Regulatory Interplay between NFIC and TGF-β1 in Apical Papilla-derived Stem Cells

Abstract

While transforming growth factor-β1 (TGF-β1) can regulate odontoblast differentiation in tooth crown morphogenesis, its effects on cells including stem cells from the apical papilla (SCAPs) involved in root formation are unclear. Nuclear factor I-C (NFIC) has been implicated in the regulation of root development, and interplay with TGF-β1 signaling has been reported in some cell types. We hypothesize that NFIC and TGF-β1 are important to the behavior of SCAPs and that the interplay between these molecules controls the regulation of the odontogenic differentiation of SCAPs. TGF-β1 inhibited the proliferation of SCAPs and their mineralization. Real-time polymerase chain-reaction (RT-PCR) and Western blot results showed that TGF-β1 significantly decreased osteogenic/dentinogenic gene expression. The inhibition of TGF-β/Smad signaling (SIS3) attenuated the suppressive effect of TGF-β1 on SCAPs. Importantly, overexpression of NFIC antagonized the effects of TGF-β1 on SCAPs, while knockdown of NFIC enhanced these effects, demonstrating a key regulatory role for NFIC in modulating TGF-β1 signaling in SCAPs. We conclude that this interplay between NFIC and TGF-β1 regulates SCAPs behavior and can determine the differentiation of these cells. These signaling interactions help inform the development of regenerative strategies aimed at root growth and development in immature teeth for endodontic treatment.

Role of ALK5/Smad2/3 and MEK1/ERK Signaling in Transforming Growth Factor Beta 1–modulated Growth, Collagen Turnover, and Differentiation of Stem Cells from Apical Papilla of Human Tooth

“…Similar stimulation of ALP at a lower TGF-b1 concentration and inhibition of ALP at a higher concentration is also noted in osteoblasts (45)(46)(47)(48) and pulp cells (data not shown) (31). However, TGF-b1 was found to inhibit the ALP activity of SCAPs cultured in mineralizing differentiation medium (36). Accordingly, Shirakawa et al (5) studied the ALP activity of pulp cells; in 1 pulp cell strain, TGF-b1 stimulated ALP activity at 0.1 ng/mL and decreased it at 5 ng/mL.…”

“…Chan et al (29) also found that TGF-b1, TGF-b2, and TGF-b3 slightly inhibited (about 20%) the growth of human dental pulp cells in the presence of 10% fetal serum. TGF-b1 inhibits the growth of SCAPs cultured in mineralizing differentiation medium (36), possibly because of its content of dexamethasone (37). On the contrary, exposure to TGF-b1 (1-5 ng/mL) increased the DNA content of human pulp cells in the presence of 10% serum (5).…”

Cellular and molecular mechanisms of tooth root development

“…Nfic signaling modulates Tgfβ signaling via dephosphorylation of phosphoSmad2/3 during late odontoblast differentiation, maturation and mineralization . Similarly, Nfic antagonizes the effects of Tgfβ1 on stem cells from the apical papilla (SCAPs) in vitro (He et al, 2014).…”

Signaling Pathways in Dental Stem Cells During Their Maintenance and Differentiation

“…TGF-β can up-regulate NGF in hDPSCs via p38 and JNK MAPK pathways [ 58 ]. Some studies suggest that TGF-β1 can inhibit the proliferation of SCAPs and their mineralization by decreasing the osteogenic/dentinogenic gene expressions [ 59 ]. In detail, TGF-β1 promotes the cell growth, collagen content and ALP activity at lower concentrations (0.1-1 ng/mL) but down-regulates the activity at higher concentrations (>5 ng/mL) by regu lating ERK1/2 and Smad2 signaling pathways [ 60 ].…”