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Basic fibroblast growth factor inhibits osteogenic differentiation of stem cells from human exfoliated deciduous teeth through ERK signaling.

ABSTRACT: Stem cells from human exfoliated deciduous teeth (SHED) are a unique postnatal stem cell population capable of regenerating mineralized tissue and treating immune disorders. However, the mechanism that controls SHED differentiation is not fully understood. Here, we showed that basic fibroblast growth factor (bFGF) treatment attenuated SHED-mediated mineralized tissue regeneration through activation of the extracellular signal-regulated kinase (ERK) 1/2 pathway.The level of mineralized nodule formation was assessed by alizarin red staining. Expression levels of osteogenic genes, osteocalcin and runt-related transcription factor 2, were examined by RT-PCR. Subcutaneous implantation approach was used to assess in vivo bone formation. Downstream signaling pathways of bFGF were examined by Western blotting.Activation of ERK1/2 signaling by bFGF treatment inhibited WNT/?-catenin pathway, leading to osteogenic deficiency of SHED. ERK1/2 inhibitor treatment rescued bFGF-induced osteogenic differentiation deficiency.These data suggest that bFGF inhibits osteogenic differentiation of SHED via ERK1/2 pathway. Blockade ERK1/2 signaling by small molecular inhibitor treatment improves bone formation of SHED after bFGF treatment.

SUBMITTER: Li B

PROVIDER: S-EPMC3292657 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Basic fibroblast growth factor inhibits osteogenic differentiation of stem cells from human exfoliated deciduous teeth through ERK signaling.

Li B B Qu C C Chen C C Liu Y Y Akiyama K K Yang R R Chen F F Zhao Y Y Shi S S

Oral diseases 20111212 3

<h4>Objective</h4>Stem cells from human exfoliated deciduous teeth (SHED) are a unique postnatal stem cell population capable of regenerating mineralized tissue and treating immune disorders. However, the mechanism that controls SHED differentiation is not fully understood. Here, we showed that basic fibroblast growth factor (bFGF) treatment attenuated SHED-mediated mineralized tissue regeneration through activation of the extracellular signal-regulated kinase (ERK) 1/2 pathway.<h4>Material and ...[more]

PMID: 22151351

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Project description:BACKGROUND:Basic fibroblast growth factor (bFGF) regulates maintenance of stemness and modulation of osteo/odontogenic differentiation and mineralization in stem cells from human exfoliated deciduous teeth (SHEDs). Mineralization in the bones and teeth is in part controlled by pericellular levels of inorganic phosphate (Pi), a component of hydroxyapatite, and inorganic pyrophosphate (PPi), an inhibitor of mineralization. The progressive ankylosis protein (gene ANKH; protein ANKH) and ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1/ENPP1) increase PPi and inhibit mineralization, while tissue-nonspecific alkaline phosphatase (ALPL; TNAP) is a critical pro-mineralization enzyme that hydrolyzes PPi. We hypothesized that regulation by bFGF of mineralization in SHEDs occurs by modulation of Pi/PPi-associated genes. METHODS:Cells were isolated from human exfoliated deciduous teeth and characterized for mesenchymal stem cell characteristics. Cells were treated with bFGF, and the osteogenic differentiation ability was determined. The mRNA expression was evaluated using real-time polymerase chain reaction. The mineralization was examined using alizarin red S staining. RESULTS:Cells isolated from primary teeth expressed mesenchymal stem cell markers, CD44, CD90, and CD105, and were able to differentiate into osteo/odontogenic and adipogenic lineages. Addition of 10?ng/ml bFGF to SHEDs during in vitro osteo/odontogenic differentiation decreased ALPL mRNA expression and ALP enzyme activity, increased ANKH mRNA, and decreased both Pi/PPi ratio and mineral deposition. Effects of bFGF on ALPL and ANKH expression were detected within 24?h. Addition of 20?mM fibroblast growth factor receptor (FGFR) inhibitor SU5402 revealed the necessity of FGFR-mediated signaling, and inclusion of 1??g/ml cyclohexamide (CHX) implicated the necessity of protein synthesis for effects on ALPL and ANKH. Addition of exogenous 10??m PPi inhibited mineralization and increased ANKH, collagen type 1a1 (COL1A1), and osteopontin (SPP1) mRNA, while addition of exogenous Pi increased mineralization and osterix (OSX), ANKH, SPP1, and dentin matrix protein 1 (DMP1) mRNA. The effects of PPi and Pi on mineralization could be replicated by short-term 3- and 7-day treatments, suggesting signaling effects in addition to physicochemical regulation of mineral deposition. CONCLUSION:This study reveals for the first time the effects of bFGF on Pi/PPi regulators in SHEDs and implicates these factors in how bFGF directs osteo/odontogenic differentiation and mineralization by these cells.

Project description:Retinal degeneration is characterized by the progressive loss of photoreceptors, and stem cell therapy has become a promising strategy. Many studies have reported that mesenchymal stem cell transplantation can sustain retinal structure and prolong retinal functions based on two mechanisms. One is cell replacement, and the other is the paracrine action of stem cells. Cells from human exfoliated deciduous teeth (SHEDs) show characteristics typical of mesenchymal stem cells. They are derived from the neural crest and are a potential cellular source for neural regeneration in stem cell therapy. In this study, we explored the potential of SHEDs to be induced towards the retinal photoreceptor phenotype and to be sustainable in an animal model of retinal degeneration. A factor-cocktail protocol was used to induce SHEDs towards retinal photoreceptors for 24 days, and the characteristics of the induced cells were identified in terms of morphological changes, biomarker expression and subcellular distribution, and calcium influx. SHEDs were labeled with firefly luciferase for in vivo tracking by bioluminescent imaging and then transplanted into the subretinal space of mice. Our results showed that SHEDs successfully transdifferentiated into photoreceptor-like cells, which displayed neuron-like morphology, and expressed specific genes and proteins associated with retinal precursors, photoreceptor precursors, and mature photoreceptors. In addition, calcium influx was significantly greater in the retinal-induced than in noninduced SHEDs. In vivo tracking confirmed at least 2 weeks of good survival by bioluminescent imaging and 3 months of sustainability of SHEDs by histological analysis. We conclude that SHEDs have the potential to transdifferentiate into retinal photoreceptor-like cells in vitro and maintain good viability in vivo after transplantation into mice with a normal immune system. This demonstrates preliminary success in generating photoreceptor-like cells from SHEDs and applying SHEDs in treating retinal degeneration.

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Basic fibroblast growth factor inhibits osteogenic differentiation of stem cells from human exfoliated deciduous teeth through ERK signaling.

Publications

Basic fibroblast growth factor inhibits osteogenic differentiation of stem cells from human exfoliated deciduous teeth through ERK signaling.

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