How to build an epithelial tree.

Nature has evolved a variety of mechanisms to build epithelial trees of diverse architectures within different organs and across species. Epithelial trees are elaborated through branch initiation and extension, and their morphogenesis ends with branch termination. Each of these steps of the branching process can be driven by the actions of epithelial cells themselves (epithelial-intrinsic mechanisms) or by the cells of their surrounding tissues (epithelial-extrinsic mechanisms). Here, we describe examples of how these mechanisms drive each stage of branching morphogenesis, drawing primarily from studies of the lung, kidney, salivary gland, mammary gland, and pancreas, all of which contain epithelial trees that form through collective cell behaviors. Much of our understanding of epithelial branching comes from experiments using mice, but we also include examples here from avian and reptilian models. Throughout, we highlight how distinct mechanisms are employed in different organs and species to build epithelial trees. We also highlight how similar morphogenetic motifs are used to carry out conserved developmental programs or repurposed to support novel ones. Understanding the unique strategies used by nature to build branched epithelia from across the tree of life can help to inspire creative solutions to problems in tissue engineering and regenerative medicine.

Interleukin-13 disrupts type 2 pneumocyte stem cell activity.

The T helper 2 (Th2) inflammatory cytokine interleukin-13 (IL-13) has been associated with both obstructive and fibrotic lung diseases; however, its specific effect on the epithelial stem cells in the gas exchange compartment of the lung (alveolar space) has not been explored. Here, we used in vivo lung models of homeostasis and repair, ex vivo organoid platforms, and potentially novel quantitative proteomic techniques to show that IL-13 disrupts the self-renewal and differentiation of both murine and human type 2 alveolar epithelial cells (AEC2s). Significantly, we find that IL-13 promotes ectopic expression of markers typically associated with bronchiolar airway cells and commonly seen in the alveolar region of lung tissue from patients with idiopathic pulmonary fibrosis. Furthermore, we identify a number of proteins that are differentially secreted by AEC2s in response to IL-13 and may provide biomarkers to identify subsets of patients with pulmonary disease driven by "Th2-high" biology.

Indispensable pre-mitotic endocycles promote aneuploidy in the Drosophila rectum.

The endocycle is a modified cell cycle that lacks M phase. Endocycles are well known for enabling continued growth of post-mitotic tissues. By contrast, we discovered pre-mitotic endocycles in precursors of Drosophila rectal papillae (papillar cells). Unlike all known proliferative Drosophila adult precursors, papillar cells endocycle before dividing. Furthermore, unlike diploid mitotic divisions, these polyploid papillar divisions are frequently error prone, suggesting papillar structures may accumulate long-term aneuploidy. Here, we demonstrate an indispensable requirement for pre-mitotic endocycles during papillar development and also demonstrate that such cycles seed papillar aneuploidy. We find blocking pre-mitotic endocycles disrupts papillar morphogenesis and causes organismal lethality under high-salt dietary stress. We further show that pre-mitotic endocycles differ from post-mitotic endocycles, as we find only the M-phase-capable polyploid cells of the papillae and female germline can retain centrioles. In papillae, this centriole retention contributes to aneuploidy, as centrioles amplify during papillar endocycles, causing multipolar anaphase. Such aneuploidy is well tolerated in papillae, as it does not significantly impair cell viability, organ formation or organ function. Together, our results demonstrate that pre-mitotic endocycles can enable specific organ construction and are a mechanism that promotes highly tolerated aneuploidy.