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Ex Utero Rescue of Cleft Lip by Exogenous Reactivation of Craniofacial Developmental Programs
Xue Dong, BA1, Wilmina N. Landford, BA1, James Hart, BA2, Elisabetta Ferretti, PhD1, Ope A. Asanbe, MD1, Kerry A. Morrison, BA1, Peipei Zhang, MD, PhD1, Licia Selleri, PhD2, Jason A. Spector, MD., F.A.C.S.1.
1Laboratory of Bioregenerative Medicine & Surgery, Weill Cornell Medical College, New York, NY, USA, 2Dept. of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY, USA.

Background:
Cleft lip/palate (CLP) is the most common congenital craniofacial anomaly, with a high global incidence. We previously developed a unique compound Pbx-deficient murine model with fully penetrant CLP and demonstrated genetic rescue strategies to reconstitute Wnt signaling and correct midface clefting. We now seek to restore Wnt-mediated craniofacial development programs in our Pbx-deficient embryonic murine model using microsurgical intervention ex utero.
Methods:
After implantation of Wnt-9b soaked type-1 collagen microspheres at the midface lambdoidal (λ)-junction, a novel whole-embryo culture method was used to grow mouse embryos ex vivo after gestation day E11.5 for 24 hours in culture. Titration assays were conducted to optimize the dose of Wnt by assessing protein content, release kinetics, and its range of action in the embryonic face with regard to space and time. Correction of CLP was assessed by gross morphology, histology, and evaluation of the restoration of apoptotic programs.
Results:
After implantation of Wnt-soaked microspheres, X-gal staining showed the increased expression of Wnt-9b at the λ junction, and Pbx-deficient embryos showed restored formation of the midface λ-junction (Figure, red circle) when compared to the untreated contralateral side.
Conclusion:
The ex vivo microsurgical correction of CLP via a collagen microsphere-based protein delivery system is a promising and innovative strategy, which may lead to prenatal surgical correction of CLP, and as well as other congenital head-and-neck disorders.


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