Abstract
New in vivo microRNA biotechnology reveals specific roles for the miR‐200 family in dental stem cell maintenance
The FASEB journal, Vol.33(S1), pp.452.22-452.22
04/2019
DOI: 10.1096/fasebj.2019.33.1_supplement.452.22
Abstract
Extracellular signaling as well as transcription factor and epigenetic regulation are well described mechanisms controlling stem cell differentiation. The regulation of these processes by microRNAs (miRs) is recognized as an important biological process that can be coopted for future stem cell‐based therapies. Previously, our group has found the miR‐200 family is highly expressed in differentiated tooth cell types, but absent in dental epithelial stem cell (DESC) precursors. Inhibition of the miR‐200 family in mice using a novel Plasmid‐based miR Inhibitor System (PMIS) demonstrates that the miR‐200 family controls DESC maintenance and compartmentalization.
Objectives
To investigate the mechanisms by which the miR‐200 family promotes the differentiation of ameloblasts and other mature tooth cell types during tooth morphogenesis, and how inhibition of the family maintains stemness.
Methods
We generated mice expressing two different PMIS constructs. One inhibitor construct is specific for the seed sequence of miR‐200a, and ‐141, while the other inhibitor is specific for the seed sequence found in miR‐200b,‐200c and ‐429. Crossing these mice allows the functional inhibition of the entire miR‐200 family (double inhibitor mice).
Results
Double inhibitor mice are neonatal lethal and have poorly differentiated lower incisors. The teeth are smaller and lack markers of mature odontoblasts and ameloblasts. Several transcription factors marking the stem cell niche of the lower incisor, including Sox2, have expanded expression domains, and BrdU labeling of proliferating cells demonstrated that miR‐200 inhibition leads to increased epithelial cell proliferation outside of the stem cell niche. Rnf126, an E‐3 ubiquitin ligase that promotes P21 degradation and a direct target of miR‐200c, is expressed at higher levels in the proliferating cells leading to the loss of P21 protein. Although more epithelial cells are proliferating, the lower incisors are shorter due to an increase in a caspase independent, programmed cell death pathway.
Conclusions
The miR‐200 family is required for the appropriate differentiation of DESCs and the family functions by reducing the expression of transcription factors promoting stemness outside of the stem cell niche compartment of the lower incisor. Overall, craniofacial development is affected due to a lack of cell differentiation.
Support or Funding Information
University of Iowa College of Dentistry
NIH, NIDCR
T90 training grant 2T90DE023520‐06
This is from the Experimental Biology 2019 Meeting. There is no full text article associated with this published in The FASEB Journal.
Details
- Title: Subtitle
- New in vivo microRNA biotechnology reveals specific roles for the miR‐200 family in dental stem cell maintenance
- Creators
- Mason E Sweat - University of IowaYan Yan Sweat - University of IowaSteven Eliason - University of IowaWenjie Yu - University of IowaHuojun Cao - University of IowaLiu Hong - University of IowaBrad A Amendt - University of Iowa
- Resource Type
- Abstract
- Publication Details
- The FASEB journal, Vol.33(S1), pp.452.22-452.22
- DOI
- 10.1096/fasebj.2019.33.1_supplement.452.22
- ISSN
- 0892-6638
- eISSN
- 1530-6860
- Publisher
- The Federation of American Societies for Experimental Biology
- Number of pages
- 1
- Grant note
- NIDCR NIH University of Iowa College of Dentistry
- Language
- English
- Date published
- 04/2019
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Orthodontics; Anatomy and Cell Biology; Endodontics; Prosthodontics; Craniofacial Anomalies Research Center; Dental Research; Internal Medicine
- Record Identifier
- 9984288758502771
Metrics
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