Chondroitin sulfate proteoglycans are required for lung growth and morphogenesis in vitro

Abstract

. Chondroitin sulfate proteoglycans are required for lung growth and morphogenesis in vitro. Am J Physiol Lung Cell Mol Physiol 285: L1323-L1336, 2003. First published August 15, 2003 10.1152/ajplung.00226. 2003 have been shown to play a key role in the development of many tissues. We have investigated the role of sulfated PGs in early rat lung development by treating cultured tissues with 30 mM sodium chlorate, a global inhibitor of PG sulfation. Chlorate treatment disrupted growth and branching of embryonic day 13 lung explants. Isolated lung epithelium (LgE) migrated toward and invaded lung mesenchyme (LgM), and chlorate irreversibly suppressed this response. Chlorate also inhibited migration of LgE toward beads soaked in FGF10. Chlorate severely decreased branching morphogenesis in tissue recombinants consisting of LgM plus either LgE or tracheal epithelium (TrE) and decreased expression of surfactant protein C gene (SP-C). Chlorate also reduced bone morphogenetic protein-4 expression in cultured tips and recombinants but had no effect on the expression of clara cell 10-kDa protein (CC10), sonic hedgehog (Shh), FGF10, and FGF receptor 2IIIb. Chlorate reduced the growth of LgE in mesenchyme-free culture but did not affect SP-C expression. In contrast, chlorate inhibited both rudiment growth and the induction of SP-C in mesenchyme-free cultured TrE. Treatment of lung tips and tissue recombinants with chondroitinase ABC abolished branching morphogenesis. Chondroitinase also suppressed growth of TrE in mesenchyme-free culture. Chondroitinase treatment, however, had no effect on the induction of SP-C expression in any of these cultures. These results demonstrate the overall importance of sulfated PGs to normal lung development and demonstrate a dynamic role for chondroitin sulfate PGs in embryonic lung growth and morphogenesis. lung; branching morphogenesis LUNG ORGANOGENESIS REQUIRES the coordinated temporal and spatial expression of multiple genes, both prenatally and after birth. Deviations from the normal developmental program resulting from improper or insufficient gene expression can have serious consequences, such as pulmonary hypoplasia, pulmonary agenesis, congenital alveolar proteinosis, and neonatal respiratory distress syndrome. Studies in both mammals (3, 67, 75) and birds (13, 52) have repeatedly shown that normal lung morphogenesis and differentiation are dependent on reciprocal interactions between the endodermal epithelium and mesenchyme derived from the splanchnic mesoderm. These interactions are responsible not only for patterning of the lung but also for the specification of the many specialized cell types that populate both the epithelial and mesenchymal tissue compartments. Elucidation of the molecular basis of these interactions has been the subject of intense recent interest. Although much remains to be learned, the results thus far demonstrate that these interactions are highly complex, involving the interplay of numerous hormones, growth factors, and downstream effectors such as trans...

Molecular Mechanisms of Early Lung Specification and Branching Morphogenesis

“…More recently, it has been shown that both heparan sulfate and chondroitin sulfate proteoglycans are required for lung branching and in fact mediate the inductive effects of FGF10 binding to the epithelium (93)(94)(95).…”

Elf5 is an epithelium‐specific, fibroblast growth factor–sensitive transcription factor in the embryonic lung

“…FGF7, which is produced by lung mesenchymal cells, is a potent mitogen for lung epithelial cells, both in vivo (Ulich et al, 1994;Simonet et al, 1995;Tichelaar et al, 2000) and in vitro (Shiratori et al, 1996;Bellusci et al, 1997;Cardoso et al, 1997;Shannon et al, 1999), as well as a strong inducer of alveolar type II cell differentiation (Chelly et al, 1999;Shannon et al, 1999). The differences in response of the lung epithelium to FGF10 and FGF7, even though both ligands signal primarily through FGFR2b, may be due to differential interactions with low-affinity proteoglycan coreceptors (Izvolsky et al, 2003;Shannon et al, 2003;Sedita et al, 2004). The differential response of epithelium to FGF10 and FGF7 is not limited to the lung.…”

Changes in versican and chondroitin sulfate proteoglycans during structural development of the lung

“…PGs are also thought to act as a reservoir for growth factor binding and regulate cell migration, as well as cell-cell and cell-matrix binding. Recent evidence indicates that CS-PGs play a critical role in the early growth and branching morphogenesis of the lung (26).…”