Intrinsic mechanisms and microenvironmental cues fine-tune plasticity of esophageal progenitors

Cell plasticity supports tissue regeneration but can also drive metaplasia, increasing cancer risk in many tissues, including the esophagus. Understanding how esophageal progenitor plasticity is regulated is therefore essential. We previously identified Sox9 as a key regulator of this plasticity downstream of Hedgehog signaling, which is reactivated by chronic acid reflux. Here, we show that Hedgehog regulates Sox9 indirectly through epithelial-stromal communication and directly via cell-autonomous mechanisms. Activation of TGF-β and BMP pathways synergistically induces Sox9 and promotes a transcriptomic state resembling squamo-columnar junction progenitors predisposed to metaplasia. We also uncover an epithelial cell-intrinsic mechanism whereby Cox-2 modulates this plasticity. Cox-2 inhibitors suppress Hedgehog-induced Sox9 expression through direct effects on epithelial cells in both mouse and human models. Together, these findings provide proof of concept that pharmacological modulation of epithelial plasticity may offer new strategies for regenerative medicine and for the prevention or treatment of metaplasia.