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.

Fgf10-positive cells represent a progenitor cell population during lung development and postnatally

“…Yet they express significant levels of Pro-Spc, as shown by immunofluorescence (of lung sections and sorted cells) and RT-PCR, and appear to have lost Fgf10 expression between P2 and P30. To date, there is no evidence for mesenchymal-to-epithelial transition events during lung development, and our previous work with the Dermo1-Cre; R26R line suggests that mesenchymal cells do not integrate into the lung epithelium Tiozzo et al, 2012). Similarly, we show here that the Fgf10-expressing lineage is purely mesenchymal by nature and labeled cells were never detected in the lung epithelium.…”

“…Northern blotting and quantitative PCR (qPCR) data show that Fgf10 transcripts progressively accumulate in the embryonic lung between E11.5 and E18.5 (Bellusci et al, 1997;El Agha et al, 2012). In situ hybridization for Fgf10 and X-Gal staining of Fgf10-lacZ lungs show that Fgf10 expression is restricted to the tips of the distal mesenchyme until E14.5, after which the expression becomes dispersed throughout the mesenchyme (El Agha et al, 2012;Mailleux et al, 2005;Ramasamy et al, 2007;Tiozzo et al, 2012). Our lineage-tracing data reveal two waves of Fgf10 expression, each of which is characterized by a distinct pattern in terms of cell localization as well as differentiation potential (Fig.…”

FOXF1 Transcription Factor Is Required for Formation of Embryonic Vasculature by Regulating VEGF Signaling in Endothelial Cells

“…7C). Deletion of FOXF1 efficiently reduced mRNAs of Flk1, Flt1, Pdgfb, Pecam-1, CD34, Tie2 and the non-coding RNA Fendrr , all of which are critical for embryonic vascular development 5–7, 32, 33 . In contrast, Angpt2, Nrp1, Dll4, Notch2 and VEGFb mRNAs were increased (Fig.…”

“…Flk1 −/− mice die in utero due to inhibition of vasculogenesis and formation of angioblast cells in the blood islands 3 , whereas Flt1 −/− embryos fail to form mature blood vessels 4 . Other signaling pathways involved in formation of embryonic vasculature include Angiopoietin/Tie2, PDGF, PI3K/ AKT, TGF-β, Shh, Wnt and Notch, as well as transcription factors Etv2, Hand1, MEF2c, Prox1, Hey1/2, COUP-TFII, Tbx4, Snail, FOXC2, GATA, Sox and KLF (reviewed in 5–7 ). Identification of additional proteins that regulate embryonic vascular development will provide information regarding pathogenesis of human vascular disorders.…”

Ultrastructural Characterization of Genetic Diffuse Lung Diseases in Infants and Children: A Cohort Study and Review

“…Genetically, ACD is a heterogeneous disease, since FOXF1 variants could not be demonstrated in more than half the published cases. Histologically, it is characterized by a scattered pattern of interalveolar septal thickening, decreased terminal bronchial ramification and alveolar number, increased muscularization in small pulmonary arteries, misalignment of pulmonary veins along small pulmonary arteries, and decreased capillary number failing to make an appropriate contact with the alveolar basal membrane, leading to pulmonary hypertension and impaired gas exchange [32]. In more than 50% cases ACD is associated with malformations in other organs involving the gastrointestinal, cardiovascular, and genitourinary systems, suggesting a more pervasive embryonic process [33].…”