Defining the profile: Characterizing cytokines in tendon injury to improve clinical therapy

Ellis, Ilene M.; Schnabel, Lauren V.; Berglund, Alix K.

doi:10.1016/j.regen.2022.100059

Cited by 11 publications

(16 citation statements)

References 66 publications

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“…Cell culture supernatant obtained from IL-1β licensed MSCs produced significantly more IL-6 ( p = 0.0126), PGE2 ( p = 0.0193), and VEGF ( p = 0.0162) compared to their paired naïve controls ( Figure 5 ). IL-6 is a pleotropic cytokine present following tendon injury and regulates leukocyte infiltration and controls duration of pro-inflammatory mediator release ( 12 , 66 ). Prostaglandin E2 is a primary mediator of equine MSC immunomodulation, is present following tendon injury, and likely plays a critical, concentration-dependent role in both the reparative response as well as the development of chronic injury ( 67 , 68 ).…”

Section: Resultsmentioning

confidence: 99%

“…Elucidating the temporal cytokine profile in tendon following injury is critical to guide development of novel therapies that aim to return the biochemical composition and biomechanical strength of healing tendon to its native state. Attempts to characterize the interplay of cytokines in the tendon microenvironment in both health and disease have employed cell culture, tissue biopsy, and subcutaneous microdialysis as recently review by Ellis et al ( 12 ). However, the inability to repeatedly sample the injured tendon microenvironment in conjunction with inconsistent standardization of samples from naturally occurring disease limit our understanding of the temporal change that occurs following injury ( 13 , 14 ).…”

Section: Discussionmentioning

confidence: 99%

“…The authors recognize that although the cytokine quantification herein is limited to the analytes present in the commercial kits and does not represent all analytes involved in the molecular cascade, the novel method employed to characterize the tendon microenvironment is an essential first step and establishes a new technique to collect further data on the microenvironment following injury and in response to therapy. Despite the associated bias when selecting cytokines to analyze tendon ultrafiltrate, published literature of the injured tendon microenvironment ( 12 , 13 , 76 ) was used to support selection of the most relevant cytokines in our custom multiplex within species-specific assay constraints.…”

Section: Discussionmentioning

confidence: 99%

“…Understanding the tissue microenvironment during injury guides our ability to develop new therapies to combat detrimental molecular mechanisms and encourage local reparative factors to improve healing. However, as recently reviewed ( 12 ), our knowledge of the temporal cytokine profile following tendon injury is limited due, in part, to the difficulty in obtaining adequate antemortem samples without compromising tendon structure and function. Our current understanding of the tendon microenvironment following injury has relied upon simplified models of injury in cell culture, intermittent post-mortem analyses in terminal animal disease models, or evaluation of human clinical patients with naturally occurring, but non-standardized tendon injuries ( 13 , 14 ).…”

Section: Introductionmentioning

confidence: 99%

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Interleukin-1β in tendon injury enhances reparative gene and protein expression in mesenchymal stem cells

et al. 2022

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Tendon injury in the horse carries a high morbidity and monetary burden. Despite appropriate therapy, reinjury is estimated to occur in 50–65% of cases. Although intralesional mesenchymal stem cell (MSC) therapy has improved tissue architecture and reinjury rates, the mechanisms by which they promote repair are still being investigated. Additionally, reevaluating our application of MSCs in tendon injury is necessary given recent evidence that suggests MSCs exposed to inflammation (deemed MSC licensing) have an enhanced reparative effect. However, applying MSC therapy in this context is limited by the inadequate quantification of the temporal cytokine profile in tendon injury, which hinders our ability to administer MSCs into an environment that could potentiate their effect. Therefore, the objectives of this study were to define the temporal cytokine microenvironment in a surgically induced model of equine tendon injury using ultrafiltration probes and subsequently evaluate changes in MSC gene and protein expression following in vitro inflammatory licensing with cytokines of similar concentration as identified in vivo. In our in vivo surgically induced tendon injury model, IL-1β and IL-6 were the predominant pro-inflammatory cytokines present in tendon ultrafiltrate where a discrete peak in cytokine concentration occurred within 48 h following injury. Thereafter, MSCs were licensed in vitro with IL-1β and IL-6 at a concentration identified from the in vivo study; however, only IL-1β induced upregulation of multiple genes beneficial to tendon healing as identified by RNA-sequencing. Specifically, vascular development, ECM synthesis and remodeling, chemokine and growth factor function alteration, and immunomodulation and tissue reparative genes were significantly upregulated. A significant increase in the protein expression of IL-6, VEGF, and PGE2 was confirmed in IL-1β-licensed MSCs compared to naïve MSCs. This study improves our knowledge of the temporal tendon cytokine microenvironment following injury, which could be beneficial for the development and determining optimal timing of administration of regenerative therapies. Furthermore, these data support the need to further study the benefit of MSCs administered within the inflamed tendon microenvironment or exogenously licensed with IL-1β in vitro prior to treatment as licensed MSCs could enhance their therapeutic benefit in the healing tendon.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Interleukin-1β in tendon injury enhances reparative gene and protein expression in mesenchymal stem cells

et al. 2022

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“…HGF, an inhibitor of myofibroblast differentiation and TGF-β-induced fibrosis [ 58 ], is downregulated in TGF-β2-treated BM-MSCs. Due to the inherent complexity of biologic systems, the timing and cell specificity of cytokine and cytokine receptors involved in fibrosis, and our minimal understanding of what is required for a tendon to remodel to its native composition and strength [ 59 ], there are still many unknowns about the full effects of TGF-β2-treated BM-MSCs on tendon healing. Further research into how TGF-β2-treated BM-MSCs affect tenocyte gene expression and function is necessary to better predict any potential adverse effects.…”

Section: Discussionmentioning

confidence: 99%

TGF-β2 enhances expression of equine bone marrow-derived mesenchymal stem cell paracrine factors with known associations to tendon healing

et al. 2022

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Background Mesenchymal stem cells (MSCs) secrete paracrine factors and extracellular matrix proteins that contribute to their ability to support tissue healing and regeneration. Both the transcriptome and the secretome of MSCs can be altered by treating the cells with cytokines, but neither have been thoroughly investigated following treatment with the specific cytokine transforming growth factor (TGF)-β2. Methods RNA-sequencing and western blotting were used to compare gene and protein expression between untreated and TGF-β2-treated equine bone marrow-derived MSCs (BM-MSCs). A co-culture system was utilized to compare equine tenocyte migration during co-culture with untreated and TGF-β2-treated BM-MSCs. Results TGF-β2 treatment significantly upregulated gene expression of collagens, extracellular matrix molecules, and growth factors. Protein expression of collagen type I and tenascin-C was also confirmed to be upregulated in TGF-β2-treated BM-MSCs compared to untreated BM-MSCs. Both untreated and TGF-β2-treated BM-MSCs increased tenocyte migration in vitro. Conclusions Treating equine BM-MSCs with TGF-β2 significantly increases production of paracrine factors and extracellular matrix molecules important for tendon healing and promotes the migration of tenocytes in vitro.

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Aged tendons lack adaptive response to acute compressive injury

Mlawer,

Frank,

Connizzo

2023

Journal Orthopaedic Research

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Rotator cuff tendinopathy has a multifactorial etiology, with both aging and external compression found to influence disease progression. However, tendon's response to these factors is still poorly understood and in vivo animal models make it difficult to decouple these effects. Therefore, we developed an explant culture model that allows us to directly apply compression to tendons and then observe their biological responses. Using this model, we applied a single acute compressive injury to C57BL/6J flexor digitorum longus tendon explants and observed changes in viability, metabolic activity, matrix composition, matrix biosynthesis, matrix structure, gene expression, and mechanical properties. We hypothesized that a single acute compressive load would result in an injury response in tendon and that this effect would be amplified in aged tendons. We found that young tendons had increased matrix turnover with a decrease in small leucine‐rich proteoglycans, increase in compression‐resistant proteoglycan aggrecan, increase in collagen synthesis, and an upregulation of collagen‐degrading MMP‐9. Aged tendons lacked any of these adaptive responses and instead had decreased metabolic activity and collagen synthesis. This implies that aged tendons lack the adaptation mechanisms required to return to homeostasis, and therefore are at greater risk for compression‐induced injury. Overall, we present a novel compressive injury model that demonstrates lasting age‐dependent changes and has the potential to examine the long‐term response of tendon to a variety of compressive loading conditions.

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Defining the profile: Characterizing cytokines in tendon injury to improve clinical therapy

Cited by 11 publications

References 66 publications

Interleukin-1β in tendon injury enhances reparative gene and protein expression in mesenchymal stem cells

Interleukin-1β in tendon injury enhances reparative gene and protein expression in mesenchymal stem cells

TGF-β2 enhances expression of equine bone marrow-derived mesenchymal stem cell paracrine factors with known associations to tendon healing

Aged tendons lack adaptive response to acute compressive injury

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