Therapeutic antibodies reveal Notch control of transdifferentiation in the adult lung

Inhibitory antibodies to two specific human and mouse Notch ligands, Jagged1 and Jagged2, are generated and shown to have beneficial effects in a goblet cell metaplasia asthma model; systemic Jagged1 inhibition transdifferentiates secretory cells into ciliated cells in the mouse, demonstrating that Jagged1 from ciliated cells normally holds back secretory cells to adopt the ciliated fate. Notch as a target in respiratory disease Notch signalling in cells of the mammalian airways dictates the differentiation of progenitors to secretory or ciliated cells, two major cell types of this tissue. Christian Siebel and colleagues have prepared inhibitory mouse and human antibodies to two specific Notch ligands, JAG1 and JAG2. They make the surprising discovery that JAG1 inhibition following injection promotes the conversion of secretory cells to ciliated cells in the mouse, demonstrating that JAG1 from ciliated cells normally holds back differentiated secretory cells from adopting this ciliated fate. These antibodies have beneficial effects in a mouse asthma model, converting mucus-producing cells into ciliated cells. Prevailing dogma holds that cell–cell communication through Notch ligands and receptors determines binary cell fate decisions during progenitor cell divisions, with differentiated lineages remaining fixed 1 . Mucociliary clearance 2 , 3 in mammalian respiratory airways depends on secretory cells (club and goblet) and ciliated cells to produce and transport mucus. During development or repair, the closely related Jagged ligands (JAG1 and JAG2) induce Notch signalling to determine the fate of these lineages as they descend from a common proliferating progenitor 4 , 5 , 6 , 7 , 8 . In contrast to such situations in which cell fate decisions are made in rapidly dividing populations 9 , 10 , cells of the homeostatic adult airway epithelium are long-lived 11 , 12 , 13 , and little is known about the role of active Notch signalling under such conditions. To disrupt Jagged signalling acutely in adult mammals, here we generate antibody antagonists that selectively target each Jagged paralogue, and determine a crystal structure that explains selectivity. We show that acute Jagged blockade induces a rapid and near-complete loss of club cells, with a concomitant gain in ciliated cells, under homeostatic conditions without increased cell death or division. Fate analyses demonstrate a direct conversion of club cells to ciliated cells without proliferation, meeting