Rotator cuff healing is regulated by the lymphatic vasculature

Tong, Xiaopeng; Zhang, Tao; Li, Shengcan; Chen, Yang; Xu, Yixin; Deng, Chao; Hu, Jianzhong; Lu, Hongbin

doi:10.1016/j.jot.2022.09.014

Cited by 5 publications

(4 citation statements)

References 40 publications

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“…performed the semiquantitative analysis of histological staining slices in a blinded manner according to previously established tendon maturation rating scoring criteria. 8,35 This scoring system included several parameters such as cellularity, vascularity, continuity, fibrocartilage cells, and tidemark, ranked on a scale from 1 to 4. A higher score indicated better healing of the tendon-bone interface, with a perfect score of 20 points representing a healthy attachment and excellent maturation.…”

Section: Methodsmentioning

confidence: 99%

A Combined Treatment of BMP2 and Soluble VEGFR1 for the Enhancement of Tendon-Bone Healing by Regulating Injury-Activated Skeletal Stem Cell Lineage

Wang,

Wan,

Zhang

et al. 2024

Am J Sports Med

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Background: Bone morphogenetic protein 2 (BMP2) is an appealing osteogenic and chondrogenic growth factor for promoting tendon-bone healing. Recently, it has been reported that soluble vascular endothelial growth factor (VEGF) receptor 1 (sVEGFR1) (a VEGF receptor antagonist) could enhance BMP2-induced bone repair and cartilage regeneration; thus, their combined application may represent a promising treatment to improve tendon-bone healing. Moreover, BMP2 could stimulate skeletal stem cell (SSC) expansion and formation, which is responsible for wounded tendon-bone interface repair. However, whether the codelivery of BMP2 and sVEGFR1 increases tendon enthesis injury–activated SSCs better than does BMP2 alone needs further research. Purpose: To study the effect of BMP2 combined with sVEGFR1 on tendon-bone healing and injury-activated SSC lineage. Study Design: Controlled laboratory study. Methods: A total of 128 C57BL/6 mice that underwent unilateral supraspinatus tendon detachment and repair were randomly assigned to 4 groups: (1) untreated control group; (2) hydrogel group, which received a local injection of the blank hydrogel at the injured site; (3) BMP2 group, which received an injection of hydrogel with BMP2; and (4) BMP2 with sVEGFR1 group, which received an injection of hydrogel with BMP2 and sVEGFR1. Histology, micro–computed tomography, and biomechanical tests were conducted to evaluate tendon-bone healing at 4 and 8 weeks after surgery. In addition, flow cytometry was performed to detect the proportion of SSCs and their downstream differentiated subtypes, including bone, cartilage, and stromal progenitors; osteoprogenitors; and pro-chondrogenic progenitors within supraspinatus tendon enthesis at 1 week postoperatively. Results: The repaired interface in BMP2 with sVEGFR1 group showed a significantly improved collagen fiber continuity, increased fibrocartilage, greater newly formed bone, and elevated mechanical properties compared with the other 3 groups. There were more SSCs; bone, cartilage, and stromal progenitors; osteoprogenitors; and pro-chondrogenic progenitors in the BMP2 with sVEGFR1 group than that in the other groups. Conclusion: Our study suggests that the combined delivery of BMP2 and sVEGFR1 could promote tendon-bone healing and stimulate the expansion of SSCs and their downstream progeny within the injured tendon-bone interface. Clinical Relevance: Combining BMP2 with sVEGFR1 may be a good clinical treatment for wounded tendon enthesis healing.

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Section: Methodsmentioning

confidence: 99%

A Combined Treatment of BMP2 and Soluble VEGFR1 for the Enhancement of Tendon-Bone Healing by Regulating Injury-Activated Skeletal Stem Cell Lineage

Wang,

Wan,

Zhang

et al. 2024

Am J Sports Med

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“…Insufficient vascularization reduces the supply of oxygen, growth factors, and other essential nutrients to cells at the enthesis, making it difficult to re-establish the normal gradient hierarchy following RCR surgery. [5] Consequently, tissue-engineering strategies focusing on promoting vascularization at the tendonto-bone enthesis have gained growing interest within the field of orthopedics. [6] Chirality is one of the basic attributes of living organisms and plays a significant role in various biological processes.…”

Section: Introductionmentioning

confidence: 99%

Hierarchical Chiral Calcium Silicate Hydrate Films Promote Vascularization for Tendon‐to‐Bone Healing

Cai,

Qu,

Song

et al. 2024

Advanced Materials

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Revascularization after rotator cuff repair is crucial for tendon‐to‐bone healing. The chirality of materials has been reported to influence their performance in tissue repair. However, data on the use of chiral structures to optimize biomaterials as a revascularization strategy remain scarce. Here, we develop calcium silicate hydrate (CSO) films with hierarchical chirality on the atomic to micrometer scale. Interestingly, levorotatory CSO (L‐CSO) films promote the migration and angiogenesis of endothelial cells, whereas dextral and racemic CSO films do not induce the same effect. Molecular analysis demonstrate that L‐chirality can be recognized by integrin receptors and lead to the formation of focal adhesion, which activates mechanosensitive ion channel transient receptor potential vanilloid 4 to conduct Ca2+ influx. Consequently, the phosphorylation of serum response factor is biased by Ca2+ influx to promote the vascular endothelial growth factor receptor 2 signaling pathway, resulting in enhanced angiogenesis. After implanted in a rat rotator cuff tear model, L‐CSO films strongly enhance vascularization at the enthesis, promoting collagen maturation, increasing bone and fibrocartilage formation, and eventually improving the biomechanical strength. This study reveals the mechanism through which chirality influences angiogenesis in endothelial cells and provides a critical theoretical foundation for the clinical application of chiral biomaterials.This article is protected by copyright. All rights reserved

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“…Most RCTs occur at the bone-tendon interface and cause disability and pain (Saveh-Shemshaki et al 2019, Lin et al 2021. Despite great advances in surgical techniques for RCT, the postoperative failure of RCT is still high due to the poor healing competence of bone-tendon interface (Tong et al 2023). Fatty infiltration after tendon injury is a very common event and compromises the outcomes of tendon injury healing process (Wang et al 2019).…”

Section: Introductionmentioning

confidence: 99%

Caveolin-1 is involved in fatty infiltration and bone-tendon healing of rotator cuff tear

Fang

You

Wang

et al. 2023

Mol Med

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Background Caveolin-1 has been predicted, based on RNA transcriptome sequencing, as a key gene in rotator cuff tear (RCT) and it is related to fatty infiltration. This study aims to elucidate the upstream and downstream mechanism of Caveolin-1 in fatty infiltration and bone-tendon healing after RCT in rat models. Methods Differentially expressed genes related to RCT were screened, followed by functional enrichment analysis and protein-protein interaction analysis. GATA6 was overexpressed and Caveolin-1 was knocked down in tendon stem cells (TSCs) to evaluate their effects on the adipogenic differentiation of TSCs. In addition, a RCT rat model was constructed and injected with lentivirus carrying oe-GATA6, oe-Caveolin-1 alone or in combination to assess their roles in fatty infiltration and bone-tendon healing. Results and conclusion Caveolin-1 was identified as a key gene involved in the RCT process. In vitro results demonstrated that Caveolin-1 knockdown inhibited adipogenic differentiation of TSCs by activating the cAMP/PKA pathway. GATA6 inhibited the transcription of Caveolin-1 and inhibited its expression, thus suppressing the adipogenic differentiation of TSCs. In vivo data confirmed that GATA6 overexpression activated the cAMP/PKA pathway by downregulating Caveolin-1 and consequently repressed fatty infiltration, promoted bone-tendon healing, improved biomechanical properties and reduced the rupture risk of injured tendon in rats after RCT. Overall, this study provides novel insights into the mechanistic action of Caveolin-1 in the fatty infiltration and bone-tendon healing after RCT.

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Rotator cuff healing is regulated by the lymphatic vasculature

Cited by 5 publications

References 40 publications

A Combined Treatment of BMP2 and Soluble VEGFR1 for the Enhancement of Tendon-Bone Healing by Regulating Injury-Activated Skeletal Stem Cell Lineage

A Combined Treatment of BMP2 and Soluble VEGFR1 for the Enhancement of Tendon-Bone Healing by Regulating Injury-Activated Skeletal Stem Cell Lineage

Hierarchical Chiral Calcium Silicate Hydrate Films Promote Vascularization for Tendon‐to‐Bone Healing

Caveolin-1 is involved in fatty infiltration and bone-tendon healing of rotator cuff tear

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