Plastic Surgery Research Council
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PSRC 60th Annual Meeting
Program and Abstracts

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Connective Tissue Growth Factor (CTGF/CCN2) is Essential for Secondary Palatogenesis
Alex G. Lambi, B.A.1, Joseph T. Tarr, B.A.1, David I. Hindin, M.D.2, Christina Mundy, Ph.D.1, Honey Hendesi, Ph.D.1, Steven N. Popoff, Ph.D.1, James P. Bradley, M.D.2.
1Temple University School of Medicine, Philadelphia, PA, USA, 2Temple University Hospital, Philadelphia, PA, USA.

BACKGROUND: Nonsyndromic cleft palate is a common craniofacial birth defect with an incidence of 1 in 700 live births. Recent studies have shown that connective tissue growth factor (CTGF/CCN2) has acted as a necessary downstream mediator of TGF-β-dependent mesenchymal stem cell proliferation in palatogenesis. In our laboratory, in CTGF knockout (KO) mice, we identified numerous craniofacial defects such as failure of secondary palate formation. Previous cleft palate studies have used TGF-beta 3 KO and IRF-6 KO models. We investigated this novel cleft (CTGF KO) model’s anatomy, histology, and cellular function compared to the wild-type (WT).
METHODS: In the first part of our study, we used microCT analysis to compare anatomic changes at various pre and postnatal time points. Routine histology was also performed on these specimens. Next, pre-osteoblasts were isolated from CTGF KO mice and compared to WT pre-osteoblasts for cellular organization, functioning, proliferation, and migration. Next, CTGF KO palatal tissue explant cultures were compared to WT explants harvested from a time point prior to normal palate closure.
RESULTS: Micro CT and histological analyses showed that CTGF KO mice had complete absence in midline convergence of mesenchymal tissue compared to wild-type (WT) mice which demonstrated closure by timepoint E17. Pre-osteoblasts isolated from CTGF KO mice exhibited decreased ability to adhere to extracellular matrices, reduced spreading, altered cytoskeletal organization, and reduced levels of total and activated Rac1 compared to WT cells compared to wild-type (WT) mice. Proliferation of CTGF KO cells was also decreased and migration of CTGF KO cells was abnormal. WT explants were brought through cleft closure, while CTGF KO palates stayed viable and clefted.
CONCLUSIONS: Cellular functions that were abnormal in our CTGF KO cells are necessary for proper formation of the secondary palate during craniofacial development. It is likely that similar defects in the mesenchyme of the developing palate account for failure of the palatal shelves to form and fuse. Our explant model is being used for rescue experimentation and elucidating the mechanism(s) responsible for secondary cleft palate in CTGF KO mice. These investigations will help with our understanding of cleft etiology, and may lead to the development of novel therapeutic approaches for the clinical management of this birth defect.


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