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IPSCs derived from esophageal atresia patients reveal SOX2 dysregulation at the anterior foregut stage.

ABSTRACT: A series of well-regulated cellular and molecular events result in the compartmentalization of the anterior foregut into the esophagus and trachea. Disruption of the compartmentalization process leads to esophageal atresia/tracheoesophageal fistula (EA/TEF). The cause of EA/TEF remains largely unknown. Therefore, to mimic the early development of the esophagus and trachea, we differentiated induced pluripotent stem cells (iPSCs) from EA/TEF patients, and iPSCs and embryonic stem cells from healthy individuals into mature three-dimensional esophageal organoids. CXCR4, SOX17 and GATA4 expression was similar in both patient-derived and healthy endodermal cells. The expression of the key transcription factor SOX2 was significantly lower in the patient-derived anterior foregut. We also observed an abnormal expression of NKX2.1 (or NKX2-1) in the patient-derived mature esophageal organoids. At the anterior foregut stage, RNA sequencing revealed the critical genes GSTM1 and RAB37 to be significantly lower in the patient-derived anterior foregut. We therefore hypothesize that a transient dysregulation of SOX2 and the abnormal expression of NKX2.1 in patient-derived cells could be responsible for the abnormal foregut compartmentalization.

SUBMITTER: Raad S

PROVIDER: S-EPMC10655818 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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iPSCs derived from esophageal atresia patients reveal SOX2 dysregulation at the anterior foregut stage.

Raad Suleen S David Anu A Sagniez Melanie M Paré Bastien B Orfi Zakaria Z Dumont Nicolas A NA Smith Martin A MA Faure Christophe C

Disease models & mechanisms 20221128 11

A series of well-regulated cellular and molecular events result in the compartmentalization of the anterior foregut into the esophagus and trachea. Disruption of the compartmentalization process leads to esophageal atresia/tracheoesophageal fistula (EA/TEF). The cause of EA/TEF remains largely unknown. Therefore, to mimic the early development of the esophagus and trachea, we differentiated induced pluripotent stem cells (iPSCs) from EA/TEF patients, and iPSCs and embryonic stem cells from healt ...[more]

PMID: 36317486

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Project description:BackgroundA communicating bronchopulmonary foregut malformation (CBPFM) group IB is very rare congenital malformation. Group IB is associated with tracheoesophageal fistula and esophageal atresia (TEF-EA) and a portion of one lung arisen from the esophagus (Gerle et al. in N Engl J Med. 278:1413-1419, 1968). The coexistence of TEF-EA and dextrocardia is also a rare and challenging setting for repair of TEF-EA. Therefore, the thoracoscopic surgery for TEF-EA require the technical devise because of the small operative space. We herein report a rare case of CBPFM group IB with intralobar sequestration of lung and a successful performing of thoracoscopic surgery for EA with dextrocardia in VACTERL association.Case presentationA 2.2-kg term male neonate was born with an anal atresia, coarctation of the aorta, TEF-EA, renal anomalies, radial hemimelia, limb abnormalities (VACTERL association) and hypoplasia of the right lung with dextrocardia. The patient developed respiratory distress after admission. A two-stage operation for the TEF-EA was planned because of multiple anomalies and cardiac condition. In the neonatal period, esophageal banding at the gastroesophageal junction and gastrostomy were performed to establish enteral nutrition. After gaining body weight and achieving a stable cardiac condition, thoracoscopic surgery for TEF-EA was performed. The thoracoscopic findings revealed a small working space due to dextrocardia. To obtain a sufficient working space and to perform secure esophageal anastomosis, an additional 3-mm assistant port was inserted. To close the upper and lower esophagus, anchoring sutures of the esophagus were placed and were pulled to suspend the anastomotic site. Esophageal anastomosis was successfully performed. An esophagogram after TEF-EA surgery showed the connection between the lower esophagus and right lower lung. The definitive diagnosis was CBPFM group IB with intralobar sequestration. The thoracoscopic surgery was performed again for establishing oral intake. After transection of the bronchoesophageal fistula, the patient could perform oral feeding without pneumonia or respiratory distress.ConclusionsCBPFM type IB with intralobar sequestration is a rare condition. CBPFM type IB should be considered for a patients with respiratory symptom after radical operation for TEF-EA. In the present case, suspending the anastomotic site was effective and useful in thoracoscopic surgery for a TEF-EA patient with dextrocardia.

Dataset Information

IPSCs derived from esophageal atresia patients reveal SOX2 dysregulation at the anterior foregut stage.

Publications

iPSCs derived from esophageal atresia patients reveal SOX2 dysregulation at the anterior foregut stage.

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