A comparison of the stem cell characteristics of murine tenocytes and tendon-derived stem cells

Lee, Katie Joanna; Clegg, Peter; Comerford, Eithne; Canty‐Laird, Elizabeth G.

doi:10.1186/s12891-018-2038-2

Cited by 38 publications

(45 citation statements)

References 43 publications

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“…Some studies have shown that cyclic tensile strain in vitro results in upregulation of proliferation and tenogenic differentiation of TDSCs 9,39 . Furthermore, TDSCs also have the potential for trilineage differentiation (osteogenesis, chondrogenesis and adipogenesis), and this capacity can be enhanced by adequate mechanical stimulation 17,30,33 . We showed that TDSCs isolated from the tendons with Botox injection into associated muscles display reduced proliferation, colony formation capacity and trilineage differentiation capacity (osteogenesis, chondrogenesis and adipogenesis).…”

Section: Discussionmentioning

confidence: 99%

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Intramuscular Injection of Botox Induces Tendon Atrophy and Senescence of Tendon-Derived Stem Cells

Chen

Mitchell

et al. 2020

Preprint

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Background: Botulinum toxin (Botox) injection is in widespread clinical use for the treatment of muscle spasms and tendinopathy but the mechanism of action is poorly understood. Hypothesis: We hypothesised that the reduction of patellar-tendon mechanical-loading following intra-muscular injection of Botox results in tendon atrophy that is at least in part mediated by the induction of senescence of tendon-derived stem cells (TDSCs). Study Design: Controlled laboratory study Methods: A total of 36 mice were randomly divided in 2 groups (18 Botox-injected and 18 vehicle-only control). Mice were injected into to right vastus lateralis of quadriceps muscles either with Botox to induce mechanical stress deprivation of the patellar tendon or with normal saline as control. At 2 weeks post-injection, animals were euthanized prior to tissues harvest for either evaluation of tendon morphology or in vitro studies. TDSCs were isolated by cell-sorting prior to determination of viability, differentiation capacity and senescence markers, as well as assessing their response to mechanical loading in a bioreactor. Finally, to examine the mechanism of tendon atrophy in vitro, key proteins in the PTEN/AKT pathway were evaluated in TDSCs in both groups. Results: Two weeks after Botox injection, patellar tendons displayed atrophic features including tissue volume reduction and collagen fibre misalignment and increased degradation. The colony formation assay revealed the significantly reduced colony units of TDSCs in Botox injected group compared to controls. Multipotent differentiation capacity of TDSCs has also diminished after Botox injection. To examine if mechanical deprived TDSC is capable of forming tendon tissue, we used an isolated bioreactor system to culture 3D TDSCs constructs. The result showed that TDSCs from the Botox-treated group failed to restore tenogenic differentiation after appropriate mechanical loading. Examination of PTEN/AKT signalling pathway revealed that injection of Botox into quadriceps muscle causes PTEN/AKT mediated cell senescence of TDSCs. Conclusion: Intramuscular injection of Botox interferes with tendon homeostasis by inducing tendon atrophy and senescence of TDSCs. Botox injection may have long-term adverse consequences for the treatment of tendinopathy. Clinical relevance: Intramuscular Botox injection for tendinopathy and tendon injury could cause adverse effects in human tendons and re-evaluation of its long-term efficacy is warranted.

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Section: Discussionmentioning

confidence: 99%

“…TDSCs are multipotent progenitor cells capable of differentiating into tendon, cartilage, bone and adipose tissue 17,38 . Therefore, we determined if injection of Botox into quadriceps muscle affected the multilineage differentiation potential of TDSC.…”

Section: Intramuscular Botox Injection Impairs the Viability And Diffmentioning

confidence: 99%

Intramuscular Injection of Botox Induces Tendon Atrophy and Senescence of Tendon-Derived Stem Cells

Chen

Mitchell

et al. 2020

Preprint

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“…Self-reported demographics were collected by questionnaire, and for the Dupuytren's patients disease stage information was collected from clinical records. Equine superficial digital flexor tendon (SDFT) and healthy canine cranial cruciate ligament (CCL) were collected as described (Ali et al, 2018;Lee et al, 2018), with local ethical approval (VREC186, VREC62 and RETH00000553). Ruptured CCL, otherwise discarded as clinical waste, was obtained from dogs undergoing stifle/knee stabilisation at the University of Liverpool's Small Animal Teaching Hospital (VREC63).…”

Section: Sample Collectionmentioning

confidence: 99%

Active synthesis of type I collagen homotrimer in Dupuytren’s fibrosis is unaffected by anti-TNF-α treatment

Williamson

Cooper

Lee

et al. 2020

Preprint

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Dupuytren's disease is a common fibroproliferative disease of the palmar fascia of the hand with severe cases treated surgically. The rate of disease recurrence following treatment is high and a continual production of matrisomal proteins could lead to disease recurrence. There is no animal model for Dupuytren's disease, but analysis of the surgically excised tissue provides an accessible means to study the mechanisms of human tissue fibrosis. Here we sought to determine how new synthesis and the composition of matrisomal proteins in Dupuytren's differs from normal palmar fascia samples, using metabolic labelling approaches and proteomics. Model non-fibrotic, but fibrous connective tissues, equine flexor tendon and canine cranial cruciate ligament, were used to analyse active collagen-1 protein synthesis in development, ageing and degenerative disease, where it was restricted to early development and ruptured tissue. Dupuytren's tissue was shown to actively synthesise type I collagen, a proportion of which comprised abnormal collagen (I) homotrimer (mean 14.3% ± 14.4), as well as fibronectin, matrix metalloproteinases (MMP2, MMP3) and their inhibitors; Tissue Inhibitor of Metalloproteinases 2 (TIMP2). Insulin-Like Growth Factor Binding Protein 7 (IGFBP7) was actively synthesised by Dupuytren's as well as control tissue. Label-free analysis implicated the TGFβ pathway in the matrisomal profile of Dupuytren's tissue whilst myocilin, a Wnt-pathway regulator, was noticeably more abundant in control samples. No collagen (I) neopeptides representing the major collagenase cleavage site were identified, however periostin neopeptides were abundant in Dupuytren's tissue and gelatin neopeptides in both tissue types. Synthesis of MMP-resistant collagen-1 homotrimer, together with altered β and Wnt signalling environments, could contribute to the persistence of the fibrotic tissue and disease recurrence following treatment.

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“…TDSCs are multipotent progenitor cells capable of differentiating into tendon, cartilage, bone and adipose tissue 17,39 . Therefore, we determined if injection of Botox into quadriceps muscle affects the multilineage differentiation potential of TDSC.…”

Section: Intramuscular Botox Injection Impairs the Growth And Differementioning

confidence: 99%

Intramuscular injection of Botox causes tendon atrophy by induction of senescence of tendon-derived stem cells

Chen¹,

Chen²,

Mitchell³

et al. 2020

Preprint

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Background: Botulinum toxin (Botox) injection is in widespread clinical use for the treatment of muscle spasms and tendinopathy but the mechanism of action is poorly understood.Hypothesis:We hypothesised that the reduction of patellar-tendon mechanical-loading following intra-muscular injection of Botox results in tendon atrophy that is at least in part mediated by the induction of senescence of tendon-derived stem cells (TDSCs).Study Design:Controlled laboratory studyMethods:A total of 36 mice were randomly divided into 2 groups (18 Botox-injected and 18 vehicle-only control). Mice were injected into the right vastus lateralis of quadriceps muscles either with Botox (to induce mechanical stress deprivation of the patellar tendon) or with normal saline as a control. At 2 weeks post-injection, animals were euthanized prior to tissues being harvested for either evaluation of tendon morphology or in vitro studies. TDSCs were isolated by cell-sorting prior to determination of viability, differentiation capacity or the presence of senescence markers, as well as assessing their response to mechanical loading in a bioreactor. Finally, to examine the mechanism of tendon atrophy in vitro, the PTEN/AKT mediated cell senescence pathway were evaluated in TDSCs from both groups.Results:Two weeks after Botox injection, patellar tendons displayed several atrophic features including tissue volume reduction, collagen fibre misalignment and increased degradation. A colony formation assay revealed a significantly reduced number of colony forming units of TDSCs in the Botox injected group compared to controls. Multipotent differentiation capacities of TDSCs were also diminished after Botox injection. To examine if mechanically deprived TDSC are capable of forming tendon tissue, we used an isolated bioreactor system to culture tendon constructs using TDSC. These results showed that TDSCs from the Botox-treated group failed to restore tenogenic differentiation after appropriate mechanical loading. Examination of the signalling pathway revealed that injection of Botox into quadriceps muscles causes PTEN/AKT mediated cell senescence of TDSCs.Conclusion:Intramuscular injection of Botox interferes with tendon homeostasis by inducing tendon atrophy and senescence of TDSCs. Botox injection may have long-term adverse consequences for the treatment of tendinopathy.Clinical relevance:Intramuscular Botox injection for tendinopathy or tendon injury could result in adverse effects in human tendons and evaluation of its long-term efficacy is warranted.

show abstract

A comparison of the stem cell characteristics of murine tenocytes and tendon-derived stem cells

Cited by 38 publications

References 43 publications

Intramuscular Injection of Botox Induces Tendon Atrophy and Senescence of Tendon-Derived Stem Cells

Intramuscular Injection of Botox Induces Tendon Atrophy and Senescence of Tendon-Derived Stem Cells

Active synthesis of type I collagen homotrimer in Dupuytren’s fibrosis is unaffected by anti-TNF-α treatment

Intramuscular injection of Botox causes tendon atrophy by induction of senescence of tendon-derived stem cells

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