Therapeutic antibodies reveal Notch control of transdifferentiation in the adult lung.

Daniel Lafkas, Amy Shelton, Cecilia Chiu, Gladys de Leon Boenig, Yongmei Chen, Scott S Stawicki, Christian Siltanen, Mike Reichelt, Meijuan Zhou, Xiumin Wu, Jeffrey Eastham-Anderson, Heather Moore, Meron Roose-Girma, Yvonne Chinn, Julie Q Hang, Søren Warming, Jackson Egen, Wyne P Lee, Cary Austin, Yan Wu, Jian Payandeh, John B Lowe, Christian W Siebel

Index: Nature 528 , 127-31, (2015)

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Abstract

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. Mucociliary clearance 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. In contrast to such situations in which cell fate decisions are made in rapidly dividing populations, cells of the homeostatic adult airway epithelium are long-lived, 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 a conservative definition of direct transdifferentiation. Jagged inhibition also reversed goblet cell metaplasia in a preclinical asthma model, providing a therapeutic foundation. Our discovery that Jagged antagonism relieves a blockade of cell-to-cell conversion unveils unexpected plasticity, and establishes a model for Notch regulation of transdifferentiation.