The tissue origin effect of extracellular vesicles on cartilage and bone regeneration

Extracellular Vesicles (EVs) are considered promising nanoscale therapeutics for bone regeneration. To date, EVs are typically procured from cells on 2D tissue culture plastic, an artificial environment that limits cell growth and does not replicate in situ biochemical or biophysical conditions. This study investigated the potential of 3D printed titanium scaffolds coated with hydroxyapatite to promote the therapeutic efficacy of osteoblast-derived EVs. Ti6Al4V titanium scaffolds with different pore sizes (500 and 1000 µm) and shapes (square and triangle) were fabricated by selective laser melting. A bone-mimetic nano-needle hydroxyapatite (nnHA) coating was then applied. EVs were procured from scaffold-cultured osteoblasts over 2 weeks and vesicle concentration was determined using the CD63 ELISA. Osteogenic differentiation of human bone marrow stromal cells (hBMSCs) following treatment with primed EVs was evaluated by assessing alkaline phosphatase activity, collagen production and calcium deposition. Triangle pore scaffolds significantly increased osteoblast mineralisation (1.5-fold) when compared to square architectures (P ≤ 0.001). Interestingly, EV yield was also significantly enhanced on these higher permeability structures (P ≤ 0.001), in particular (2.2-fold) for the larger pore structures (1000 µm). Furthermore osteoblast-derived EVs isolated from triangular pore scaffolds significantly increased hBMSCs mineralisation when compared to EVs acquired from square pore scaffolds (1.7-fold) and 2D culture (2.2-fold) (P ≤ 0.001). Coating with nnHA significantly improved osteoblast mineralisation (>2.6-fold) and EV production (4.5-fold) when compared to uncoated scaffolds (P ≤ 0.001). Together, these findings demonstrate the potential of harnessing bone-mimetic culture platforms to enhance the production of pro-regenerative EVs as an acellular tool for bone repair.

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MSC-Derived Extracellular Vesicles in Tumors and Therapy

Cancers ◽

10.3390/cancers13205212 ◽

2021 ◽

Vol 13 (20) ◽

pp. 5212

Author(s):

Tianjiao Luo ◽

Juliane von der Ohe ◽

Ralf Hass

Keyword(s):

Communication Network ◽

Wound Healing ◽

Stem Cell ◽

Extracellular Vesicles ◽

Normal Tissue ◽

Tumor Development ◽

Cytotoxic Effects ◽

Functional Changes ◽

Tissue Origin ◽

Stem Cell Niches

Exosomes derived from mesenchymal stroma-/stem-like cells (MSCs) as part of extracellular vesicles are considered cell-free biocompatible nanovesicles that promote repair activities of damaged tissues or organs by exhibiting low immunogenic and cytotoxic effects. Contributions to regenerative activities include wound healing, maintenance of stem cell niches, beneficial regenerative effects in various diseases, and reduction of senescence. However, the mode of action in MSC-derived exosomes strongly depends on the biological content like different regulatory microRNAs that are determined by the tissue origin of MSCs. In tumors, MSCs use indirect and direct pathways in a communication network to interact with cancer cells. This leads to mutual functional changes with the acquisition of an aberrant tumor-associated MSC phenotype accompanied by altered cargo in the exosomes. Consequently, MSC-derived exosomes either from normal tissue-originating MSCs or from aberrant tumor-associated MSCs can confer different actions on tumor development. These processes exhibiting tumor-inhibitory and tumor-supportive effects with a focus on exosome microRNA content will be discriminated and discussed within this review.

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The Role of Extracellular Vesicles Secreted From Thermal Stress-Induced Adipose-Derived Stem Cells on Bone Regeneration

Journal of Craniofacial Surgery ◽

10.1097/scs.0000000000007901 ◽

2021 ◽

Vol Publish Ahead of Print ◽

Author(s):

Zeynep Akdeniz-Dogan ◽

Samet Sendur ◽

Betul Karademir-Yilmaz ◽

Onur Bugdayci ◽

Ozlem T. Kaya ◽

...

Keyword(s):

Stem Cells ◽

Thermal Stress ◽

Bone Regeneration ◽

Extracellular Vesicles ◽

Adipose Derived Stem Cells

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The Delivery of Extracellular Vesicles Loaded in Biomaterial Scaffolds for Bone Regeneration

Frontiers in Bioengineering and Biotechnology ◽

10.3389/fbioe.2020.01015 ◽

2020 ◽

Vol 8 ◽

Author(s):

Hui-Chun Yan ◽

Ting-Ting Yu ◽

Jing Li ◽

Yi-Qiang Qiao ◽

Lin-Chuan Wang ◽

...

Keyword(s):

Bone Regeneration ◽

Extracellular Vesicles ◽

Biomaterial Scaffolds

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Could the Enrichment of a Biomaterial with Conditioned Medium or Extracellular Vesicles Modify Bone-Remodeling Kinetics during a Defect Healing? Evaluations on Rat Calvaria with Synchrotron-Based Microtomography

Applied Sciences ◽

10.3390/app10072336 ◽

2020 ◽

Vol 10 (7) ◽

pp. 2336

Author(s):

Alessandra Giuliani ◽

Gabriela Sena ◽

Giuliana Tromba ◽

Emanuela Mazzon ◽

Antonella Fontana ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Bone Regeneration ◽

Conditioned Medium ◽

Bone Remodeling ◽

Extracellular Vesicles ◽

Bone Tissue Regeneration ◽

Bone Mass Density ◽

Defect Healing ◽

Defect Site

Tissue engineering has been shown to offer promising approaches for bone regeneration, mostly based on replacement with biomaterials that provide specific environments and support for bone growth. In this context, we previously showed that mesenchymal stem cells (MSCs) and their derivatives, such as conditioned medium (CM) and extracellular vesicles (EV), when seeded on collagen membranes (COL) or polylactide (PLA) biomaterials, are able to favor bone tissue regeneration, especially evidenced in animal model calvary defects. In the present study, we investigated whether the enrichment of a rat calvary defect site with CM, EVs and polyethylenimine (PEI)-engineered EVs could substantially modify the bone remodeling kinetics during defect healing, as these products were reported to favor bone regeneration. In particular, we focused the study, performed by synchrotron radiation-based high-resolution tomography, on the analysis of the bone mass density distribution. We proved that the enrichment of a defect site with CM, EVs and PEI-EVs substantially modifies, often accelerating, bone remodeling kinetics and the related mineralization process during defect healing. Moreover, different biomaterials (COL or PLA) in combination with stem cells of different origin (namely, human periodontal ligament stem cells-hPDLSCs and human gingival mesenchymal stem cells-hGMSCs) and their own CM, EVs and PEI-EVs products were shown to exhibit different mineralization kinetics.

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Engineered Extracellular Vesicles From Human Periodontal-Ligament Stem Cells Increase VEGF/VEGFR2 Expression During Bone Regeneration

Frontiers in Physiology ◽

10.3389/fphys.2019.00512 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 42

Author(s):

Jacopo Pizzicannella ◽

Agnese Gugliandolo ◽

Tiziana Orsini ◽

Antonella Fontana ◽

Alessia Ventrella ◽

...

Keyword(s):

Stem Cells ◽

Bone Regeneration ◽

Extracellular Vesicles ◽

Periodontal Ligament ◽

Periodontal Ligament Stem Cells

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Bone-targeted extracellular vesicles from mesenchymal stem cells for osteoporosis therapy

10.21203/rs.3.rs-18279/v1 ◽

2020 ◽

Author(s):

Yayu Wang ◽

Jie Yao ◽

Lizhao Cai ◽

Tong Liu ◽

Xiaogang Wang ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Side Effects ◽

Bone Regeneration ◽

Click Chemistry ◽

Extracellular Vesicles ◽

Osteoporosis Therapy ◽

High Affinity ◽

Bone Targeting

Abstract Background Osteoporosis (OP) is one of the most common chronic diseases, but the drugs used to treat OP have strong side effects. Recently, bone regeneration in stem cell derivatives represented by extracellular vesicles (EVs) has provided a new strategy for the prevention and treatment of OP. EVs derived from mouse mesenchymal stem cells (mMSCs) have a positive effect on bone regeneration, yet their clinical application has been hampered by the lack of bone-targeting. Alendronate (Ale) has a specifically affinity for bone tissue through a high affinity with hydroxyapatite. Herein, we used copper-free "click chemistry” to combine EVs with Ale together for OP targeted therapy. Bone targeting was facilitated via Ale binding to hydroxyapatite, which is highly expressed on the bone surface. Methods In vitro, bone targeting of Ale-EVs was confirmed by flow cytometry. Also, Ex vivo ﬂuorescent imaging data revealed strong ﬂuorescent signals in bone tissues in mice treated with Ale-EVs-DiD compared to bone tissues of mice treated with EVs-DiD. Importantly, the modified EVs were well tolerated and showed no evidence of nonspecific side effects or immune response. Besides, our results showed that Ale-EVs could promote the proliferation and differentiation of mouse mesenchymal stem cells in vitro. And it had the antiosteoporotic effects in ovariectomy (OVX)-induced osteoporosis rat model. Conclusions A novel bone-targeting nanoparticle delivery system was developed for osteoporosis therapy. We used the Ale-N3 to modify mMSCs derived EVs by copper-free "click chemistry” to generate a Ale-EVs system. The Ale-EVs had a high affinity for bone and have great potential for clinical applications in osteoporosis therapy with low systemic toxicity.

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