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EXTRACELLULAR MATRIX, CELL INTERACTIONS

Hepatocyte growth factor induces MDCK cell morphogenesis without causing loss of tight junction functional integrity

¹Department of Anatomy, Department of Biochemistry and Biophysics, and Cardiovascular Research Institute,University of California San Francisco School of Medicine, San Francisco, California 94143-2140; ²Department of Cell Biology, University of Arizona, Tucson, Arizona 85724-5044; and ³Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, Pennsylvania 15261

Submitted 3 September 2003 ; accepted in final form 19 October 2003

Hepatocyte growth factor (HGF) induces mitogenesis, motogenesis, and tubulogenesis of cultured Madin-Darby canine kidney (MDCK) epithelial cells. We report that in addition to these effects HGF stimulates morphogenesis of tight, polarized MDCK cell monolayers into pseudostratified layers without loss of tight junction (TJ) functional integrity. We tested TJ functional integrity during formation of pseudostratified layers. In response to HGF, the TJ 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 two- to threefold 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.

c-met protooncogene; transepithelial resistance; Madin-Darby canine kidney cell

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