Endothelial Transcription Factor KLF2 Negatively Regulates Liver Regeneration Via Induction of Activin A

Significance Regeneration of the liver after injury is essential for proper hepatic function. Endothelial cells contribute to liver homeostasis via paracrine interaction with hepatocytes. Here we show that endothelial-derived activin A, as a transcriptional target of Krüppel-like factor 2 (KLF2), negatively regulates hepatocyte proliferation and liver regeneration. This study highlights a mechanism by which endothelial cells control liver regeneration. Endothelial cells (ECs) not only are important for oxygen delivery but also act as a paracrine source for signals that determine the balance between tissue regeneration and fibrosis. Here we show that genetic inactivation of flow-induced transcription factor Krüppel-like factor 2 (KLF2) in ECs results in reduced liver damage and augmentation of hepatocyte proliferation after chronic liver injury by treatment with carbon tetrachloride (CCl4). Serum levels of GLDH3 and ALT were significantly reduced in CCl4-treated EC-specific KLF2-deficient mice. In contrast, transgenic overexpression of KLF2 in liver sinusoidal ECs reduced hepatocyte proliferation. KLF2 induced activin A expression and secretion from endothelial cells in vitro and in vivo, which inhibited hepatocyte proliferation. However, loss or gain of KLF2 expression did not change capillary density and liver fibrosis, but significantly affected hepatocyte proliferation. Taken together, the data demonstrate that KLF2 induces an antiproliferative secretome, including activin A, which attenuates liver regeneration.