Exosomes Derived From Kartogenin-Preconditioned Mesenchymal Stem Cells Promote Cartilage Formation and Collagen Maturation for Enthesis Regeneration in a Rat Model of Chronic Rotator Cuff Tear

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Abstract

Background:

Poor tendon-to-bone healing in chronic rotator cuff tears (RCTs) is related to unsatisfactory outcomes. Exosomes derived from mesenchymal stem cells reportedly enhance rotator cuff healing. However, the difficulty in producing exosomes with a stronger effect on enthesis regeneration must be resolved.

Purpose:

To study the effect of exosomes derived from kartogenin (KGN)-preconditioned human bone marrow mesenchymal stem cells (KGN-Exos) on tendon-to-bone healing in a rat model of chronic RCT.

Study Design:

Controlled laboratory study.

Methods:

Exosome-loaded sodium alginate hydrogel (SAH) was prepared. Moreover, exosomes were labeled with 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindotricarbocyanine iodide (DiR) or 1,1′-dioctadecyl-3,3,3′3′-tetramethylindocarbocyanine perchlorate (Dil) for in vivo tracking. Bilateral rotator cuff repair (RCR) was conducted in an established chronic RCT rat model. A total of 66 rats were randomized to control, untreated exosome (un-Exos), and KGN-Exos groups to receive local injections of pure SAH, un-Exos, or KGN-Exos SAH at the repaired site. The presence of DiR/Dil-labeled exosomes was assessed at 1 day and 1 week, and tendon-to-bone healing was evaluated histologically, immunohistochemically, and biomechanically at 4 and 8 weeks.

Results:

Both un-Exos and KGN-Exos exhibited sustained release from SAH for up to 96 hours. In vivo study revealed that un-Exos and KGN-Exos were localized to the repaired site at 1 week. Moreover, the KGN-Exos group showed a higher histological score and increased glycosaminoglycan and collagen II expression at 4 and 8 weeks. In addition, more mature and better-organized collagen fibers with higher ratios of collagen I to collagen III were observed at 8 weeks in the tendon-to-bone interface compared with those in the control and un-Exos groups. Biomechanically, the KGN-Exos group had the highest failure load (28.12 ± 2.40 N) and stiffness (28.57 ± 2.49 N/mm) among the 3 groups at 8 weeks.

Conclusion:

Local injection of SAH with sustained KGN-Exos release could effectively promote cartilage formation as well as collagen maturation and organization for enthesis regeneration, contributing to enhanced biomechanical properties after RCR.

Clinical Relevance:

KGN-Exos injection may be used as a cell-free therapeutic option to accelerate tendon-to-bone healing in chronic RCT.

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Most cited references 46

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The outcome and repair integrity of completely arthroscopically repaired large and massive rotator cuff tears.

Leesa Galatz, Craig Ball, Sharlene A Teefey … (2004)

The impact of a recurrent defect on the outcome after rotator cuff repair has been controversial. The purpose of this study was to evaluate the functional and anatomic results after arthroscopic repair of large and massive rotator cuff tears with use of ultrasound as an imaging modality to determine the postoperative integrity of the repair. Eighteen patients who had complete arthroscopic repair of a tear measuring >2 cm in the transverse dimension were evaluated at a minimum of twelve months after surgery and again at two years after surgery. The evaluation consisted of a standardized history and physical examination as well as calculation of the preoperative and postoperative shoulder scores according to the system of the American Shoulder and Elbow Surgeons. The strength of both shoulders was quantitated postoperatively with use of a portable dynamometer. Ultrasound studies were performed with use of an established and validated protocol at a minimum of twelve months after surgery. Recurrent tears were seen in seventeen of the eighteen patients. Despite the absence of healing at twelve months after surgery, thirteen patients had an American Shoulder and Elbow Surgeons score of >/=90 points. Sixteen patients had an improvement in the functional outcome score, which increased from an average of 48.3 to 84.6 points. Sixteen patients had a decrease in pain, and twelve had no pain. Although eight patients had preoperative forward elevation to /=90 points, and six patients had a score of /=80.

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Mesenchymal stem cell-derived extracellular vesicles: novel frontiers in regenerative medicine

Somayeh Keshtkar, Negar Azarpira, Mohammad Ghahremani (2018)

Mesenchymal stem cells (MSCs) are multipotent stem cells that have gained significant attention in the field of regenerative medicine. The differentiation potential along with paracrine properties of MSCs have made them a key option for tissue repair. The paracrine functions of MSCs are applied through secreting soluble factors and releasing extracellular vesicles like exosomes and microvesicles. Extracellular vesicles are predominantly endosomal in origin and contain a cargo of miRNA, mRNA, and proteins that are transferred from their original cells to target cells. Recently it has emerged that extracellular vesicles alone are responsible for the therapeutic effect of MSCs in plenty of animal diseases models. Hence, MSC-derived extracellular vesicles may be used as an alternative MSC-based therapy in regenerative medicine. In this review we discuss MSC-derived extracellular vesicles and their therapeutic potential in various diseases.

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Kristen Johnson, Shoutian Zhu, Matthew S Tremblay … (2012)

Osteoarthritis (OA) is a degenerative joint disease that involves the destruction of articular cartilage and eventually leads to disability. Molecules that promote the selective differentiation of multipotent mesenchymal stem cells (MSCs) into chondrocytes may stimulate the repair of damaged cartilage. Using an image-based high-throughput screen, we identified the small molecule kartogenin, which promotes chondrocyte differentiation (median effective concentration = 100 nM), shows chondroprotective effects in vitro, and is efficacious in two OA animal models. Kartogenin binds filamin A, disrupts its interaction with the transcription factor core-binding factor β subunit (CBFβ), and induces chondrogenesis by regulating the CBFβ-RUNX1 transcriptional program. This work provides new insights into the control of chondrogenesis that may ultimately lead to a stem cell-based therapy for osteoarthritis.