title: Transdifferentiation of alveolar epithelial type II to type I cells is controlled by opposing TGF-β and BMP signaling.
abstract: Alveolar epithelial type II (ATII) cells are essential for maintaining normal lung homeostasis because they produce surfactant, express innate immune proteins, and can function as progenitors for alveolar epithelial type I (ATI) cells. Although autocrine production of transforming growth factor (TGF)-β1 has been shown to promote the transdifferentiation of primary rat ATII to ATI cells in vitro, mechanisms controlling this process still remain poorly defined. Here, evidence is provided that Tgf-β1, -2, -3 mRNA and phosphorylated SMAD2 and SMAD3 significantly increase as primary cultures of mouse ATII cells transdifferentiate to ATI cells. Concomitantly, bone morphogenetic protein (Bmp)-2 and -4 mRNA, and phosphorylated SMAD1/5/8 expression decrease. Exogenously supplied recombinant human TGF-β1 inhibited BMP signaling and enhanced transdifferentiation by promoting the loss of ATII cell-specific gene expression and weakly stimulating ATI cell-specific gene expression. On the other hand, exogenously supplied recombinant human BMP-4 inhibited TGF-β signaling and delayed transdifferentiation by inhibiting the gain in ATI cell-specific gene expression and weakly delaying the loss of ATII cell-specific gene expression. In mouse lung epithelial (MLE15) cells, small-interfering RNA (siRNA) knockdown of TGF-β receptor type-1 enhanced basal expression of ATII genes while siRNA RNA knockdown of BMP receptors type-1a and -1b enhanced basal expression of ATI genes. Together, these results suggest that the rate of ATII cell transdifferentiation is controlled by the opposing actions of BMP and TGF-β signaling that switch during the process of transdifferentiation.
authors.affiliation: Dept. of Pediatrics, Box 850, The Univ. of Rochester, School of Medicine and Dentistry, 601 Elmwood Ave., Rochester NY 14642. michael_oreilly@urmc.rochester.edu.
authors.forename: Lan
authors.initials: L
authors.lastname: Zhao
authors.forename: Min
authors.initials: M
authors.lastname: Yee
authors.forename: Michael A
authors.initials: MA
authors.lastname: O'Reilly
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology*; D006801:Humans; D051379:Mice; D011650:Pulmonary Alveoli / Q000166:cytology*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051785:Smad Proteins / Q000502:physiology*; D051899:Smad2 Protein / Q000096:biosynthesis; D051900:Smad3 Protein / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D012333:RNA, Messenger; D051785:Smad Proteins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta
keywords: bone morphogenetic protein; epithelium; transforming growth factor-β