Periodontal ligament cells as alternative source for cell-based therapy of tendon injuries: in vivo study of full-size Achilles tendon defect in a rat model

Hsieh, Chi-Fen; Alberton, Paolo; Loffredo-Verde, Eva; Volkmer, Elias; Pietschmann, Matthias F.; Müller, Peter E.; Schieker, Matthias; Docheva, Denitsa

doi:10.22203/ecm.v032a15

Cited by 30 publications

(24 citation statements)

References 14 publications

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“…1) compared to vehicle treated ones can be interpreted as a reduction of edema and consequent scar formation. This finding is also supported by the observation that Bevacizumab treatment leads to an increase in extracellular matrix organization, a hallmark of improved tendon healing [19]. Further, to some extent, both groups showed signs of chondrification, with no detectable difference between the groups (Fig.…”

Section: Discussionsupporting

confidence: 71%

Bevacizumab Improves Achilles Tendon Repair in a Rat Model

Tempfer

Kaser-Eichberger

Lehner

et al. 2018

Cell Physiol Biochem

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Background/Aims: Effective wound-healing generally requires efficient re-vascularization after injury, ensuring sufficient supply with oxygen, nutrients, and various cell populations. While this applies to most tissues, tendons are mostly avascular in nature and harbor relatively few cells, probably contributing to their poor regenerative capacity. Considering the minimal vascularization of healthy tendons, we hypothesize that controlling angiogenesis in early tendon healing is beneficial for repair tissue quality and function. Methods: To address this hypothesis, Bevacizumab, a monoclonal antibody blocking VEGF-A signaling, was locally injected into the defect area of a complete tenotomy in rat Achilles tendon. At 28 days postsurgery, the defect region was investigated using immunohistochemistry against vascular and lymphatic epitopes. Polarization microscopy and biomechanical testing was used to determine tendon integrity and gait analysis for functional testing in treated vs non-treated animals. Results: Angiogenesis was found to be significantly reduced in the Bevacizumab treated repair tissue, accompanied by significantly reduced cross sectional area, improved matrix organization, increased stiffness and Young's modulus, maximum load and stress. Further, we observed an improved gait pattern when compared to the vehicle injected control group. Conclusion: Based on the results of this study we propose that reducing angiogenesis after tendon injury can improve tendon repair, potentially representing a novel treatment-option.

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Section: Discussionsupporting

confidence: 71%

Bevacizumab Improves Achilles Tendon Repair in a Rat Model

Tempfer

Kaser-Eichberger

Lehner

et al. 2018

Cell Physiol Biochem

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“…Photomicrographs were taken on the Observer Z1 microscope equipped with the Axiocam MRm camera (Carl Zeiss). Quantitative histomorphometry was carried out via an automated quantitative image analysis according to algorithms from literature (Hsieh et al, ; Lin et al, ). In brief, using ImageJ (National Institutes of Health), the following algorithm was applied: (a) area of interest was manually designated using the “drawing/selection” tool; (b) “set measurements” for area, integrated density and mean gray value was selected from the analyze menu; and (c) lastly, the corrected total cryosections fluorescence (CTCF) representing the Acan, Col I, Col X, Fmod, Fn, Lum, MMP3, MMP‐9, p65, and Tnmd expression were exported and calculated in Excel (Microsoft) as follows CTCF = media of integrated density − (media of area of selected area × mean fluorescence).…”

Section: Methodsmentioning

confidence: 99%

Section: Histology Immunohistology and Histomorphometrymentioning

confidence: 99%

Loss of tenomodulin expression is a risk factor for age‐related intervertebral disc degeneration

et al. 2020

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The intervertebral disc (IVD) degeneration is thought to be closely related to ingrowth of new blood vessels. However, the impact of anti‐angiogenic factors in the maintenance of IVD avascularity remains unknown. Tenomodulin (Tnmd) is a tendon/ligament‐specific marker and anti‐angiogenic factor with abundant expression in the IVD. It is still unclear whether Tnmd contributes to the maintenance of IVD homeostasis, acting to inhibit vascular ingrowth into this normally avascular tissue. Herein, we investigated whether IVD degeneration could be induced spontaneously by the absence of Tnmd. Our results showed that Tnmd was expressed in an age‐dependent manner primarily in the outer annulus fibrous (OAF) and it was downregulated at 6 months of age corresponding to the early IVD degeneration stage in mice. Tnmd knockout (Tnmd−/−) mice exhibited more rapid progression of age‐related IVD degeneration. These signs include smaller collagen fibril diameter, markedly lower compressive stiffness, reduced multiple IVD‐ and tendon/ligament‐related gene expression, induced angiogenesis, and macrophage infiltration in OAF, as well as more hypertrophic‐like chondrocytes in the nucleus pulposus. In addition, Tnmd and chondromodulin I (Chm1, the only homologous gene to Tnmd) double knockout (Tnmd−/−Chm1−/−) mice displayed not only accelerated IVD degeneration, but also ectopic bone formation of IVD. Lastly, the absence of Tnmd in OAF‐derived cells promoted p65 and matrix metalloproteinases upregulation, and increased migratory capacity of human umbilical vein endothelial cells. In sum, our data provide clear evidences that Tnmd acts as an angiogenic inhibitor in the IVD homeostasis and protects against age‐related IVD degeneration. Targeting Tnmd may represent a novel therapeutic strategy for attenuating age‐related IVD degeneration.

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“…Next day, corresponding secondary antibodies were added for 1 h. After washing, short counterstaining with 4′,6-diamidino-2-phenylindole (DAPI) (Life technology, Carlsbad, SD, USA) was performed and slides were mounted with fluoroshield (Sigma-Aldrich, Steinheim, Nordrhein-Westfalen, Germany). An automated quantitative image analysis was performed as described in Hsieh et al 2016 [9] with slight modifications. In brief, using ImageJ (National Institutes of Health, Bethesda, MD, USA), the following algorithm was applied: (1) nine images with a 40× magnification were taken per staining and cell types; (2) areas of all cells were manually designated using the “drawing/selection” tool; (3) the “set measurements” for area, integrated density and mean grey value was selected from the “analyze” menu; (4) lastly, the corrected total fluorescence (CTF) representing the expression of CD146, Nestin and STRO1 was exported and calculated in Excel (Microsoft) as follows: CTF = media of integrated density−media of the selected area x mean fluorescence.…”

Section: Methodsmentioning

confidence: 99%

“…The hTSPCs exhibit typical adult stem cell features: positivity for stem cell markers (CD73, CD90, CD105, CD146, Nestin and STRO-1), trilineage differentiation potential and expression of high levels of tendon-related genes, such as collagen type I (COL1) and collagen type III, and the proteoglycans biglycan (BGN), cartilage oligomeric matrix protein (COMP), decorin (DCN), fibromodulin (FMOD), lumican (LUM), tenascin C (TNC), and versican [6,7]. Moreover, using a full-size injury model in rat Achilles tendon, we demonstrated that hTSPCs implanted as pellets or together with carriers lead to enhanced tissue repair [8,9]. Despite their multiple benefits, the major disadvantages of autologous hTSPCs are the comorbidity and the time required for their isolation and expansion prior to use.…”

Section: Introductionmentioning

confidence: 99%

In Vitro Comparison of 2D-Cell Culture and 3D-Cell Sheets of Scleraxis-Programmed Bone Marrow Derived Mesenchymal Stem Cells to Primary Tendon Stem/Progenitor Cells for Tendon Repair

Hsieh

Zhi-yong

Schumann

et al. 2018

IJMS

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The poor and slow healing capacity of tendons requires novel strategies to speed up the tendon repair process. Hence, new and promising developments in tendon tissue engineering have become increasingly relevant. Previously, we have established a tendon progenitor cell line via ectopic expression of the tendon-related basic helix-loop-helix (bHLH) transcription factor Scleraxis (Scx) in human bone marrow mesenchymal stem cells (hMSC-Scx). The aim of this study was to directly compare the characteristics of hMSC-Scx cells to that of primary human tendon stem/progenitors cells (hTSPCs) via assessment of self-renewal and multipotency, gene marker expression profiling, in vitro wound healing assay and three-dimensional cell sheet formation. As expected, hTSPCs were more naive than hMSC-Scx cells because of higher clonogenicity, trilineage differentiation potential, and expression of stem cell markers, as well as higher mRNA levels of several gene factors associated with early tendon development. Interestingly, with regards to wound healing, both cell types demonstrate a comparable speed of scratch closure, as well as migratory velocity and distance in various migration experiments. In the three-dimensional cell sheet model, hMSC-Scx cells and hTSPCs form compact tendinous sheets as histological staining, and transmission electron microscopy shows spindle-shaped cells and collagen type I fibrils with similar average diameter size and distribution. Taken together, hTSPCs exceed hMSC-Scx cells in several characteristics, namely clonogenicity, multipotentiality, gene expression profile and rates of tendon-like sheet formation, whilst in three-dimensional cell sheets, both cell types have comparable in vitro healing potential and collagenous composition of their three-dimensional cell sheets, making both cell types a suitable cell source for tendon tissue engineering and healing.

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Periodontal ligament cells as alternative source for cell-based therapy of tendon injuries: in vivo study of full-size Achilles tendon defect in a rat model

Abstract: Tendon's natural healing potential is extremely low and inefficient, with significant dysfunction and disability due to hypocellularity and hypovascularity of tendon tissues.

Cited by 30 publications

References 14 publications

Bevacizumab Improves Achilles Tendon Repair in a Rat Model

Bevacizumab Improves Achilles Tendon Repair in a Rat Model

Loss of tenomodulin expression is a risk factor for age‐related intervertebral disc degeneration

In Vitro Comparison of 2D-Cell Culture and 3D-Cell Sheets of Scleraxis-Programmed Bone Marrow Derived Mesenchymal Stem Cells to Primary Tendon Stem/Progenitor Cells for Tendon Repair

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