Date of Award

2019

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Oral Health Sciences

College

College of Graduate Studies

First Advisor

James J. Cray

Second Advisor

Amanda C. LaRue

Third Advisor

Jeremy L. Barth

Fourth Advisor

Michael J. Kern

Fifth Advisor

Robin C. Muise-Helmericks

Abstract

The joints between the craniofacial bones (sutures) are vital for proper brain and craniofacial development and have recently been identified as a niche for stem cells. The Centers for Disease Control and Prevention, National Birth Defects Study has published data suggesting that “environmental” exposures including maternal thyroid diseases, maternal nicotine use, and use of selective serotonin reuptake inhibitors (SSRIs) in pregnant mothers may exacerbate incidence and or severity of craniofacial anomalies including craniosynostosis. Craniosynostosis is a birth defect defined as the premature fusion of the suture(s) of the skull occurring in 1:1800-2500 births. A proposed mechanism of craniosynostosis is the disruption of the balance of proliferation and differentiation of cells in the perisutural area leading to bone overgrowth. The newly identified stem cell population characterized as Gli1+ may be the target of pharmacological exposures that result in aberrant craniofacial growth. For these reasons, we hypothesize that in utero pharmacological exposures will deplete these multilineage cells, resulting in alterations in craniofacial growth and development. In order to test this hypothesis, pregnant wild-type mice were exposed to scaled circulating levels of levothyroxine, citalopram, and nicotine and the resultant pups were assessed via μCT, x-ray cephalometry, and histology of the coronal and posterior interfrontal sutures. Additionally, the effect of pharmacological exposure on multilineage CD44+ Sca1+ CD45- CD34- cells was investigated using flow cytometry and cell activity assays. Exposure to levothyroxine resulted in aberrantly timed suture fusion, alterations to the suture matrix, and decreased cell turnover consistent with quiescence, however there was little stem cell specific effect. Nicotine exposure resulted in increased risk for posterior interfrontal suture fusion precipitating a narrowed face and skull, increased cell differentiation and apoptosis causing a reduction in stem cell presence within the sutures. The citalopram exposure resulted in a dramatically increased risk of suture fusion (craniosynostosis), alterations to the suture matrix, increased adipogenesis, and a reduction in stem cells within the sutures. Investigating these newly defined cells and their relationship to suture maintenance provides insight into future manipulation of these cells for therapeutic benefit as a means of decreasing the need for neurosurgical intervention in cases of craniosynostosis.

Rights

All rights reserved. Copyright is held by the author.

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