Human postnatal dental mesenchymal stem cells (DMSCs) are unique precursor populations which are isolated from the dental pulp, root apex and periodontal ligament based on the primary characteristics of mesenchymal stem cells (MSCs) from bone marrow. DMSCs offer an attractive cell therapy for the regeneration and repair of dental and craniofacial tissue defects due to their convenient isolation and lack of immunogenicity. However, very little is known with respect to the molecular and epigenetic events that control DMSC commitment and differentiation to dental and craniofacial bone tissues. DNA and histone demethylases are newly-identified enzymes for removing DNA and histone methyl markers associated with gene activation or silencing. Using molecular and epigenetic approaches, we found that estrogen potently promoted odonto/osteogenic differentiation of DMSCs by inducing the histone lysine (K)-specific demethylase 6B (KDM6B) and DNA demethylase Ten-Eleven Translocation 2 (TET2). Contrary to estrogen, pro-inflammatory cytokines such as tumor necrosis factor (TNF) activated nuclear factor-kappa B (NF-?B) to inhibit DMSC differentiation. Very intriguingly, we observed that estrogen abolished TNF inhibition of DMSC differentiation by blocking NF-?B. In the realm of therapeutic dental and craniofacial tissue regeneration, the defective or injured tissues are frequently inflamed with pro-inflammatory cytokines. It is critical to control inflammation in order to achieve a successful regenerative therapy. In this competing renewal, based on our novel findings, we hypothesize that estrogen epigenetically promotes DMSC differentiation by histone and DNA demethylation while simultaneously inhibiting NF-?B and inflammation. To test our hypothesis, we proposed the following three specific aims: 1) Determine how estrogen induces KDM6B to enhance odonto/osteogenic differentiation of DMSCs by demethylating repressive H3K27me3 marks; 2) Determine how estrogen induces TET2 to enhance DMSC differentiation by DNA demethylation; and 3) Determine whether estrogen circumvents TNF inhibition of DMSC differentiation and promotes DMSC-mediated craniofacial bone regeneration and repair in vivo. Taken together, identifying whether estrogen not only promotes odonto/osteogenesis of DMSC but also inhibits inflammation would be a major therapeutic advance. Our work may help to develop novel strategies for promoting dental and craniofacial tissue regeneration and repair and for controlling inflammation.

Public Health Relevance

Statement Our application is to examine how estrogen regulates dental stem cell differentiation and inhibits inflammation. The discoveries from this study will have important implications in developing novel strategies for dental and craniofacial tissue regeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE016513-13
Application #
9095280
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Lumelsky, Nadya L
Project Start
2005-05-01
Project End
2020-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
13
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Cheng, Yingduan; Yuan, Quan; Vergnes, Laurent et al. (2018) KDM4B protects against obesity and metabolic dysfunction. Proc Natl Acad Sci U S A 115:E5566-E5575
Hong, Christine; Song, Dayoung; Lee, Dong-Keun et al. (2017) Reducing posttreatment relapse in cleft lip palatal expansion using an injectable estrogen-nanodiamond hydrogel. Proc Natl Acad Sci U S A 114:E7218-E7225
Fan, Jiabing; Im, Choong Sung; Guo, Mian et al. (2016) Enhanced Osteogenesis of Adipose-Derived Stem Cells by Regulating Bone Morphogenetic Protein Signaling Antagonists and Agonists. Stem Cells Transl Med 5:539-51
Hu, Youjin; Huang, Kevin; An, Qin et al. (2016) Simultaneous profiling of transcriptome and DNA methylome from a single cell. Genome Biol 17:88
Deng, Peng; Zhou, Chenchen; Alvarez, Ruth et al. (2016) Inhibition of IKK/NF-?B Signaling Enhances Differentiation of Mesenchymal Stromal Cells from Human Embryonic Stem Cells. Stem Cell Reports 6:456-465
Lee, Hye-Lim; Yu, Bo; Deng, Peng et al. (2016) Transforming Growth Factor-?-Induced KDM4B Promotes Chondrogenic Differentiation of Human Mesenchymal Stem Cells. Stem Cells 34:711-9
Yu, Bo; Wang, Cun-Yu (2016) Osteoporosis: The Result of an 'Aged' Bone Microenvironment. Trends Mol Med 22:641-644
Hoang, Michael; Kim, Jeffrey J; Kim, Yiyoung et al. (2016) Alcohol-induced suppression of KDM6B dysregulates the mineralization potential in dental pulp stem cells. Stem Cell Res 17:111-21
Deng, Peng; Chen, Qian-Ming; Hong, Christine et al. (2015) Histone methyltransferases and demethylases: regulators in balancing osteogenic and adipogenic differentiation of mesenchymal stem cells. Int J Oral Sci 7:197-204
Alvarez, Ruth; Lee, Hye-Lim; Hong, Christine et al. (2015) Single CD271 marker isolates mesenchymal stem cells from human dental pulp. Int J Oral Sci 7:205-12

Showing the most recent 10 out of 27 publications