Negative regulation of myofibroblast differentiation by PTEN (Phosphatase and Tensin Homolog Deleted on chromosome 10).
BACKGROUND
Myofibroblasts are primary effector cells in idiopathic pulmonary fibrosis (IPF). Defining mechanisms of myofibroblast differentiation may be critical to the development of novel therapeutic agents.


OBJECTIVE
To show that myofibroblast differentiation is regulated by phosphatase and tensin homolog deleted on chromosome 10 (PTEN) activity in vivo, and to identify a potential mechanism by which this occurs.


METHODS
We used tissue sections of surgical lung biopsies from patients with IPF to localize expression of PTEN and alpha-smooth muscle actin (alpha-SMA). We used cell culture of pten(-/-) and wild-type fibroblasts, as well as adenoviral strategies and pharmacologic inhibitors, to determine the mechanism by which PTEN inhibits alpha-SMA, fibroblast proliferation, and collagen production.


RESULTS
In human lung specimens of IPF, myofibroblasts within fibroblastic foci demonstrated diminished PTEN expression. Furthermore, inhibition of PTEN in mice worsened bleomycin-induced fibrosis. In pten(-/-) fibroblasts, and in normal fibroblasts in which PTEN was inhibited, alpha-SMA, proliferation, and collagen production was upregulated. Addition of transforming growth factor-beta to wild-type cells, but not pten(-/-) cells, resulted in increased alpha-SMA expression in a time-dependent fashion. In pten(-/-) cells, reconstitution of PTEN decreased alpha-SMA expression, proliferation, and collagen production, whereas overexpression of PTEN in wild-type cells inhibited transforming growth factor-beta-induced myofibroblast differentiation. It was observed that both the protein and lipid phosphatase actions of PTEN were capable of modulating the myofibroblast phenotype.


CONCLUSIONS
The results indicate that in IPF, myofibroblasts have diminished PTEN expression. Inhibition of PTEN in vivo promotes fibrosis, and PTEN inhibits myofibroblast differentiation in vitro.
White
Eric S
ES
Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, 6301 MSRB III/0642, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0642, USA. docew@umich.edu
Atrasz
Rachelle G
RG
Hu
Biao
B
Phan
Sem H
SH
Stambolic
Vuk
V
Mak
Tak W
TW
Hogaboam
Cory M
CM
Flaherty
Kevin R
KR
Martinez
Fernando J
FJ
Kontos
Christopher D
CD
Toews
Galen B
GB
D000199:Actins / Q000096:biosynthesis; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics; D001761:Bleomycin / Q000494:pharmacology; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000502:physiology*; D005347:Fibroblasts / Q000502:physiology*; D005355:Fibrosis / Q000139:chemically induced / Q000235:genetics; D006801:Humans; D017563:Lung Diseases, Interstitial / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011658:Pulmonary Fibrosis / Q000503:physiopathology*; D016212:Transforming Growth Factor beta / Q000502:physiology
D000199:Actins; D000903:Antibiotics, Antineoplastic; D016212:Transforming Growth Factor beta; D001761:Bleomycin; D051059:PTEN Phosphohydrolase