The role of bioactive nanofibers in enamel regeneration mediated through integrin signals acting upon C/EBPα and c-Jun

Z. Huang, C. J. Newcomb, Y. Zhou, Y. P. Lei, P. Bringas, Samuel I Stupp, M. L. Snead

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Enamel formation involves highly orchestrated intracellular and extracellular events; following development, the tissue is unable to regenerate, making it a challenging target for tissue engineering. We previously demonstrated the ability to trigger enamel differentiation and regeneration in the embryonic mouse incisor using a self-assembling matrix that displayed the integrin-binding epitope RGDS (Arg-Gly-Asp-Ser). To further elucidate the intracellular signaling pathways responsible for this phenomenon, we explore here the coupling response of integrin receptors to the biomaterial and subsequent downstream gene expression profiles. We demonstrate that the artificial matrix activates focal adhesion kinase (FAK) to increase phosphorylation of both c-Jun N-terminal kinase (JNK) and its downstream transcription factor c-Jun (c-Jun). Inhibition of FAK blocked activation of the identified matrix-mediated pathways, while independent inhibition of JNK nearly abolished phosphorylated-c-Jun (p-c-Jun) and attenuated the pathways identified to promote enamel regeneration. Cognate binding sites in the amelogenin promoter were identified to be transcriptionally up-regulated in response to p-c-Jun. Furthermore, the artificial matrix induced gene expression as evidenced by an increased abundance of amelogenin, the main protein expressed during enamel formation, and the CCAAT enhancer binding protein alpha (C/EBPα), which is the known activator of amelogenin expression. Elucidating these cues not only provides guidelines for the design of synthetic regenerative strategies and opportunities to manipulate pathways to regulate enamel regeneration, but can provide insight into the molecular mechanisms involved in tissue formation.

Original languageEnglish
Pages (from-to)3303-3314
Number of pages12
JournalBiomaterials
Volume34
Issue number13
DOIs
Publication statusPublished - Apr 2013

Fingerprint

CCAAT-Enhancer-Binding Protein-alpha
Nanofibers
Enamels
Dental Enamel
Integrins
Regeneration
Amelogenin
Focal Adhesion Protein-Tyrosine Kinases
JNK Mitogen-Activated Protein Kinases
Gene expression
arginyl-glycyl-aspartyl-serine
Adhesion
Tissue
Epitopes
Phosphorylation
Aptitude
Transcription factors
Biocompatible Materials
Binding sites
Incisor

Keywords

  • Artificial extracellular matrix
  • Cell signaling
  • Integrin
  • Peptide amphiphile
  • Regenerated enamel
  • RGDS

ASJC Scopus subject areas

  • Biomaterials
  • Bioengineering
  • Ceramics and Composites
  • Mechanics of Materials
  • Biophysics

Cite this

The role of bioactive nanofibers in enamel regeneration mediated through integrin signals acting upon C/EBPα and c-Jun. / Huang, Z.; Newcomb, C. J.; Zhou, Y.; Lei, Y. P.; Bringas, P.; Stupp, Samuel I; Snead, M. L.

In: Biomaterials, Vol. 34, No. 13, 04.2013, p. 3303-3314.

Research output: Contribution to journalArticle

Huang, Z. ; Newcomb, C. J. ; Zhou, Y. ; Lei, Y. P. ; Bringas, P. ; Stupp, Samuel I ; Snead, M. L. / The role of bioactive nanofibers in enamel regeneration mediated through integrin signals acting upon C/EBPα and c-Jun. In: Biomaterials. 2013 ; Vol. 34, No. 13. pp. 3303-3314.
@article{a02de05e32924e53844522a3b651d9fa,
title = "The role of bioactive nanofibers in enamel regeneration mediated through integrin signals acting upon C/EBPα and c-Jun",
abstract = "Enamel formation involves highly orchestrated intracellular and extracellular events; following development, the tissue is unable to regenerate, making it a challenging target for tissue engineering. We previously demonstrated the ability to trigger enamel differentiation and regeneration in the embryonic mouse incisor using a self-assembling matrix that displayed the integrin-binding epitope RGDS (Arg-Gly-Asp-Ser). To further elucidate the intracellular signaling pathways responsible for this phenomenon, we explore here the coupling response of integrin receptors to the biomaterial and subsequent downstream gene expression profiles. We demonstrate that the artificial matrix activates focal adhesion kinase (FAK) to increase phosphorylation of both c-Jun N-terminal kinase (JNK) and its downstream transcription factor c-Jun (c-Jun). Inhibition of FAK blocked activation of the identified matrix-mediated pathways, while independent inhibition of JNK nearly abolished phosphorylated-c-Jun (p-c-Jun) and attenuated the pathways identified to promote enamel regeneration. Cognate binding sites in the amelogenin promoter were identified to be transcriptionally up-regulated in response to p-c-Jun. Furthermore, the artificial matrix induced gene expression as evidenced by an increased abundance of amelogenin, the main protein expressed during enamel formation, and the CCAAT enhancer binding protein alpha (C/EBPα), which is the known activator of amelogenin expression. Elucidating these cues not only provides guidelines for the design of synthetic regenerative strategies and opportunities to manipulate pathways to regulate enamel regeneration, but can provide insight into the molecular mechanisms involved in tissue formation.",
keywords = "Artificial extracellular matrix, Cell signaling, Integrin, Peptide amphiphile, Regenerated enamel, RGDS",
author = "Z. Huang and Newcomb, {C. J.} and Y. Zhou and Lei, {Y. P.} and P. Bringas and Stupp, {Samuel I} and Snead, {M. L.}",
year = "2013",
month = "4",
doi = "10.1016/j.biomaterials.2013.01.054",
language = "English",
volume = "34",
pages = "3303--3314",
journal = "Biomaterials",
issn = "0142-9612",
publisher = "Elsevier BV",
number = "13",

}

TY - JOUR

T1 - The role of bioactive nanofibers in enamel regeneration mediated through integrin signals acting upon C/EBPα and c-Jun

AU - Huang, Z.

AU - Newcomb, C. J.

AU - Zhou, Y.

AU - Lei, Y. P.

AU - Bringas, P.

AU - Stupp, Samuel I

AU - Snead, M. L.

PY - 2013/4

Y1 - 2013/4

N2 - Enamel formation involves highly orchestrated intracellular and extracellular events; following development, the tissue is unable to regenerate, making it a challenging target for tissue engineering. We previously demonstrated the ability to trigger enamel differentiation and regeneration in the embryonic mouse incisor using a self-assembling matrix that displayed the integrin-binding epitope RGDS (Arg-Gly-Asp-Ser). To further elucidate the intracellular signaling pathways responsible for this phenomenon, we explore here the coupling response of integrin receptors to the biomaterial and subsequent downstream gene expression profiles. We demonstrate that the artificial matrix activates focal adhesion kinase (FAK) to increase phosphorylation of both c-Jun N-terminal kinase (JNK) and its downstream transcription factor c-Jun (c-Jun). Inhibition of FAK blocked activation of the identified matrix-mediated pathways, while independent inhibition of JNK nearly abolished phosphorylated-c-Jun (p-c-Jun) and attenuated the pathways identified to promote enamel regeneration. Cognate binding sites in the amelogenin promoter were identified to be transcriptionally up-regulated in response to p-c-Jun. Furthermore, the artificial matrix induced gene expression as evidenced by an increased abundance of amelogenin, the main protein expressed during enamel formation, and the CCAAT enhancer binding protein alpha (C/EBPα), which is the known activator of amelogenin expression. Elucidating these cues not only provides guidelines for the design of synthetic regenerative strategies and opportunities to manipulate pathways to regulate enamel regeneration, but can provide insight into the molecular mechanisms involved in tissue formation.

AB - Enamel formation involves highly orchestrated intracellular and extracellular events; following development, the tissue is unable to regenerate, making it a challenging target for tissue engineering. We previously demonstrated the ability to trigger enamel differentiation and regeneration in the embryonic mouse incisor using a self-assembling matrix that displayed the integrin-binding epitope RGDS (Arg-Gly-Asp-Ser). To further elucidate the intracellular signaling pathways responsible for this phenomenon, we explore here the coupling response of integrin receptors to the biomaterial and subsequent downstream gene expression profiles. We demonstrate that the artificial matrix activates focal adhesion kinase (FAK) to increase phosphorylation of both c-Jun N-terminal kinase (JNK) and its downstream transcription factor c-Jun (c-Jun). Inhibition of FAK blocked activation of the identified matrix-mediated pathways, while independent inhibition of JNK nearly abolished phosphorylated-c-Jun (p-c-Jun) and attenuated the pathways identified to promote enamel regeneration. Cognate binding sites in the amelogenin promoter were identified to be transcriptionally up-regulated in response to p-c-Jun. Furthermore, the artificial matrix induced gene expression as evidenced by an increased abundance of amelogenin, the main protein expressed during enamel formation, and the CCAAT enhancer binding protein alpha (C/EBPα), which is the known activator of amelogenin expression. Elucidating these cues not only provides guidelines for the design of synthetic regenerative strategies and opportunities to manipulate pathways to regulate enamel regeneration, but can provide insight into the molecular mechanisms involved in tissue formation.

KW - Artificial extracellular matrix

KW - Cell signaling

KW - Integrin

KW - Peptide amphiphile

KW - Regenerated enamel

KW - RGDS

UR - http://www.scopus.com/inward/record.url?scp=84874271109&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84874271109&partnerID=8YFLogxK

U2 - 10.1016/j.biomaterials.2013.01.054

DO - 10.1016/j.biomaterials.2013.01.054

M3 - Article

C2 - 23398885

AN - SCOPUS:84874271109

VL - 34

SP - 3303

EP - 3314

JO - Biomaterials

JF - Biomaterials

SN - 0142-9612

IS - 13

ER -