CD146/MCAM distinguishes stem cell subpopulations with distinct migration and regenerative potential in degenerative intervertebral discs

Abstract

Objective: This study aimed to characterize the mesenchymal stem cell (MSC) subpopulation migrating towards a degenerated intervertebral disc (IVD) and to assess its regenerative potential. Design: Based on initial screening for migration towards CC motif chemokine ligand 5 (CCL5), the migration potential of CD146þ and CD146-mesenchymal stem cells (MSCs) was evaluated in vitro and in a degenerated organ culture model (degeneration by high-frequency loading in a bioreactor). Discogenic differentiation potential of CD146þ and CD146-MSCs was investigated by in vitro pellet culture assay with supplementation of growth and differentiation factor-6 (GDF6). Furthermore, trypsin degenerated IVDs were treated by either homing or injection of CD146þ or CD146-MSCs and glycosaminoglycan synthesis was evaluated by Sulphur 35 incorporation after 35 days of culture. Results: Surface expression of CD146 led to a higher number of migrated MSCs both in vitro and in organ culture. CD146þ and CD146-pellets responded with a similar up-regulation of anabolic markers. A higher production of sulfated glycosaminoglycans (sGAG)/DNA was observed for CD146þ pellets, while in organ cultures, sGAG synthesis rate was higher for IVDs treated with CD146-MSCs by either homing or injection. Conclusions: The CD146þ MSC subpopulation held greater migration potential towards degenerative IVDs, while the CD146-cells induced a stronger regenerative response in the resident IVD cells. These findings were independent of the application route (injection vs migration). From a translational point of view, our data suggests that CD146þ MSCs may be suitable for re-population, while CD146-MSCs may represent the primary choice for stimulation of endogenous IVD cells.

Mesenchymal Stem Cell Homing Into Intervertebral Discs Enhances the Tie2-positive Progenitor Cell Population, Prevents Cell Death, and Induces a Proliferative Response

“…Several earlier organ culture studies have demonstrated migration of exogenously applied MSCs through the endplate into the IVD. [5][6][7][8] Although bovine IVDs have been used for those studies, results of the present work showed that MSCs could migrate through the endplate into an intact human IVD ( Supplementary Fig. 2, http://links.lww.com/ BRS/B443).…”

“…Migration of exogenously delivered bone marrowderived MSCs through the endplate into the IVD has been described as an alternative approach for intradiscal cell application in several whole IVD organ culture models. [5][6][7][8] Hereby, MSC migration through the IVD tissue was enhanced in IVDs cultured under degeneration-inducing conditions. 5 The homed MSCs were shown to promote matrix remodeling, whereby more sustained effects are expected by cell homing compared to injection of potentially unphysiological sources and numbers of cells.…”

“…An established IVD organ culture model of MSC migration through the endplate was used as previously described ( Figure 1B). [5][6][7][8] IVDs were harvested from bovine tails (n ¼ 27, 6-8 months old) obtained from the local abattoir within 2 hours of death. Discs were excised with a band saw (Exakt Apparatebau) and rinsed in phosphate buffered saline (PBS) containing 10% penicillin-streptomycin.…”

Senescence in Mesenchymal Stem Cells: Functional Alterations, Molecular Mechanisms, and Rejuvenation Strategies

“…For example, the expression of CD146-also known as melanoma cell adhesion molecule (MCAM)-was downregulated in MSCs derived from aged donors compared to those from young donors, as well as in MSCs after prolonged in vitro expansion (Gnani et al, 2019). Furthermore, low but not high CD146 expression was associated with a senescent phenotype in MSCs (Jin et al, 2016), and CD146 + MSCs showed increased migratory potential toward degenerating tissues (Wangler et al, 2019). CD264 is another surface marker of in vitro aging in MSCs that is unrelated to the chronologic age of the donor (Madsen et al, 2017); cells expressing this protein exhibit increased senescence-associated β-galactosidase (SA-β-gal) activity and reduced differentiation potential and colony-forming efficiency compared to CD264 − MSCs (Madsen et al, 2020).…”

Vessel Wall-Derived Mesenchymal Stromal Cells Share Similar Differentiation Potential and Immunomodulatory Properties with Bone Marrow-Derived Stromal Cells

“…The only significant difference identified was the higher expression of CD146 on the surface of BM-MSCs than on that of SV-MSCs. Previous findings in in vitro and animal models suggest that higher CD146 level on MSCs is associated with more plasticity, better ability for transendothelial migration but lower regenerative potential of the cells [ 29 , 30 ]. Further studies examining the human relevance of these observations need to be performed.…”