Esophageal Development and Engineering Laboratory, CHU Sainte-Justine Research Center, 3175 Côte Sainte-Catherine, Montréal, Quebec H3T 1C5, Canada.
CHU Sainte-Justine Research Center, 3175 Côte Sainte-Catherine, Montréal, Quebec H3T 1C5, Canada.
Dis Model Mech. 2022 Nov 1;15(11). doi: 10.1242/dmm.049541. Epub 2022 Nov 28.
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.
一系列经过严格调控的细胞和分子事件导致前肠前部分隔成食管和气管。分隔过程的破坏导致食管闭锁/气管食管瘘（EA/TEF）。EA/TEF 的病因仍很大程度上未知。因此，为了模拟食管和气管的早期发育，我们从 EA/TEF 患者中诱导多能干细胞（iPSC）分化，并从健康个体中诱导 iPSC 和胚胎干细胞分化为成熟的三维食管类器官。患者来源的内胚层细胞和健康个体来源的内胚层细胞中 CXCR4、SOX17 和 GATA4 的表达相似。关键转录因子 SOX2 在患者来源的前肠中的表达显著降低。我们还观察到患者来源的成熟食管类器官中 NKX2.1（或 NKX2-1）的异常表达。在前肠前体阶段，RNA 测序显示 GSTM1 和 RAB37 这两个关键基因在患者来源的前肠中显著降低。因此，我们假设患者来源的细胞中 SOX2 的短暂失调和 NKX2.1 的异常表达可能是导致前肠异常分隔的原因。
