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1 Cell Biology and Anatomy, University of Arizona School of Medicine, Tucson, AZ, USA
2 Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, PA, USA
3 Department of Anatomy and Department of Biochemistry and Biophysics, University of California School of Medicine, San Francisco, CA, USA
* To whom correspondence should be addressed. E-mail: apollack{at}u.arizona.edu.
Hepatocyte growth factor (HGF) induces mitogenesis, motogenesis, and tubulogenesis of cultured MDCK epithelial cells. We report that in addition to these effects HGF stimulated morphogenesis of tight, polarized MDCK cell monolayers into pseudostratified layers without loss of tight junction (TJ) functional integrity. We tested the functional integrity of TJs during the formation of pseudostratified layers. In response to HGF, the tight junction marker ZO-1 remained in morphologically complete rings, and functional barriers to paracellular diffusion of ruthenium red were maintained in pseudostratified layers. Transepithelial resistance (TER) increased transiently 2-3-fold during the morphogenetic transition from monolayers to pseudostratified layers and then declined to baseline levels once pseudostratified layers were formed. In MDCK cells expressing the trk/met chimera, both HGF and NGF at concentrations of 2.5 ng/ml induced scattering. However, 2.5 ng/ml HGF did not affect TER. The peak effect of HGF on TER was at a concentration of 100 ng/ml. In contrast, NGF at concentrations as high as 25 µg/ml had no effect on TER or pseudostratified layer morphogenesis of trk/met-expressing cultures. These results suggest that altered presentation of the stimulus, such as through HGF interaction with low-affinity sites, may change the downstream signaling response. In addition, our results demonstrate that HGF stimulates pseudostratified layer morphogenesis while inducing an increase in TER and maintaining the overall tightness of the epithelial layer. Stimulation of epithelial cell movements by HGF without loss of functional TJs may be important for maintaining epithelial integrity during morphogenetic events such as formation of pseudostratified epithelia, organ regeneration and tissue repair.
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