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

Hongyuan Xing,Ning Zhang,Youlong Zhou,Haibin Xu,Shaojun Hu,Qijiang Mao,Liwei Ying,Xiaopeng Zhou,Chenggui Wang,Zengjie Zhang

doi:10.1186/s12951-021-00991-5

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.

Highlights

Intervertebral disc degeneration (IVDD) is a chronic degenerative disease that consumes a substantial amount of medical resources [1,2,3]
By testing the DNA content, we found that more than 99% of the DNA in the dECM had been removed. (Fig. 1C)
According to the NTA results, the exosome samples were unimodal in the range of 30–150 nm, which concurs with previous reports (Fig. 1H)

Summary

Introduction

Intervertebral disc degeneration (IVDD) is a chronic degenerative disease that consumes a substantial amount of medical resources [1,2,3]. The main mechanism of IVDD are the disorder of catabolism and anabolism in the extracellular matrix (ECM) and changes in the intervertebral disc (IVD) microenvironment [4]. IVDD, the abnormal expression of matrix metalloproteinases (MMPs) and reduced collagen II decreased the secretion of type II collagen from the nucleus pulposus (NP), resulting in the disruption of the ECM balance [5, 6]. IVD microenvironment remodeling and the aggregation of inflammatory factors as well as the death of NPCs result in a cascade of worsening reactions [7,8,9]. Restoring the IVD microenvironment and protecting nucleus pulposus cells can ameliorate IVDD. Mesenchymal stem cell (MSC) transplantation, as a representative cell therapy, is becoming prevalent in the field of fracture healing [10], cartilage repair [11, 12], spinal cord injury repair [13] and intervertebral disc

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