Local delivery of USC-derived exosomes harboring ANGPTL3 enhances spinal cord functional recovery after injury by promoting angiogenesis

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Abstract

Background

Spinal cord injury is a devastating clinical condition for which there are currently no effective therapeutic options. In the present study, we aim to investigate if the effect of an administered injection of exosomes derived from human urine stem cell (USC-Exo) embedded in hydrogel could improve the spinal cord functional recovery after injury and the underlying mechanism.

Methods

Exosomes were isolated from USC and identified by transmission electron microscopy (TEM) and Western blot. Functional assays in vitro were performed to assess the effects of USC-Exo on tube formation and migration, as well as their regulatory role in the PI3K/AKT signaling pathway activation. A locally administered injection of exosome embedded in hydrogel was used for SCI treatment. The effects of USC-Exo on functional recovery and the role of the candidate protein ANGPTL3 harboring in USC-Exo for promoting angiogenesis in SCI model were assessed.

Results

In the current study, we demonstrate that a locally administered injection of USC-Exo embedded in hydrogel can pass the spinal cord blood-brain barrier and deliver ANGPTL3 to the injured spinal cord region. In addition, the administration of human USC-Exo could enhance spinal cord neurological functional recovery by promoting angiogenesis. The results of mechanistic studies revealed that ANGPTL3 is enriched in USC-Exo and is required for their ability to promote angiogenesis. Functional studies further confirmed that the effects of USC-Exo on angiogenesis are mediated by the PI3K/AKT signaling pathway.

Conclusion

Collectively, our results indicate that USC-Exo serve as a crucial regulator of angiogenesis by delivering ANGPTL3 and may represent a promising novel therapeutic agent for SCI repair.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13287-020-02078-8.

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Most cited references 36

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Concise Review: MSC-Derived Exosomes for Cell-Free Therapy.

Donald Phinney, Mark F. Pittenger (2017)

Mesenchymal stem cell transplantation is undergoing extensive evaluation as a cellular therapy in human clinical trials. Because MSCs are easily isolated and amenable to culture expansion in vitro there is a natural desire to test MSCs in many diverse clinical indications. This is exemplified by the rapidly expanding literature base that includes many in vivo animal models. More recently, MSC-derived extracellular vesicles (EVs), which include exosomes and microvesicles (MV), are being examined for their role in MSC-based cellular therapy. These vesicles are involved in cell-to-cell communication, cell signaling, and altering cell or tissue metabolism at short or long distances in the body. The exosomes and MVs can influence tissue responses to injury, infection, and disease. MSC-derived exosomes have a content that includes cytokines and growth factors, signaling lipids, mRNAs, and regulatory miRNAs. To the extent that MSC exosomes can be used for cell-free regenerative medicine, much will depend on the quality, reproducibility, and potency of their production, in the same manner that these parameters dictate the development of cell-based MSC therapies. However, the MSC exosome's contents are not static, but rather a product of the MSC tissue origin, its activities and the immediate intercellular neighbors of the MSCs. As such, the exosome content produced by MSCs appears to be altered when MSCs are cultured with tumor cells or in the in vivo tumor microenvironment. Therefore, careful attention to detail in producing MSC exosomes may provide a new therapeutic paradigm for cell-free MSC-based therapies with decreased risk. Stem Cells 2017;35:851-858.

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Traumatic spinal cord injury

Christopher Ahuja, Jefferson R Wilson, Satoshi Nori … (2017)

Traumatic spinal cord injury (SCI) has devastating consequences for the physical, social and vocational well-being of patients. The demographic of SCIs is shifting such that an increasing proportion of older individuals are being affected. Pathophysiologically, the initial mechanical trauma (the primary injury) permeabilizes neurons and glia and initiates a secondary injury cascade that leads to progressive cell death and spinal cord damage over the subsequent weeks. Over time, the lesion remodels and is composed of cystic cavitations and a glial scar, both of which potently inhibit regeneration. Several animal models and complementary behavioural tests of SCI have been developed to mimic this pathological process and form the basis for the development of preclinical and translational neuroprotective and neuroregenerative strategies. Diagnosis requires a thorough patient history, standardized neurological physical examination and radiographic imaging of the spinal cord. Following diagnosis, several interventions need to be rapidly applied, including haemodynamic monitoring in the intensive care unit, early surgical decompression, blood pressure augmentation and, potentially, the administration of methylprednisolone. Managing the complications of SCI, such as bowel and bladder dysfunction, the formation of pressure sores and infections, is key to address all facets of the patient's injury experience.

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Is Open Access

Exosome Theranostics: Biology and Translational Medicine

Chuanjiang He, Shu Zheng, Yan Luo … (2018)

Exosomes are common membrane-bound nanovesicles that contain diverse biomolecules, such as lipids, proteins, and nucleic acids. Exosomes are derived from cells through exocytosis, are ingested by target cells, and can transfer biological signals between local or distant cells. Exosome secretion is a constitutive phenomenon that is involved in both physiological and pathological processes and determines both the exosomal surface molecules and the contents. Hence, we can exploit exosomes as biomarkers, vaccines and drug carriers and modify them rationally for therapeutic interventions. However, it is still a challenge to identify, isolate and quantify exosomes accurately, efficiently and selectively. Further studies on exosomes will explore their potential in translational medicine and provide new avenues for the creation of effective clinical diagnostics and therapeutic strategies; the use of exosomes in these applications can be called exosome theranostics. This review describes the fundamental processes of exosome formation and uptake. In addition, the physiological and pathological roles of exosomes in biology are also illustrated with a focus on how exosomes can be exploited or engineered as powerful tools in translational medicine.

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Author and article information

Contributors

Hui Xie: Huixie@csu.edu.cn

Jianzhong Hu: jianzhonghu@hotmail.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): 7 January 2021

Publication date PMC-release: 7 January 2021

Publication date Collection: 2021

Volume: 12

Electronic Location Identifier: 20

Affiliations

[1 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Department of Spine Surgery and Orthopedics, Xiangya Hospital, , Central South University, ; Changsha, 410008 China

[2 ]Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008 China

[3 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, , Central South University, ; Changsha, 410008 China

[4 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Department of Sports Medicine, Xiangya Hospital, , Central South University, ; Changsha, 410008 China

[5 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Movement System Injury and Repair Research Center, Xiangya Hospital, , Central South University, ; Changsha, 410008 Hunan China

Article

Publisher ID: 2078

DOI: 10.1186/s13287-020-02078-8

PMC ID: 7791988

PubMed ID: 33413639

SO-VID: 63d20d88-01ea-4baf-9be3-5f77e0ea9285

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 : 29 June 2020

Date accepted : 7 December 2020

Funding

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

Award ID: 81874004, 81672174

Custom metadata

ScienceOpen disciplines: Molecular medicine

Keywords: spinal cord injury,human urine stem cell,exosome,angiopoietin-like protein 3,angiogenesis

Data availability:

ScienceOpen disciplines: Molecular medicine

Keywords: spinal cord injury, human urine stem cell, exosome, angiopoietin-like protein 3, angiogenesis

Local delivery of USC-derived exosomes harboring ANGPTL3 enhances spinal cord functional recovery after injury by promoting angiogenesis

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Abstract

Background

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Conclusion

Supplementary Information

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Bacterial extracellular vesicles

Most cited references 36

Concise Review: MSC-Derived Exosomes for Cell-Free Therapy.

Traumatic spinal cord injury

Exosome Theranostics: Biology and Translational Medicine

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