Transient depletion of the transcription elongation factor SPT6 in the keratinocyte has been recently shown to inhibit epidermal differentiation and stratification; instead, they transdifferentiate into a gut-like lineage. We show here that this phenomenon of transdifferentiation recapitulates Barrett’s metaplasia, the only human pathophysiologic condition in which a stratified squamous epithelium that is injured due to chronic acid reflux is trans-committed into an intestinal fate. The evidence we present here not only lend support to the notion that the keratinocytes are potentially the cell of origin of Barrett’s metaplasia but also provide mechanistic insights linking transient acid exposure, downregulation of SPT6, stalled transcription of the master regulator of epidermal fate TP63, loss of epidermal fate, and metaplastic progression. Because Barrett’s metaplasia in the esophagus is a pre-neoplastic condition with no preclinical human models, these findings have a profound impact on the modeling Barrett’s metaplasia-in-a-dish.

最近研究表明，角质形成细胞中转录延伸因子 SPT6 的瞬时缺失会抑制表皮分化和分层。相反，它们转分化为类似肠道的谱系。我们在这里表明，这种转分化现象概括了巴雷特化生，巴雷特化生是唯一一种人类病理生理状况，其中由于慢性胃酸反流而损伤的复层鳞状上皮转入肠道命运。我们在此提供的证据不仅支持角质形成细胞可能是 Barrett 化生的起源细胞这一观点，而且还提供了与短暂酸暴露、SPT6 下调、表皮命运主调节因子 TP63 转录停滞、丢失有关的机制见解。表皮命运和化生进展。由于巴雷特食管化生是一种肿瘤前期病症，没有临床前人体模型，因此这些发现对巴雷特培养皿化生建模具有深远的影响。