Notochordal-Cell-Derived Exosomes Induced by Compressive Load Inhibit Angiogenesis via the miR-140-5p/Wnt/β-Catenin Axis

Abstract

Angiogenesis is a pathological signature of intervertebral disc degeneration (IDD). Accumulating evidence has shown that notochordal cells (NCs) play an essential role in maintaining intervertebral disc development and homeostasis with inhibitive effect on blood vessel in-growth. However, the anti-angiogenesis mechanism of NCs is still unclear. In the current study, we, for the first time, isolated NC-derived exosomes (NC-exos) and showed their increased concentration following compressive load cultures. We further found that NC-exos from 0.5 MPa compressive load cultures (0.5 MPa/NC-exos) inhibit angiogenesis via transferring high expressed microRNA (miR)-140-5p to endothelial cells and regulating the downstream Wnt/β-catenin pathway. Clinical evidence showed that exosomal miR-140-5p expression of the nucleus pulposus is negatively correlated with angiogenesis in IDD. Finally, 0.5 MPa/NC-exos were demonstrated to have a therapeutical impact on the degenerated disc with an anti-angiogenesis effect in an IDD model. Consequently, our present findings provide insights into the anti-angiogenesis mechanism of NC-exos, indicating their therapeutic potential for IDD.

EGFL6 regulates angiogenesis and osteogenesis in distraction osteogenesis via Wnt/β-catenin signaling

“…At the same time, Wnt/β-catenin pathway signaling was also critically involved in the modulation of EC migration and vascular sprouting. Wnt/ β-catenin signaling is also fundamental to normal CNS vascularization [64], as well as vascularization in chondrogenesis [65]. Here, we observed increased expression of βcatenin in HUVECs following EGFL6 treatment in vitro, suggesting that Wnt and downstream β-catenin signaling are potential functional targets involved in angiogenesisosteogenesis coupling.…”

EGFL6 Regulates the Interaction Between Angiogenesis and Osteogenesis via Wnt/β-catenin Signaling in Distraction Osteogenesis

“…At the same time, Wnt/β-catenin pathway signaling was also critically involved in the modulation of EC migration and vascular sprouting. Wnt/β-catenin signaling is also fundamental to normal CNS vascularization [65], as well as vascularization in cartilagenesis [66]. Here, we observed increased expression of β-catenin in HUVECs following EGFL6 treatment in vitro, suggesting that Wnt and downstream β-catenin signaling are potential functional targets involved in angiogenesis-osteogenesis coupling.…”

Stem cells in intervertebral disc regeneration–more talk than action?

“…The exosome phospholipid-bilayer would provide necessary protection for signaling molecules. Exosomes isolated from NC conditioned medium showed similar transforming properties (Sun et al, 2020) and the described bidirectional exchange of membrane components via multisize vesicles during NP cell and MSC coculture (Strassburg et al, 2012) supports such mechanisms. While the key-proteome of exosomes was recently identified (Kugeratski et al, 2021), exosome cargo can be specific to the cell line of origin and trigger diverse outcomes in target cells (Edgar, 2016;Kalluri and LeBleu, 2020).…”

“…Furthermore, iPSC and TDSC might be impractical and uneconomical if derived de-novo for each patient (Kamao et al, 2014); ESC bear ethical concerns and TDSC are ideally based on detailed knowledge of interacting signaling pathways, which is still lacking for most vertebrate cell types. Autologous or allogeneic mesenchymal stem cells (MSC) however might take in cues from their environment to mold their multipotent potential into the necessary cell type, or, as recently demonstrated, send cues to residual stem cell populations to refurbish ailing tissue (Chen et al, 2010;Sun et al, 2020;Zhang et al, 2020;Luo et al, 2021).…”