Mesodermal Pten inactivation leads to alveolar capillary dysplasia-like phenotype
Caterina Tiozzo, … , Saverio Bellusci, Parviz Minoo
Caterina Tiozzo, … , Saverio Bellusci, Parviz Minoo
Published October 1, 2012
Citation Information: J Clin Invest. 2012;122(11):3862-3872. https://doi.org/10.1172/JCI61334.
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Research Article Pulmonology

Mesodermal Pten inactivation leads to alveolar capillary dysplasia-like phenotype

Abstract

Alveolar capillary dysplasia (ACD) is a congenital, lethal disorder of the pulmonary vasculature. Phosphatase and tensin homologue deleted from chromosome 10 (Pten) encodes a lipid phosphatase controlling key cellular functions, including stem/progenitor cell proliferation and differentiation; however, the role of PTEN in mesodermal lung cell lineage formation remains unexamined. To determine the role of mesodermal PTEN in the ontogeny of various mesenchymal cell lineages during lung development, we specifically deleted Pten in early embryonic lung mesenchyme in mice. Pups lacking Pten died at birth, with evidence of failure in blood oxygenation. Analysis at the cellular level showed defects in angioblast differentiation to endothelial cells and an accompanying accumulation of the angioblast cell population that was associated with disorganized capillary beds. We also found decreased expression of Forkhead box protein F1 (Foxf1), a gene associated with the ACD human phenotype. Analysis of human samples for ACD revealed a significant decrease in PTEN and increased activated protein kinase B (AKT). These studies demonstrate that mesodermal PTEN has a key role in controlling the amplification of angioblasts as well as their differentiation into endothelial cells, thereby directing the establishment of a functional gas exchange interface. Additionally, these mice could serve as a murine model of ACD.

Authors

Caterina Tiozzo, Gianni Carraro, Denise Al Alam, Sheryl Baptista, Soula Danopoulos, Aimin Li, Maria Lavarreda-Pearce, Changgong Li, Stijn De Langhe, Belinda Chan, Zea Borok, Saverio Bellusci, Parviz Minoo

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Figure 1

Absence of Pten in the mesenchyme does not affect lung morphogenesis, but leads to increased mesenchymal cell proliferation.

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Absence of Pten in the mesenchyme does not affect lung morphogenesis, bu...
(A–D) Histological analysis of E18.5 lungs. Ptenfl/fl and Ptenfl/fl;Dermo-Cre lungs were H&E stained. Representative WT and KO sections are shown. No macroscopic differences were detected between the WT and mutant embryos except for increased cell density (D versus C). Scale bars: 100 μm (A and B); 50 μm (lower magnification), 20 μm (higher magnification) (C and D). (E and F) Increased cell proliferation in Pten conditional KO (cKO) mice compared with controls. IF for E-CAD and PH3, showing increased proliferation in Ptenfl/fl;Dermo-Cre mesenchyme (F) compared with Ptenfl/fl (E). Scale bars: 50 μm. (G) Total number of E-CAD–negative cells was counted. Data are expressed as mean total lung cells ± SEM for 3 mice/group. *P < 0.01, Student’s t test. (H) Increased proliferation (PH3-positive cells) of total cell numbers in the E-CAD–negative population of the cKO mice. Data expressed as percentage of PH3-positive cells and E-CAD–negative over the total E-CAD–negative cells in 3 mice/group. (I) Statistical analysis of the SatO2 in control and mutant mice at birth, confirming hypoxia in mutants immediately after birth.