The extracellular matrix in hepatic regeneration.

After partial hepatectomy, as a consequence of hepatocyte proliferation, cell clusters containing 10-14 hepatocytes are formed. These clusters are devoid of sinusoids and extracellular matrix; therefore, many hepatocytes are two to three cells removed from the vascular spaces. Four days after hepatectomy, Ito cells send delicate cell processes between the hepatocytes in the clusters. This "invasion" of the clusters coincides with the activation in Ito cells of genes encoding for several laminin chains. The penetration of Ito cells into the clusters is followed by fenestrated endothelial cells, and in this manner the normal hepatocyte vascular relationship is restored. As soon as the normal vascular structure is reestablished, the laminin genes are turned off. This chain of events is similar to the one taking place during hepatogenesis when continuous capillaries are converted into sinusoids. This similarity in hepatogenesis and regeneration suggests that the secreted laminin chains may be signals for the vascularization of the clusters by fenestrated sinusoids. During this process neither entactin nor laminin alpha chains are secreted. The vascularization of the regenerating clusters contrasts sharply to the vascularization of cirrhotic nodules. In the latter case, entactin and perhaps laminin alpha 1 chains are secreted, and the final result is the formation of basement membranes and continuous capillaries rather than fenestrated sinusoids. We suggest that entactin and specific laminin chains play a crucial role in determining the outcome of hepatic injury. Definition of the roles of entactin and laminin chains in vascularization and modulation of the endothelial phenotype will not only elucidate important aspects of regeneration, but may provide a better understanding of cirrhosis and even suggest therapeutic approaches.