Robust cellular reprogramming occurs spontaneously during liver regeneration

TLDR

Cellular reprogramming—interconversion of distinct cell types with defined factors—is transforming regenerative medicine, yet it is rarely observed in vivo without exogenous factors. Activation of Notch is sufficient to reprogram hepatocytes into biliary epithelial cells, and lineage tracing shows widespread hepatocyte‑to‑BEC reprogramming after biliary injury, demonstrating that mammalian regeneration induces extensive cellular identity changes.

Abstract

Cellular reprogramming—the ability to interconvert distinct cell types with defined factors—is transforming the field of regenerative medicine. However, this phenomenon has rarely been observed in vivo without exogenous factors. Here, we report that activation of Notch, a signaling pathway that mediates lineage segregation during liver development, is sufficient to reprogram hepatocytes into biliary epithelial cells (BECs). Moreover, using lineage tracing, we show that hepatocytes undergo widespread hepatocyte-to-BEC reprogramming following injuries that provoke a biliary response, a process requiring Notch. These results provide direct evidence that mammalian regeneration prompts extensive and dramatic changes in cellular identity under injury conditions.