Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Cell Mol Life Sci. 2023 Sep 26;80(10):305. doi: 10.1007/s00018-023-04952-z.
Self-renewing, damage-repair and differentiation of mammalian stratified squamous epithelia are subject to tissue homeostasis, but the regulation mechanisms remain elusive. Here, we investigate the esophageal squamous epithelial tissue homeostasis in vitro and in vivo. We establish a rat esophageal organoid (rEO) in vitro system and show that the landscapes of rEO formation, development and maturation trajectories can mimic those of rat esophageal epithelia in vivo. Single-cell RNA sequencing (scRNA-seq), snapshot immunostaining and functional analyses of stratified "matured" rEOs define that the epithelial pluripotent stem cell determinants, p63 and Sox2, play crucial but distinctive roles for regulating mammalian esophageal tissue homeostasis. We identify two cell populations, p63Sox2 and p63Sox2, of which the p63Sox2 population presented at the basal layer is the cells of origin required for esophageal epithelial stemness maintenance and proliferation, whereas the p63Sox2 population presented at the suprabasal layers is the cells of origin having a dual role for esophageal epithelial differentiation (differentiation-prone fate) and rapid tissue damage-repair responses (proliferation-prone fate). Given the fact that p63 and Sox2 are developmental lineage oncogenes and commonly overexpressed in ESCC tissues, p63Sox2 population could not be detected in organoids formed by esophageal squamous cell carcinoma (ESCC) cell lines. Taken together, these findings reveal that the tissue homeostasis is maintained distinctively by p63 and/or Sox2-dependent cell lineage populations required for the tissue renewing, damage-repair and protection of carcinogenesis in mammalian esophagi.
哺乳动物分层鳞状上皮组织的自我更新、损伤修复和分化受组织内稳态调控，但调控机制仍不清楚。本研究在体外和体内研究了食管鳞状上皮组织的内稳态。建立了大鼠食管类器官（rEO）体外系统，并表明 rEO 的形成、发育和成熟轨迹景观可以模拟体内大鼠食管上皮的情况。单细胞 RNA 测序（scRNA-seq）、瞬时免疫染色和分层“成熟”rEO 的功能分析表明，上皮多能干细胞决定因子 p63 和 Sox2 在调节哺乳动物食管组织内稳态方面发挥着关键但不同的作用。我们鉴定了两个细胞群，p63Sox2 和 p63Sox2，其中位于基底层的 p63Sox2 群体是维持食管上皮干细胞特性和增殖所必需的细胞起源，而位于上基底层的 p63Sox2 群体具有双重作用，既能促进食管上皮分化（分化倾向命运），又能快速响应组织损伤修复（增殖倾向命运）。鉴于 p63 和 Sox2 是发育谱系致癌基因，并且在 ESCC 组织中普遍过表达，p63Sox2 群体不能在食管鳞状细胞癌（ESCC）细胞系形成的类器官中检测到。总之，这些发现表明，组织内稳态是由 p63 和/或 Sox2 依赖性细胞谱系群体维持的，这些群体对于哺乳动物食管的组织更新、损伤修复和保护致癌作用至关重要。
