Keratinocyte growth factor and embryonic rat lung morphogenesis.

Abstract

We examined possible roles of keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF) in lung morphogenesis. By polymerase chain reaction, transcripts for both KGF and its receptor were detected early (rat gestational days 16 and 14, respectively) and their abundance increased during lung morphogenesis. To evaluate possible role of KGF in lung morphogenesis, day 14 lung explants were cultured in Dulbecco's modified Eagle medium + 10% fetal calf serum for 1 to 4 days in the presence (5-50 ng/ml) or absence of KGF (control). KGF (at 25 and 50 ng/ml) induced a marked reduction in the number of terminal branches and destination of the distal epithelium into cyst-like structures. These effects of exogenous KGF were progressively diminished by increasing concentrations of anti-KGF (2-16 micrograms/ml). Electron microscopic examination revealed that the epithelial cells of the cystic structures contained lamellar bodies, and were therefore type II cells and/or their progenitors. Northern blot analysis showed higher expression of surfactant protein C (SP-C) mRNA (a marker for alveolar epithelial type II cells) in KGF-treated fetal lungs. In situ hybridization of the KGF-treated lungs revealed that the SP-C mRNA-expressing cells were arranged distally in the form of linear arrays, a pattern distinctly different from that in control lungs. Acidic fibroblast growth factor, which also binds KGF receptors, in the presence of heparin mimicked the effect of KGF on branching. Transforming growth factor-beta(1) (TGF-beta 1) inhibited branching of fetal lungs in culture, and this effect dominated over that induced by KGF. Blocking of endogenous HGF with antibodies or addition of HGF to cultures of fetal lung explants had no significant effect on branching or growth. In conclusion, KGF markedly influences branching, and epithelial growth, differentiation, and patterning during lung morphogenesis.

Generation of multiciliated cells in functional airway epithelia from human induced pluripotent stem cells

“…FGF10 is expressed in the lung mesenchyme and is a critical regulator of endoderm proliferation and lung bud morphogenesis (14,15). FGF7 [also known as keratinocyte growth factor (KGF)] can also be detected early in lung development and is known to interact with other factors to regulate epithelial branching and epithelial proliferation (16,17). A combination of these factors in addition to the careful regulation of BMP4 expression can induce expression of the transcription factor NK2 homeobox 1 (NKx2.1) and push differentiation toward the ventral anterior endoderm (6,18,19).…”

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

“…Furthermore, mice harboring a hypomorphic FGF10 allele display a decrease in embryonic lung branching, indicating that FGF10 is required for secondary branching (Mailleux et al, 2005). 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).…”

Keratinocyte growth factor-induced proliferation of rat airway epithelium is restricted to Clara cellsin vivo

“…rHuKGF induces proliferation of bronchial epithelial cells in primary culture and bronchial cell lines such as Calu-3, BEAS-2B and 4MBR-5 cells [22,23]. Polymerase chain reaction and northern blot analyses demonstrated the presence of transcripts of the KGF receptor in foetal and adult rat lung [24], as well as in primary cultures of normal human bronchial epithelial cells and in the bronchial epithelial cell line BEAS-2B [23]. Transgenic mice that express human KGF under the control of the Clara cell secretory protein 10 kD (CC10) promoter upon doxycycline administration exhibited marked transient airway epithelial hyperplasia with thickening of the columnar epithelium and frequent transitions to a pseudostratified epithelium [8].…”