Therapeutic Potential of Extracellular Vesicles in Degenerative Diseases of the Intervertebral Disc

Abstract

Extracellular vesicles (EVs) are lipid membrane particles carrying proteins, lipids, DNA, and various types of RNA that are involved in intercellular communication. EVs derived from mesenchymal stem cells (MSCs) have been investigated extensively in many different fields due to their crucial role as regeneration drivers, but research for their use in degenerative diseases of the intervertebral disc (IVD) has only started recently. MSC-derived EVs not only promote extracellular matrix synthesis and proliferation in IVD cells, but also reduce apoptosis and inflammation, hence having multifunctional beneficial effects that seem to be mediated by specific miRNAs (such as miR-233 and miR-21) within the EVs. Aside from MSC-derived EVs, IVD-derived EVs (e.g., stemming from notochordal cells) also have important functions in IVD health and disease. This article will summarize the current knowledge on MSC-derived and IVDderived EVs and will highlight areas of future research, including the isolation and analysis of EV subpopulations or exposure of MSCs to cues that may enhance the therapeutic potential of released EVs.

MSC-Derived Exosomes Protect Vertebral Endplate Chondrocytes against Apoptosis and Calcification via the miR-31-5p/ATF6 Axis

“… 21 Although systemic delivery of exosomes is generally considered the easiest approach, biodistribution patterns indicate accumulation in the liver, spleen, and lungs. 23 Especially when taking the avascular nature of IVD into account, local delivery in the sub-endplate region was regarded as a good alternative choice. Meanwhile, sub-endplate injection can avoid repeated puncture in tail disc tissues.…”

Genetic Therapy for Intervertebral Disc Degeneration

“…After delivery to DRG neurons, epigenome editing vectors induced increased neuronal activity [ 69 , 80 ]. Krupkova et al suggested that CRISPR/Cas9 can be applied to gene knockout, gene editing, inhibition, and gene expression activation, suggesting that these methods could be promising new tools that may play a role in IVDD treatment [ 53 , 81 ].…”

Electrospinning and 3D bioprinting for intervertebral disc tissue engineering

“…55 Future research should furthermore investigate the incorporation of (eg, MSC-derived) extracellular vesicles into bioinks, which may represent an alternative to growth factor treatment and may provide an even more efficient means to protect embedded cells from apoptosis and inflammation, and enhance ECM production. 56 Furthermore, future research efforts should focus on the use of bioreactor systems for the mechanical stimulation of 3D bioprinted construct, in order to improve the maturation of IVD substitutes and increase their therapeutic effect. 61 Fiber orientation (random vs aligned)…”

“…In the years to come, the potential of CRISPR‐modulated MSCs will likely become increasingly evident, especially when considering the possibility for CRISPR multiplexing, that is, the simultaneous modulation of several targets 55 . Future research should furthermore investigate the incorporation of (eg, MSC‐derived) extracellular vesicles into bioinks, which may represent an alternative to growth factor treatment and may provide an even more efficient means to protect embedded cells from apoptosis and inflammation, and enhance ECM production 56 . Furthermore, future research efforts should focus on the use of bioreactor systems for the mechanical stimulation of 3D bioprinted construct, in order to improve the maturation of IVD substitutes and increase their therapeutic effect.…”