title: Insulin-like growth factor-I stimulates differentiation of ATII cells to ATI-like cells through activation of Wnt5a.
abstract: Alveolar type II (ATII) epithelial cells play a crucial role in the repair and remodeling of the lung following injury. ATII cells have the capability to proliferate and differentiate into alveolar type I (ATI) cells in vivo and into an ATI-like phenotype in vitro. While previous reports indicate that the differentiation of ATII cells into ATI cells is a complex biological process, the underlying mechanism responsible for differentiation is not fully understood. To investigate factors involved in this differentiation in culture, we used a PCR array and identified several genes that were either up- or downregulated in ATI-like cells (day 6 in culture) compared with day 2 ATII cells. Insulin-like growth factor-I (IGF-I) mRNA was increased nearly eightfold. We found that IGF-I was increased in the culture media of ATI-like cells and demonstrated a significant role in the differentiation process. Treatment of ATII cells with recombinant IGF-I accelerated the differentiation process, and this effect was abrogated by the IGF-I receptor blocker PQ401. We found that Wnt5a, a member of the Wnt-Frizzled pathway, was activated during IGF-I-mediated differentiation. Both protein kinase C and β-catenin were transiently activated during transdifferentiation. Knocking down Wnt5a using small-interfering RNA abrogated the differentiation process as indicated by changes in the expression of an ATII cell marker (prosurfactant protein-C). Treatment of wounded cells with either IGF-I or Wnt5a stimulated wound closure. These results suggest that IGF-I promotes differentiation of ATII to ATI cells through the activation of a noncanonical Wnt pathway.
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Manik C
authors.initials: MC
authors.lastname: Ghosh
authors.forename: Vijay
authors.initials: V
authors.lastname: Gorantla
authors.forename: Patrudu S
authors.initials: PS
authors.lastname: Makena
authors.forename: Charlean
authors.initials: C
authors.lastname: Luellen
authors.forename: Scott E
authors.initials: SE
authors.lastname: Sinclair
authors.forename: Andreas
authors.initials: A
authors.lastname: Schwingshackl
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Waters
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D004789:Enzyme Activation; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D010671:Phenylurea Compounds / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000166:cytology* / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000071818:Wnt-5a Protein; D014945:Wound Healing; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000634:Aminoquinolines; C569479:PQ 401; D010671:Phenylurea Compounds; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C491837:Wnt5a protein, rat; D051176:beta Catenin; C548904:insulin-like growth factor-1, rat; D007334:Insulin-Like Growth Factor I; D011493:Protein Kinase C
keywords: alveolar epithelial cell; alveolar type I; alveolar type II; prosurfactant protein-C