Abstract
BackgroundTelomerase deficiency has been associated with inadequate differentiation of mesenchymal stem cells. However, the effect of telomerase deficiency on differential regulation of osteoblast specific genes, based on functional gene grouping, during in vitro osteoblast differentiation has not been reported before.ResultsTo examine these effects, Terc-/- BMSCs (bone marrow stromal stem cells) were employed which exhibited reduced proliferation during in vitro osteogenesis along with increased population doubling time and level compared to wild type (WT) BMSCs during the normal culture. Osteogenic super array at day 10 of osteoblast differentiation revealed that telomerase deficiency strongly affected the osteoblast commitment by down-regulating Runx2, Twist and Vdr – known transcription regulators of osteogenesis. Similarly, in Terc-/- BMSCs a marked reduction in other genes engaged in various phases of osteoblast differentiation were observed, such as Fgfr2 involved in bone mineralization, Phex and Dmp1 engaged in ossification, and Col11a1 and Col2a1 involved in cartilage condensation. A similar trend was observed for genes involved in osteoblast proliferation (Tgfb1, Fgfr2 and Pdgfa) and bone mineral metabolism (Col1a1, Col2a1, Col1a2 and Col11a1). More profound changes were observed in genes engaged in extracellular matrix production: Col1a1, Col1a2, Mmp10, Serpinh1 and Col4a1.ConclusionTaken together, these data suggest that telomerase deficiency causes impairment of BMSCs differentiation into osteoblasts affecting commitment, proliferation, matrix mineralization and maturation. Thus, modulating telomerase in BMSCs with advanced aging could improve BMSCs responsiveness towards osteoblast differentiation signals, optimal for osteoblast commitment, proliferation and maturation processes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12929-015-0116-4) contains supplementary material, which is available to authorized users.
Highlights
Telomerase deficiency has been associated with inadequate differentiation of mesenchymal stem cells
Defective proliferation of Terc-/- bone marrow stromal cells (BMSCs) during in vitro osteoblast differentiation We have previously shown that Terc-/- BMSCs exhibit stunted proliferation as evident by BrdU labelling during normal culture [12], while proliferation was not assessed during in vitro osteoblast differentiation
Population doubling analysis during normal culture revealed that Terc-/- BMSCs took more time to double with population doubling level (PDL) of 2.44 initially to PDL of 0.214 after 40 days compared to wild type (WT) BMSC’s PDL of 2.64, which later dropped to PDL of 1.3 after 40 days (Figure 1B)
Summary
Telomerase deficiency has been associated with inadequate differentiation of mesenchymal stem cells. Results: To examine these effects, Terc-/- BMSCs (bone marrow stromal stem cells) were employed which exhibited reduced proliferation during in vitro osteogenesis along with increased population doubling time and level compared to wild type (WT) BMSCs during the normal culture. Disruption in any of these above mentioned processes leads to skeletal/bone fragility i-e., osteoporosis [3]. In this regard, role of osteoclasts in bone resoption have extensively been studied. With aging, owing to several factors including telomerase deficiency, functional and numerical decline of BMSCs resulted in the compromised ability of BMSCs to repair the skeleton and maintain skeletal homeostasis [10,11,12]
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