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A Road Map to Tendon Regeneration
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A Road Map to Tendon Regeneration

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (15 September 2023) | Viewed by 7339

Special Issue Editors

Dr. Márcia T. Rodrigues

E-Mail Website
Guest Editor
3B’s Research Group, I3Bs—Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, 4805-017 Barco, Guimarães, Portugal
Interests: inflammation; stem cells; musculoskeletal tissues; magnetic assisted technologies; biomaterials; inflammation models; tissue engineering; regenerative medicine
Dr. Manuela E. Gomes

E-Mail Website
Guest Editor
3B’s Research Group, University of Minho, Barco, 4805‐017 Guimarães, Portugal
Interests: tissue engineering; stem cells; bioreactors; scaffolds; musculoskeletal tissues

Special Issue Information

Dear Colleagues,

The repair of tendon injuries still represents an unmet clinical challenge, and the dynamic interactions as well as cooperation between cellular subsets and the extracellular matrix are critical for biological processes and microenvironmental homeostasis.

Unveiling the mechanisms that modulate the phenotypes of tendon-resident cell populations, the recreation of biomechanical stimuli, and the deep understanding of the cell–matrix interplay to assure tendon functional competence and structural integrity could pave the way to effective tendon regenerative responses. Moreover, the disruption of tissue functionalities may facilitate an inflammatory milieu and the development of tendon pathologies, offering opportunities for identifying therapeutic targets and pathophysiological mediators. Thus, it is timely and relevant to propose new strategies and models that determine the specificities of tendon tissues according to tendon function and mechanoelastic properties.

This Special Issue will cover recent insights into the mechanisms associated with tendon regeneration, considering both physiological and pathological environments with the potential to elucidate cell phenotypic roles and cell communication mediators as well as to identify potential therapeutic targets with which to mitigate inflammation and drive tendon regeneration.

Dr. Márcia T. Rodrigues
Prof. Dr. Manuela E. Gomes
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

 

Keywords

  • tendon regeneration
  • tendon repair
  • tendon functional
  • cell communication

Published Papers (4 papers)

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Research

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19 pages, 2588 KiB  
Article
Examining the Potential of Vitamin C Supplementation in Tissue-Engineered Equine Superficial Digital Flexor Tendon Constructs
by Michael J. Mienaltowski, Mitchell Callahan, Nicole L. Gonzales and Angelique Wong
Int. J. Mol. Sci. 2023, 24(23), 17098; https://doi.org/10.3390/ijms242317098 - 04 Dec 2023
Viewed by 1141
Abstract
Because equine tendinopathies are slow to heal and often recur, therapeutic strategies are being considered that aid tendon repair. Given the success of utilizing vitamin C to promote tenogenesis in other species, we hypothesized that vitamin C supplementation would produce dose-dependent improvements in [...] Read more.
Because equine tendinopathies are slow to heal and often recur, therapeutic strategies are being considered that aid tendon repair. Given the success of utilizing vitamin C to promote tenogenesis in other species, we hypothesized that vitamin C supplementation would produce dose-dependent improvements in the tenogenic properties of tendon proper (TP) and peritenon (PERI) cells of the equine superficial digital flexor tendon (SDFT). Equine TP- and PERI-progenitor-cell-seeded fibrin three-dimensional constructs were supplemented with four concentrations of vitamin C. The gene expression profiles of the constructs were assessed with 3′-Tag-Seq and real-time quantitative polymerase chain reaction (RT-qPCR); collagen content and fibril ultrastructure were also analyzed. Moreover, cells were challenged with dexamethasone to determine the levels of cytoprotection afforded by vitamin C. Expression profiling demonstrated that vitamin C had an anti-inflammatory effect on TP and PERI cell constructs. Moreover, vitamin C supplementation mitigated the degenerative pathways seen in tendinopathy and increased collagen content in tendon constructs. When challenged with dexamethasone in two-dimensional culture, vitamin C had a cytoprotective effect for TP cells but not necessarily for PERI cells. Future studies will explore the effects of vitamin C on these cells during inflammation and within the tendon niche in vivo. Full article
(This article belongs to the Special Issue A Road Map to Tendon Regeneration)
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23 pages, 11537 KiB  
Article
Endotenon-Derived Type II Tendon Stem Cells Have Enhanced Proliferative and Tenogenic Potential
by Marta Clerici, Vera Citro, Amy L. Byrne, Tina P. Dale, Aldo R. Boccaccini, Giovanna Della Porta, Nicola Maffulli and Nicholas R. Forsyth
Int. J. Mol. Sci. 2023, 24(20), 15107; https://doi.org/10.3390/ijms242015107 - 12 Oct 2023
Cited by 1 | Viewed by 1079
Abstract
Tendon injuries caused by overuse or age-related deterioration are frequent. Incomplete knowledge of somatic tendon cell biology and their progenitors has hindered interventions for the effective repair of injured tendons. Here, we sought to compare and contrast distinct tendon-derived cell populations: type I [...] Read more.
Tendon injuries caused by overuse or age-related deterioration are frequent. Incomplete knowledge of somatic tendon cell biology and their progenitors has hindered interventions for the effective repair of injured tendons. Here, we sought to compare and contrast distinct tendon-derived cell populations: type I and II tendon stem cells (TSCs) and tenocytes (TNCs). Porcine type I and II TSCs were isolated via the enzymatic digestion of distinct membranes (paratenon and endotenon, respectively), while tenocytes were isolated through an explant method. Resultant cell populations were characterized by morphology, differentiation, molecular, flow cytometry, and immunofluorescence analysis. Cells were isolated, cultured, and evaluated in two alternate oxygen concentrations (physiological (2%) and air (21%)) to determine the role of oxygen in cell biology determination within this relatively avascular tissue. The different cell populations demonstrated distinct proliferative potential, morphology, and transcript levels (both for tenogenic and stem cell markers). In contrast, all tendon-derived cell populations displayed multipotent differentiation potential and immunophenotypes (positive for CD90 and CD44). Type II TSCs emerged as the most promising tendon-derived cell population for expansion, given their enhanced proliferative potential, multipotency, and maintenance of a tenogenic profile at early and late passage. Moreover, in all cases, physoxia promoted the enhanced proliferation and maintenance of a tenogenic profile. These observations help shed light on the biological mechanisms of tendon cells, with the potential to aid in the development of novel therapeutic approaches for tendon disorders. Full article
(This article belongs to the Special Issue A Road Map to Tendon Regeneration)
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21 pages, 11595 KiB  
Article
MiRNAs as Potential Regulators of Enthesis Healing: Findings in a Rodent Injury Model
by Carlos Julio Peniche Silva, Rodolfo E. De La Vega, Joseph Panos, Virginie Joris, Christopher H. Evans, Elizabeth R. Balmayor and Martijn van Griensven
Int. J. Mol. Sci. 2023, 24(10), 8556; https://doi.org/10.3390/ijms24108556 - 10 May 2023
Cited by 1 | Viewed by 1770
Abstract
MicroRNAs (miRNAs) are short non-coding RNA sequences with the ability to inhibit the expression of a target mRNA at the post-transcriptional level, acting as modulators of both the degenerative and regenerative processes. Therefore, these molecules constitute a potential source of novel therapeutic tools. [...] Read more.
MicroRNAs (miRNAs) are short non-coding RNA sequences with the ability to inhibit the expression of a target mRNA at the post-transcriptional level, acting as modulators of both the degenerative and regenerative processes. Therefore, these molecules constitute a potential source of novel therapeutic tools. In this study, we investigated the miRNA expression profile that presented in enthesis tissue upon injury. For this, a rodent enthesis injury model was developed by creating a defect at a rat’s patellar enthesis. Following injury, explants were collected on days 1 (n = 10) and 10 (n = 10). Contra lateral samples (n = 10) were harvested to be used for normalization. The expression of miRNAs was investigated using a “Fibrosis” pathway-focused miScript qPCR array. Later, target prediction for the aberrantly expressed miRNAs was performed by means of the Ingenuity Pathway Analysis, and the expression of mRNA targets relevant for enthesis healing was confirmed using qPCRs. Additionally, the protein expression levels of collagens I, II, III, and X were investigated using Western blotting. The mRNA expression pattern of EGR1, COL2A1, RUNX2, SMAD1, and SMAD3 in the injured samples indicated their possible regulation by their respective targeting miRNA, which included miR-16, -17, -100, -124, -133a, -155 and -182. Furthermore, the protein levels of collagens I and II were reduced directly after the injury (i.e., day 1) and increased 10 days post-injury, while collagens III and X showed the opposite pattern of expression. Full article
(This article belongs to the Special Issue A Road Map to Tendon Regeneration)
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Review

Jump to: Research

22 pages, 1107 KiB  
Review
Anatomical Tissue Engineering of the Anterior Cruciate Ligament Entheses
by Clemens Gögele, Judith Hahn and Gundula Schulze-Tanzil
Int. J. Mol. Sci. 2023, 24(11), 9745; https://doi.org/10.3390/ijms24119745 - 05 Jun 2023
Cited by 4 | Viewed by 2619
Abstract
The firm integration of anterior cruciate ligament (ACL) grafts into bones remains the most demanding challenge in ACL reconstruction, since graft loosening means graft failure. For a functional-tissue-engineered ACL substitute to be realized in future, robust bone attachment sites (entheses) have to be [...] Read more.
The firm integration of anterior cruciate ligament (ACL) grafts into bones remains the most demanding challenge in ACL reconstruction, since graft loosening means graft failure. For a functional-tissue-engineered ACL substitute to be realized in future, robust bone attachment sites (entheses) have to be re-established. The latter comprise four tissue compartments (ligament, non-calcified and calcified fibrocartilage, separated by the tidemark, bone) forming a histological and biomechanical gradient at the attachment interface between the ACL and bone. The ACL enthesis is surrounded by the synovium and exposed to the intra-articular micromilieu. This review will picture and explain the peculiarities of these synovioentheseal complexes at the femoral and tibial attachment sites based on published data. Using this, emerging tissue engineering (TE) strategies addressing them will be discussed. Several material composites (e.g., polycaprolactone and silk fibroin) and manufacturing techniques (e.g., three-dimensional-/bio-printing, electrospinning, braiding and embroidering) have been applied to create zonal cell carriers (bi- or triphasic scaffolds) mimicking the ACL enthesis tissue gradients with appropriate topological parameters for zones. Functionalized or bioactive materials (e.g., collagen, tricalcium phosphate, hydroxyapatite and bioactive glass (BG)) or growth factors (e.g., bone morphogenetic proteins [BMP]-2) have been integrated to achieve the zone-dependent differentiation of precursor cells. However, the ACL entheses comprise individual (loading history) asymmetric and polar histoarchitectures. They result from the unique biomechanical microenvironment of overlapping tensile, compressive and shear forces involved in enthesis formation, maturation and maintenance. This review should provide a road map of key parameters to be considered in future in ACL interface TE approaches. Full article
(This article belongs to the Special Issue A Road Map to Tendon Regeneration)
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