Engineering stem cells to produce exosomes with enhanced bone regeneration effects: an alternative strategy for gene therapy

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Abstract

Background

Exosomes derived from stem cells have been widely studied for promoting regeneration and reconstruction of multiple tissues as “cell-free” therapies. However, the applications of exosomes have been hindered by limited sources and insufficient therapeutic potency.

Results

In this study, a stem cell-mediated gene therapy strategy is developed in which mediator mesenchymal stem cells are genetically engineered by bone morphogenetic protein-2 gene to produce exosomes (MSC-BMP2-Exo) with enhanced bone regeneration potency. This effect is attributed to the synergistic effect of the content derived from MSCs and the up-regulated BMP2 gene expression. The MSC-BMP2-Exo also present homing ability to the injured site. The toxic effect of genetical transfection vehicles is borne by mediator MSCs, while the produced exosomes exhibit excellent biocompatibility. In addition, by plasmid tracking, it is interesting to find a portion of plasmid DNA can be encapsulated by exosomes and delivered to recipient cells.

Conclusions

In this strategy, engineered MSCs function as cellular factories, which effectively produce exosomes with designed and enhanced therapeutic effects. The accelerating effect in bone healing and the good biocompatibility suggest the potential clinical application of this strategy.

Graphical Abstract

Supplementary Information

The online version contains supplementary material available at 10.1186/s12951-022-01347-3.

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Most cited references 65

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The biology, function, and biomedical applications of exosomes

Raghu Kalluri, Valerie LeBleu (2020)

The study of extracellular vesicles (EVs) has the potential to identify unknown cellular and molecular mechanisms in intercellular communication and in organ homeostasis and disease. Exosomes, with an average diameter of ~100 nanometers, are a subset of EVs. The biogenesis of exosomes involves their origin in endosomes, and subsequent interactions with other intracellular vesicles and organelles generate the final content of the exosomes. Their diverse constituents include nucleic acids, proteins, lipids, amino acids, and metabolites, which can reflect their cell of origin. In various diseases, exosomes offer a window into altered cellular or tissue states, and their detection in biological fluids potentially offers a multicomponent diagnostic readout. The efficient exchange of cellular components through exosomes can inform their applied use in designing exosome-based therapeutics.

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Shedding light on the cell biology of extracellular vesicles

Guillaume van Niel, Gisela D'Angelo, Graça Raposo (2018)

Extracellular vesicles are a heterogeneous group of cell-derived membranous structures comprising exosomes and microvesicles, which originate from the endosomal system or which are shed from the plasma membrane, respectively. They are present in biological fluids and are involved in multiple physiological and pathological processes. Extracellular vesicles are now considered as an additional mechanism for intercellular communication, allowing cells to exchange proteins, lipids and genetic material. Knowledge of the cellular processes that govern extracellular vesicle biology is essential to shed light on the physiological and pathological functions of these vesicles as well as on clinical applications involving their use and/or analysis. However, in this expanding field, much remains unknown regarding the origin, biogenesis, secretion, targeting and fate of these vesicles.

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Reassessment of Exosome Composition

Dennis Jeppesen, Aidan M. Fenix, Jeffrey L. Franklin … (2019)

The heterogeneity of small extracellular vesicles and presence of non-vesicular extracellular matter have led to debate about contents and functional properties of exosomes. Here, we employ high-resolution density gradient fractionation and direct immunoaffinity capture to precisely characterize the RNA, DNA, and protein constituents of exosomes and other non-vesicle material. Extracellular RNA, RNA-binding proteins and other cellular proteins are differentially expressed in exosomes and non-vesicle compartments. Argonaute 1–4, glycolytic enzymes and cytoskeletal proteins are absent from exosomes. We identify Annexin A1 as a specific marker for microvesicles that are shed directly from the plasma membrane. We further show that small extracellular vesicles are not vehicles of active DNA release. Instead, we propose a new model for active secretion of extracellular DNA through an autophagy- and multivesicular endosome-dependent, but exosome-independent mechanism. This study demonstrates the need for a reassessment of exosome composition and offers a framework for a clearer understanding of extracellular vesicle heterogeneity. A reassessment of exosome composition establishes the differential distribution of protein, RNA, and DNA between small extracellular vesicles and non-vesicular extracellular matter and establishes that small extracellular vesicles are not vehicles of active DNA release.

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Author and article information

Contributors

Tak Man Wong: wongtm@hku.hk

Xiaoli Zhao:

ORCID: http://orcid.org/0000-0003-1524-1993

zhao.xl@siat.ac.cn

Journal

Journal ID (nlm-ta): J Nanobiotechnology

Journal ID (iso-abbrev): J Nanobiotechnology

Title: Journal of Nanobiotechnology

Publisher: BioMed Central (London )

ISSN (Electronic): 1477-3155

Publication date (Electronic): 15 March 2022

Publication date PMC-release: 15 March 2022

Publication date Collection: 2022

Volume: 20

Electronic Location Identifier: 135

Affiliations

[1 ]GRID grid.458489.c, ISNI 0000 0001 0483 7922, Research Center for Human Tissue and Organs Degeneration, Institute of Biomedicine and Biotechnology, , Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, ; Shenzhen, 518055 China

[2 ]GRID grid.440671.0, ISNI 0000 0004 5373 5131, Shenzhen Key Laboratory for Innovative Technology in Orthopaedic Trauma, , The University of Hong Kong-Shenzhen Hospital, ; Shenzhen, 518053 China

[3 ]GRID grid.410726.6, ISNI 0000 0004 1797 8419, University of Chinese Academy of Sciences, ; Beijing, 100049 China

[4 ]GRID grid.194645.b, ISNI 0000000121742757, Department of Orthopaedics and Traumatology, , The University of Hong Kong, ; Hong Kong, 999077 China

Author information

Xiaoli Zhao http://orcid.org/0000-0003-1524-1993

Article

Publisher ID: 1347

DOI: 10.1186/s12951-022-01347-3

PMC ID: 8922796

PubMed ID: 35292020

SO-VID: b5f79c12-b6d8-49ad-9e68-6baceb6c4f06

License:

Open AccessThis 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/. 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 in a credit line to the data.

History

Date received : 24 December 2021

Date accepted : 2 March 2022

Funding

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

Award ID: 81972071

Award ID: 81802959

Award Recipient : Jun Wu Xiaoli Zhao

Funded by: Guangdong Basic and Applied Basic Research Foundation

Award ID: 2021A1515010191

Award ID: 2018A030313888

Award Recipient : Tak Man Wong Xiaoli Zhao

Funded by: Science and Technology Research Funding of Shenzhen

Award ID: JCYJ20210324102001003

Award ID: JSGG20180507183242702

Award ID: JCYJ20200109150420892

Award Recipient : Tak Man Wong Xiaoli Zhao

Funded by: HKU-SZH Fund for Shenzhen Key Medical Discipline

Award ID: SZXK2020084

Award Recipient : Tak Man Wong

Custom metadata

ScienceOpen disciplines: Biotechnology

Keywords: exosomes,stem cell,gene therapy,tissue regeneration,cell-free therapy

Data availability:

ScienceOpen disciplines: Biotechnology

Keywords: exosomes, stem cell, gene therapy, tissue regeneration, cell-free therapy

Engineering stem cells to produce exosomes with enhanced bone regeneration effects: an alternative strategy for gene therapy

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Abstract

Background

Results

Conclusions

Graphical Abstract

Supplementary Information

Related collections

Stress signalling in stem cells

Most cited references 65

The biology, function, and biomedical applications of exosomes

Shedding light on the cell biology of extracellular vesicles

Reassessment of Exosome Composition

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Contributors

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