Abstract
The need for an autologous cell source for bone tissue engineering and medical applications has led researchers to explore multipotent mesenchymal stromal cells (MSC), which show stem cell plasticity, in various human tissues. However, MSC with different tissue origins vary in their biological properties and their capability for osteogenic differentiation. Furthermore, MSC-based therapies require large-scale ex vivo expansion, accompanied by cell type-specific replicative senescence, which affects osteogenic differentiation. To elucidate cell type-specific differences in the osteogenic differentiation potential and replicative senescence, we analysed the impact of BMP and TGF-β signaling in adipose-derived stromal cells (ASC), fibroblasts (FB), and dental pulp stromal cells (DSC). We used inhibitors of BMP and TGF-β signaling, such as SB431542, dorsomorphin and/or a supplemental addition of BMP-2. The expression of high-affinity binding receptors for BMP-2 and calcium deposition with alizarin red S were evaluated to assess osteogenic differentiation potential. Our study demonstrated that TGF-β signaling inhibits osteogenic differentiation of ASC, DSC and FB in the early cell culture passages. Moreover, DSC had the best osteogenic differentiation potential and an activation of BMP signaling with BMP-2 could further enhance this capacity. This phenomenon is likely due to an increased expression of activin receptor-like kinase-3 and -6. However, in DSC with replicative senescence (in cell culture passage 10), osteogenic differentiation sharply decreased, and the simultaneous use of BMP-2 and SB431542 did not result in further improvement of this process. In comparison, ASC retain a similar osteogenic differentiation potential regardless of whether they were in the early (cell culture passage 3) or later (cell culture passage 10) stages. Our study elucidated that ASC, DSC, and FB vary functionally in their osteogenic differentiation, depending on their tissue origin and replicative senescence. Therefore, our study provides important insights for cell-based therapies to optimize prospective bone tissue engineering strategies.
Highlights
The need for an autologous cell source for bone tissue engineering and medical applications has led researchers to explore multipotent mesenchymal stromal cells (MSC), which show stem cell plasticity, in various human tissues
Runx[2] Runt-related transcription factor 2 Dlx[5] Distal less homebox 5 Smad Similar to mothers against decapentaplegic ALK Activin receptor-like kinase P3 3, -6, 7, Cell culture passage 3 P10 Cell culture passage 10 osteogenic differentiation medium (OM) Cell differentiated with osteogenic differentiation media OM + SB Cell differentiated with osteogenic differentiation media + SB431542 OM + DM Cell differentiated with osteogenic differentiation media + dorsomorphin OM + BMP2 Cell differentiated with osteogenic differentiation media + BMP-2 OM + SB + BMP Cell differentiated with osteogenic differentiation media + SB431542 + BMP2 OM + DM + BMP Cell differentiated with osteogenic differentiation media + dorsomorphin + BMP2
CD26 was decreased expressed in dental pulp stromal cells (DSC) compared to adiposederived stromal cells (ASC) and FB
Summary
The need for an autologous cell source for bone tissue engineering and medical applications has led researchers to explore multipotent mesenchymal stromal cells (MSC), which show stem cell plasticity, in various human tissues. To elucidate cell type-specific differences in the osteogenic differentiation potential and replicative senescence, we analysed the impact of BMP and TGF-β signaling in adiposederived stromal cells (ASC), fibroblasts (FB), and dental pulp stromal cells (DSC). The most common regenerative approach is the use of autologous bone grafts, but this option is often limited by restricted availability as well as substantial donor-site morbidity[2] Osteogenic cells such as mesenchymal stromal cells (MSC) and fibroblasts (FB) have been investigated in regenerative bone tissue engineering strategies, and promising results have already been p ublished[3,4]. One reason could be that MSC with different tissue origins use different modes of action to become osteoblastic cells In this context, the TGF-β and BMP signaling pathways have a major role because these signaling cascades show crosstalk and are important for osteogenic differentiation since dysregulated signaling results in multiple bone disorders[16]. There is a consensus that endogenous TGF-β21 impairs osteoblastic maturation, in C2C12 cells, TGF-β induced the transcription of Runx[2], an essential transcription factor required for bone formation[22]
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