Endothelial-monocyte activating polypeptide II disrupts alveolar epithelial type II to type I cell transdifferentiation.
BACKGROUND
Distal alveolar morphogenesis is marked by differentiation of alveolar type (AT)-II to AT-I cells that give rise to the primary site of gas exchange, the alveolar/vascular interface. Endothelial-Monocyte Activating Polypeptide (EMAP) II, an endogenous protein with anti-angiogenic properties, profoundly disrupts distal lung neovascularization and alveolar formation during lung morphogenesis, and is robustly expressed in the dysplastic alveolar regions of infants with Bronchopulmonary dysplasia. Determination as to whether EMAP II has a direct or indirect affect on ATII → ATI trans-differentiation has not been explored.


METHODS
In a controlled nonvascular environment, an in vitro model of ATII → ATI cell trans-differentiation was utilized to demonstrate the contribution that one vascular mediator has on distal epithelial cell differentiation.


RESULTS
Here, we show that EMAP II significantly blocked ATII → ATI cell transdifferentiation by increasing cellular apoptosis and inhibiting expression of ATI markers. Moreover, EMAP II-treated ATII cells displayed myofibroblast characteristics, including elevated cellular proliferation, increased actin cytoskeleton stress fibers and Rho-GTPase activity, and increased nuclear:cytoplasmic volume. However, EMAP II-treated cells did not express the myofibroblast markers desmin or αSMA.


CONCLUSIONS
Our findings demonstrate that EMAP II interferes with ATII → ATI transdifferentiation resulting in a proliferating non-myofibroblast cell. These data identify the transdifferentiating alveolar cell as a possible target for EMAP II's induction of alveolar dysplasia.
Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, TX, USA.
Yao
Y
Chen
Susan K
SK
Legan
Anne
A
Mahan
Janet
J
Thornton
Haiming
H
Xu
Margaret A
MA
Schwarz
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D009024:Morphogenesis / Q000187:drug effects / Q000502:physiology; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009363:Neoplasm Proteins / Q000494:pharmacology / Q000502:physiology*; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000494:pharmacology / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D022502:Stress Fibers / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D015415:Biomarkers; D016207:Cytokines; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; C077219:small inducible cytokine subfamily E, member 1; D020741:rho GTP-Binding Proteins