Insulin-like growth factor-I stimulates differentiation of ATII cells to ATI-like cells through activation of Wnt5a

Manik C. Ghosh, Vijay Gorantla, Patrudu S. Makena, Charlean Luellen, Scott Sinclair, Andreas Schwingshackl, Christopher Waters

Research output: Contribution to journalArticle

28 Citations (Scopus)

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 smallinterfering 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume305
Issue number3
DOIs
StatePublished - Aug 1 2013

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Alveolar Epithelial Cells
Insulin-Like Growth Factor I
Wnt Signaling Pathway
Biological Phenomena
Catenins
IGF Type 1 Receptor
Lung Injury
Protein C
Protein Kinase C
Culture Media
Down-Regulation
RNA
Phenotype
Polymerase Chain Reaction
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

Cite this

Insulin-like growth factor-I stimulates differentiation of ATII cells to ATI-like cells through activation of Wnt5a. / Ghosh, Manik C.; Gorantla, Vijay; Makena, Patrudu S.; Luellen, Charlean; Sinclair, Scott; Schwingshackl, Andreas; Waters, Christopher.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 305, No. 3, 01.08.2013.

Research output: Contribution to journalArticle

Ghosh, Manik C. ; Gorantla, Vijay ; Makena, Patrudu S. ; Luellen, Charlean ; Sinclair, Scott ; Schwingshackl, Andreas ; Waters, Christopher. / Insulin-like growth factor-I stimulates differentiation of ATII cells to ATI-like cells through activation of Wnt5a. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2013 ; Vol. 305, No. 3.
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