title: Photoactivation of endogenous latent transforming growth factor-β1 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-β1 (TGF-β1), 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-β1 (LTGF-β1) via a specific methionine residue (at position 253 on LAP). Laser-activated TGF-β1 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-β receptor II (TGF-βRII) conditional knockout (DSPP(Cre)TGF-βRII(fl/fl)) mice or when wild-type mice were given a TGF-βRI inhibitor. These findings indicate a pivotal role for TGF-β 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.
authors.affiliation: Harvard School of Engineering and Applied Sciences, Cambridge, MA 02138, USA. Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115, USA. Harvard School of Dental Medicine, Boston, MA 02115, USA. Leder Human Biology and Translational Medicine, Boston, MA 02115, USA. National Institute of Dental and Craniofacial Research, Bethesda, MD 20892, USA.
authors.forename: Praveen R
authors.initials: PR
authors.lastname: Arany
authors.affiliation: National Institute of Dental and Craniofacial Research, Bethesda, MD 20892, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Cho
authors.affiliation: Harvard School of Engineering and Applied Sciences, Cambridge, MA 02138, USA.
authors.forename: Tristan D
authors.initials: TD
authors.lastname: Hunt
authors.affiliation: Harvard School of Engineering and Applied Sciences, Cambridge, MA 02138, USA.
authors.forename: Gursimran
authors.initials: G
authors.lastname: Sidhu
authors.affiliation: Harvard School of Engineering and Applied Sciences, Cambridge, MA 02138, USA. Harvard School of Dental Medicine, Boston, MA 02115, USA.
authors.forename: Kyungsup
authors.initials: K
authors.lastname: Shin
authors.affiliation: Harvard School of Engineering and Applied Sciences, Cambridge, MA 02138, USA.
authors.forename: Eason
authors.initials: E
authors.lastname: Hahm
authors.affiliation: Harvard School of Engineering and Applied Sciences, Cambridge, MA 02138, USA.
authors.forename: George X
authors.initials: GX
authors.lastname: Huang
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115, USA.
authors.forename: James
authors.initials: J
authors.lastname: Weaver
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Aaron Chih-Hao
authors.initials: AC
authors.lastname: Chen
authors.affiliation: Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: Bonnie L
authors.initials: BL
authors.lastname: Padwa
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA. Department of Dermatology, Harvard Medical School, Boston, MA 02115, USA. Harvard-MIT Division of Health Sciences and Technology, Boston, MA 02139, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hamblin
authors.affiliation: New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Mary Helen
authors.initials: MH
authors.lastname: Barcellos-Hoff
authors.affiliation: National Institute of Dental and Craniofacial Research, Bethesda, MD 20892, USA.
authors.forename: Ashok B
authors.initials: AB
authors.lastname: Kulkarni
authors.affiliation: Harvard School of Engineering and Applied Sciences, Cambridge, MA 02138, USA. Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115, USA. mooneyd@seas.harvard.edu.
authors.forename: David
authors.initials: D
authors.lastname: J Mooney
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology / Q000528:radiation effects*; D003804:Dentin / Q000378:metabolism; D051379:Mice; D044968:Regenerative Medicine; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D014070:Tooth / Q000166:cytology* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000502:physiology / Q000528:radiation effects*
chemical_list: D053773:Transforming Growth Factor beta1