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PLoS One. 2012;7(3):e33165. doi: 10.1371/journal.pone.0033165. Epub 2012 Mar 28.

Human embryonic stem cells differentiated to lung lineage-specific cells ameliorate pulmonary fibrosis in a xenograft transplant mouse model.

Author information

  • 1Center for Allergy and Inflammation and Institute for Stem Cell and Regenerative Medicine, Department of Medicine, University of Washington, Seattle, Washington, United States of America.

Abstract

BACKGROUND:

Our aim was to differentiate human (h) embryonic stem (ES) cells into lung epithelial lineage-specific cells [i.e., alveolar epithelial type I (AEI) and type II (AEII) cells and Clara cells] as the first step in the development of cell-based strategies to repair lung injury in the bleomycin mouse model of idiopathic pulmonary fibrosis (IPF). A heterogeneous population of non-ciliated lung lineage-specific cells was derived by a novel method of embryoid body (EB) differentiation. This differentiated human cell population was used to modulate the profibrotic phenotype in transplanted animals.

METHODOLOGY AND PRINCIPAL FINDINGS:

Omission or inclusion of one or more components in the differentiation medium skewed differentiation of H7 hES cells into varying proportions of AEI, AEII, and Clara cells. ICG-001, a small molecule inhibitor of Wnt/β-catenin/Creb-binding protein (CBP) transcription, changed marker expression of the differentiated ES cells from an AEII-like phenotype to a predominantly AEI-like phenotype. The differentiated cells were used in xenograft transplantation studies in bleomycin-treated Rag2γC(-/-) mice. Human cells were detected in lungs of the transplanted groups receiving differentiated ES cells treated with or without ICG-001. The increased lung collagen content found in bleomycin-treated mice receiving saline was significantly reduced by transplantation with the lung-lineage specific epithelial cells differentiated from ES cells. A significant increase in progenitor number was observed in the airways of bleomycin-treated mice after transplantation of differentiated hES cells.

CONCLUSIONS:

This study indicates that ES cell-based therapy may be a powerful novel approach to ameliorate lung fibrosis.

PMID:
22470441
[PubMed - indexed for MEDLINE]
PMCID:
PMC3314647
Free PMC Article

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