MSC exosomes alleviate temporomandibular joint osteoarthritis by attenuating inflammation and restoring matrix homeostasis

Zhang, Shipin; Teo, Kejia; Chuah, S.; Lai, Ruenn Chai; Lim, Sai Kiang; Toh, Wei Seong

doi:10.1016/j.biomaterials.2019.02.006

Cited by 406 publications

(388 citation statements)

References 57 publications

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“…These results suggest a role for miRNA in the anti‐inflammatory/regenerative function displayed by the CSSC EVs. Such a function is consistent with a number of recent studies that have linked miRNA delivery by EVs to regenerative, antifibrotic, and immune suppressive properties of the vesicles . Some authors have suggested that the small amount of miRNA in EVs makes it more likely that a protein cargo is involved in their biological properties .…”

Section: Discussionsupporting

confidence: 88%

Mesenchymal Stem Cells Reduce Corneal Fibrosis and Inflammation via Extracellular Vesicle-Mediated Delivery of miRNA

Shojaati

Khandaker

Funderburgh

et al. 2019

Stem Cells Translational Medicine

132

114

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Mesenchymal stem cells from corneal stromal stem cells (CSSC) prevent fibrotic scarring and stimulate regeneration of transparent stromal tissue after corneal wounding in mice. These effects rely on the ability of CSSC to block neutrophil infiltration into the damaged cornea. The current study investigated the hypothesis that tissue regeneration by CSSC is mediated by secreted extracellular vesicles (EVs). CSSC produced EVs 130–150 nm in diameter with surface proteins that include CD63, CD81, and CD9. EVs from CSSC reduced visual scarring in murine corneal wounds as effectively as did live cells, but EVs from human embryonic kidney (HEK)293T cells had no regenerative properties. CSSC EV treatment of wounds decreased expression of fibrotic genes Col3a1 and Acta2, blocked neutrophil infiltration, and restored normal tissue morphology. CSSC EVs labeled with carboxyfluorescein succinimidyl ester dye, rapidly fused with corneal epithelial and stromal cells in culture, transferring microRNA (miRNA) to the target cells. Knockdown of mRNA for Alix, a component of the endosomal sorting complex required for transport, using siRNA, resulted in an 85% reduction of miRNA in the secreted EVs. The EVs with reduced miRNA were ineffective at blocking corneal scarring. Furthermore, CSSC with reduced Alix expression also lost their regenerative function, suggesting EVs as an obligate component in the delivery of miRNA. The results of these studies support an essential role for extracellular vesicles in the process by which CSSC cells block scarring and initiate regeneration of transparent corneal tissue after wounding. EVs appear to serve as a delivery vehicle for miRNA, which affects the regenerative action. Stem Cells Translational Medicine 2019;8:1192–1201

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Section: Discussionsupporting

confidence: 88%

Mesenchymal Stem Cells Reduce Corneal Fibrosis and Inflammation via Extracellular Vesicle-Mediated Delivery of miRNA

Shojaati

Khandaker

Funderburgh

et al. 2019

Stem Cells Translational Medicine

132

114

View full text Add to dashboard Cite

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“…Nonetheless, the screening and confirmation of candidate factors participating in the chondrogenic enhancement observed with PCM is far from complete. In addition, the possible role of exosomal CD73-mediated adenosine activation of AKT, ERK, and AMPK signaling [14,64] and the participation of exosomal microRNAs [65,66] that have been previously implicated in regulating chondrocyte anabolic activity and cartilage degradation have yet to be examined. Further work will be required to fully decipher the paracrine mechanisms responsible for the enhanced anabolic and protective effect observed here in response to PCM administration, including the examination of the contribution of EVs to our reported PEMF-mediated secretome responses.…”

Section: Discussionmentioning

confidence: 99%

Pulsed electromagnetic fields potentiate the paracrine function of mesenchymal stem cells for cartilage regeneration

et al. 2020

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Background: The mesenchymal stem cell (MSC) secretome, via the combined actions of its plethora of biologically active factors, is capable of orchestrating the regenerative responses of numerous tissues by both eliciting and amplifying biological responses within recipient cells. MSCs are "environmentally responsive" to local micro-environmental cues and biophysical perturbations, influencing their differentiation as well as secretion of bioactive factors. We have previously shown that exposures of MSCs to pulsed electromagnetic fields (PEMFs) enhanced MSC chondrogenesis. Here, we investigate the influence of PEMF exposure over the paracrine activity of MSCs and its significance to cartilage regeneration.Methods: Conditioned medium (CM) was generated from MSCs subjected to either 3D or 2D culturing platforms, with or without PEMF exposure. The paracrine effects of CM over chondrocytes and MSC chondrogenesis, migration and proliferation, as well as the inflammatory status and induced apoptosis in chondrocytes and MSCs was assessed.Results: We show that benefits of magnetic field stimulation over MSC-derived chondrogenesis can be partly ascribed to its ability to modulate the MSC secretome. MSCs cultured on either 2D or 3D platforms displayed distinct magnetic sensitivities, whereby MSCs grown in 2D or 3D platforms responded most favorably to PEMF exposure at 2 mT and 3 mT amplitudes, respectively. Ten minutes of PEMF exposure was sufficient to substantially augment the chondrogenic potential of MSC-derived CM generated from either platform. Furthermore, PEMF-induced CM was capable of enhancing the migration of chondrocytes and MSCs as well as mitigating cellular inflammation and apoptosis. Conclusions:The findings reported here demonstrate that PEMF stimulation is capable of modulating the paracrine function of MSCs for the enhancement and re-establishment of cartilage regeneration in states of cellular stress. The PEMF-induced modulation of the MSC-derived paracrine function for directed biological responses in recipient cells or tissues has broad clinical and practical ramifications with high translational value across numerous clinical applications.

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“…Oral MSC-derived exosomes have been reported of therapeutic benefit in a number of inflammatory-related disease, through different molecular mechanisms. BM-MSC-derived exosomes promoted the regeneration/repair of the periodontal ligament and temporomandibular joint, through activation of AKT, ERK, and AMPK signaling pathways that suppress the inflammatory response by chondrocyte and increase the proliferation and migration of periodontal ligament cells [104,105]. Following stimulation by Pg-LPS, microRNA-155-5p expression in PDLSC-derived exosomes significantly decreased and the exosome was ingested by CD4 + T cells.…”

Section: Oral Msc-derived Extracellular Vesicles (Evs) In Conditionedmentioning

confidence: 99%

Oral Mesenchymal Stem/Progenitor Cells: The Immunomodulatory Masters

Zhou

Liu

et al. 2020

Stem Cells International

103

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Oral mesenchymal stem/progenitor cells (MSCs) are renowned in the field of tissue engineering/regeneration for their multilineage differentiation potential and easy acquisition. These cells encompass the periodontal ligament stem/progenitor cells (PDLSCs), the dental pulp stem/progenitor cells (DPSCs), the stem/progenitor cells from human exfoliated deciduous teeth (SHED), the gingival mesenchymal stem/progenitor cells (GMSCs), the stem/progenitor cells from the apical papilla (SCAP), the dental follicle stem/progenitor cells (DFSCs), the bone marrow mesenchymal stem/progenitor cells (BM-MSCs) from the alveolar bone proper, and the human periapical cyst-mesenchymal stem cells (hPCy-MSCs). Apart from their remarkable regenerative potential, oral MSCs possess the capacity to interact with an inflammatory microenvironment. Although inflammation might affect the properties of oral MSCs, they could inversely exert a multitude of immunological actions to the local inflammatory microenvironment. The present review discusses the current understanding about the immunomodulatory role of oral MSCs both in periodontitis and systemic diseases, their “double-edged sword” uniqueness in inflammatory regulation, their affection of the immune system, and the underlying mechanisms, involving oral MSC-derived extracellular vesicles.

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MSC exosomes alleviate temporomandibular joint osteoarthritis by attenuating inflammation and restoring matrix homeostasis

Cited by 406 publications

References 57 publications

Mesenchymal Stem Cells Reduce Corneal Fibrosis and Inflammation via Extracellular Vesicle-Mediated Delivery of miRNA

Mesenchymal Stem Cells Reduce Corneal Fibrosis and Inflammation via Extracellular Vesicle-Mediated Delivery of miRNA

Pulsed electromagnetic fields potentiate the paracrine function of mesenchymal stem cells for cartilage regeneration

Oral Mesenchymal Stem/Progenitor Cells: The Immunomodulatory Masters

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