Exosomes produced from 3D cultures of umbilical cord mesenchymal stem cells in a hollow-fiber bioreactor show improved osteochondral regeneration activity

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Abstract

Animal and clinical studies have shown that mesenchymal stem cells (MSCs) play an important role in cartilage repair. The therapeutic effect of mesenchymal stem cells based therapies has been increasingly demonstrated to exosome-mediated paracrine secretion. Here, we investigated the cellular processes and mechanism of exosomes produced by conventional 2D culture (2D-Exos) and exosomes produced from 3D culture (3D-Exos) of umbilical MSCs (U-MSCs) in a hollow-fiber bioreactor for the treatment of cartilage repair. We found that the yield of 3D-Exos was 7.5-fold higher than that of 2D-Exos. The in vitro experiments indicated that both 2D-Exos and 3D-Exos can stimulate chondrocyte proliferation, migration, and matrix synthesis, and inhibit apoptosis, with 3D-Exos exerting a stronger effect than 2D-Exos. This effect was partly attributed to the activation of transforming growth factor beta 1 and Smad2/3 signaling. The injection of 2D-Exos and 3D-Exos showed enhanced gross appearance and attenuated cartilage defect; however, 3D-Exos showed a superior therapeutic effect than 2D-Exos. In summary, our study provides novel insights into the chondroprotective effects of exosomes produced from 3D culture of U-MSCs in a hollow-fiber bioreactor. Because of its promising biological function and high yield, 3D-Exos may become a promising therapeutic method for the treatment of cartilage defects.

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Integration of stem cell-derived exosomes with in situ hydrogel glue as a promising tissue patch for articular cartilage regeneration.

Bizeng Zhao, Xin Niu, Xiaolin Liu … (2017)

The regeneration of articular cartilage, which scarcely shows innate self-healing ability, is a great challenge in clinical treatment. Stem cell-derived exosomes (SC-Exos), an important type of extracellular nanovesicle, exhibit great potential for cartilage regeneration to replace stem cell-based therapy. Cartilage regeneration often takes a relatively long time and there is currently no effective administration method to durably retain exosomes at cartilage defect sites to effectively exert their reparative effect. Therefore, in this study, we exploited a photoinduced imine crosslinking hydrogel glue, which presents excellent operation ability, biocompatibility and most importantly, cartilage-integration, as an exosome scaffold to prepare an acellular tissue patch (EHG) for cartilage regeneration. It was found that EHG can retain SC-Exos and positively regulate both chondrocytes and hBMSCs in vitro. Furthermore, EHG can integrate with native cartilage matrix and promote cell deposition at cartilage defect sites, finally resulting in the promotion of cartilage defect repair. The EHG tissue patch therefore provides a novel, cell-free scaffold material for wound repair.

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Exosomes derived from miR-92a-3p-overexpressing human mesenchymal stem cells enhance chondrogenesis and suppress cartilage degradation via targeting WNT5A

Guping Mao, Ziji Zhang, Shu Hu … (2018)

Background WNT5A is known to be involved in the pathogenesis of osteoarthritis. This study investigated the molecular mechanism of exosomal miR-92a-3p and WNT5A in chondrogenesis and cartilage degeneration. Methods Exosomal miR-92a-3p expression was assessed in vitro in a human mesenchymal stem cell (MSC) model of chondrogenesis and in normal and OA primary human chondrocytes (PHCs). MSCs and PHCs were treated with exosomes derived from MSC-miR-92a-3p (MSC-miR-92a-3p-Exos) or its antisense inhibitor (MSC-anti-miR-92a-3p-Exos), respectively. Small interfering RNAs (siRNAs) and luciferase reporter assay were used to reveal the molecular role of exosomal miR-92a-3p and WNT5A in chondrogenesis. The protective effect of exosomes in vivo was measured using Safranin-O and Fast Green staining and immunohistochemical staining. Results Exosomal miR-92a-3p expression was elevated in the MSC chondrogenic exosome, while it was significantly reduced in the OA chondrocyte-secreted exosome compared with normal cartilage. Treatment with MSC-miR-92a-3p-Exos promoted cartilage proliferation and matrix genes expression in MSCs and PHCs, respectively. In contrast, treatment with MSC-anti-miR-92a-3p-Exos repressed chondrogenic differentiation and reduced cartilage matrix synthesis by enhancing the expression of WNT5A. Luciferase reporter assay demonstrated that miR-92a-3p suppressed the activity of a reporter construct containing the 3’-UTR and inhibited WNT5A expression in both MSCs and PHCs. MSC-miR-92a-3p-Exos inhibit cartilage degradation in the OA mice model. Conclusions Our results suggest that exosomal miR-92a-3p regulates cartilage development and homeostasis by directly targeting WNT5A. This indicates that exosomal miR-92a-3p may act as a Wnt inhibitor and exhibits potential as a disease-modifying osteoarthritis drug. Electronic supplementary material The online version of this article (10.1186/s13287-018-1004-0) contains supplementary material, which is available to authorized users.

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Efficient production and enhanced tumor delivery of engineered extracellular vesicles.

Dionysios C. Watson, Defne Bayik, Avinash Srivatsan … (2016)

Extracellular vesicles (EV), including exosomes and microvesicles, are nano-sized intercellular communication vehicles that participate in a multitude of physiological processes. Due to their biological properties, they are also promising candidates for the systemic delivery of therapeutic compounds, such as cytokines, chemotherapeutic drugs, siRNAs and viral vectors. However, low EV production yield and rapid clearance of administered EV by liver macrophages limit their potential use as therapeutic vehicles. We have used a hollow-fiber bioreactor for the efficient production of bioactive EV bearing the heterodimeric cytokine complex Interleukin-15:Interleukin-15 receptor alpha. Bioreactor culture yielded ∼40-fold more EV per mL conditioned medium, as compared to conventional cell culture. Biophysical analysis and comparative proteomics suggested a more diverse population of EV in the bioreactor preparations, while serum protein contaminants were detectable only in conventional culture EV preparations. We also identified the Scavenger Receptor Class A family (SR-A) as a novel monocyte/macrophage uptake receptor for EV. In vivo blockade of SR-A with dextran sulfate dramatically decreased EV liver clearance in mice, while enhancing tumor accumulation. These findings facilitate development of EV therapeutic methods.

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Author and article information

Contributors

Litao Yan: yanlitaodtc@163.com

Xing Wu: wxing123@yeah.net , sykyc@vip.163.com

Journal

Journal ID (nlm-ta): Cell Biol Toxicol

Journal ID (iso-abbrev): Cell Biol. Toxicol

Title: Cell Biology and Toxicology

Publisher: Springer Netherlands (Dordrecht )

ISSN (Print): 0742-2091

ISSN (Electronic): 1573-6822

Publication date (Electronic): 9 December 2019

Publication date PMC-release: 9 December 2019

Publication date (Print): 2020

Volume: 36

Issue: 2

Pages: 165-178

Affiliations

GRID grid.24516.34, ISNI 0000000123704535, Department of Orthopedics, Shanghai Tenth People’s Hospital, School of Medicine, , Tongji University, ; Shanghai, 200072 People’s Republic of China

Article

Publisher ID: 9504

DOI: 10.1007/s10565-019-09504-5

PMC ID: 7196084

PubMed ID: 31820164

SO-VID: 058a28e2-b7aa-4126-93da-ce318cf8bb8f

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 18 July 2019

Date accepted : 21 November 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81772324

Award Recipient : Xing Wu

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ScienceOpen disciplines: Cell biology

Keywords: osteochondral regeneration,umbilical cord mesenchymal stem cell,exosome,3d culture

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ScienceOpen disciplines: Cell biology

Keywords: osteochondral regeneration, umbilical cord mesenchymal stem cell, exosome, 3d culture

Exosomes produced from 3D cultures of umbilical cord mesenchymal stem cells in a hollow-fiber bioreactor show improved osteochondral regeneration activity

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Most cited references 16

Integration of stem cell-derived exosomes with in situ hydrogel glue as a promising tissue patch for articular cartilage regeneration.

Exosomes derived from miR-92a-3p-overexpressing human mesenchymal stem cells enhance chondrogenesis and suppress cartilage degradation via targeting WNT5A

Efficient production and enhanced tumor delivery of engineered extracellular vesicles.

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