α1-and α5-containing Laminins Regulate the Development of Bile Ducts via β1 Integrin Signals

Signals derived from basal lamina components are important for developing three-dimensional architecture of epithelial tissues. Laminins consisting of alpha, beta, and gamma subunits in basal lamina play pivotal roles in the formation and maintenance of epithelial tissue structures. However, it remains unclear which laminin iso-forms transmit signals and how epithelial cells receive them to regulate multiple developmental processes. In three-dimensional culture of a liver progenitor cell line, Hepatic Progenitor Cells Proliferating on Laminin (HPPL), the cells establish apicobasal polarity and form cysts with a central lumen. Neutralizing antibody against beta 1 integrin blocked the formation and maintenance of the cyst structure, indicating that beta 1 integrin signaling was necessary throughout the morphogenesis. Although the addition of alpha 1-containing laminin, a ligand of beta 1 integrin, induced cyst formation, it was dispensable for the maintenance of the cyst, suggesting that HPPL produces another ligand for beta 1 integrin to maintain the structure. Indeed, we found that HPPL produced alpha 5-containing laminin, and siRNA against laminin alpha 5 partially inhibited the lumen formation. In fetal liver, p75NTR(+) periportal fibroblasts and bile duct epithelial cells, known as cholangiocytes, expressed alpha 1- and alpha 5-containing laminins, respectively. In laminin alpha 5 KO liver, cholangiocytes normally emerged, but the number of bile ducts was decreased. These results suggest that alpha 1-containing laminin is sufficient as a component of the basal lamina for the commitment of bipotential liver progenitors to cholangiocytes and the apicobasal polarization, whereas alpha 5-containing laminin is necessary for the formation of mature duct structures. Thus, alpha 1- and alpha 5-containing laminins differentially regulate the sequential events to form epithelial tissues via beta 1 integrin signals.