Depletion of Cranial Suture Stem Cells by Pharmacological Exposures May Precipitate Premature Suture Fusion

Abstract

The CDC National Birth Defects Prevention Study has published data suggesting that “environmental” exposures including maternal thyroid diseases, use of selective serotonin reuptake inhibitors (SSRIs), and maternal nicotine use may increase the incidence and or severity of craniofacial anomalies including craniosynostosis. Craniosynostosis is 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 proliferation and differentiation of stem cells in the perisutural area. Here, we hypothesize that the aforementioned teratogenic exposures can cause a depletion of stem cells within the suture resulting in premature suture fusion. To determine if in utero pharmacological exposures deplete stem cells within the calvarial sutures, we exposed pregnant wild‐type mice to levothyroxine, citalopram (SSRI), and nicotine and investigated suture fusion and the presence of stem cell markers ex vivo. Additionally, we exposed primary calvarial suture derived cells to clinically relevant doses levothyroxine, citalopram, and nicotine in vitro and assessed the presence of stem markers via flow cytometry. Micro‐CT assessment of coronal and posterior interfrontal suture fusion revealed that in utero exposure to nicotine and citalopram increased the risk of premature posterior interfrontal suture fusion and exposure to citalopram resulted in an increased likelihood for coronal suture fusion at post‐natal day 15. Further, we confirmed a reduction in Gli1+ cells ex vivo in correlation with in utero teratogen exposure. Our in vitro analysis also indicates a depletion of stem cell populations with teratogen exposure via flow cytometry. Teratogenic exposures including maternal thyroid disorder, maternal use of SSRIs and maternal nicotine use may target calvarial stem cell populations for depletion precipitating an increased risk for craniosynostosis. Investigating the newly defined stem cell niche of the calvarial sutures and its relationship to suture maintenance will provide insight into future manipulation of these cells for therapeutic benefit.Support or Funding InformationNational Institute of Dental and Craniofacial Research [F31DE026684 to ELD; R03DE023350A and R03DE02619‐01A to JC; 5T32DE017551 to MUSC]Cleft Palate Foundation Cleft/Craniofacial Anomalies Grant Award to JCPlastic Surgery Education Foundation Pilot Award to JCNational Institute on Aging (NIA) 1P01AG036675 (Augusta University)National Institutes of Health National Institute of General Medicine [P30GM103331]South Carolina Clinical and Translational Research Institute (NIH/NCATS NIH/NCATS UL1TR000062)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.