The authors do not elaborate on other possible mechanisms, but given the rapidity of the effect whereby the LSECs induce a maximal proliferative response in the hepatocytes within 2 days of hepatectomy, one possibility

is that Daporinad cell line it acts through a stress response that is induced through the large reduction in liver function which must accompany a 70% reduction in liver size. Indeed, there are a number of metabolic sensors that activate an angiogenic response,4 with many acting through VEGF. Previous studies have shown a significant up-regulation of VEGF5 within 24 hours after hepatectomy, and because the LSECs express VEGFR2, one could postulate this results in activation of the LSECs, leading to the release of signals that result in hepatocyte proliferation. In support of the idea that LSECs are activated through a stress response pathway is the spectrum of genes identified as being altered in the regenerative liver, a large number of which are involved in a stress response leading to a DNA damage response. Genes such as RAD51 and RAD54 (RecA homologs, E. coli) and their associated proteins were highly up-regulated in the array. These are members of genes associated

with machinery for the detection and repair of DNA double-stranded breaks, part of the DNA damage response. Also up-regulated were a number of S100 binding proteins, proteins known to regulate inflammation and to confer protection from oxidative damage. Hydroxychloroquine In addition, a large number of genes involved in cell cycle control were highly increased. Finally, this study demonstrates the requirement for LSEC–hepatocyte interactions in the response to injury. In general, the endothelium is heavily dependent on juxtacrine signals (i.e., ones delivered by direct cell contact) in contrast to the endocrine and hematopoietic systems. These signals can be delivered through cells such as smooth muscle cells, pericytes, glial cells in the brain, or astrocytes in the eye. In the liver, previous studies have shown that the maintenance of

the specialized phenotype of both the LSEC and the hepatocyte requires cell-to-cell contact. Isolated LSECs show a loss of their characteristic find more features within 24 hours, such as rounded cell shape and fenestrations, indicating that normal LSEC differentiation in vivo depends on the hepatic microenvironment, the nature of which has not been adequately addressed. Three-dimensional coculture also improves hepatocyte function.6 The study further shows that cellular contact between the activated LSECs and hepatocytes is also essential for the induction of proliferation of the hepatocytes. Wnt2 (Wnts are secreted factors that act through the Frizzled receptors and are involved in cell fate determination and progenitor cell proliferation) and hepatocyte growth factor were identified as crucial factors in driving the proliferative response of hepatocytes.