Figure 7. Diagram of CEBPA restricting AT2 cell plasticity during development and injury-repair.

Top: in a wild type lung, SOX9 progenitors undergo specification and maturation to become neonatal/nascent and mature AT2 cells, sequentially, expressing CEBPA. A small fraction of AT2 cells at both stages become AT1-like cells with varying levels of HOPX. Sendai virus (SeV) infection induces KRT8/CLDN4 transitional cells as well as AT1-like cells, as a sequential or parallel response of injury-repair. Cebpa deletion in neonatal, but not mature, AT2 cells leads to reversion to the progenitor program and proliferation, in addition to an increase of AT1-like cells upon either deletion. Sendai virus infection bestows mature AT2 cells with the plasticity to revert to progenitors as well as to more readily transition to the KRT8/CLDN4 state. Bottom: in an aerial view of the cell plasticity landscape, the progenitor program, although still present in neonatal AT2 cells, is submerged under the AT2 program promoted by CEBPA. Without CEBPA, the AT2 program subcedes to expose the progenitor program. As AT2 cells mature, the progenitor program disappears so that, even without the AT2 program, no progenitor program is visible. After infection, mature AT2 cells reshape their plasticity landscape, but only the KRT8/CLDN4 transitional program rises enough to manifest over the AT2 program. Without CEBPA and the AT2 program, the progenitor program is visible and the transitional program more evident.