Therapeutic potential of exosomes in rotator cuff tendon healing

Connor, Denton; Paulus, Jordan A.; Dabestani, Parinaz J.; Thankam, Finosh K.; Dilisio, Matthew F.; Gross, R. Michael; Agrawal, Devendra K.

doi:10.1007/s00774-019-01013-z

Cited by 51 publications

(31 citation statements)

References 55 publications

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“…Exosome uptake by cells significantly reduces pro-inflammatory gene expression and level of M1 phenotypic marker, increase cell migration, and increase expression of osteogenic markers, which play a unique osteo-immunomodulatory role in regulation of bone dynamics [48]. Exosomes stimulate secretion of favorable cellular factors required to accelerate the healing response for tendon injuries including rotator cuff tears [49,50]. Exosomes also promote cartilage a b repair and chondrocyte proliferation in osteoarthritis [51].…”

Section: Discussionmentioning

confidence: 99%

Umbilical cord-derived Wharton’s jelly for regenerative medicine applications

Gupta

El-Amin²,

Levy

et al. 2020

J Orthop Surg Res

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Background: The last decade has seen an explosion in the interest in using biologics for regenerative medicine applications, including umbilical cord-derived Wharton's Jelly. There is insufficient literature assessing the amount of growth factors, cytokines, hyaluronic acid, and extracellular vesicles including exosomes in these products. The present study reports the development of a novel Wharton's jelly formulation and evaluates the presence of growth factors, cytokines, hyaluronic acid, and extracellular vesicles including exosomes. Methods: Human umbilical cords were obtained from consenting caesarian section donors. The Wharton's jelly was then isolated from the procured umbilical cord and formulated into an injectable form. Randomly selected samples from different batches were analyzed for sterility testing and to quantify the presence of growth factors, cytokines, hyaluronic acid, and extracellular vesicles. Results: All samples passed the sterility test. Growth factors including IGFBP 1, 2, 3, 4, and 6, TGF-α, and PDGF-AA were detected. Several immunomodulatory cytokines, such as RANTES, IL-6R, and IL-16, were also detected. Proinflammatory cytokines MCSFR, MIP-1a; anti-inflammatory cytokines TNF-RI, TNF-RII, and IL-1RA; and homeostatic cytokines TIMP-1 and TIMP-2 were observed. Cytokines associated with wound healing, ICAM-1, G-CSF, GDF-15, and regenerative properties, GH, were also expressed. High concentrations of hyaluronic acid were observed. Particles in the extracellular vesicle size range were also detected and were enclosed by the membrane, indicative of true extracellular vesicles. Conclusion: There are numerous growth factors, cytokines, hyaluronic acid, and extracellular vesicles present in the Wharton's jelly formulation analyzed. The amount of these factors in Wharton's jelly is higher compared with other biologics and may play a role in reducing inflammation and pain and augment healing of musculoskeletal injuries.

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Section: Discussionmentioning

confidence: 99%

Umbilical cord-derived Wharton’s jelly for regenerative medicine applications

Gupta

El-Amin²,

Levy

et al. 2020

J Orthop Surg Res

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“…Exosomes can transfer messages of cells encoded in protein, lipids, mRNA and miRNA enclosed within a lipid bilayer acting in an autocrine and paracrine manner, in response to activation and stress inducing stimuli. 22 Incorporation of MNPs and SMF has been confirmed to enhance wound healing by improving fibrogenesis and angiogenesis. 16 In order to further improve the paracrine activities of BMSC-Exos for accelerating wound healing, we successfully fabricated a novel exosome, mag-BMSC-Exo, to transmit the stimulatory effects of MNPs and and SMF with only very little residual Fe 3 O 4 nanoparticles (7.48nmol/mL) in this study.…”

Section: Discussionmentioning

confidence: 99%

Exosomes Derived from Bone Mesenchymal Stem Cells with the Stimulation of Fe3O4 Nanoparticles and Static Magnetic Field Enhance Wound Healing Through Upregulated miR-21-5p

Wu¹,

Kang²,

Tian³

et al. 2020

IJN

104

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Background: Both magnetic nanoparticles (MNPs) and exosomes derived from bone mesenchymal stem cells (BMSC-Exos) have been reported to improve wound healing. In this study, novel exosomes (mag-BMSC-Exos) would be fabricated from BMSCs with the stimulation of MNPs and a static magnetic field (SMF) to further enhance wound repair. Methods: Mag-BMSC-Exos, namely, exosomes derived from BMSCs preconditioned with Fe 3 O 4 nanoparticles and a SMF, together with BMSC-Exos were both first isolated by ultracentrifugation, respectively. Afterwards, we conducted in vitro experiments, including scratch wound assays, transwell assays, and tube formation assays, and established an in vivo wound healing model. The miRNA expression profiles were compared between BMSC-Exos and mag-BMSC-Exos to detect the potential mechanism of improving wound healing. At last, the function of exosomal miR-21-5p during wound healing was confirmed by utilizing a series of gain-and loss-of-function experiments in vitro. Results: The optimal working magnetic condition was 50 µg/mL Fe 3 O 4 nanoparticles combined with 100 mT SMF. In vitro, mag-BMSC-Exo administration promoted proliferation, migration and angiogenesis to a greater extent than BMSC-Exo administration. Local transplantation of mag-BMSC-Exos into rat skin wounds resulted in accelerated wound closure, narrower scar widths and enhanced angiogenesis compared with BMSC-Exo transplantation. Notably, miR-21-5p was found to be highly enriched in mag-BMSC-Exos and served as a critical mediator in mag-BMSC-Exo-induced regulatory effects through inhibition of SPRY2 and activation of the PI3K/AKT and ERK1/2 signaling pathways. Conclusion: Mag-BMSC-Exos can further enhance wound healing than BMSC-Exos by improving angiogenesis and fibroblast function, and miR-21-5p upregulation in mag-BMSC-Exos might be the potential mechanism. This work offers an effective and promising protocol to improve wound healing in clinic.

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“…14,62 Exosomes have been found to play a role in the biological function of activated platelets and MSCs. 30,41 Platelets and MSCs both contain exosomes that are important in cell-to-cell signaling and also contain a multitude of growth factors, which have been associated with improved healing of damaged tissue, such as tendon, 16,65 muscle, 2,6,7,45 and bone. ¶…”

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confidence: 99%

Exosomes Isolated From Platelet-Rich Plasma and Mesenchymal Stem Cells Promote Recovery of Function After Muscle Injury

et al. 2020

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Background: Clinical use of platelet-rich plasma (PRP) and mesenchymal stem cells (MSCs) has gained momentum as treatment for muscle injuries. Exosomes, or small cell–derived vesicles, could be helpful if they could deliver the same or better physiological effect without cell transplantation into the muscle. Hypothesis: Local delivery of exosomes derived from PRP (PRP-exos) or MSCs (MSC-exos) to injured muscles hastens recovery of contractile function. Study Design: Controlled laboratory study. Methods: In a rat model, platelets were isolated from blood, and MSCs were isolated from bone marrow and expanded in culture; exosomes from both were isolated through ultracentrifugation. The tibialis anterior muscles were injured in vivo using maximal lengthening contractions. Muscles were injected with PRP-exos or MSC-exos (immediately after injury and 5 and 10 days after injury); controls received an equal volume of saline. Histological and biochemical analysis was performed on tissues for all groups. Results: Injury resulted in a significant loss of maximal isometric torque (66% ± 3%) that gradually recovered over 2 weeks. Both PRP-exos and MSC-exos accelerated recovery, with similar faster recovery of contractile function over the saline-treated group at 5, 10, and 15 days after injury ( P < .001). A significant increase in centrally nucleated fibers was seen with both types of exosome groups by day 15 ( P < .01). Genes involved in skeletal muscle regeneration were modulated by different exosomes. Muscles treated with PRP-exos had increased expression of Myogenin gene ( P < .05), whereas muscles treated with MSC-exos had reduced expression of TGF-β ( P < .05) at 10 days after muscle injury. Conclusion: Exosomes derived from PRP or MSCs can facilitate recovery after a muscle strain injury in a small-animal model likely because of factors that can modulate inflammation, fibrosis, and myogenesis. Clinical Relevance: Given their small size, low immunogenicity, and ease with which they can be obtained, exosomes could represent a novel therapy for many orthopaedic ailments.

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Therapeutic potential of exosomes in rotator cuff tendon healing

Cited by 51 publications

References 55 publications

Umbilical cord-derived Wharton’s jelly for regenerative medicine applications

Umbilical cord-derived Wharton’s jelly for regenerative medicine applications

<p>Exosomes Derived from Bone Mesenchymal Stem Cells with the Stimulation of Fe<sub>3</sub>O<sub>4</sub> Nanoparticles and Static Magnetic Field Enhance Wound Healing Through Upregulated miR-21-5p</p>

Exosomes Isolated From Platelet-Rich Plasma and Mesenchymal Stem Cells Promote Recovery of Function After Muscle Injury

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