Type IV collagen drives alveolar epithelial–endothelial association and the morphogenetic movements of septation

Abstract

BackgroundType IV collagen is the main component of the basement membrane that gives strength to the blood–gas barrier (BGB). In mammals, the formation of a mature BGB occurs primarily after birth during alveologenesis and requires the formation of septa from the walls of the saccule. In contrast, in avians, the formation of the BGB occurs rapidly and prior to hatching. Mutation in basement membrane components results in an abnormal alveolar phenotype; however, the specific role of type IV collagen in regulating alveologenesis remains unknown.ResultsWe have performed a microarray expression analysis in late chick lung development and found that COL4A1 and COL4A2 were among the most significantly upregulated genes during the formation of the avian BGB. Using mouse models, we discovered that mutations in murine Col4a1 and Col4a2 genes affected the balance between lung epithelial progenitors and differentiated cells. Mutations in Col4a1 derived from the vascular component were sufficient to cause defects in vascular development and the BGB. We also show that Col4a1 and Col4a2 mutants displayed disrupted myofibroblast proliferation, differentiation and migration. Lastly, we revealed that addition of type IV collagen protein induced myofibroblast proliferation and migration in monolayer culture and increased the formation of mesenchymal–epithelial septal-like structures in co-culture.ConclusionsOur study showed that type IV collagen and, therefore the basement membrane, play fundamental roles in coordinating alveolar morphogenesis. In addition to its role in the formation of epithelium and vasculature, type IV collagen appears to be key for alveolar myofibroblast development by inducing their proliferation, differentiation and migration throughout the developing septum.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-016-0281-2) contains supplementary material, which is available to authorized users.

Secondary crest myofibroblast PDGFRα controls the elastogenesis pathway via a secondary tier of signaling networks during alveologenesis

“…Type IV collagens localize to the basement membrane of epithelial and interstitial endothelial cells where SCMFs are anchored. In previous reports, postnatal inactivation of Type IV collagen caused defective ELN production and deposition, and defects in alveologenesis and epithelial cell differentiation (Loscertales et al, 2016). In our study, we also found significant changes in multiple integrins (e.g.…”

Polygenic Causes of Congenital Diaphragmatic Hernia Produce Common Lung Pathologies

“…A complementary set of mammalian genetic, genomic, physiologic, and three-dimensional morphologic approaches have pointed to myofibroblasts and extracellular matrix constituents, such as elastin, as key players in these latestage CDH-associated pulmonary abnormalities. 27,50 Lipofibroblasts, a lipid-containing population of interstitial fibroblasts first identified during the canalicular phase of lung development, were also reduced in rats treated with the CDH-inducing teratogen nitrofen. 51,52 Lipofibroblast signaling is critical for the completion of alveologenesis, possibly in directing the production of surfactant phospholipids in type 2 pneumocytes.…”

“…Reduced elastic fiber deposition may be responsible for the abnormal alveolar walls in patients with CDH, 102 more specifically, defects of secondary alveologenesis possibly linked to insufficient fibroblast growth factor-18 expression. 103 Reduced tropoelastin and elastin fibers result in stunted secondary septa with immature alveolar myofibroblasts ectopically displaced into the lung interstitium, 50,103 where they disrupt oxygen exchange. 27 Because this phenotype mimics the pathologic findings in humans surviving with CDH, it offers a good model in which to test for therapeutic rescue.…”

Transcriptional control of lung alveolar type 1 cell development and maintenance by NK homeobox 2-1

“…For example, reducing mechanical tension from fetal breathing by depleting the amniotic fluid or lowering the stiffness of cell culture surface favors AT2 over AT1 cell differentiation (6). Loss of an extracellular matrix protein, COL4A1, also leads to an increased ratio of AT2 to AT1 cells (7). Inside the epithelial cells, betacatenin-mediated canonical WNT signaling as well as fibroblast growth factor signaling inhibit AT1 cell differentiation (6,(8)(9)(10) and HDAC3-dependent TGF-beta signaling is required for proper epithelium expansion and AT1 cell spacing (8,11).…”