**12. Conclusions**

We know that in the lung, ATII epithelial progenitors are recruited during alveolar regeneration to replace lost ATI—and sometimes ATII—cells. Although we understand that the process of alveolar regeneration occurs in proliferation and differentiation stages, our understanding of the mechanisms of differentiation is still in its infancy. Recent studies have significantly advanced our understanding of some signaling mechanisms shown to be involved in ATII-to-ATI differentiation. Signaling pathways shown to play a role in ATII-to-ATI cell differentiation include BMP, Notch, TGFβ, β-catenin, Etv5, Cdc42, and Yap/Taz (Figure 1). Cells present in the alveolus that appear to contribute to ATI cell differentiation include fibroblasts and monocyte-derived macrophages.

These various signaling pathways have all been shown to be involved in alveolar regeneration, with various mechanistic steps from each pathway likely interacting with one another to control differentiation. These investigations establish the foundation for further studies in this field. Using this understanding of the signaling pathways behind ATII-to-ATI differentiation during alveolar repair, similar studies can be devised to understand the interaction between these various mechanisms in coordination to control differentiation. Additionally, a strengthened understanding of these molecular pathways involved in differentiation may lead to development of new clinical treatments that accelerate lung repair in individuals with excessive lung damage.

**Figure 1.** The alveolar epithelium consists of ATI and ATII cells. ATI cells are very susceptible to injury. ATII cells regenerate ATI cells. ATII cells proliferate and then differentiate into ATI cells. Many pathways have been identified that promote ATII cell proliferation: KGF [16], HGF [17,54], EGF [19,20], GM-CSF [33], FoxM1 [10], Wnt/β-catenin [13–15], Etv5 [37], and YAP/TAZ [24,26], whereas downregulation of BMP signaling induces proliferation [23]. Recent studies suggest that multiple pathways are also involved in ATII-to-ATI cell differentiation: YAP/TAZ [24,26], Cdc42 [35], and BMP [23] promote differentiation, whereas Wnt/β-catenin [14,15], Etv5 [37], and Notch [22] maintain the ATII cell phenotype. We recently identified a novel transitional state through which ATII cells pass as they differentiate into ATI cells [38]. Our data suggested that TGFβ promotes cell cycle exit and entry into the transitional state, whereas TGFβ downregulation permits terminal differentiation. Further studies are necessary to confirm these findings and elucidate how these pathways intersect in a coordinated manner to regulate ATII-to-ATI cell differentiation.

**Funding:** This work was funded by the National Institutes of Health R01 HL131608.

**Conflicts of Interest:** The authors declare no conflict of interest.
