Differential effects of dexamethasone on the chondrogenesis of mesenchymal stromal cells: Influence of microenvironment, tissue origin and growth factor

Abstract

Mesenchymal stromal cells (MSCs), which reside within various tissues, are utilized in the engineering of cartilage tissue. Dexamethasone (DEX) -a synthetic glucocorticoid -is almost invariably applied to potentiate the growthfactor-induced chondrogenesis of MSCs in vitro, albeit that this effect has been experimentally demonstrated only for transforming-growth-factor-beta (TGF-β)-stimulated bone-marrow-derived MSCs. Clinically, systemic glucocorticoid therapy is associated with untoward side effects (e.g., bone loss and increased susceptibility to infection). Hence, the use of these agents should be avoided or limited. We hypothesize that the infl uence of DEX on the chondrogenesis of MSCs depends upon their tissue origin and microenvironment [absence or presence of an extracellular matrix (ECM)], as well as upon the nature of the growth factor. We investigated its effects upon the TGF-β1-and bone-morphogenetic-protein 2 (BMP-2)-induced chondrogenesis of MSCs as a function of tissue source (bone marrow vs. synovium) and microenvironment [cell aggregates (no ECM) vs. explants (presence of a natural ECM)]. In aggregates of bone-marrow-derived MSCs, DEX enhanced TGF-β1-induced chondrogenesis by an up-regulation of cartilaginous genes, but had little infl uence on the BMP-2-induced response. In aggregates of synovial MSCs, DEX exerted no remarkable effect on either TGF-β1-or BMP-2-induced chondrogenesis. In synovial explants, DEX inhibited BMP-2-induced chondrogenesis almost completely, but had little impact on the TGF-β1-induced response. Our data reveal that steroids are not indispensable for the chondrogenesis of MSCs in vitro. Their infl uence is context dependent (tissue source of the MSCs, their microenvironment and the nature of the growth factor). This fi nding has important implications for MSCbased approaches to cartilage repair.

Enhancing adipose stem cell chondrogenesis: A study on the roles of dexamethasone, transforming growth factor β3 and ascorbate supplements and their combination

“…Kawakami et al [64], named SOX9 as the key intracellular molecule in chondrogenesis; Bell et al [65], correlated the expression of SOX9 as a marker for expression of Col II; and Zhao et al suggested SOX9 is needed for expression of the chondrocyte phenotype. Limited literature shows SOX9 upregulated 1.25-fold [66], for hADSCs with TGF-β3 at day 28 consistent with our 1.2-fold increase at day 25, 2-fold for ATDC5 micromass with Asc at day 21 [23], consistent with the 3.9-fold increase we observed at day 25, and 2-fold for bovine BMSC micromass with Dex at day 14 [67], consistent with our 1.1-fold increase at day 14. However, the BMSC study shows no signi icant difference between Dex and DT, similar to our comparative observations between Dex and DT though both our study and the BMSC study show that addition of Dex enhances TGF-β induced SOX9 expression at day 14.…”

“…Collagen ibrils are essential for AC structural stabilization [73] and Col XI, while abundant in AC [74] is necessary for skeletal development [75]. Similar to what we observed here, Shintani et al [67] observed no signi icant differences in Col XI expression between NC-, Dex-and TGF-β1-treated micromass samples of bovine BMSCs but found signi icant differences between NC and DT at day 14.…”

“…For example, the exact role of Dex in modulating MSC chondrogenesis, its cross-talk with BMP-2 and TGF-β1, and the elasticity of the constructs obtained is still not fully understood [67]. Only when the roles of individual factors and their synergistic interplay are known as a function of time, using whole mRNA sequencing, can a gold standard differentiation cocktail be developed.…”

Impact of Tissue-Specific Stem Cells on Lineage-Specific Differentiation: A Focus on the Musculoskeletal System

“…Afizah and colleagues demonstrated that human BMSCs synthesized more GAG and collagen II following TGFβ3 treatment than donor-matched ADSCs (114). It has further been shown that dexamethasone augmented the TGFβ1-induced chondrogenesis in 4-month-old bovine BMSCs, but not in 4-month-old bovine SDSCs (115). Human BMSCs exhibited greater expression of HLA-DR (an MHC class II cell surface receptor encoded by the human leukocyte antigen complex on chromosome 6 region 6p21.31) than stem cells from amniotic membrane after stimulation by tumor necrosis factor alpha and interferon gamma (60).…”

Effect of Hydrocortisone on Multipotent Human Mesenchymal Stromal Cells

“…HC had practically no effect of the expression of osteogenic and adipogenic differentiation markers at early passages, but by the 5th passage, the expression of osteogenic differentiation markers drastically changed: expression of the early marker osteopontin completely disappeared, while expression of osteocalcin considerably decreased. Clinically, systemic GCS therapy leads to osteoporosis and bone resorption [11]. It is known that the number of adipocytes increased in patients with osteoporosis.…”