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Photoactivation of endogenous latent transforming growth factor-?1 directs dental stem cell differentiation for regeneration.

ABSTRACT: Rapid advancements in the field of stem cell biology have led to many current efforts to exploit stem cells as therapeutic agents in regenerative medicine. However, current ex vivo cell manipulations common to most regenerative approaches create a variety of technical and regulatory hurdles to their clinical translation, and even simpler approaches that use exogenous factors to differentiate tissue-resident stem cells carry significant off-target side effects. We show that non-ionizing, low-power laser (LPL) treatment can instead be used as a minimally invasive tool to activate an endogenous latent growth factor complex, transforming growth factor-?1 (TGF-?1), that subsequently differentiates host stem cells to promote tissue regeneration. LPL treatment induced reactive oxygen species (ROS) in a dose-dependent manner, which, in turn, activated latent TGF-?1 (LTGF-?1) via a specific methionine residue (at position 253 on LAP). Laser-activated TGF-?1 was capable of differentiating human dental stem cells in vitro. Further, an in vivo pulp capping model in rat teeth demonstrated significant increase in dentin regeneration after LPL treatment. These in vivo effects were abrogated in TGF-? receptor II (TGF-?RII) conditional knockout (DSPP(Cre)TGF-?RII(fl/fl)) mice or when wild-type mice were given a TGF-?RI inhibitor. These findings indicate a pivotal role for TGF-? in mediating LPL-induced dental tissue regeneration. More broadly, this work outlines a mechanistic basis for harnessing resident stem cells with a light-activated endogenous cue for clinical regenerative applications.

SUBMITTER: Arany PR

PROVIDER: S-EPMC4113395 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Photoactivation of endogenous latent transforming growth factor-β1 directs dental stem cell differentiation for regeneration.

Arany Praveen R PR Cho Andrew A Hunt Tristan D TD Sidhu Gursimran G Shin Kyungsup K Hahm Eason E Huang George X GX Weaver James J Chen Aaron Chih-Hao AC Padwa Bonnie L BL Hamblin Michael R MR Barcellos-Hoff Mary Helen MH Kulkarni Ashok B AB J Mooney David D

Science translational medicine 20140501 238

Rapid advancements in the field of stem cell biology have led to many current efforts to exploit stem cells as therapeutic agents in regenerative medicine. However, current ex vivo cell manipulations common to most regenerative approaches create a variety of technical and regulatory hurdles to their clinical translation, and even simpler approaches that use exogenous factors to differentiate tissue-resident stem cells carry significant off-target side effects. We show that non-ionizing, low-powe ...[more]

PMID: 24871130

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Project description:To understand the functions of secretory proteins in odontogenesis and to further the understanding of the different molecular events during odontogenesis and osteogenesis, we induced the odonto/osteogenic differentiation of stem cells from dental apical papilla (SCAPs) and bone marrow-derived stem cells (BMSCs) in vitro and compared the expression of secretory proteins during early odonto/osteogenic differentiation using high-performance liquid chromatography with tandem mass spectrometry. The results revealed significant changes by at least 50% in 139 SCAP proteins and 203 BMSC proteins during differentiation. Of these, 92 were significantly upregulated and 47 were significantly downregulated during the differentiation of SCAPs. Most of these proteins showed the same trend during the differentiation of BMSCs. Among the proteins that showed significantly changes during the differentiation of SCAPs and BMSCs, we found that transforming growth factor-?2 (TGF?2) is a key protein in the network with powerful mediation ability. TGF?2 was secreted more by SCAPs than BMSCs, was significantly upregulated during the differentiation of SCAPs and was significantly downregulated during the differentiation of BMSCs. Furthermore, the effects of recombinant human TGF?2 and TGF?1 on the odonto/osteogenic differentiation of SCAPs and BMSCs were investigated. Real-time reverse transcription polymerase chain reaction (RT-PCR) and western blotting data revealed that TGF?2 enhanced the odontogenic-related markers [dentin sialophosphoprotein (DSPP), dentin matrix protein 1 (DMP1)] and inhibited the osteogenic-related marker bone sialoprotein (BSP) in SCAPs, whereas TGF?1 enhanced the BSP expression and inhibited the DSPP and DMP1 expression at early odonto/osteogenic differentiation of SCAPs. However, in BMSCs, TGF?2 enhanced the expression of alkaline phosphatase (ALP), runt-related transcription factor 2 (RUNX2), DSPP, and DMP1, whereas TGF?1 enhanced the expression of ALP and RUNX2, with no significant intergroup difference of DSPP at the early odonto/osteogenic differentiation of BMSCs. TGF?2 is a potentially important molecule with a distinct function in the regulation of odontogenesis and osteogenesis.

Dataset Information

Photoactivation of endogenous latent transforming growth factor-?1 directs dental stem cell differentiation for regeneration.

Publications

Photoactivation of endogenous latent transforming growth factor-β1 directs dental stem cell differentiation for regeneration.

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