Injectable exosome-functionalized extracellular matrix hydrogel for metabolism balance and pyroptosis regulation in intervertebral disc degeneration

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Abstract

Exosome therapy is a promising therapeutic approach for intervertebral disc degeneration (IVDD) and achieves its therapeutic effects by regulating metabolic disorders, the microenvironment and cell homeostasis with the sustained release of microRNAs, proteins, and transcription factors. However, the rapid clearance and disruption of exosomes are the two major challenges for the application of exosome therapy in IVDD. Herein, a thermosensitive acellular extracellular matrix (ECM) hydrogel coupled with adipose-derived mesenchymal stem cell (ADSC) exosomes (dECM@exo) that inherits the superior properties of nucleus pulposus tissue and ADSCs was fabricated to ameliorate IVDD. This thermosensitive dECM@exo hydrogel system can provide not only in situ gelation to replenish ECM leakage in nucleus pulposus cells (NPCs) but also an environment for the growth of NPCs. In addition, sustained release of ADSC-derived exosomes from this system regulates matrix synthesis and degradation by regulating matrix metalloproteinases (MMPs) and inhibits pyroptosis by mitigating the inflammatory response in vitro. Animal results demonstrated that the dECM@exo hydrogel system maintained early IVD microenvironment homeostasis and ameliorated IVDD. This functional system can serve as a powerful platform for IVD drug delivery and biotherapy and an alternative therapy for IVDD.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12951-021-00991-5.

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The global burden of low back pain: estimates from the Global Burden of Disease 2010 study.

Damian Hoy, Lyn March, Peter Brooks … (2014)

To estimate the global burden of low back pain (LBP). LBP was defined as pain in the area on the posterior aspect of the body from the lower margin of the twelfth ribs to the lower glutaeal folds with or without pain referred into one or both lower limbs that lasts for at least one day. Systematic reviews were performed of the prevalence, incidence, remission, duration, and mortality risk of LBP. Four levels of severity were identified for LBP with and without leg pain, each with their own disability weights. The disability weights were applied to prevalence values to derive the overall disability of LBP expressed as years lived with disability (YLDs). As there is no mortality from LBP, YLDs are the same as disability-adjusted life years (DALYs). Out of all 291 conditions studied in the Global Burden of Disease 2010 Study, LBP ranked highest in terms of disability (YLDs), and sixth in terms of overall burden (DALYs). The global point prevalence of LBP was 9.4% (95% CI 9.0 to 9.8). DALYs increased from 58.2 million (M) (95% CI 39.9M to 78.1M) in 1990 to 83.0M (95% CI 56.6M to 111.9M) in 2010. Prevalence and burden increased with age. LBP causes more global disability than any other condition. With the ageing population, there is an urgent need for further research to better understand LBP across different settings.

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Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases

Changshun Shao, Keli Liu, Qing Li … (2018)

Mesenchymal stem cells (MSCs; also referred to as mesenchymal stromal cells) have attracted much attention for their ability to regulate inflammatory processes. Their therapeutic potential is currently being investigated in various degenerative and inflammatory disorders such as Crohn's disease, graft-versus-host disease, diabetic nephropathy and organ fibrosis. The mechanisms by which MSCs exert their therapeutic effects are multifaceted, but in general, these cells are thought to enable damaged tissues to form a balanced inflammatory and regenerative microenvironment in the presence of vigorous inflammation. Studies over the past few years have demonstrated that when exposed to an inflammatory environment, MSCs can orchestrate local and systemic innate and adaptive immune responses through the release of various mediators, including immunosuppressive molecules, growth factors, exosomes, chemokines, complement components and various metabolites. Interestingly, even nonviable MSCs can exert beneficial effects, with apoptotic MSCs showing immunosuppressive functions in vivo. Because the immunomodulatory capabilities of MSCs are not constitutive but rather are licensed by inflammatory cytokines, the net outcomes of MSC activation might vary depending on the levels and the types of inflammation within the residing tissues. Here, we review current understanding of the immunomodulatory mechanisms of MSCs and the issues related to their therapeutic applications.

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Author and article information

Contributors

Ning Zhang:

ORCID: http://orcid.org/0000-0003-2990-7442

zhangning@zju.edu.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): 6 September 2021

Publication date PMC-release: 6 September 2021

Publication date Collection: 2021

Volume: 19

Electronic Location Identifier: 264

Affiliations

[1 ]GRID grid.13402.34, ISNI 0000 0004 1759 700X, Department of Orthopedics Surgery, 2nd Affiliated Hospital, School of Medicine, , Zhejiang University, ; Hangzhou, 310009 Zhejiang People’s Republic of China

[2 ]GRID grid.13402.34, ISNI 0000 0004 1759 700X, Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, , Zhejiang University, ; Hangzhou, 310028 China

[3 ]GRID grid.411634.5, ISNI 0000 0004 0632 4559, Department of Orthopedics, , Changxing People’s Hospital, ; Changxing, China

Author information

Ning Zhang http://orcid.org/0000-0003-2990-7442

Article

Publisher ID: 991

DOI: 10.1186/s12951-021-00991-5

PMC ID: 8419940

PubMed ID: 34488795

SO-VID: 00e0262d-a283-4499-82b6-0e99182556cb

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 : 30 June 2021

Date accepted : 5 August 2021

Funding

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

Award ID: 81972514

Award ID: 81603126

Award ID: 82002327

Award Recipient : Xiaopeng Zhou Ning Zhang

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ScienceOpen disciplines: Biotechnology

Keywords: intervertebral disc degeneration,exosome,extracellular matrix,pyroptosis,tissue engineering

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ScienceOpen disciplines: Biotechnology

Keywords: intervertebral disc degeneration, exosome, extracellular matrix, pyroptosis, tissue engineering

Injectable exosome-functionalized extracellular matrix hydrogel for metabolism balance and pyroptosis regulation in intervertebral disc degeneration

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Most cited references 48

An overview of tissue and whole organ decellularization processes.

The global burden of low back pain: estimates from the Global Burden of Disease 2010 study.

Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases

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