biostudies-literatureArany PRIntramural NIH HHSNIDCR NIH HHSNCATS NIH HHSNIAID NIH HHS238ra69https://www.ebi.ac.uk/biostudies/studies/S-EPMC4113395biostudies-literatureUnknown6(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-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.Science translational medicinePhotoactivation of endogenous latent transforming growth factor-?1 directs dental stem cell differentiation for regeneration.PMC4113395R01 DE013349R01 AI050875R01-DE019023-01ZIA DE000698UL1 TR001102ZIA DE000698-11R01-AI-0508751UL1 TR001102-01R01 DE013033R37-DE-013349RL1 DE019023Sidhu GHahm EShin KCho AWeaver JBarcellos-Hoff MHChen ACJ Mooney DHuang GXPadwa BLHunt TDArany PRHamblin MRKulkarni ABfalsePhotoactivation of endogenous latent transforming growth factor-?1 directs dental stem cell differentiation for regeneration.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.2014-01-01T00:00:00Z2014 May2020-10-29T13:27:26Z2019-03-27T01:32:57ZS-EPMC41133952487113010.1126/scitranslmed.3008234