Comparison of exosomes secreted by induced pluripotent stem cell-derived mesenchymal stem cells and synovial membrane-derived mesenchymal stem cells for the treatment of osteoarthritis

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Abstract

Background

Osteoarthritis (OA) is the most common joint disease worldwide. In the past decade, mesenchymal stem cells (MSCs) have been used widely for the treatment of OA. A potential mechanism of MSC-based therapies has been attributed to the paracrine secretion of trophic factors, in which exosomes may play a major role. In this study, we aimed to compare the effectiveness of exosomes secreted by synovial membrane MSCs (SMMSC-Exos) and exosomes secreted by induced pluripotent stem cell-derived MSCs (iMSC-Exos) on the treatment of OA.

Methods

Induced pluripotent stem cell-derived MSCs and synovial membrane MSCs were characterized by flow cytometry. iMSC-Exos and SMMSC-Exos were isolated using an ultrafiltration method. Tunable resistive pulse-sensing analysis, transmission electron microscopy, and western blots were used to identify exosomes. iMSC-Exos and SMMSC-Exos were injected intra-articularly in a mouse model of collagenase-induced OA and the efficacy of exosome injections was assessed by macroscopic, histological, and immunohistochemistry analysis. We also evaluated the effects of iMSC-Exos and SMMSC-Exos on proliferation and migration of human chondrocytes by cell-counting and scratch assays, respectively.

Results

The majority of iMSC-Exos and SMMSC-Exos were approximately 50–150 nm in diameter and expressed CD9, CD63, and TSG101. The injection of iMSC-Exos and SMMSC-Exos both attenuated OA in the mouse OA model, but iMSC-Exos had a superior therapeutic effect compared with SMMSC-Exos. Similarly, chondrocyte migration and proliferation were stimulated by both iMSC-Exos and SMMSC-Exos, with iMSC-Exos exerting a stronger effect.

Conclusions

The present study demonstrated that iMSC-Exos have a greater therapeutic effect on OA than SMMSC-Exos. Because autologous iMSCs are theoretically inexhaustible, iMSC-Exos may represent a novel therapeutic approach for the treatment of OA.

Electronic supplementary material

The online version of this article (doi:10.1186/s13287-017-0510-9) contains supplementary material, which is available to authorized users.

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Paracrine mechanisms of mesenchymal stem cell-based therapy: current status and perspectives.

Xiaoting Liang, Yue Ding, Yuelin Zhang … (2014)

Mesenchymal stem cells (MSCs) are one of a few stem cell types to be applied in clinical practice as therapeutic agents for immunomodulation and ischemic tissue repair. In addition to their multipotent differentiation potential, a strong paracrine capacity has been proposed as the principal mechanism that contributes to tissue repair. Apart from cytokine/chemokine secretion, MSCs also display a strong capacity for mitochondrial transfer and microvesicle (exosomes) secretion in response to injury with subsequent promotion of tissue regeneration. These unique properties of MSCs make them an invaluable cell type to repair damaged tissues/organs. Although MSCs offer great promise in the treatment of degenerative diseases and inflammatory disorders, there are still many challenges to overcome prior to their widespread clinical application. Particularly, their in-depth paracrine mechanisms remain a matter for debate and exploration. This review will highlight the discovery of the paracrine mechanism of MSCs, regulation of the paracrine biology of MSCs, important paracrine factors of MSCs in modulation of tissue repair, exosome and mitochondrial transfer for tissue repair, and the future perspective for MSC-based therapy.

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Exosomes released from human induced pluripotent stem cells-derived MSCs facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis

Jieyuan Zhang, Junjie Guan, Xin Niu … (2015)

Background Human induced pluripotent stem cell-derived mesenchymal stem cells (hiPSC-MSCs) have emerged as a promising alternative for stem cell transplantation therapy. Exosomes derived from mesenchymal stem cells (MSC-Exos) can play important roles in repairing injured tissues. However, to date, no reports have demonstrated the use of hiPSC-MSC-Exos in cutaneous wound healing, and little is known regarding their underlying mechanisms in tissue repair. Methods hiPSC-MSC-Exos were injected subcutaneously around wound sites in a rat model and the efficacy of hiPSC-MSC-Exos was assessed by measuring wound closure areas, by histological and immunofluorescence examinations. We also evaluated the in vitro effects of hiPSC-MSC-Exos on both the proliferation and migration of human dermal fibroblasts and human umbilical vein endothelial cells (HUVECs) by cell-counting and scratch assays, respectively. The effects of exosomes on fibroblast collagen and elastin secretion were studied in enzyme-linked immunosorbent assays and quantitative reverse-transcriptase–polymerase chain reaction (qRT-PCR). In vitro capillary network formation was determined in tube-formation assays. Results Transplanting hiPSC-MSC-Exos to wound sites resulted in accelerated re-epithelialization, reduced scar widths, and the promotion of collagen maturity. Moreover, hiPSC-MSC-Exos not only promoted the generation of newly formed vessels, but also accelerated their maturation in wound sites. We found that hiPSC-MSC-Exos stimulated the proliferation and migration of human dermal fibroblasts and HUVECs in a dose-dependent manner in vitro. Similarly, Type I, III collagen and elastin secretion and mRNA expression by fibroblasts and tube formation by HUVECs were also increased with increasing hiPSC-MSC-Exos concentrations. Conclusions Our findings suggest that hiPSC-MSC-Exos can facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis. These data provide the first evidence for the potential of hiPSC-MSC-Exos in treating cutaneous wounds.

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A stem cell-based approach to cartilage repair.

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.

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Author and article information

Contributors

Yu Zhu: 06-zhuyu@sjtu.edu.cn

Yuchen Wang: wycsjtu@sjtu.edu.cn

Bizeng Zhao: zhaobizeng@aliyun.com

Xin Niu: Niuxin999@163.com

Bin Hu: bin_hu22@163.com

Qing Li: Liqing_236@aliyun.com

Juntao Zhang: zhangjuntao789@163.com

Jian Ding: dingjian3246@163.com

Yunfeng Chen: drchenyf@126.com

Yang Wang: wangy63cn@126.com

Journal

Journal ID (nlm-ta): Stem Cell Res Ther

Journal ID (iso-abbrev): Stem Cell Res Ther

Title: Stem Cell Research & Therapy

Publisher: BioMed Central (London )

ISSN (Electronic): 1757-6512

Publication date (Electronic): 9 March 2017

Publication date PMC-release: 9 March 2017

Publication date Collection: 2017

Volume: 8

Electronic Location Identifier: 64

Affiliations

[1 ]ISNI 0000 0004 1798 5117, GRID grid.412528.8, Department of Orthopedic Surgery, , Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, ; 600 Yishan Road, Shanghai, 200233 China

[2 ]ISNI 0000 0004 1798 5117, GRID grid.412528.8, , Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, ; 600 Yishan Road, Shanghai, 200233 China

Article

Publisher ID: 510

DOI: 10.1186/s13287-017-0510-9

PMC ID: 5345222

PubMed ID: 28279188

SO-VID: 151d0afa-3e14-4112-95b2-aecc28c62e86

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 16 November 2016

Date revision received : 24 January 2017

Date accepted : 14 February 2017

Funding

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

Award ID: 81672254

Award ID: 81171861

Award Recipient : Jian Ding Yang Wang

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ScienceOpen disciplines: Molecular medicine

Keywords: exosomes,induced pluripotent stem cell-derived mesenchymal stem cell,synovial membrane-derived mesenchymal stem cell,osteoarthritis

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ScienceOpen disciplines: Molecular medicine

Keywords: exosomes, induced pluripotent stem cell-derived mesenchymal stem cell, synovial membrane-derived mesenchymal stem cell, osteoarthritis

Comparison of exosomes secreted by induced pluripotent stem cell-derived mesenchymal stem cells and synovial membrane-derived mesenchymal stem cells for the treatment of osteoarthritis

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cGMP: Generators, Effectors and Therapeutic Implications Conference

Most cited references 25

Paracrine mechanisms of mesenchymal stem cell-based therapy: current status and perspectives.

Exosomes released from human induced pluripotent stem cells-derived MSCs facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis

A stem cell-based approach to cartilage repair.

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