Abstract
Mesenchymal stem/stromal cell (MSC)–based therapies for low back pain and intervertebral disc (IVD) degeneration have been emerging, despite the poor knowledge of their full mechanism of action. As failure of the annulus fibrosus (AF) is often associated with IVD herniation and inflammation, the objective of the present study was to investigate the impact of the MSC secretome on human AF cells exposed to mechanical loading and a pro-inflammatory environment. Human AF cells isolated from IVD biopsies from patients with adolescent idiopathic scoliosis (AIS) or disc degeneration (DD) were exposed to physiological cyclic tensile strain (CTS) for 72 h in a custom-made device, with or without interleukin (IL)-1β medium supplementation. AF cells stimulated with CTS + IL-1β were then treated with secretome from IL-1β–preconditioned MSCs for 48 h. AF cell metabolic activity, gene expression, protein secretion, matrix metalloproteinase (MMP) activity, and tissue inhibitor of MMPs (TIMP) concentration were evaluated. Expanded AF cells from AIS and DD patients revealed similar metabolic activity and gene expression profiles. CTS stimulation upregulated collagen type I (COL1A1) expression, while IL-1β significantly stimulated IL-6, IL-8, MMP-1, and MMP-3 gene expression and prostaglandin E2 production by AF cells but downregulated COL1A1. The combination of CTS + IL-1β had a similar outcome as IL-1β alone, accompanied by a significant upregulation of elastin. The MSC secretome did not show any immunomodulatory effect on CTS + IL-1β–stimulated AF cells but significantly decreased MMP-1, MMP-2, MMP-3, and MMP-9, while increasing the production of TIMP-1. The obtained results demonstrate a stronger impact of the inflammatory milieu on human AF cells than upper physiologic mechanical stress. In addition, a new MSC mechanism of action in degenerated IVD consisting of the modulation of AF MMP activity was also evidenced, contributing to the advancement of knowledge in AF tissue metabolism.
Highlights
Low back pain (LBP) is one of the top 10 disorders in the number of years lived with disability for adolescents and young adults, affecting 70–85% of the world population and compromising healthy aging (Vos et al, 2020)
To evaluate the effect of mechanical loading and inflammatory stimuli on human annulus fibrosus (AF) cells’ inflammatory profile, they were cultured in silicone dishes and stimulated with 1) cyclic tensile strain (CTS) (2%, 1 Hz, 3 h/day), 2) IL-1β (10 ng/ml), or 3) CTS + IL-1β
The results show that the Mesenchymal stem/stromal cell (MSC) secretome was able to reduce the activity of gelatin-degrading enzymes produced by human AF cells, namely, the active form of MMP9 (p 0.06; Figure 5G)
Summary
Low back pain (LBP) is one of the top 10 disorders in the number of years lived with disability for adolescents and young adults (from 10 to 49 years old), affecting 70–85% of the world population and compromising healthy aging (Vos et al, 2020). LBP can be considered a multifactorial disorder but has been strongly associated with degeneration of the intervertebral disc (IVD). Current therapies include physical therapy or antiinflammatory drugs, and if LBP does not improve, invasive surgery such as discectomy, spinal fusion, or IVD prosthesis can be used (Maher et al, 2017). Such treatments may alleviate LBP symptoms but reduce patients’ mobility, might be temporary, and, overall, do not target the underlying problem. Factors that induce AF failure include mechanical stress, which has been previously shown to increase pro-inflammatory gene expression in human AF cells (Pratsinis et al, 2016). The pathomechanism of AF mechanical weakening and consequent disc herniation remains to be fully understood
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
