Sox9-dependent plasticity of esophageal progenitors is fine-tuned by cues from the microenvironment

Cell plasticity governs tissue regeneration but can also drive metaplasia, the replacement of one cell type with another. This process increases the risk of cancer development in several tissues, including esophagus. Esophageal metaplasia development partly depends on keratinocyte plasticity, making regulation of esophageal progenitor fate critical.

We previously identified Sox9 as instrumental in regulating esophageal cell plasticity following Hedgehog pathway activation. Our current study reveals that Hedgehog indirectly regulates Sox9 by modifying epithelial-stromal communication. This activates TGF-β and BMP pathways in epithelial cells, which synergistically regulate Sox9 and stimulate a transcriptomic program resembling squamo-columnar junction progenitors, which are prone to initiate metaplasia. Importantly, we demonstrate pharmacological modulation of this plasticity in vivo . Indeed, Ibuprofen inhibits Hedgehog-induced Sox9 expression by directly targeting epithelial cells, providing proof of concept for pharmacological intervention in cell plasticity with implications for regenerative medicine and metaplasia treatment.