Engineered Cell Sheets for the Effective Delivery of Adipose-Derived Stem Cells for Tendon-to-Bone Healing

Shin, Myung Jin; Shim, In Kyong; Kim, Dong-Min; Choi, Jae-Hyeog; Lee, Yu Na; Kim, Hyojune; Park, Dongjun; Kholinne, Erica; Yang, Hee Joo; Koh, Kyoung Hwan

doi:10.1177/0363546520964445

Cited by 35 publications

(34 citation statements)

References 47 publications

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“…TDSCs have reparative properties in tendon injury, exhibiting spontaneous tenogenic differentiation potentials in vitro. 22 H19 has previously been reported to promote tenogenic differentiation of human TDSCs. 18 To confirm this, rat TDSCs were isolated and cultured, and stable H19-overexpression (H19) and H19-shRNA (shH19) TDSCs were generated using a lentiviral system and confirmed by RT-qPCR.…”

Section: Resultsmentioning

confidence: 96%

Long noncoding RNA H19 accelerates tenogenic differentiation by modulating miR-140-5p/VEGFA signaling

et al. 2021

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Rotator cuff tear (RCT) is a common tendon injury, but the mechanisms of tendon healing remain incompletely understood. Elucidating the molecular mechanisms of tenogenic differentiation is essential to develop novel therapeutic strategies in clinical treatment of RCT. The long noncoding RNA H19 plays a regulatory role in tenogenic differentiation and tendon healing, but its detailed mechanism of action remains unknown. To elucidate the role of H19 in tenogenic differentiation and tendon healing, tendon-derived stem cells were harvested from the Achilles tendons of Sprague Dawley rats and a rat model of cuff tear was established for the exploration of the function of H19 in promoting tenogenic differentiation. The results showed that H19 overexpression promoted, while H19 silencing suppressed, tenogenic differentiation of tendon-derived stem cells (TDSCs). Furthermore, bioinformatic analyses and a luciferase reporter gene assay showed that H19 directly targeted and inhibited miR-140-5p to promote tenogenic differentiation. Further, inhibiting miR-140-5p directly increased VEGFA expression, revealing a novel regulatory axis between H19, miR-140-5p, and VEGFA in modulating tenogenic differentiation. In rats with RTC, implantation of H19-overexpressing TDSCs at the lesion promoted tendon healing and functional recovery. In general, the data suggest that H19 promotes tenogenic differentiation and tendon-bone healing by targeting miR-140-5p and increasing VEGFA levels. Modulation of the H19/miR-140-5p/VEGFA axis in TDSCs is a new potential strategy for clinical treatment of tendon injury.

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Section: Resultsmentioning

confidence: 96%

Long noncoding RNA H19 accelerates tenogenic differentiation by modulating miR-140-5p/VEGFA signaling

et al. 2021

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“…studied a scaffold free tissue-engineered tendon graft designed for rotator cuff repair, compared with the suture group, the graft group had more orderly collagenous fiber arrangement. Shin, M. J [ 129 ] investigated the results of adipose stem cell sheets and found that there was more fibrochondrogenic formation in the cell sheet group compared with the simple suture group. Varvitsiotis, D [ 130 ] studied allograft fascia lata and compared with simple suture, both groups showed fibroblast growth and collagen fibers at the tendon-bone interface without significant differences.…”

Section: Resultsmentioning

confidence: 99%

Evaluation of patches for rotator cuff repair: A systematic review and meta-analysis based on animal studies

Yang

Kang

Zhao

et al. 2022

Bioactive Materials

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Based on the published animal studies, we systematically evaluated the outcomes of various materials for rotator cuff repair in animal models and the potentials of their clinical translation. 74 animal studies were finally included, of which naturally derived biomaterials were applied the most widely (50.0%), rats were the most commonly used animal model (47.0%), and autologous tissue demonstrated the best outcomes in all animal models. The biomechanical properties of naturally derived biomaterials (maximum failure load: WMD 18.68 [95%CI 7.71–29.66]; P = 0.001, and stiffness: WMD 1.30 [95%CI 0.01–2.60]; P = 0.048) was statistically significant in the rabbit model. The rabbit model showed better outcomes even though the injury was severer compared with the rat model.

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“…After the deltoid was split, the supraspinatus tendon was separated and transected from its footprint on the greater tuberosity. Thereafter, the distal supraspinatus tendon was wrapped with a small elastic drainage tube to prevent spontaneous reattachment of the supraspinatus tendon to the greater tuberosity (see Appendix Figure A1, available in the online version of this article), 22,38 followed by a routine layer-by-layer closure.…”

Section: Methodsmentioning

confidence: 99%

“…Keywords: rotator cuff repair; osteoporosis; anabolic; abaloparatide; antiresorptive; denosumab; tendon-to-bone Rotator cuff tears (RCTs) are among the most common disorders that result in shoulder pain and functional disabilities. 10,12,38 Despite rapid improvements in repair techniques and instrumentation, high rates of failure are reported, as high as 94% in patients with massive tears. 26,37,48 Multiple reasons account for healing failure after a rotator cuff repair, such as fatty infiltration, muscle atrophy, and degeneration of the tendon.…”

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confidence: 99%

Abaloparatide Improves Rotator Cuff Healing via Anabolic Effects on Bone Remodeling in a Chronic Rotator Cuff Tear Model of Rat With Osteoporosis: A Comparison With Denosumab

Chen

et al. 2022

Am J Sports Med

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Background: Because of poor clinical outcomes, rotator cuff healing in patients with osteoporosis has recently gained attention. Antiresorptive therapy for osteoporosis has been reported to improve healing after repair. However, the comparative effectiveness of anabolic and antiresorptive agents has not been investigated. Hypothesis: Anabolic therapy with abaloparatide (ABL) would outperform antiresorptive therapy with denosumab (Dmab) to improve rotator cuff healing in the osteoporotic status. Study Design: Controlled laboratory study. Methods: A chronic rotator cuff tear model was established in ovariectomy-induced postmenopausal osteoporotic rats. Then, bilateral rotator cuff repairs were conducted in all experimental rats, which were randomly divided into control (CON), Dmab, and ABL groups to receive the corresponding subcutaneous injections. The rats sacrificed at 2 weeks (the early healing period) were used to detect osteoblast and osteoclast activities, related gene expression (osteoclastogenesis, osteogenesis, and chondrogenesis), new bone formation, and mineralization. In the rats sacrificed at 4 and 8 weeks, the bone mineral density and bone architecture at the repaired site were assessed by micro–computed tomography, and rotator cuff healing was evaluated using histological and biomechanical analyses. Results: At 8 weeks, significantly higher failure load and stiffness were observed in the ABL (25.13 ± 3.54 N, P < .001; 21.65 ± 3.08 N/mm, P < .001; respectively), and Dmab (21.21 ± 2.55 N, P < .001; 16.15 ± 2.07 N/mm, P = .008; respectively) groups than in the CON group (13.36 ± 1.70 N; 11.20 ± 2.59 N/mm; respectively), whereas the ABL treatment provided better failure load and stiffness than Dmab ( P = .019; P = .003). Although tendon-to-bone healing was improved by Dmab, the most mature tendon insertion at the interface was observed in the ABL group, including a more organized collagen and fibrocartilage and higher bone quality. ABL significantly promoted bone remodeling via coupling between osteoclasts and osteoblasts (osteoblast to osteoclast ratio: 4.80 ± 0.39; P = .022), thereby stimulating more new bone formation and mineralization at the tendon-to-bone healing interface than Dmab (osteoblast to osteoclast ratio: 3.21 ± 0.75) at 2 weeks. Moreover, ABL had significant effects on gene expression [Runt-realted transcription factor 2 ( Runx2, collagen type I-alpha 1 ( Col1A1]), and sclerostin for osteogenesis; aggrecan and collagen type II ( Col2) for chondrogenesis] in mineralized tissues, indicative of enhanced bone and fibrocartilage formation when compared with the CON and Dmab groups. Conclusion: ABL promoted rotator cuff healing in osteoporotic rats by significantly increasing the mineralized tissue quality and collagen maturity at the reattachment site, leading to improved biomechanical properties, and was superior to Dmab in both biomechanical and histological analyses. Clinical Relevance: Anabolic therapy with ABL may outperform antiresorptive therapy with Dmab in improving outcomes after rotator cuff repair in osteoporotic patients.

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Engineered Cell Sheets for the Effective Delivery of Adipose-Derived Stem Cells for Tendon-to-Bone Healing

Cited by 35 publications

References 47 publications

Long noncoding RNA H19 accelerates tenogenic differentiation by modulating miR-140-5p/VEGFA signaling

Long noncoding RNA H19 accelerates tenogenic differentiation by modulating miR-140-5p/VEGFA signaling

Evaluation of patches for rotator cuff repair: A systematic review and meta-analysis based on animal studies

Abaloparatide Improves Rotator Cuff Healing via Anabolic Effects on Bone Remodeling in a Chronic Rotator Cuff Tear Model of Rat With Osteoporosis: A Comparison With Denosumab

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