exhaustion of endogenous tendon stem cells. Tendon regeneration requires rejuvenation of these endogenous tendon stem/progenitor cells (TSPCs) prior to their growth phase. TSPCs exhibit clonogenicity, multipotency, and self-renewal properties; they express classical stem cell markers and genes associated with the tendon lineage. However, specific markers for TSPC are yet to be identified. In this review, we introduce novel TSPC markers and discuss various strategies for TSPC reprogramming. With further research, TSPC reprogramming technology could be adapted to treat age-related degenerative diseases, providing a new strategy for regenerative medicine.
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Affiliation(s)
- Sung Yong Ahn
- Department of Physiology, Ajou University School of Medicine, Suwon 16499, Republic of Korea
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3
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Tsutsumi H, Chiba T, Fujii Y, Matsushima T, Kimura T, Kanai A, Kishida A, Suzuki Y, Asahara H. Single-nucleus transcriptional and chromatin accessibility analyses of maturing mouse Achilles tendon uncover the molecular landscape of tendon stem/progenitor cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.24.619991. [PMID: 39484401 PMCID: PMC11527174 DOI: 10.1101/2024.10.24.619991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2024]
Abstract
Tendons and ligaments are crucial connective tissues linking bones and muscles, yet achieving full functional recovery after injury remains challenging. We investigated the characteristics of tendon stem/progenitor cells (TSPCs) by focusing on the declining tendon repair capacity with growth. Using single-cell RNA sequencing on Achilles tendon cells from 2- and 6-week-old mice, we identified Cd55 and Cd248 as novel surface antigen markers for TSPCs. Combining single-nucleus ATAC and RNA sequencing analyses revealed that Cd55 and Cd248 positive fractions in tendon tissue are TSPCs, with this population decreasing at 1 weeks. We also identified candidate upstream transcription factors regulating these fractions. Functional analyses of isolated CD55/CD248 positive cells demonstrated high clonogenic potential and tendon differentiation capacity, forming functional tendon-like tissue in vitro . This study establishes CD55 and CD248 as novel TSPC surface antigens, potentially advancing tendon regenerative medicine and contributing to the development of new treatment strategies for tendon and ligament injuries.
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Darrieutort-Laffite C, Blanchard F, Soslowsky LJ, Le Goff B. Biology and physiology of tendon healing. Joint Bone Spine 2024; 91:105696. [PMID: 38307405 DOI: 10.1016/j.jbspin.2024.105696] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 01/11/2024] [Accepted: 01/23/2024] [Indexed: 02/04/2024]
Abstract
Tendon disorders affect people of all ages, from elite and recreational athletes and workers to elderly patients. After an acute injury, 3 successive phases are described to achieve healing: an inflammatory phase followed by a proliferative phase, and finally by a remodeling phase. Despite this process, healed tendon fails to recover its original mechanical properties. In this review, we proposed to describe the key factors involved in the process such as cells, transcription factors, extracellular matrix components, cytokines and growth factors and vascularization among others. A better understanding of this healing process could help provide new therapeutic approaches to improve patients' recovery while tendon disorders management remains a medical challenge.
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Affiliation(s)
- Christelle Darrieutort-Laffite
- Service de rhumatologie, CHU de Nantes, Nantes, France; Oniris, Regenerative Medicine and Skeleton, RMeS, UMR 1229, Inserm, CHU de Nantes, Nantes université, 44000 Nantes, France.
| | - Frédéric Blanchard
- Oniris, Regenerative Medicine and Skeleton, RMeS, UMR 1229, Inserm, CHU de Nantes, Nantes université, 44000 Nantes, France
| | - Louis J Soslowsky
- Department of Orthopaedic Surgery, McKay Orthopaedic Research Laboratory, University of Pennsylvania, Philadelphia, PA, USA
| | - Benoit Le Goff
- Service de rhumatologie, CHU de Nantes, Nantes, France; Oniris, Regenerative Medicine and Skeleton, RMeS, UMR 1229, Inserm, CHU de Nantes, Nantes université, 44000 Nantes, France
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Pechanec MY, Beall JM, Katzman S, Maga EA, Mienaltowski MJ. Examining the Effects of In Vitro Co-Culture of Equine Adipose-Derived Mesenchymal Stem Cells With Tendon Proper and Peritenon Cells. J Equine Vet Sci 2023; 126:104262. [PMID: 36841345 DOI: 10.1016/j.jevs.2023.104262] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 01/26/2023] [Accepted: 02/20/2023] [Indexed: 02/27/2023]
Abstract
Tendinopathies remain the leading contributor to career-ending injuries in horses because of the complexity of tendon repair. As such, cell-based therapies like injections of adipose-derived mesenchymal stem cells (ADMSCs, or MSCs) into injured tendons are becoming increasingly popular though their long-term efficacy on a molecular and wholistic level remains contentious. Thus, we co-cultured equine MSCs with intrinsic (tendon proper) and extrinsic (peritenon) tendon cell populations to examine interactions between these cells. Gene expression for common tenogenic, perivascular, and differentiation markers was quantified at 48 and 120 hours. Additionally, cellular metabolism of proliferation was examined every 24 hours for peritenon and tendon proper cells co-cultured with MSCs. MSCs co-cultured with tendon proper or peritenon cells had altered expression profiles demonstrating trend toward tenogenic phenotype with the exception of decreases in type I collagen (COL1A1). Peritenon cells co-cultured with MSCs had a trending and significant decrease in biglycan (BGN) and CSPG4 at 48 hours and 120 hours but overall significant increases in lysyl oxidase (LOX), mohawk (MKX), and scleraxis (SCX) within 48 hours. Tendon proper cells co-cultured with MSCs also exhibited increases in LOX and SCX at 48 hours. Furthermore, cell proliferation improved overall for tendon proper cells co-cultured with MSCs. The co-culture study results suggest that adipose-derived MSCs contribute beneficially to tenogenic stimulation of peritenon or tendon proper cells.
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Affiliation(s)
- Monica Y Pechanec
- Department of Animal Science, University of California Davis, Davis, CA
| | - Jessica M Beall
- Department of Animal Science, University of California Davis, Davis, CA
| | - Scott Katzman
- School of Veterinary Medicine, University of California Davis, Davis, CA
| | - Elizabeth A Maga
- Department of Animal Science, University of California Davis, Davis, CA
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Biological and Mechanical Factors and Epigenetic Regulation Involved in Tendon Healing. Stem Cells Int 2023; 2023:4387630. [PMID: 36655033 PMCID: PMC9842431 DOI: 10.1155/2023/4387630] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 12/18/2022] [Accepted: 12/28/2022] [Indexed: 01/11/2023] Open
Abstract
Tendons are an important part of the musculoskeletal system. Connecting muscles to bones, tendons convert force into movement. Tendon injury can be acute or chronic. Noticeably, tendon healing requires a long time span and includes inflammation, proliferation, and remodeling processes. The mismatch between endogenous and exogenous healing may lead to adhesion causing further negative effects. Management of tendon injuries and complications such as subsequent adhesion formation are still challenges for clinicians. Due to numerous factors, tendon healing is a complex process. This review introduces the role of various biological and mechanical factors and epigenetic regulation processes involved in tendon healing.
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7
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Graça AL, Gomez-Florit M, Gomes ME, Docheva D. Tendon Aging. Subcell Biochem 2023; 103:121-147. [PMID: 37120467 DOI: 10.1007/978-3-031-26576-1_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/01/2023]
Abstract
Tendons are mechanosensitive connective tissues responsible for the connection between muscles and bones by transmitting forces that allow the movement of the body, yet, with advancing age, tendons become more prone to degeneration followed by injuries. Tendon diseases are one of the main causes of incapacity worldwide, leading to changes in tendon composition, structure, and biomechanical properties, as well as a decline in regenerative potential. There is still a great lack of knowledge regarding tendon cellular and molecular biology, interplay between biochemistry and biomechanics, and the complex pathomechanisms involved in tendon diseases. Consequently, this reflects a huge need for basic and clinical research to better elucidate the nature of healthy tendon tissue and also tendon aging process and associated diseases. This chapter concisely describes the effects that the aging process has on tendons at the tissue, cellular, and molecular levels and briefly reviews potential biological predictors of tendon aging. Recent research findings that are herein reviewed and discussed might contribute to the development of precision tendon therapies targeting the elderly population.
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Affiliation(s)
- Ana Luísa Graça
- 3B's Research Group, I3Bs-Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Manuel Gomez-Florit
- Health Research Institute of the Balearic Islands (IdISBa), Palma de Mallorca, Spain
| | - Manuela Estima Gomes
- 3B's Research Group, I3Bs-Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Denitsa Docheva
- Department of Musculoskeletal Tissue Regeneration, Orthopaedic Hospital König-Ludwig-Haus, University of Würzburg, Würzburg, Germany.
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8
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Schulze-Tanzil GG, Delgado-Calcares M, Stange R, Wildemann B, Docheva D. Tendon healing: a concise review on cellular and molecular mechanisms with a particular focus on the Achilles tendon. Bone Joint Res 2022; 11:561-574. [PMID: 35920195 PMCID: PMC9396922 DOI: 10.1302/2046-3758.118.bjr-2021-0576.r1] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Tendon is a bradytrophic and hypovascular tissue, hence, healing remains a major challenge. The molecular key events involved in successful repair have to be unravelled to develop novel strategies that reduce the risk of unfavourable outcomes such as non-healing, adhesion formation, and scarring. This review will consider the diverse pathophysiological features of tendon-derived cells that lead to failed healing, including misrouted differentiation (e.g. de- or transdifferentiation) and premature cell senescence, as well as the loss of functional progenitors. Many of these features can be attributed to disturbed cell-extracellular matrix (ECM) or unbalanced soluble mediators involving not only resident tendon cells, but also the cross-talk with immigrating immune cell populations. Unrestrained post-traumatic inflammation could hinder successful healing. Pro-angiogenic mediators trigger hypervascularization and lead to persistence of an immature repair tissue, which does not provide sufficient mechano-competence. Tendon repair tissue needs to achieve an ECM composition, structure, strength, and stiffness that resembles the undamaged highly hierarchically ordered tendon ECM. Adequate mechano-sensation and -transduction by tendon cells orchestrate ECM synthesis, stabilization by cross-linking, and remodelling as a prerequisite for the adaptation to the increased mechanical challenges during healing. Lastly, this review will discuss, from the cell biological point of view, possible optimization strategies for augmenting Achilles tendon (AT) healing outcomes, including adapted mechanostimulation and novel approaches by restraining neoangiogenesis, modifying stem cell niche parameters, tissue engineering, the modulation of the inflammatory cells, and the application of stimulatory factors.Cite this article: Bone Joint Res 2022;11(8):561-574.
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Affiliation(s)
| | - Manuel Delgado-Calcares
- Experimental Trauma Surgery, Department of Trauma Surgery, University Regensburg Medical Centre, Regensburg, Germany
| | - Richard Stange
- Department of Regenerative Musculoskeletal Medicine, Institute for Musculoskeletal Medicine (IMM), University Hospital Münster, Münster, Germany
| | - Britt Wildemann
- Department of Experimental Trauma Surgery, University Hospital Jena, Jena, Germany
| | - Denitsa Docheva
- Department of Musculoskeletal Tissue Regeneration, Orthopaedic Hospital König-Ludwig-Haus, University of Würzburg, Würzburg, Germany
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9
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Gomez-Florit M, Labrador-Rached CJ, Domingues RM, Gomes ME. The tendon microenvironment: Engineered in vitro models to study cellular crosstalk. Adv Drug Deliv Rev 2022; 185:114299. [PMID: 35436570 DOI: 10.1016/j.addr.2022.114299] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 04/11/2022] [Accepted: 04/12/2022] [Indexed: 12/12/2022]
Abstract
Tendinopathy is a multi-faceted pathology characterized by alterations in tendon microstructure, cellularity and collagen composition. Challenged by the possibility of regenerating pathological or ruptured tendons, the healing mechanisms of this tissue have been widely researched over the past decades. However, so far, most of the cellular players and processes influencing tendon repair remain unknown, which emphasizes the need for developing relevant in vitro models enabling to study the complex multicellular crosstalk occurring in tendon microenvironments. In this review, we critically discuss the insights on the interaction between tenocytes and the other tendon resident cells that have been devised through different types of existing in vitro models. Building on the generated knowledge, we stress the need for advanced models able to mimic the hierarchical architecture, cellularity and physiological signaling of tendon niche under dynamic culture conditions, along with the recreation of the integrated gradients of its tissue interfaces. In a forward-looking vision of the field, we discuss how the convergence of multiple bioengineering technologies can be leveraged as potential platforms to develop the next generation of relevant in vitro models that can contribute for a deeper fundamental knowledge to develop more effective treatments.
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10
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Pedaprolu K, Szczesny S. A Novel, Open Source, Low-Cost Bioreactor for Load-Controlled Cyclic Loading of Tendon Explants. J Biomech Eng 2022; 144:1135618. [PMID: 35147179 DOI: 10.1115/1.4053795] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Indexed: 11/08/2022]
Abstract
A major risk factor for tendinopathy is tendon overuse (i.e., fatigue loading). Fatigue loading of tendon damages the extracellular matrix and induces tissue degeneration. However, the specific mechanisms linking tendon fatigue damage with tissue degeneration are unclear. While explant models of tendon fatigue loading have been used to address this knowledge gap, they predominantly employ bioreactors that apply cyclic displacements/strains rather than loads/stresses, which are more physiologically relevant. This is because of the technical complexity and cost of building a load-controlled bioreactor, which requires multiple motors, load cells, and computationally intensive feedback loops. Here, we present a novel, low-cost, load-controlled bioreactor that applies cyclic loading to multiple tendon explants by offloading weights from a single motorized stage. Using an optional load cell, we validated that the bioreactor can effectively provide load-controlled fatigue testing of mouse and rat tendon explants while maintaining tissue viability. Furthermore, all the design files, bill of materials, and operating software are available "open source" (https://github.com/Szczesnytendon/Bioreactor) so that anyone can easily manufacture and use the bioreactor for their own research. Therefore, this novel load-controlled bioreactor will enable researchers to study the mechanisms driving fatigue-induced tendon degeneration in a more physiologically relevant and cost-effective manner.
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Affiliation(s)
- Krishna Pedaprolu
- Department of Biomedical Engineering, Pennsylvania State University, University Park, Pennsylvania, Pennsylvania State University, CBE Building Suite 122, University Park, PA 16802
| | - Spencer Szczesny
- Department of Biomedical Engineering, Pennsylvania State University, University Park, Pennsylvania, Department of Orthopaedics and Rehabilitation, Pennsylvania State University, Hershey, Pennsylvania, Pennsylvania State University, CBE Building Suite 122, University Park, PA 16802
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11
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He P, Ruan D, Huang Z, Wang C, Xu Y, Cai H, Liu H, Fei Y, Heng BC, Chen W, Shen W. Comparison of Tendon Development Versus Tendon Healing and Regeneration. Front Cell Dev Biol 2022; 10:821667. [PMID: 35141224 PMCID: PMC8819183 DOI: 10.3389/fcell.2022.821667] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 01/07/2022] [Indexed: 12/27/2022] Open
Abstract
Tendon is a vital connective tissue in human skeletal muscle system, and tendon injury is very common and intractable in clinic. Tendon development and repair are two closely related but still not fully understood processes. Tendon development involves multiple germ layer, as well as the regulation of diversity transcription factors (Scx et al.), proteins (Tnmd et al.) and signaling pathways (TGFβ et al.). The nature process of tendon repair is roughly divided in three stages, which are dominated by various cells and cell factors. This review will describe the whole process of tendon development and compare it with the process of tendon repair, focusing on the understanding and recent advances in the regulation of tendon development and repair. The study and comparison of tendon development and repair process can thus provide references and guidelines for treatment of tendon injuries.
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Affiliation(s)
- Peiwen He
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, China
- Institute of Sports Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, China
| | - Dengfeng Ruan
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, China
- Institute of Sports Medicine, Zhejiang University, Hangzhou, China
| | - Zizhan Huang
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, China
- Institute of Sports Medicine, Zhejiang University, Hangzhou, China
| | - Canlong Wang
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, China
- Institute of Sports Medicine, Zhejiang University, Hangzhou, China
| | - Yiwen Xu
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, China
- Institute of Sports Medicine, Zhejiang University, Hangzhou, China
| | - Honglu Cai
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, China
- Institute of Sports Medicine, Zhejiang University, Hangzhou, China
| | - Hengzhi Liu
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, China
- Institute of Sports Medicine, Zhejiang University, Hangzhou, China
| | - Yang Fei
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, China
- Institute of Sports Medicine, Zhejiang University, Hangzhou, China
| | - Boon Chin Heng
- Central Laboratory, Peking University School of Stomatology, Bejing, China
| | - Weishan Chen
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, China
- Institute of Sports Medicine, Zhejiang University, Hangzhou, China
- *Correspondence: Weishan Chen, ; Weiliang Shen,
| | - Weiliang Shen
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Orthopedics Research Institute of Zhejiang University, Hangzhou, China
- Institute of Sports Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, China
- Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou, China
- China Orthopaedic Regenerative Medicine (CORMed), Hangzhou, China
- *Correspondence: Weishan Chen, ; Weiliang Shen,
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12
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Atta G, Tempfer H, Kaser-Eichberger A, Traweger A, Heindl LM, Schroedl F. Is the human sclera a tendon-like tissue? A structural and functional comparison. Ann Anat 2021; 240:151858. [PMID: 34798297 DOI: 10.1016/j.aanat.2021.151858] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 09/22/2021] [Accepted: 11/09/2021] [Indexed: 12/17/2022]
Abstract
Collagen rich connective tissues fulfill a variety of important functions throughout the human body, most of which having to resist mechanical challenges. This review aims to compare structural and functional aspects of tendons and sclera, two tissues with distinct location and function, but with striking similarities regarding their cellular content, their extracellular matrix and their low degree of vascularization. The description of these similarities meant to provide potential novel insight for both the fields of orthopedic research and ophthalmology.
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Affiliation(s)
- Ghada Atta
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Institute for Tendon and Bone Regeneration, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, Salzburg, Austria
| | - Herbert Tempfer
- Institute for Tendon and Bone Regeneration, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, Salzburg, Austria; Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Alexandra Kaser-Eichberger
- Center for Anatomy and Cell Biology, Institute of Anatomy and Cell Biology - Salzburg, Paracelsus Medical University, Strubergasse 21, 5020 Salzburg, Austria
| | - Andreas Traweger
- Institute for Tendon and Bone Regeneration, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, Salzburg, Austria; Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Ludwig M Heindl
- Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Center for Integrated Oncology (CIO) Aachen - Bonn - Cologne - Düsseldorf, Cologne, Germany
| | - Falk Schroedl
- Center for Anatomy and Cell Biology, Institute of Anatomy and Cell Biology - Salzburg, Paracelsus Medical University, Strubergasse 21, 5020 Salzburg, Austria.
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13
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Liu X, Zhu B, Li Y, Liu X, Guo S, Wang C, Li S, Wang D. The Role of Vascular Endothelial Growth Factor in Tendon Healing. Front Physiol 2021; 12:766080. [PMID: 34777022 PMCID: PMC8579915 DOI: 10.3389/fphys.2021.766080] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 09/27/2021] [Indexed: 11/13/2022] Open
Abstract
Angiogenesis is crucial to facilitate tendon healing, such as delivering oxygen and nutrients, removing waste products, and controlling immune responses. Vascular endothelial growth factor (VEGF) is one of the most vital angiogenic factors that regulate blood vessel formation in tendon healing. Recently, biological therapies, including the application of exogenous VEGF, have been attracting increasing attention. However, at present, the effect of the application of exogenous VEGF in tendon healing is controversial, as the role of endogenous VEGF in tendons has also not been fully elucidated. This article will summarize the role of both endogenous and exogenous VEGF in tendon healing and discuss possible reasons for the controversy. The present review shows that tendon repair is facilitated only by proper angiogenesis and VEGF at the early stage, whereas the persistent high VEGF expression and prolonged presence of blood vessels may impair tendon repair at a later stage.
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Affiliation(s)
- Xueli Liu
- Institute of Physical Education, Southwest Medical University, Luzhou, China.,Department of Rehabilitation, Sichuan Vocational College of Health and Rehabilitation, Zigong, China
| | - Bin Zhu
- Institute of Physical Education, Southwest Medical University, Luzhou, China
| | - Yujie Li
- Institute of Physical Education, Southwest Medical University, Luzhou, China
| | - Xinyue Liu
- Institute of Physical Education, Southwest Medical University, Luzhou, China
| | - Sheng Guo
- Spinal Surgery Department, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Chenglong Wang
- Spinal Surgery Department, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Sen Li
- Spinal Surgery Department, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Dingxuan Wang
- Institute of Physical Education, Southwest Medical University, Luzhou, China
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14
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Xu K, Shao Y, Xia Y, Qian Y, Jiang N, Liu X, Yang L, Wang C. Tenascin-C regulates migration of SOX10 tendon stem cells via integrin-α9 for promoting patellar tendon remodeling. Biofactors 2021; 47:768-777. [PMID: 34058037 DOI: 10.1002/biof.1759] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 05/14/2021] [Indexed: 12/24/2022]
Abstract
Insufficient attention has been focused on the directional migration of SOX10+ tendon stem cells (STSCs) during tendon remodeling. Here, we investigate whether tenascin-C (TNC) promotes STSC motility and migration. Based on the hypothesis that TNCs induce STSC migration, RNA-sequencing (RNA-seq) was conducted, identifying 2107 differentially expressed genes (DEGs), of which 1272 were up-regulated and 835 down-regulated following treatment with TNC versus the control. The DEGs were principally involved in cell adhesion and cell membrane signal transduction. Highly enriched-related signaling included the PI3K-Akt, focal adhesion, and ECM-receptor interaction pathways. Protein interaction analysis established that TNC was positively correlated with ITGA9 (integrin-α9). Furthermore, TNC activated the phosphorylation levels of FAK and Akt, and knockdown of ITGA9 with siRNA revealed that TNC contributes to STSC migration via the targeting of ITGA9. In addition, in vivo administration of TNC promoted tissue regeneration of injured tendons. In conclusion, TNC regulated the migration of STSCs via ITGA9, thereby promoting the regeneration of tendon injuries.
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Affiliation(s)
- Kang Xu
- Hubei Engineering Technology Research Center of Chinese Materia Medica Processing, College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
- Engineering Research Center of Clinical Functional Materials and Diagnosis & Treatment Devices of Zhejiang Province, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang, China
| | - Yibo Shao
- National Innovation and Attracting Talents "111" base, Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
| | - Yi Xia
- Hubei University of Chinese Medicine, Huangjiahu Hospital, Wuhan, China
| | - Yuna Qian
- Engineering Research Center of Clinical Functional Materials and Diagnosis & Treatment Devices of Zhejiang Province, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang, China
| | - Nan Jiang
- Hubei Engineering Technology Research Center of Chinese Materia Medica Processing, College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
| | - Xianqiong Liu
- Hubei Engineering Technology Research Center of Chinese Materia Medica Processing, College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
| | - Li Yang
- National Innovation and Attracting Talents "111" base, Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
| | - Chunli Wang
- National Innovation and Attracting Talents "111" base, Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
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15
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Gonçalves AI, Vinhas A, Rodrigues MT, Gomes ME. The impact of cryopreservation in signature markers and immunomodulatory profile of tendon and ligament derived cells. J Cell Physiol 2021; 237:675-686. [PMID: 34368976 DOI: 10.1002/jcp.30540] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 06/09/2021] [Accepted: 07/10/2021] [Indexed: 11/07/2022]
Abstract
Tendon and ligament (T/L) engineering strategies towards clinical practice have been challenged by a paucity of understanding in the identification and still poorly described characterization of cellular niches. Prospecting how resident cell populations behave in vitro, and how cryopreservation may influence T/ L-promoting factors, can provide insights into T/ L-cellular profiles for novel regenerative solutions. Therefore, we studied human T/ L-derived cells isolated from patellar tendons and cruciate ligaments as suitable cellular models to anticipate tendon and ligament niches responses for advanced strategies with predictive tenogenic and ligamentogenic value. Our results show that the crude populations isolated from tendon and ligament tissues hold a stem cell subset and share a similar behavior in terms of tenogenic/ligamentogenic commitment. Both T/ L-derived cells successfully undergo cryopreservation/thawing maintaining the tenogenic/ligamentogenic profiles. The major differences between cryopreserved and fresh populations were observed at the gene expression of MKX, SCX, and TNMD as well as at the protein levels of collagen type I and III, in which cells from tendon origin (hTDCs) evidence increased values in comparison to the ones from ligament (hLDCs, p < 0.05). In addition, low-temperature storage was shown to potentiate an immunomodulatory profile of cells, especially in hTDCs leading to an increase in the gene expression of the anti-inflammatory factors IL-4 and IL-10 (p < 0.05), as well as in the protein secretion of IL-10 (p < 0.01) and IL-4 (p < 0.001). Overall, the outcomes highlight the relevance of the cryopreserved T/ L-derived cells and their promising immunomodulatory cues as in vitro models for investigating cell-mediated mechanisms driving tissue healing and regeneration.
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Affiliation(s)
- Ana I Gonçalves
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Avepark - Zona Industrial da Gandra, Barco, Guimarães, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Adriana Vinhas
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Avepark - Zona Industrial da Gandra, Barco, Guimarães, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Márcia T Rodrigues
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Avepark - Zona Industrial da Gandra, Barco, Guimarães, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Manuela E Gomes
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Avepark - Zona Industrial da Gandra, Barco, Guimarães, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
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16
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Huang Z, Yin Z, Xu J, Fei Y, Heng BC, Jiang X, Chen W, Shen W. Tendon Stem/Progenitor Cell Subpopulations and Their Implications in Tendon Biology. Front Cell Dev Biol 2021; 9:631272. [PMID: 33681210 PMCID: PMC7930382 DOI: 10.3389/fcell.2021.631272] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 01/27/2021] [Indexed: 12/28/2022] Open
Abstract
Tendon harbors a cell population that possesses stem cell characteristics such as clonogenicity, multipotency and self-renewal capacity, commonly referred to as tendon stem/progenitor cells (TSPCs). Various techniques have been employed to study how TSPCs are implicated in tendon development, homeostasis and healing. Recent advances in single-cell analysis have enabled much progress in identifying and characterizing distinct subpopulations of TSPCs, which provides a more comprehensive view of TSPCs function in tendon biology. Understanding the mechanisms of physiological and pathological processes regulated by TSPCs, especially a particular subpopulation, would greatly benefit treatment of diseased tendons. Here, we summarize the current scientific literature on the various subpopulations of TSPCs, and discuss how TSPCs can contribute to tissue homeostasis and pathogenesis, as well as examine the key modulatory signaling pathways that determine stem/progenitor cell state. A better understanding of the roles that TSPCs play in tendon biology may facilitate the development of novel treatment strategies for tendon diseases.
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Affiliation(s)
- Zizhan Huang
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Orthopedics Research Institute, Zhejiang University, Hangzhou, China.,Institute of Sports Medicine, Zhejiang University, Hangzhou, China
| | - Zi Yin
- Institute of Sports Medicine, Zhejiang University, Hangzhou, China.,Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou, China.,China Orthopedic Regenerative Medicine (CORMed), Hangzhou, China
| | - Jialu Xu
- Department of Infectious Diseases, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Yang Fei
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Orthopedics Research Institute, Zhejiang University, Hangzhou, China.,Institute of Sports Medicine, Zhejiang University, Hangzhou, China
| | - Boon Chin Heng
- School of Stomatology, Peking University, Beijing, China
| | - Xuesheng Jiang
- Department of Orthopedic Surgery, Huzhou Hospital, Zhejiang University, Huzhou, China
| | - Weishan Chen
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Orthopedics Research Institute, Zhejiang University, Hangzhou, China
| | - Weiliang Shen
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Orthopedics Research Institute, Zhejiang University, Hangzhou, China.,Institute of Sports Medicine, Zhejiang University, Hangzhou, China.,Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou, China.,China Orthopedic Regenerative Medicine (CORMed), Hangzhou, China
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17
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Characterization of the structure, vascularity, and stem/progenitor cell populations in porcine Achilles tendon (PAT). Cell Tissue Res 2021; 384:367-387. [PMID: 33496880 DOI: 10.1007/s00441-020-03379-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 12/03/2020] [Indexed: 01/26/2023]
Abstract
This study aimed to characterize porcine Achilles tendon (PAT) in terms of its structural components, vascularity, and resident tendon cells. We found that PAT is composed of a paratenon sheath, a core of fascicles, and an endotenon/interfascicular matrix (IFM) that encases the fascicle bundles. We analyzed each of these three tendon components structurally using tissue sections and by isolating cells from each component and analyzing in vitro. Many blood vessel-like tissues were present in the paratenon and IFM but not in fascicles, and the vessels in the paratenon and IFM appeared to be inter-connected. Cells isolated from the paratenon and IFM displayed characteristics of vascular stem/progenitor cells expressing the markers CD105, CD31, with α-smooth muscle actin (α-SMA) localized surrounding blood vessels. The isolated cells from paratenon and IFM also harbored abundant stem/progenitor cells as evidenced by their ability to form colonies and express stem cell markers including CD73 and CD146. Furthermore, we demonstrate that both paratenon and IFM-isolated cells were capable of undergoing multi-differentiation. In addition, both paratenon and IFM cells expressed elastin, osteocalcin, tubulin polymerization promoting protein (TPPP), and collagen IV, whereas fascicle cells expressed none of these markers, except collagen I. The neurotransmitter substance P (SP) was also found in the paratenon and IFM-localized surrounding blood vessels. The findings of this study will help us to better understand the vascular and cellular mechanisms of tendon homeostasis, injury, healing, and regeneration.
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18
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Bianchi E, Ruggeri M, Rossi S, Vigani B, Miele D, Bonferoni MC, Sandri G, Ferrari F. Innovative Strategies in Tendon Tissue Engineering. Pharmaceutics 2021; 13:89. [PMID: 33440840 PMCID: PMC7827834 DOI: 10.3390/pharmaceutics13010089] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 12/31/2020] [Accepted: 01/08/2021] [Indexed: 12/15/2022] Open
Abstract
The tendon is a highly aligned connective tissue that transmits force from muscle to bone. Each year, more than 32 million tendon injuries have been reported, in fact, tendinopathies represent at least 50% of all sports injuries, and their incidence rates have increased in recent decades due to the aging population. Current clinical grafts used in tendon treatment are subject to several restrictions and there is a significant demand for alternative engineered tissue. For this reason, innovative strategies need to be explored. Tendon replacement and regeneration are complex since scaffolds need to guarantee an adequate hierarchical structured morphology and mechanical properties to stand the load. Moreover, to guide cell proliferation and growth, scaffolds should provide a fibrous network that mimics the collagen arrangement of the extracellular matrix in the tendons. This review focuses on tendon repair and regeneration. Particular attention has been devoted to the innovative approaches in tissue engineering. Advanced manufacturing techniques, such as electrospinning, soft lithography, and three-dimensional (3D) printing, have been described. Furthermore, biological augmentation has been considered, as an emerging strategy with great therapeutic potential.
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Affiliation(s)
| | | | | | | | | | | | - Giuseppina Sandri
- Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy; (E.B.); (M.R.); (S.R.); (B.V.); (D.M.); (M.C.B.); (F.F.)
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19
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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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20
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Chu J, Lu M, Pfeifer CG, Alt V, Docheva D. Rebuilding Tendons: A Concise Review on the Potential of Dermal Fibroblasts. Cells 2020; 9:E2047. [PMID: 32911760 PMCID: PMC7563185 DOI: 10.3390/cells9092047] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 08/26/2020] [Accepted: 09/02/2020] [Indexed: 12/26/2022] Open
Abstract
Tendons are vital to joint movement by connecting muscles to bones. Along with an increasing incidence of tendon injuries, tendon disorders can burden the quality of life of patients or the career of athletes. Current treatments involve surgical reconstruction and conservative therapy. Especially in the elderly population, tendon recovery requires lengthy periods and it may result in unsatisfactory outcome. Cell-mediated tendon engineering is a rapidly progressing experimental and pre-clinical field, which holds great potential for an alternative approach to established medical treatments. The selection of an appropriate cell source is critical and remains under investigation. Dermal fibroblasts exhibit multiple similarities to tendon cells, suggesting they may be a promising cell source for tendon engineering. Hence, the purpose of this review article was in brief, to compare tendon to dermis tissues, and summarize in vitro studies on tenogenic differentiation of dermal fibroblasts. Furthermore, analysis of an open source Gene Expression Omnibus (GEO) data repository was carried out, revealing great overlap in the molecular profiles of both cell types. Lastly, a summary of in vivo studies employing dermal fibroblasts in tendon repair as well as pilot clinical studies in this area is included. Altogether, dermal fibroblasts hold therapeutic potential and are attractive cells for rebuilding injured tendons.
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Affiliation(s)
- Jin Chu
- Laboratory for Experimental Trauma Surgery, Department of Trauma Surgery, University Regensburg Medical Centre, 93053 Regensburg, Germany; (J.C.); (C.G.P.); (V.A.)
| | - Ming Lu
- Department of Orthopaedic Surgery, First Affiliated Hospital of Dalian Medical University, Dalian 116023, China;
| | - Christian G. Pfeifer
- Laboratory for Experimental Trauma Surgery, Department of Trauma Surgery, University Regensburg Medical Centre, 93053 Regensburg, Germany; (J.C.); (C.G.P.); (V.A.)
- Department of Trauma Surgery, University Regensburg Medical Centre, 93053 Regensburg, Germany
| | - Volker Alt
- Laboratory for Experimental Trauma Surgery, Department of Trauma Surgery, University Regensburg Medical Centre, 93053 Regensburg, Germany; (J.C.); (C.G.P.); (V.A.)
- Department of Trauma Surgery, University Regensburg Medical Centre, 93053 Regensburg, Germany
| | - Denitsa Docheva
- Laboratory for Experimental Trauma Surgery, Department of Trauma Surgery, University Regensburg Medical Centre, 93053 Regensburg, Germany; (J.C.); (C.G.P.); (V.A.)
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21
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Transient Existence of Circulating Mesenchymal Stem Cells in the Deep Veins in Humans Following Long Bone Intramedullary Reaming. J Clin Med 2020; 9:jcm9040968. [PMID: 32244388 PMCID: PMC7230570 DOI: 10.3390/jcm9040968] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 03/24/2020] [Accepted: 03/26/2020] [Indexed: 12/24/2022] Open
Abstract
The biology of mesenchymal stem cells (MSCs) in humans is incompletely understood and a possible role of systemically circulating cells in health and autoimmune disease remains controversial. Physiological movement of bone marrow MSCs to sites of injury would support the rationale for intravenous administration for relocation to damaged organs. We hypothesized that biophysical skeletal trauma rather than molecular cues may explain reported MSC circulation phenomena. Deep-femoral vein (FV) and matched peripheral vein blood samples (PVBs) were collected from patients undergoing lower-limb orthopaedic procedures during surgery (tibia using conventional sequential reaming, n = 9, femur using reamer/irrigator/aspirator (RIA), n = 15). PVBs were also taken from early (n = 15) and established (n = 12) rheumatoid arthritis (RA) patients and healthy donors (n = 12). Colony-forming unit-fibroblasts (CFU-Fs) were found in 17/36 FVBs but only 7/74 PVBs (mostly from femoral RIA); highly proliferative clonogenic cells were not generated. Only one colony was found in control/RA samples (n = 28). The rare CFU-Fs’ MSC nature was confirmed by phenotypic: CD105+/CD73+/CD90+ and CD19−/CD31−/CD33−/CD34−/CD45−/CD61−, and molecular profiles with 39/80 genes (including osteo-, chondro-, adipo-genic and immaturity markers) similar across multiple MSC tissue controls, but not dermal fibroblasts. Analysis of FVB-MSCs suggested that their likely origin was bone marrow as only two differences were observed between FVB-MSCs and IC-BM-MSCs (ACVR2A, p = 0.032 and MSX1, p = 0.003). Stromal cells with the phenotype and molecular profile of MSCs were scarcely found in the circulation, supporting the hypothesis that their very rare presence is likely linked to biophysical micro-damage caused by skeletal trauma (here orthopaedic manipulation) rather than specific molecular cues to a circulatory pool of MSCs capable of repair of remote organs or tissues. These findings support the use of organ resident cells or MSCs placed in situ to repair tissues rather than systemic administration.
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22
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Matos AM, Gonçalves AI, El Haj AJ, Gomes ME. Magnetic biomaterials and nano-instructive tools as mediators of tendon mechanotransduction. NANOSCALE ADVANCES 2020; 2:140-148. [PMID: 36133967 PMCID: PMC9417540 DOI: 10.1039/c9na00615j] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 11/29/2019] [Indexed: 05/29/2023]
Abstract
Tendon tissues connect muscle to bone allowing the transmission of forces resulting in joint movement. Tendon injuries are prevalent in society and the impact on public health is of utmost concern. Thus, clinical options for tendon treatments are in demand, and tissue engineering aims to provide reliable and successful long-term regenerative solutions. Moreover, the possibility of regulating cell fate by triggering intracellular pathways is a current challenge in regenerative medicine. In the last decade, the use of magnetic nanoparticles as nano-instructive tools has led to great advances in diagnostics and therapeutics. Recent advances using magnetic nanomaterials for regenerative medicine applications include the incorporation of magnetic biomaterials within 3D scaffolds resulting in mechanoresponsive systems with unprecedented properties and the use of nanomagnetic actuators to control cell signaling. Mechano-responsive scaffolds and nanomagnetic systems can act as mechanostimulation platforms to apply forces directly to single cells and multicellular biological tissues. As transmitters of forces in a localized manner, the approaches enable the downstream activation of key tenogenic signaling pathways. In this minireview, we provide a brief outlook on the tenogenic signaling pathways which are most associated with the conversion of mechanical input into biochemical signals, the novel bio-magnetic approaches which can activate these pathways, and the efforts to translate magnetic biomaterials into regenerative platforms for tendon repair.
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Affiliation(s)
- Ana M Matos
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine Avepark - Zona Industrial da Gandra, 4805-017 Barco Guimarães Portugal
- ICVS/3B's - PT Government Associate Laboratory Braga/Guimarães Portugal
| | - Ana I Gonçalves
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine Avepark - Zona Industrial da Gandra, 4805-017 Barco Guimarães Portugal
- ICVS/3B's - PT Government Associate Laboratory Braga/Guimarães Portugal
| | - Alicia J El Haj
- Healthcare Technologies Institute, Birmingham University B15 2TT Birmingham UK
| | - Manuela E Gomes
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine Avepark - Zona Industrial da Gandra, 4805-017 Barco Guimarães Portugal
- ICVS/3B's - PT Government Associate Laboratory Braga/Guimarães Portugal
- The Discoveries Centre for Regenerative and Precision Medicine, Headquarters at the University of Minho Avepark, 4805-017 Barco Guimarães Portugal
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23
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Leong NL, Kator JL, Clemens TL, James A, Enamoto-Iwamoto M, Jiang J. Tendon and Ligament Healing and Current Approaches to Tendon and Ligament Regeneration. J Orthop Res 2020; 38:7-12. [PMID: 31529731 PMCID: PMC7307866 DOI: 10.1002/jor.24475] [Citation(s) in RCA: 125] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Accepted: 09/10/2019] [Indexed: 02/04/2023]
Abstract
Ligament and tendon injuries are common problems in orthopedics. There is a need for treatments that can expedite nonoperative healing or improve the efficacy of surgical repair or reconstruction of ligaments and tendons. Successful biologically-based attempts at repair and reconstruction would require a thorough understanding of normal tendon and ligament healing. The inflammatory, proliferative, and remodeling phases, and the cells involved in tendon and ligament healing will be reviewed. Then, current research efforts focusing on biologically-based treatments of ligament and tendon injuries will be summarized, with a focus on stem cells endogenous to tendons and ligaments. Statement of clinical significance: This paper details mechanisms of ligament and tendon healing, as well as attempts to apply stem cells to ligament and tendon healing. Understanding of these topics could lead to more efficacious therapies to treat ligament and tendon injuries. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:7-12, 2020.
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Affiliation(s)
- Natalie L Leong
- Department of Orthopaedic Surgery, University of Maryland, 10 N. Greene St., Baltimore, Maryland, 21201
- Department of Surgery, Baltimore VA Medical Center, Baltimore, Maryland
| | - Jamie L Kator
- Department of Orthopaedic Surgery, University of Maryland, 10 N. Greene St., Baltimore, Maryland, 21201
| | - Thomas L Clemens
- Department of Orthopaedic Surgery, University of Maryland, 10 N. Greene St., Baltimore, Maryland, 21201
- Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, Maryland
| | - Aaron James
- Department of Pathology, Johns Hopkins University, Baltimore, Maryland
| | - Motomi Enamoto-Iwamoto
- Department of Orthopaedic Surgery, University of Maryland, 10 N. Greene St., Baltimore, Maryland, 21201
| | - Jie Jiang
- Department of Orthopaedic Surgery, University of Maryland, 10 N. Greene St., Baltimore, Maryland, 21201
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24
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Zhang C, Zhu J, Zhou Y, Thampatty BP, Wang JHC. Tendon Stem/Progenitor Cells and Their Interactions with Extracellular Matrix and Mechanical Loading. Stem Cells Int 2019; 2019:3674647. [PMID: 31737075 PMCID: PMC6815631 DOI: 10.1155/2019/3674647] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 08/04/2019] [Accepted: 08/17/2019] [Indexed: 12/11/2022] Open
Abstract
Tendons are unique connective tissues in the sense that their biological properties are largely determined by their tendon-specific stem cells, extracellular matrix (ECM) surrounding the stem cells, mechanical loading conditions placed on the tendon, and the complex interactions among them. This review is aimed at providing an overview of recent advances in the identification and characterization of tendon stem/progenitor cells (TSPCs) and their interactions with ECM and mechanical loading. In addition, the effects of such interactions on the maintenance of tendon homeostasis and the initiation of tendon pathological conditions are discussed. Moreover, the challenges in further investigations of TSPC mechanobiology in vitro and in vivo are outlined. Finally, future research efforts are suggested, which include using specific gene knockout models and single-cell transcription profiling to enable a broad and deep understanding of the physiology and pathophysiology of tendons.
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Affiliation(s)
- Chuanxin Zhang
- Joint Surgery and Sports Medicine Department, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Jun Zhu
- Joint Surgery and Sports Medicine Department, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Yiqin Zhou
- Joint Surgery and Sports Medicine Department, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Bhavani P. Thampatty
- MechanoBiology Laboratory, Departments of Orthopaedic Surgery, Bioengineering, and Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - James H-C. Wang
- MechanoBiology Laboratory, Departments of Orthopaedic Surgery, Bioengineering, and Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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25
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Conrad S, Weber K, Walliser U, Geburek F, Skutella T. Stem Cell Therapy for Tendon Regeneration: Current Status and Future Directions. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1084:61-93. [PMID: 30043235 DOI: 10.1007/5584_2018_194] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
In adults the healing tendon generates fibrovascular scar tissue and recovers never histologically, mechanically, and functionally which leads to chronic and to degenerative diseases. In this review, the processes and mechanisms of tendon development and fetal regeneration in comparison to adult defect repair and degeneration are discussed in relation to regenerative therapeutic options. We focused on the application of stem cells, growth factors, transcription factors, and gene therapy in tendon injury therapies in order to intervene the scarring process and to induce functional regeneration of the lesioned tissue. Outlines for future therapeutic approaches for tendon injuries will be provided.
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Affiliation(s)
| | - Kathrin Weber
- Tierärztliches Zentrum für Pferde in Kirchheim Altano GmbH, Kirchheim unter Teck, Germany
| | - Ulrich Walliser
- Tierärztliches Zentrum für Pferde in Kirchheim Altano GmbH, Kirchheim unter Teck, Germany
| | - Florian Geburek
- Justus-Liebig-University Giessen, Faculty of Veterinary Medicine, Clinic for Horses - Department of Surgery, Giessen, Germany
| | - Thomas Skutella
- Institute for Anatomy and Cell Biology, Medical Faculty, University of Heidelberg, Heidelberg, Germany.
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26
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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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Nichols AEC, Best KT, Loiselle AE. The cellular basis of fibrotic tendon healing: challenges and opportunities. Transl Res 2019; 209:156-168. [PMID: 30776336 PMCID: PMC6545261 DOI: 10.1016/j.trsl.2019.02.002] [Citation(s) in RCA: 147] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 01/30/2019] [Accepted: 02/04/2019] [Indexed: 12/11/2022]
Abstract
Tendon injuries are common and can dramatically impair patient mobility and productivity, resulting in a significant socioeconomic burden and reduced quality of life. Because the tendon healing process results in the formation of a fibrotic scar, injured tendons never regain the mechanical strength of the uninjured tendon, leading to frequent reinjury. Many tendons are also prone to the development of peritendinous adhesions and excess scar formation, which further reduce tendon function and lead to chronic complications. Despite this, there are currently no treatments that adequately improve the tendon healing process due in part to a lack of information regarding the contributions of various cell types to tendon healing and how their activity may be modulated for therapeutic value. In this review, we summarize recent efforts to identify and characterize the distinct cell populations involved at each stage of tendon healing. In addition, we examine the mechanisms through which different cell populations contribute to the fibrotic response to tendon injury, and how these responses can be affected by systemic factors and comorbidities. We then discuss gaps in our current understanding of tendon fibrosis and highlight how new technologies and research areas are shedding light on this clinically important and intractable challenge. A better understanding of the complex cellular environment during tendon healing is crucial to the development of new therapies to prevent fibrosis and promote tissue regeneration.
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Affiliation(s)
- Anne E C Nichols
- Department of Orthopedics & Rehabilitation, Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York
| | - Katherine T Best
- Department of Orthopedics & Rehabilitation, Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York
| | - Alayna E Loiselle
- Department of Orthopedics & Rehabilitation, Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York.
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Walia B, Huang AH. Tendon stem progenitor cells: Understanding the biology to inform therapeutic strategies for tendon repair. J Orthop Res 2019; 37:1270-1280. [PMID: 30270569 PMCID: PMC6823601 DOI: 10.1002/jor.24156] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 09/24/2018] [Indexed: 02/04/2023]
Abstract
Tendon and ligament injuries are a leading cause of healthcare visits with significant impact in terms of economic cost and reduced quality of life. To date, reparative strategies remain largely restricted to conservative treatment or surgical repair. However, these therapies fail to restore native tendon structure and function; thus, the tissue may re-rupture or degenerate with time. To improve tendon healing, one promising strategy may be harnessing the innate potential of resident tendon stem/progenitor cells (TSPCs) to guide tenogenic regeneration. In this review, we outline recent advances in the identification and characterization of putative TSPC populations, and discuss biochemical, biomechanical, and biomaterial methods employed for their culture and differentiation. Finally, we identify limitations in our current understanding of TSPC biology, key challenges for their use, and potential therapeutic strategies to inform cell-based tendon repair. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1270-1280, 2019.
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Affiliation(s)
- Bhavita Walia
- Leni & Peter W. May Department of Orthopedics, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Alice H. Huang
- Leni & Peter W. May Department of Orthopedics, Icahn School of Medicine at Mount Sinai, New York, New York
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29
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Abstract
Tendons harbor various cell populations, including cells displaying classical adult mesenchymal stromal cell criteria. Previous studies have shown that a tenogenic phenotype is more effectively maintained in a 3D cell culture model under mechanical load. This chapter describes a method to isolate tendon-derived cells from rat Achilles tendons and the subsequent formation of 3D-embedded cell cultures. These tendon-like constructs can then be analyzed by various means, including histology, immunohistochemistry, qPCR, or standard protein analysis techniques.
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Abate M, Di Carlo L, Verna S, Di Gregorio P, Schiavone C, Salini V. Synergistic activity of platelet rich plasma and high volume image guided injection for patellar tendinopathy. Knee Surg Sports Traumatol Arthrosc 2018; 26:3645-3651. [PMID: 29605861 DOI: 10.1007/s00167-018-4930-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Accepted: 03/26/2018] [Indexed: 02/06/2023]
Abstract
PURPOSE Platelet rich plasma and high volume image guided injections of saline have been used in the treatment of patellar tendinopathy with positive results. As the different mechanisms of action do not interfere each other, it can be hypothesized that they can be used in combination. Aim of this study was twofold: first, to evaluate the efficacy of these two treatments in the management of patellar tendinopathy; second, to verify whether the combination of these therapies could provide further advantages. METHODS Fifty-four patients suffering from patellar tendinopathy were enrolled. After clinical (VAS and VISA-P) and sonographic evaluation, two ultrasound guided injections (2 weeks apart) of platelet rich plasma, high-volume image-guided injections of saline, or both in association were performed. The VAS and VISA-P scores obtained from the three treatments groups (18 patients in each group) were compared across the different follow-up times (3 and 6 months). RESULTS In the short term both treatments showed comparable efficacy, whereas in the medium term the positive effects of high-volume image-guided injections gradually diminished and platelet rich plasma showed greater efficacy. Better results (reduced pain, improved function and increased number of subjects who exhibited optimal recovery [> 20 points in VISA-P score]) were observed when both procedures were associated. CONCLUSIONS The contemporaneous administration of platelet rich plasma and high volume image guided injections of saline treatments, which influence tendon repair by means of different mechanisms, grants a greater improvement for patellar tendinopathy. This finding has clinical relevance, given that this condition has a substantial impact on sports and work performance. LEVEL OF EVIDENCE III.
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Affiliation(s)
- Michele Abate
- Department of Medicine and Science of Aging, University G. d'Annunzio, Chieti-Pescara, Via dei Vestini 31, Chieti Scalo, 66013, Chieti, CH, Italy.
| | - Luigi Di Carlo
- Department of Medicine and Science of Aging, University G. d'Annunzio, Chieti-Pescara, Via dei Vestini 31, Chieti Scalo, 66013, Chieti, CH, Italy
| | - Sandra Verna
- Immunohaematology and Transfusional Medicine Service, "SS. Annunziata" Hospital, Chieti Scalo, Chieti, Italy
| | - Patrizia Di Gregorio
- Immunohaematology and Transfusional Medicine Service, "SS. Annunziata" Hospital, Chieti Scalo, Chieti, Italy
| | - Cosima Schiavone
- Department of Medicine and Science of Aging, University G. d'Annunzio, Chieti-Pescara, Via dei Vestini 31, Chieti Scalo, 66013, Chieti, CH, Italy
| | - Vincenzo Salini
- Department of Medicine and Science of Aging, University G. d'Annunzio, Chieti-Pescara, Via dei Vestini 31, Chieti Scalo, 66013, Chieti, CH, Italy
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31
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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: 107] [Impact Index Per Article: 15.3] [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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32
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Mucke HA. Patent highlights August-September 2017. Pharm Pat Anal 2018; 7:7-14. [PMID: 29219751 DOI: 10.4155/ppa-2017-0037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2017] [Accepted: 11/07/2017] [Indexed: 11/17/2022]
Abstract
A snapshot of noteworthy recent developments in the patent literature of relevance to pharmaceutical and medical research and development.
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34
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Wu S, Peng H, Li X, Streubel PN, Liu Y, Duan B. Effect of scaffold morphology and cell co-culture on tenogenic differentiation of HADMSC on centrifugal melt electrospun poly (L‑lactic acid) fibrous meshes. Biofabrication 2017; 9:044106. [PMID: 29134948 PMCID: PMC5849472 DOI: 10.1088/1758-5090/aa8fb8] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Engineered tendon grafts offer a promising alternative for grafting during the reconstruction of complex tendon tears. The tissue-engineered tendon substitutes have the advantage of increased biosafety and the option to customize their biochemical and biophysical properties to promote tendon regeneration. In this study, we developed a novel centrifugal melt electrospinning (CME) technique, with the goal of optimizing the fabrication parameters to generate fibrous scaffolds for tendon tissue engineering. The effects of CME processing parameters, including rotational speed, voltage, and temperature, on fiber properties (i.e. orientation, mean diameter, and productivity) were systematically investigated. By using this solvent-free and environmentally friendly method, we fabricated both random and aligned poly (L-lactic acid) (PLLA) fibrous scaffolds with controllable mesh thickness. We also investigated and compared their morphology, surface hydrophilicity, and mechanical properties. We seeded human adipose derived mesenchymal stem cells (HADMSC) on various PLLA fibrous scaffolds and conditioned the constructs in tenogenic differentiation medium for up to 21 days, to investigate the effects of fiber alignment and scaffold thickness on cell behavior. Aligned fibrous scaffolds induced cell elongation and orientation through a contact guidance phenomenon and promoted HADMSC proliferation and differentiation towards tenocytes. At the early stage, thinner scaffolds were beneficial for HADMSC proliferation, but the scaffold thickness had no significant effects on cell proliferation for longer-term cell culture. We further co-seeded HADMSC and human umbilical vein endothelial cells (HUVEC) on aligned PLLA fibrous mats and determined how the vascularization affected HADMSC tenogenesis. We found that co-cultured HADMSC-HUVEC expressed more tendon-related markers on the aligned fibrous scaffold. The co-culture systems promoted in vitro HADMSC differentiation towards tenocytes. These aligned fibrous scaffolds fabricated by CME technique could potentially be utilized to repair and regenerate tendon defects and injuries with cell co-culture and controlled vascularization.
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Affiliation(s)
- Shaohua Wu
- Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE, USA
- Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Hao Peng
- College of Mechanical and Electric Engineering, Beijing University of Chemical Technology, Beijing 100029, China
| | - Xiuhong Li
- College of Mechanical and Electric Engineering, Beijing University of Chemical Technology, Beijing 100029, China
| | - Philipp N. Streubel
- Department of Orthopedic Surgery and Rehabilitation, University of Nebraska Medical Center, Omaha, NE, USA
| | - Yong Liu
- College of Mechanical and Electric Engineering, Beijing University of Chemical Technology, Beijing 100029, China
| | - Bin Duan
- Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE, USA
- Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
- Department of Surgery, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
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35
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Wu S, Wang Y, Streubel PN, Duan B. Living nanofiber yarn-based woven biotextiles for tendon tissue engineering using cell tri-culture and mechanical stimulation. Acta Biomater 2017; 62:102-115. [PMID: 28864251 PMCID: PMC5623069 DOI: 10.1016/j.actbio.2017.08.043] [Citation(s) in RCA: 123] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Revised: 08/16/2017] [Accepted: 08/28/2017] [Indexed: 12/28/2022]
Abstract
Non-woven nanofibrous scaffolds have been developed for tendon graft application by using electrospinning strategies. However, electrospun nanofibrous scaffolds face some obstacles and limitations, including suboptimal scaffold structure, weak tensile and suture-retention strengths, and compact structure for cell infiltration. In this work, a novel nanofibrous, woven biotextile, fabricated based on electrospun nanofiber yarns, was implemented as a tissue engineered tendon scaffold. Based on our modified electrospinning setup, polycaprolactone (PCL) nanofiber yarns were fabricated with reproducible quality, and were further processed into plain-weaving fabrics interlaced with polylactic acid (PLA) multifilaments. Nonwoven nanofibrous PCL meshes with random or aligned fiber structures were generated using typical electrospinning as comparative counterparts. The woven fabrics contained 3D aligned microstructures with significantly larger pore size and obviously enhanced tensile mechanical properties than their nonwoven counterparts. The biological results revealed that cell proliferation and infiltration, along with the expression of tendon-specific genes by human adipose derived mesenchymal stem cells (HADMSC) and human tenocytes (HT), were significantly enhanced on the woven fabrics compared with those on randomly-oriented or aligned nanofiber meshes. Co-cultures of HADMSC with HT or human umbilical vein endothelial cells (HUVEC) on woven fabrics significantly upregulated the functional expression of most tenogenic markers. HADMSC/HT/HUVEC tri-culture on woven fabrics showed the highest upregulation of most tendon-associated markers than all the other mono- and co-culture groups. Furthermore, we conditioned the tri-cultured constructs with dynamic conditioning and demonstrated that dynamic stretch promoted total collagen secretion and tenogenic differentiation. Our nanofiber yarn-based biotextiles have significant potential to be used as engineered scaffolds to synergize the multiple cell interaction and mechanical stimulation for promoting tendon regeneration. STATEMENT OF SIGNIFICANCE Tendon grafts are essential for the treatment of various tendon-related conditions due to the inherently poor healing capacity of native tendon tissues. In this study, we combined electrospun nanofiber yarns with textile manufacturing strategies to fabricate nanofibrous woven biotextiles with hierarchical features, aligned fibrous topography, and sufficient mechanical properties as tendon tissue engineered scaffolds. Comparing to traditional electrospun random or aligned meshes, our novel nanofibrous woven fabrics possess strong tensile and suture-retention strengths and larger pore size. We also demonstrated that the incorporation of tendon cells and vascular cells promoted the tenogenic differentiation of the engineered tendon constructs, especially under dynamic stretch. This study not only presents a novel tissue engineered tendon scaffold fabrication technique but also provides a useful strategy to promote tendon differentiation and regeneration.
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Affiliation(s)
- Shaohua Wu
- Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE, USA; Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Ying Wang
- Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE, USA; Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Philipp N Streubel
- Department of Orthopedic Surgery and Rehabilitation, University of Nebraska Medical Center, Omaha, NE, USA
| | - Bin Duan
- Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE, USA; Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA; Department of Surgery, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
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Abstract
Tendons connect muscles to bones, ensuring joint movement. With advanced age, tendons become more prone to degeneration followed by injuries. Tendon repair often requires lengthy periods of rehabilitation, especially in elderly patients. Existing medical and surgical treatments often fail to regain full tendon function. The development of novel treatment methods has been hampered due to limited understanding of basic tendon biology. Recently, it was discovered that tendons, similar to other mesenchymal tissues, contain tendon stem/progenitor cells (TSPCs) which possess the common stem cell properties. The current strategies for enhancing tendon repair consist mainly of applying stem cells, growth factors, natural and artificial biomaterials alone or in combination. In this review, we summarise the basic biology of tendon tissues and provide an update on the latest repair proposals for tendon tears. Cite this article: EFORT Open Rev 2017;2:332-342. DOI: 10.1302/2058-5241.2.160075
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Affiliation(s)
- Fan Wu
- Experimental Surgery and Regenerative Medicine, Department of Surgery, Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Michael Nerlich
- Department of Trauma Surgery, University Regensburg Medical Center, Regensburg, Germany
| | - Denitsa Docheva
- Experimental Trauma Surgery, Department of Trauma Surgery, University Regensburg Medical Center, Regensburg, Germany and Department of Medical Biology, Medical University-Plovdiv, Plovdiv, Bulgaria
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37
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Downregulation of CITED2 contributes to TGFβ-mediated senescence of tendon-derived stem cells. Cell Tissue Res 2017; 368:93-104. [PMID: 28084522 DOI: 10.1007/s00441-016-2552-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2016] [Accepted: 11/29/2016] [Indexed: 02/07/2023]
Abstract
Tendon-derived stem cells (TDSCs) are multipotent adult stem cells with potential applications in tendon and tendon-bone junction repair. However, cellular characteristics change during in vitro passaging. Therefore, elucidation of the molecular and cellular mechanisms of tendon aging will be essential for the development of TDSC-based therapies. The aim of this study is to investigate the effect of CITED2, a nuclear regulator and transforming growth factor β2 (TGFβ2) on TDSC proliferation and senescence by comparing cells derived from Achilles tendon biopsies of young individuals (Y-TDSC) with those of older patients (O-TDSC). Our results showed that CITED2 mRNA and protein expression levels were significantly higher in Y-TDSCs than in O-TDSCs and O-TDSCs displayed decreased proliferation and increased senescence compared with Y-TDSCs. Furthermore, high levels of CITED2 protein expression in Y-TDSCs correlated with the downregulation of SP1 and p21 and the upregulation of MYC, potentially indicating the mechanism by which CITED2 upregulates TDSC proliferation. TGFβ2 was found to downregulate the expression of the CITED2 gene and knockdown of CITED2 abolished the effect of TGFβ2 on TDSC proliferation and senescence. Thus, the downregulation of CITED2 contributes to TGFβ-mediated senescence providing an insight into the molecular and cellular mechanisms that contribute to tendon aging and degeneration. Our findings may aid the development of cell-based therapies for tendon repair.
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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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Dex S, Lin D, Shukunami C, Docheva D. Tenogenic modulating insider factor: Systematic assessment on the functions of tenomodulin gene. Gene 2016; 587:1-17. [PMID: 27129941 DOI: 10.1016/j.gene.2016.04.051] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Revised: 04/20/2016] [Accepted: 04/25/2016] [Indexed: 02/08/2023]
Abstract
Tenomodulin (TNMD, Tnmd) is a gene highly expressed in tendon known to be important for tendon maturation with key implications for the residing tendon stem/progenitor cells as well as for the regulation of endothelial cell migration in chordae tendineae cordis in the heart and in experimental tumour models. This review aims at providing an encompassing overview of this gene and its protein. In addition, its known expression pattern as well as putative signalling pathways will be described. A chronological overview of the discovered functions of this gene in tendon and other tissues and cells is provided as well as its use as a tendon and ligament lineage marker is assessed in detail and discussed. Last, information about the possible connections between TNMD genomic mutations and mRNA expression to various diseases is delivered. Taken together this review offers a solid synopsis on the up-to-date information available about TNMD and aids at directing and focusing the future research to fully uncover the roles and implications of this interesting gene.
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Affiliation(s)
- Sarah Dex
- Experimental Surgery and Regenerative Medicine, Department of Surgery, Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Dasheng Lin
- Experimental Surgery and Regenerative Medicine, Department of Surgery, Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Chisa Shukunami
- Department of Molecular Biology and Biochemistry, Division of Basic Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Denitsa Docheva
- Experimental Surgery and Regenerative Medicine, Department of Surgery, Ludwig-Maximilians-University (LMU), Munich, Germany; Department of Medical Biology, Medical University-Plovdiv, Plovdiv, Bulgaria.
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Influence of Ageing on Tendon Homeostasis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 920:247-60. [DOI: 10.1007/978-3-319-33943-6_24] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Salini V, Vanni D, Pantalone A, Abate M. Platelet Rich Plasma Therapy in Non-insertional Achilles Tendinopathy: The Efficacy is Reduced in 60-years Old People Compared to Young and Middle-Age Individuals. Front Aging Neurosci 2015; 7:228. [PMID: 26696880 PMCID: PMC4674567 DOI: 10.3389/fnagi.2015.00228] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Accepted: 11/23/2015] [Indexed: 12/15/2022] Open
Abstract
Background: Platelet Rich Plasma (PRP) has shown positive and long-lasting effects in patients with tendinopathies. However, information about age-related differences in the clinical outcome is limited. Aim of this retrospective study was to compare the efficacy of PRP therapy in young and elderly subjects suffering for Achilles tendinopathy. Materials and method: Patients with recalcitrant non-insertional Achilles tendinopathy were enrolled. Clinical (VISA-A) and instrumental (ultrasonography) data were collected at baseline and after 1, 3, 6, and 12 months. PRP injections (once a week for 3 weeks) were performed in sterile conditions and under ultrasound (US) control. Results: Forty-four subjects (29 young: mean age 39.5 ± 6.9; 15 elderly: mean age 61.5 ± 5.3) were retrospectively evaluated. At baseline, no significant differences were observed in the clinical and US parameters. Throughout the whole length of the study, a significant increase of VISA-A score was seen in both groups (from 50.3 ± 8.8 to 76.1 ± 6.6 in the young group, and from 48.7 ± 7.6 to 61.1 ± 9.4 in the elderly group); however, the infra-groups comparison showed better results in young patients, compared to the aged counterpart. Conclusion: Our results show that PRP is less effective in aged people. This finding can be ascribed to several biochemical and biomechanical differences documented in tendons of young and elderly subjects (reduced number and functionality of tenocytes and tenoblasts), which becomes more evident in the long-term tissue healing. However, prospective trials, using different PRP preparations and enrolling a larger number of subjects, are needed to draw more sound and definitive conclusions.
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Affiliation(s)
- Vincenzo Salini
- Orthopaedic and Traumatalogical Clinic, Department of Medicine and Science of Aging, Università degli Studi "G. d'Annunzio" Chieti-Pescara Chieti, Italy
| | - Daniele Vanni
- Orthopaedic and Traumatalogical Clinic, Department of Medicine and Science of Aging, Università degli Studi "G. d'Annunzio" Chieti-Pescara Chieti, Italy
| | - Andrea Pantalone
- Orthopaedic and Traumatalogical Clinic, Department of Medicine and Science of Aging, Università degli Studi "G. d'Annunzio" Chieti-Pescara Chieti, Italy
| | - Michele Abate
- Orthopaedic and Traumatalogical Clinic, Department of Medicine and Science of Aging, Università degli Studi "G. d'Annunzio" Chieti-Pescara Chieti, Italy
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Tempfer H, Traweger A. Tendon Vasculature in Health and Disease. Front Physiol 2015; 6:330. [PMID: 26635616 PMCID: PMC4650849 DOI: 10.3389/fphys.2015.00330] [Citation(s) in RCA: 95] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Accepted: 11/02/2015] [Indexed: 01/24/2023] Open
Abstract
Tendons represent a bradytrophic tissue which is poorly vascularized and, compared to bone or skin, heal poorly. Usually, a vascularized connective scar tissue with inferior functional properties forms at the injury site. Whether the increased vascularization is the root cause of tissue impairments such as loss of collagen fiber orientation, ectopic formation of bone, fat or cartilage, or is a consequence of these pathological changes remains unclear. This review provides an overview of the role of tendon vasculature in healthy and chronically diseased tendon tissue as well as its relevance for tendon repair. Further, the nature and the role of perivascular tendon stem/progenitor cells residing in the vascular niche will be discussed and compared to multipotent stromal cells in other tissues.
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Affiliation(s)
- Herbert Tempfer
- Spinal Cord Injury and Tissue Regeneration Centre Salzburg, Institute of Tendon and Bone Regeneration, Paracelsus Medical University Salzburg, Austria ; Austrian Cluster for Tissue Regeneration Vienna, Austria
| | - Andreas Traweger
- Spinal Cord Injury and Tissue Regeneration Centre Salzburg, Institute of Tendon and Bone Regeneration, Paracelsus Medical University Salzburg, Austria ; Austrian Cluster for Tissue Regeneration Vienna, Austria
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Kunkel N, Wagner A, Gehwolf R, Heimel P, Tempfer H, Korntner S, Augat P, Resch H, Redl H, Betz O, Bauer HC, Traweger A. Comparing the osteogenic potential of bone marrow and tendon-derived stromal cells to repair a critical-sized defect in the rat femur. J Tissue Eng Regen Med 2015; 11:2014-2023. [PMID: 26510918 DOI: 10.1002/term.2097] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Revised: 06/23/2015] [Accepted: 09/15/2015] [Indexed: 12/24/2022]
Abstract
Despite significant advancements in bone tissue-engineering applications, the clinical impact of bone marrow stromal cells (BMSCs) for the treatment of large osseous defects remains limited. Therefore, other cell sources are under investigation for their osteogenic potential to repair bone. In this study, tendon-derived stromal cells (TDSCs) were evaluated in comparison to BMSCs to support the functional repair of a 5 mm critical-sized, segmental defect in the rat femur. Analysis of the trilineage differentiation capacity of TDSCs and BMSCs cultured on collagen sponges revealed impaired osteogenic differentiation and mineral deposition of TDSCs in vitro, whereas chondrogenic and adipogenic differentiation was evident for both cell types. Radiographic assessment demonstrated that neither cell type significantly improved the healing rate of a challenging 5 mm segmental femoral defect. Transplanted TDSCs and BMSCs both led to the formation of only small amounts of bone in the defect area, and histological evaluation revealed non-mineralized, collagen-rich scar tissue to be present within the defect area. Newly formed lamellar bone was restricted to the defect margins, resulting in closure of the medullary cavity. Interestingly, in comparison to BMSCs, significantly more TDSC-derived cells were present at the osteotomy gap up to 8 weeks after transplantation and were also found to be located within newly formed lamellar bone, suggesting their capacity to directly contribute to de novo bone formation. To our knowledge, this is the first study investigating the in vivo capacity of TDSCs to regenerate a critical-sized defect in the rat femur. Copyright © 2015 John Wiley & Sons, Ltd.
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Affiliation(s)
- Nadja Kunkel
- Institute of Tendon and Bone Regeneration, Paracelsus Medical University, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Austria.,Department of Traumatology and Sports Injuries, Paracelsus Medical University, Salzburg, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Andrea Wagner
- Institute of Tendon and Bone Regeneration, Paracelsus Medical University, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Renate Gehwolf
- Institute of Tendon and Bone Regeneration, Paracelsus Medical University, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Patrick Heimel
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Herbert Tempfer
- Institute of Tendon and Bone Regeneration, Paracelsus Medical University, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Stefanie Korntner
- Institute of Tendon and Bone Regeneration, Paracelsus Medical University, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Peter Augat
- Institute of Biomechanics, Trauma Center Murnau, Germany
| | - Herbert Resch
- Department of Traumatology and Sports Injuries, Paracelsus Medical University, Salzburg, Austria
| | - Heinz Redl
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Oliver Betz
- Laboratory for Biomechanics and Experimental Orthopaedics, Department of Orthopaedic Surgery, Hospital Grosshadern, Munich, Germany
| | - Hans-Christian Bauer
- Institute of Tendon and Bone Regeneration, Paracelsus Medical University, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Andreas Traweger
- Institute of Tendon and Bone Regeneration, Paracelsus Medical University, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Austria.,Austrian Cluster for Tissue Regeneration, Vienna, Austria
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Study of Bone Marrow Mesenchymal and Tendon-Derived Stem Cells Transplantation on the Regenerating Effect of Achilles Tendon Ruptures in Rats. Stem Cells Int 2015; 2015:984146. [PMID: 26339252 PMCID: PMC4539207 DOI: 10.1155/2015/984146] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Accepted: 12/23/2014] [Indexed: 12/19/2022] Open
Abstract
Comparative therapeutic significance of tendon-derived stem cells (TDSCs) and bone marrow mesenchymal stem cells (BMSCs) transplantation to treat ruptured Achilles tendon was studied. Three groups of SD rats comprising 24 rats each, designated as TDSCs and BMSCs, and nontreated were studied for regenerative effects through morpho-histological evaluations and ultimate failure load. For possible mechanism in tendon repair/regeneration through TDSCs and BMSCs, we measured Collagen-I (Col-I), Col-III gene expression level by RT-PCR, and Tenascin-C expression via immunofluorescent assay. TDSCs showed higher agility in tendon healing with better appearance density and well-organized longitudinal fibrous structure, though BMSCs also showed positive effects. Initially the ultimate failure load was considerably higher in TDSCs than other two study groups during the weeks 1 and 2, but at week 4 it attained an average or healthy tendon strength of 30.2 N. Similar higher tendency in Col-I/III gene expression level during weeks 1, 2, and 4 was observed in TDSCs treated group with an upregulation of 1.5-fold and 1.1-fold than the other two study groups. Immunofluorescent assay revealed higher expression of Tenascin-C in TDSCs at week 1, while both TDSCs and BMSCs treated groups showed detectable CM-Dil-labelled cells at week 4. Compared with BMSCs, TDSCs showed higher regenerative potential while treating ruptured Achilles tendons in rats.
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Dyment NA, Galloway JL. Regenerative biology of tendon: mechanisms for renewal and repair. ACTA ACUST UNITED AC 2015; 1:124-131. [PMID: 26389023 DOI: 10.1007/s40610-015-0021-3] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Understanding the molecular and cellular mechanisms underlying tissue turnover and repair are essential towards addressing pathologies in aging, injury and disease. Each tissue has distinct means of maintaining homeostasis and healing after injury. For some, resident stem cell populations mediate both of these processes. These stem cells, by definition, are self renewing and give rise to all the differentiated cells of that tissue. However, not all organs fit with this traditional stem cell model of regeneration, and some do not appear to harbor somatic stem or progenitor cells capable of multilineage in vivo reconstitution. Despite recent progress in tendon progenitor cell research, our current knowledge of the mechanisms regulating tendon cell homeostasis and injury response is limited. Understanding the role of resident tendon cell populations is of great importance for regenerative medicine based approaches to tendon injuries and disease. The goal of this review is to bring to light our current knowledge regarding tendon progenitor cells and their role in tissue maintenance and repair. We will focus on pressing questions in the field and the new tools, including model systems, available to address them.
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Affiliation(s)
- Nathaniel A Dyment
- Center for Regenerative Medicine and Skeletal Development, Department of Reconstructive Sciences, School of Dental Medicine, University of Connecticut Health Center
| | - Jenna L Galloway
- Center for Regenerative Medicine, Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, Harvard Stem Cell Institute
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46
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Sun HB, Schaniel C, Leong DJ, Wang JHC. Biology and mechano-response of tendon cells: Progress overview and perspectives. J Orthop Res 2015; 33:785-92. [PMID: 25728946 PMCID: PMC4422159 DOI: 10.1002/jor.22885] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 02/24/2015] [Indexed: 02/04/2023]
Abstract
In this review, we summarize the group discussions on Cell Biology & Mechanics from the 2014 ORS/ISMMS New Frontiers in Tendon Research Conference. The major discussion topics included: (1) the biology of tendon stem/progenitor cells (TSPCs) and the potential of stem cell-based tendon therapy using TSPCs and other types of stem cells, namely, embryonic and/or induced pluripotent stem cells (iPSCs), (2) the biological concept and potential impact of cellular senescence on tendon aging, tendon injury repair and the development of degenerative disease, and (3) the effects of tendon cells' mechano-response on tendon cell fate and metabolism. For each topic, a brief overview is presented which summarizes the major points discussed by the group participants. The focus of the discussions ranged from current research progress, challenges and opportunities, to future directions on these topics. In the preparation of this manuscript, authors consulted relevant references as a part of their efforts to present an accurate view on the topics discussed.
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Affiliation(s)
- Hui B. Sun
- Department of Orthopaedic Surgery, Albert Einstein College of Medicine, Bronx, NY
,Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, NY
,Corresponding Author: 1300 Morris Park Avenue, Golding 101 Bronx, NY 10461 USA Tel: (718) 430-4291 Fax: (718) 430-3259
| | - Christoph Schaniel
- Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY
,Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY
,Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Daniel J. Leong
- Department of Orthopaedic Surgery, Albert Einstein College of Medicine, Bronx, NY
,Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, NY
| | - James H-C. Wang
- Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA
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Abstract
Tendon injuries are common and present a clinical challenge to orthopedic surgery mainly because these injuries often respond poorly to treatment and require prolonged rehabilitation. Therapeutic options used to repair ruptured tendons have consisted of suture, autografts, allografts, and synthetic prostheses. To date, none of these alternatives has provided a successful long-term solution, and often the restored tendons do not recover their complete strength and functionality. Unfortunately, our understanding of tendon biology lags far behind that of other musculoskeletal tissues, thus impeding the development of new treatment options for tendon conditions. Hence, in this review, after introducing the clinical significance of tendon diseases and the present understanding of tendon biology, we describe and critically assess the current strategies for enhancing tendon repair by biological means. These consist mainly of applying growth factors, stem cells, natural biomaterials and genes, alone or in combination, to the site of tendon damage. A deeper understanding of how tendon tissue and cells operate, combined with practical applications of modern molecular and cellular tools could provide the long awaited breakthrough in designing effective tendon-specific therapeutics and overall improvement of tendon disease management.
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Gaspar D, Spanoudes K, Holladay C, Pandit A, Zeugolis D. Progress in cell-based therapies for tendon repair. Adv Drug Deliv Rev 2015; 84:240-56. [PMID: 25543005 DOI: 10.1016/j.addr.2014.11.023] [Citation(s) in RCA: 134] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Revised: 11/08/2014] [Accepted: 11/12/2014] [Indexed: 02/07/2023]
Abstract
The last decade has seen significant developments in cell therapies, based on permanently differentiated, reprogrammed or engineered stem cells, for tendon injuries and degenerative conditions. In vitro studies assess the influence of biophysical, biochemical and biological signals on tenogenic phenotype maintenance and/or differentiation towards tenogenic lineage. However, the ideal culture environment has yet to be identified due to the lack of standardised experimental setup and readout system. Bone marrow mesenchymal stem cells and tenocytes/dermal fibroblasts appear to be the cell populations of choice for clinical translation in equine and human patients respectively based on circumstantial, rather than on hard evidence. Collaborative, inter- and multi-disciplinary efforts are expected to provide clinically relevant and commercially viable cell-based therapies for tendon repair and regeneration in the years to come.
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Affiliation(s)
- Diana Gaspar
- Network of Excellence for Functional Biomaterials (NFB), National University of Ireland, Galway (NUI Galway), Galway, Ireland
| | - Kyriakos Spanoudes
- Network of Excellence for Functional Biomaterials (NFB), National University of Ireland, Galway (NUI Galway), Galway, Ireland
| | - Carolyn Holladay
- Network of Excellence for Functional Biomaterials (NFB), National University of Ireland, Galway (NUI Galway), Galway, Ireland
| | - Abhay Pandit
- Network of Excellence for Functional Biomaterials (NFB), National University of Ireland, Galway (NUI Galway), Galway, Ireland
| | - Dimitrios Zeugolis
- Network of Excellence for Functional Biomaterials (NFB), National University of Ireland, Galway (NUI Galway), Galway, Ireland.
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Lomas A, Ryan C, Sorushanova A, Shologu N, Sideri A, Tsioli V, Fthenakis G, Tzora A, Skoufos I, Quinlan L, O'Laighin G, Mullen A, Kelly J, Kearns S, Biggs M, Pandit A, Zeugolis D. The past, present and future in scaffold-based tendon treatments. Adv Drug Deliv Rev 2015; 84:257-77. [PMID: 25499820 DOI: 10.1016/j.addr.2014.11.022] [Citation(s) in RCA: 150] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Revised: 11/08/2014] [Accepted: 11/12/2014] [Indexed: 02/07/2023]
Abstract
Tendon injuries represent a significant clinical burden on healthcare systems worldwide. As the human population ages and the life expectancy increases, tendon injuries will become more prevalent, especially among young individuals with long life ahead of them. Advancements in engineering, chemistry and biology have made available an array of three-dimensional scaffold-based intervention strategies, natural or synthetic in origin. Further, functionalisation strategies, based on biophysical, biochemical and biological cues, offer control over cellular functions; localisation and sustained release of therapeutics/biologics; and the ability to positively interact with the host to promote repair and regeneration. Herein, we critically discuss current therapies and emerging technologies that aim to transform tendon treatments in the years to come.
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Mechanical stimulation of human tendon stem/progenitor cells results in upregulation of matrix proteins, integrins and MMPs, and activation of p38 and ERK1/2 kinases. BMC Mol Biol 2015; 16:6. [PMID: 25880261 PMCID: PMC4373449 DOI: 10.1186/s12867-015-0036-6] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Accepted: 02/24/2015] [Indexed: 01/07/2023] Open
Abstract
Background Tendons are dense connective tissues subjected periodically to mechanical stress upon which complex responsive mechanisms are activated. These mechanisms affect not only the development of these tissues but also their healing. Despite of the acknowledged importance of the mechanical stress for tendon function and repair, the mechanotransduction mechanisms in tendon cells are still unclear and the elucidation of these mechanisms is a key goal in tendon research. Tendon stem/progenitor cells (TSPC) possess common adult stem cell characteristics, and are suggested to actively participate in tendon development, tissue homeostasis as well as repair. This makes them an important cell population for tendon repair, and also an interesting research target for various open questions in tendon cell biology. Therefore, in our study we focused on TSPC, subjected them to five different mechanical protocols, and investigated the gene expression changes by using semi-quantitative, quantitative PCR and western blotting technologies. Results Among the 25 different genes analyzed, we can convincingly report that the tendon-related genes - fibromodulin, lumican and versican, the collagen I-binding integrins - α1, α2 and α11, the matrix metalloproteinases - MMP9, 13 and 14 were strongly upregulated in TSPC after 3 days of mechanical stimulation with 8% amplitude. Molecular signaling analyses of five key integrin downstream kinases suggested that mechanical stimuli are mediated through ERK1/2 and p38, which were significantly activated in 8% biaxial-loaded TSPC. Conclusions Our results demonstrate the positive effect of 8% mechanical loading on the gene expression of matrix proteins, integrins and matrix metalloproteinases, and activation of integrin downstream kinases p38 and ERK1/2 in TSPC. Taken together, our study contributes to better understanding of mechanotransduction mechanisms in TPSC, which in long term, after further translational research between tendon cell biology and orthopedics, can be beneficial to the management of tendon repair. Electronic supplementary material The online version of this article (doi:10.1186/s12867-015-0036-6) contains supplementary material, which is available to authorized users.
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