Tenomodulin knockout mice exhibit worse late healing outcomes with augmented trauma-induced heterotopic ossification of Achilles tendon

Caceres, Manuel Delgado; Angerpointner, Katharina; Galler, Michael A.; Lin, Dasheng; Michel, P.; Brochhausen, Christoph; Lü, Xin; Varadarajan, Adithi R.; Warfsmann, Jens; Stange, Richard; Alt, Volker; Pfeifer, Christian; Docheva, Denitsa

doi:10.1038/s41419-021-04298-z

Cited by 22 publications

(15 citation statements)

References 52 publications

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“…TGF‐β1 and iNOS, which were used as scar and inflammation markers, respectively, 46 were most prominent in the Scaffold only group (Figure 6C,D). CD45 and CD68, which were employed as leukocyte markers, 47 , 48 showed lymphocyte and macrophage infiltration mostly in the Suture only group (Figure 6E,F). In comparison, only a few CD45 + and CD68 + cells were observed in the Scaffold only group, and little to no immune cells were detected in the Scaffold + iMSC SCX+ group.…”

Section: Resultsmentioning

confidence: 96%

“…In comparison, only a few CD45 + and CD68 + cells were observed in the Scaffold only group, and little to no immune cells were detected in the Scaffold + iMSC SCX+ group. COMP, FBN, and BGN, which were used as markers of tendon scarring, 46–48 were found to be most highly expressed in the Suture only group, with less prominent expression in the Scaffold only and the Scaffold + iMSC SCX+ groups (Figure 6D–F).…”

Section: Resultsmentioning

confidence: 98%

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iPSC‐derived tenocytes seeded on microgrooved 3D printed scaffolds for Achilles tendon regeneration

Kaneda

Chan

Castaneda

et al. 2023

Journal Orthopaedic Research

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Tendons and ligaments have a poor innate healing capacity, yet account for 50% of musculoskeletal injuries in the United States. Full structure and function restoration postinjury remains an unmet clinical need. This study aimed to assess the application of novel three dimensional (3D) printed scaffolds and induced pluripotent stem cell‐derived mesenchymal stem cells (iMSCs) overexpressing the transcription factor Scleraxis (SCX, iMSCSCX+) as a new strategy for tendon defect repair. The polycaprolactone (PCL) scaffolds were fabricated by extrusion through a patterned nozzle or conventional round nozzle. Scaffolds were seeded with iMSCSCX+ and outcomes were assessed in vitro via gene expression analysis and immunofluorescence. In vivo, rat Achilles tendon defects were repaired with iMSCSCX+‐seeded microgrooved scaffolds, microgrooved scaffolds only, or suture only and assessed via gait, gene expression, biomechanical testing, histology, and immunofluorescence. iMSCSCX+‐seeded on microgrooved scaffolds showed upregulation of tendon markers and increased organization and linearity of cells compared to non‐patterned scaffolds in vitro. In vivo gait analysis showed improvement in the Scaffold + iMSCSCX+‐treated group compared to the controls. Tensile testing of the tendons demonstrated improved biomechanical properties of the Scaffold + iMSCSCX+ group compared with the controls. Histology and immunofluorescence demonstrated more regular tissue formation in the Scaffold + iMSCSCX+ group. This study demonstrates the potential of 3D‐printed scaffolds with cell‐instructive surface topography seeded with iMSCSCX+ as an approach to tendon defect repair. Further studies of cell‐scaffold constructs can potentially revolutionize tendon reconstruction by advancing the application of 3D printing‐based technologies toward patient‐specific therapies that improve healing and functional outcomes at both the cellular and tissue level.

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 98%

iPSC‐derived tenocytes seeded on microgrooved 3D printed scaffolds for Achilles tendon regeneration

Kaneda

Chan

Castaneda

et al. 2023

Journal Orthopaedic Research

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“…Previous investigations have shown that aggravated heterotopic ossification can hamper tendon regeneration. [ 26 ] We observed that GM@PDA&SHED‐Exos had additional therapeutic effects on reducing heterotopic ossification, possibly by inhibiting NF‐κB. Furthermore, persistent inflammation from senescent cells could retard the process of tendon repair.…”

Section: Discussionmentioning

confidence: 99%

Young Exosome Bio‐Nanoparticles Restore Aging‐Impaired Tendon Stem/Progenitor Cell Function and Reparative Capacity

Jin¹,

Wang²,

Wu³

et al. 2023

Advanced Materials

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Tendon aging is frequently accompanied by extrinsic inflammation-aging harassment and intrinsic TSPC senescence, resulting in impaired reparative and regenerative capacities. [2] Although the functional decline of senescent TSPCs is accepted well, an efficient and precise method to rejuvenate aged TSPC (AT-SC) function and recover aging-impaired tendon reparative capacity remains to be further explored.Extracellular vesicles (EVs) are membrane-enclosed structures mainly that are classified into two main groups: exosomes and microvesicles. Among them, exosomes range from 40 to 150 nm in diameter and are mainly derived from the endosomal system, [3] whereas microvesicles range from 100 to 1000 nm in diameter and are generated by shedding of the plasma membrane. EVs could facilitate intercellular communication by transferring mRNA, microRNA, proteins, and organelle cargoes into recipient cells; [4] therefore, EVs have been suggested as excellent candidates for therapeutic methods for tissue regeneration and repair. Recently, EVs have been proven to be beneficial components of young blood in extending the life span of mice, suggesting that some specific EVs may possess an anti-senescent function. [5] Aging impairs tendon stem/progenitor cell function and tendon homeostasis, however, effective treatments for aging-induced tendon diseases are lacking. Exosomes are naturally derived nanoparticles that contain bioactive molecules, and therefore, have attracted great interest in tissue engineering and regenerative medicine. In this study, it is shown that young exosomes secreted by stem cells from human exfoliated deciduous teeth (SHED-Exos) possess abundant anti-aging signals. These young bio-nanoparticles can alleviate the aging phenotypes of aged tendon stem/progenitor cells (AT-SCs) and maintain their tenogenic capacity. Mechanistically, SHED-Exos modulate histone methylation and inhibit nuclear factor-κB to reverse AT-SC aging. In a naturally aging mouse model, systemic administration of SHED-Exo bio-nanoparticles retards tendon degeneration. Interestingly, local delivery of SHED-Exos-loaded microspheres confers anti-aging phenotypes, including reduced senescent cells and decreased ectopic bone formation, thereby functionally and structurally rescuing endogenous tendon regeneration and repair capacity in aged rats. Overall, SHED-Exos, as natural bioactive nanoparticles, have promising translational and therapeutic potential for aging-related diseases.

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“… 100 Interestingly, loss of TNMD in mice could lead to misrouted differentiation towards adipocytes in the early repair phase, 89 and osteocytes via endochondral ossification in the late repair phase. 101 The presence of adipocytes might weaken the compact tendon structure, structural integrity, and biomechanical properties, thereby increasing the risk of rupture. 102 In addition, these cells are known to be paracrine-active, 8 hence it can be hypothesized that paracrine signals from adipose tissue-derived cells might also interfere with AT homeostasis.…”

Section: Pathophysiology Of Tendon Tissue and Cells Affecting At Repairmentioning

confidence: 99%

“… 89 Interestingly, when assessed at later timepoints of the healing process, TNMD -knockout tendons exhibited markedly increased heterotopic ossification (HO) paralleled by diminished biomechanical and functional properties of the ATs. 101 …”

Section: Key Mediators and Processes During At Healingmentioning

confidence: 99%

Tendon healing: a concise review on cellular and molecular mechanisms with a particular focus on the Achilles tendon

Schulze‐Tanzil

Caceres

Stange

et al. 2022

Bone & Joint Research

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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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Tenomodulin knockout mice exhibit worse late healing outcomes with augmented trauma-induced heterotopic ossification of Achilles tendon

Cited by 22 publications

References 52 publications

iPSC‐derived tenocytes seeded on microgrooved 3D printed scaffolds for Achilles tendon regeneration

iPSC‐derived tenocytes seeded on microgrooved 3D printed scaffolds for Achilles tendon regeneration

Young Exosome Bio‐Nanoparticles Restore Aging‐Impaired Tendon Stem/Progenitor Cell Function and Reparative Capacity

Tendon healing: a concise review on cellular and molecular mechanisms with a particular focus on the Achilles tendon

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