Noggin regulates foregut progenitor cell programming, and misexpression leads to esophageal atresia
Carolina Pinzon-Guzman, … , Scott D. Boden, James R. Goldenring
Carolina Pinzon-Guzman, … , Scott D. Boden, James R. Goldenring
Published May 19, 2020
Citation Information: J Clin Invest. 2020;130(8):4396-4410. https://doi.org/10.1172/JCI123597.
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Noggin regulates foregut progenitor cell programming, and misexpression leads to esophageal atresia

Abstract

Esophageal atresia (EA/TEF) is a common congenital abnormality present in 1 of 4000 births. Here we show that atretic esophagi lack Noggin (NOG) expression, resulting in immature esophagus that contains respiratory glands. Moreover, when using mouse esophageal organoid units (EOUs) or tracheal organoid units (TOUs) as a model of foregut development and differentiation in vitro, NOG determines whether foregut progenitors differentiate toward esophageal or tracheal epithelium. These results indicate that NOG is a critical regulator of cell fate decisions between esophageal and pulmonary morphogenesis, and its lack of expression results in EA/TEF.

Authors

Carolina Pinzon-Guzman, Sreedhara Sangadala, Katherine M. Riera, Evgenya Y. Popova, Elizabeth Manning, Won Jae Huh, Matthew S. Alexander, Julia S. Shelton, Scott D. Boden, James R. Goldenring

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Figure 2

EOU culture is a suitable model for mammalian esophageal differentiation in vitro.

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EOU culture is a suitable model for mammalian esophageal differentiation...
mEOUs cultured for 4–12 days and either embedded in paraffin or taken as whole mount. IHC was used to detect expression of esophageal markers. Red scale bars: 100 μm; white scale bars: 1000 μm. (A) mEOUs 4 days in culture showing that most cells were Ki67+. (B) mEOUs 12 days in culture, larger in size, fewer cells were Ki67+. H&E staining demonstrates squamous epithelium surrounded by stromal components. Squamous epithelium shows maturation from basal layer to superficial layer. Differentiated cells expressed the squamous epithelium markers CK4 and involucrin, smooth muscle marker SMA, neuron marker TUJ, and other molecules important in foregut development: SHH, BMP4, NOG, SMAD1/5/9. (C) mEOUs 12 days in culture examined in whole-mount 3D images showing how different cells types come together to form EOUs.