Pro-fibrotic phenotype of bone marrow stromal cells in Modic type 1 changes

Abstract

Modic type 1 changes (MC1) are painful vertebral bone marrow lesions frequently found in patients suffering from chronic low-back pain. Marrow fibrosis is a hallmark of MC1. Bone marrow stromal cells (BMSCs) are key players in other fibrotic bone marrow pathologies, yet their role in MC1 is unknown. The present study aimed to characterise MC1 BMSCs and hypothesised a pro-fibrotic role of BMSCs in MC1. BMSCs were isolated from patients undergoing lumbar spinal fusion from MC1 and adjacent control vertebrae. Frequency of colony-forming unit fibroblast (CFU-F), expression of stem cell surface markers, differentiation capacity, transcriptome, matrix adhesion, cell contractility as well as expression of pro-collagen type I alpha 1, α-smooth muscle actin, integrins and focal adhesion kinase (FAK) were compared. More CFU-F and increased expression of C-X-C-motif-chemokine 12 were found in MC1 BMSCs, possibly indicating overrepresentation of a perisinusoidal BMSC population. RNA sequencing analysis showed enrichment in extracellular matrix proteins and fibrosis-related signalling genes. Increases in pro-collagen type I alpha 1 expression, cell adhesion, cell contractility and phosphorylation of FAK provided further evidence for their pro-fibrotic phenotype. Moreover, a leptin receptor high expressing (LEPRhigh) BMSC population was identified that differentiated under transforming growth factor beta 1 stimulation into myofibroblasts in MC1 but not in control BMSCs. In conclusion, pro-fibrotic changes in MC1 BMSCs and a LEPRhigh MC1 BMSC subpopulation susceptible to myofibroblast differentiation were found. Fibrosis is a hallmark of MC1 and a potential therapeutic target. A causal link between the pro-fibrotic phenotype and clinical characteristics needs to be demonstrated.

Role of C‐reactive protein in the bone marrow of Modic type 1 changes

“…Aspirates were taken with Jamshidi needles through the pedicle screw trajectory shortly before the screws were placed 13,30 . Intraoperative X-ray confirmed proper position of the needle before 2-3 ml aspirates were taken.…”

“…has been reported in one study 37 , but could not be replicated with transcriptomic analysis of uncultured disc cells from MC1 levels 13,38 . Inconsistent results could also be attributed to the dynamic nature of MC and the timepoint of analysis; inflammatory phases in MC1 could be followed by consolidating phases with healing attempts and fibrotic mechanisms 30 . Recent in-depth analysis of MC1 bone marrow provide now new evidence that the hematopoietic elements in MC1 are indeed in an inflammatory state.…”

Extrinsic Macrophages Protect While Tendon Progenitors Degrade: Insights from a Tissue Engineered Model of Tendon Compartmental Crosstalk

“…Migration patterns of extrinsic Scx-lineage cells indicated their activation and recruitment to the stressed and underloaded tendon core, an in vitro behavior consistent with a major hallmark of pathologies affecting tendon and other musculoskeletal tissues. [14,21,[45][46][47][48] While the extrinsic progenitor compartment accelerated core degeneration, the underlying tissue breakdown was already detectable in core//cell-free tenostructs and is therefore probably core-induced. The major differences in core gene expression signatures between degrading core//progenitor, core//cell-free tenostructs, and nondegrading core//macrophage tenostructs were increases in core Il-6, MMP-3, and Col1a1.…”

“…Migration patterns of extrinsic Scx‐lineage cells indicated their activation and recruitment to the stressed and underloaded tendon core, an in vitro behavior consistent with a major hallmark of pathologies affecting tendon and other musculoskeletal tissues. [ 14,21,45–48 ]…”

Should Degenerated Intervertebral Discs of Patients with Modic Type 1 Changes Be Treated with Mesenchymal Stem Cells?

“…There are no studies on vertebral CEP regeneration. However, clinical trials on MSCs for cartilage repair in patients with cartilage degeneration—including osteoarthritis—have demonstrated encouraging results [ 150 ]. Single intra-articular administration of MSCs into the knee of patients suffering from degenerative joint disease or osteoarthritis showed cartilage maintenance or growth.…”