Kariuki Secunda W, Mitani Yosuke, Bailey Dominique D, Efe Gizem, Tripathi Ved V, Tekin Halil, Suzuki Kensuke, Que Jianwen, Gabre Joel, Cruz-Acuña Ricardo
Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Columbia University Irving Medical Center, New York, NY, USA.
Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.
bioRxiv. 2025 Aug 1:2025.08.01.668154. doi: 10.1101/2025.08.01.668154.
The transcription factor STAT3 plays broad roles in epithelial biology, yet its function in human esophageal development remains undefined. Using 2D and 3D human induced pluripotent stem cell (hiPSC)-derived platforms, we investigated how STAT3 regulates esophageal epithelial differentiation. We find that STAT3 is dispensable for definitive endoderm and anterior foregut endoderm specification but becomes essential during the transition to esophageal progenitor cells (EPCs). Inhibition of STAT3, via CRISPR-mediated knockout or siRNA, impairs the expression of key EPC and differentiation markers, including , and disrupts 3D organoid formation. These defects are accompanied by reduced epithelial proliferation. Notably, STAT3 is highly expressed in human fetal esophageal tissues and hiPSC-derived organoids, while its deletion in the developing mouse esophagus does not affect epithelial architecture, highlighting species-specific differences. Together, these findings identify STAT3 as a critical determinant of basal cell identity and epithelial morphogenesis, revealing a developmental checkpoint in early human esophageal lineage commitment.
转录因子信号转导和转录激活因子3（STAT3）在上皮生物学中发挥着广泛作用，但其在人类食管发育中的功能仍不明确。利用二维和三维人诱导多能干细胞（hiPSC）衍生平台，我们研究了STAT3如何调节食管上皮分化。我们发现，STAT3对于确定内胚层和前肠内胚层的特化并非必需，但在向食管祖细胞（EPC）转变过程中变得至关重要。通过CRISPR介导的基因敲除或小干扰RNA抑制STAT3，会损害关键EPC和分化标志物的表达，包括……，并破坏三维类器官的形成。这些缺陷伴随着上皮增殖的减少。值得注意的是，STAT3在人类胎儿食管组织和hiPSC衍生的类器官中高度表达，而在发育中的小鼠食管中缺失STAT3并不影响上皮结构，这突出了物种特异性差异。总之，这些发现确定STAT3是基底细胞身份和上皮形态发生的关键决定因素，揭示了人类食管早期谱系定向中的一个发育检查点。
