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

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.

GABAA Receptors Are Well Preserved in the Hippocampus of Aged Mice.

GABA is the primary inhibitory neurotransmitter in the nervous system. GABAA receptors (GABAARs) are pentameric ionotropic channels. Subunit composition of the receptors is associated with the affinity of GABA binding and its downstream inhibitory actions. Fluctuations in subunit expression levels with increasing age have been demonstrated in animal and human studies. However, our knowledge regarding the age-related hippocampal GABAAR expression changes is limited and based on rat studies. This study is the first analysis of the aging-related changes of the GABAAR subunit expression in the CA1, CA2/3, and dentate gyrus regions of the mouse hippocampus. Using Western blotting and immunohistochemistry we found that the GABAergic system is robust, with no significant age-related differences in GABAAR α1, α2, α3, α5, ß3, and γ2 subunit expression level differences found between the young (6 months) and old (21 months) age groups in any of the hippocampal regions examined. However, we detected a localized decrease of α2 subunit expression around the soma, proximal dendrites, and in the axon initial segment of pyramidal cells in the CA1 and CA3 regions that is accompanied by a pronounced upregulation of the α2 subunit immunoreactivity in the neuropil of aged mice. In summary, GABAARs are well preserved in the mouse hippocampus during normal aging although GABAARs in the hippocampus are severely affected in age-related neurological disorders, including Alzheimer's disease.