Endothelial transcription factor KLF2 negatively regulates liver regeneration via induction of activin A

Abstract

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.

Tissue Repair in the Mouse Liver Following Acute Carbon Tetrachloride Depends on Injury‐Induced Wnt/β‐Catenin Signaling

“…Activation of the stroma‐derived factor 1 receptor chemokine (C‐X‐C motif) receptor 7 on liver sinusoidal endothelial cells promotes a proregenerative environment by inducing hepatocyte growth factor and Wnt2 production following injury . On the other hand, activation of the endothelial shear‐stress inducible transcription factor Krüppel‐like factor 2 upon injury inhibits hepatocyte proliferation, in part by promoting activin A production . Therefore, paracrine signaling derived from liver endothelial cells serves as a check‐and‐balance system in regulating injury‐induced hepatocyte proliferation.…”

“…Our functional studies also showed that in vivo blockade of endothelial Wnt secretion resulted in a dampening of the proliferative response following injury. Together, our findings are in line with previous reports that have highlighted the importance of endothelial cells as a paracrine signaling center for regulating hepatocyte proliferation following injury . Activation of the stroma‐derived factor 1 receptor chemokine (C‐X‐C motif) receptor 7 on liver sinusoidal endothelial cells promotes a proregenerative environment by inducing hepatocyte growth factor and Wnt2 production following injury .…”

Endothelial Notch activation reshapes the angiocrine of sinusoidal endothelia to aggravate liver fibrosis and blunt regeneration in mice

“…LSECs secrete Wnt ligands and HGF to support replenishment and functional zonation of hepatocytes under steady state . LSECs also contribute to LR . In mice, partial hepatoctemy (PHx)‐induced LR is accompanied by downregulation of angiopoietin‐2 (Angpt2) and transforming growth factor (TGF)‐β1, and increased secretion of Wnt2a and HGF through the VEGF receptor (VEGFR) 2/inhibitor of differentiation‐1 (Id1) pathway in LSECs, leading to enhanced hepatocyte proliferation on day 2 .…”

“…(18)(19)(20)(21) LSECs also contribute to LR. (14)(15)(16)(17)(22)(23)(24) In mice, partial hepatoctemy (PHx)-induced LR is accompanied by downregulation of angiopoietin-2 (Angpt2) and transforming growth factor (TGF)-b1, and increased secretion of Wnt2a and HGF through the VEGF receptor (VEGFR) 2/inhibitor of differentiation-1 (Id1) pathway in LSECs, leading to enhanced hepatocyte proliferation on day 2. (19,25) VEGFR2-Id1 signaling and re-expressed Angpt2 also promote LSEC-mediated angiogenesis on day 4 post-PHx to re-establish hepatic circulation.…”

Krüppel-like factor 2- induced microRNAs: implications for treatment of pulmonary hypertension

“…Inhibition of KLF2 expression correlates with increased PH severity in apelin knockout mice exposed to hypoxia (Chandra, Razavi et al, 2011). KLF2 overexpression improves pulmonary haemodynamics in hypoxic rats (Dungey, Deng et al, 2011), but can compromise liver function (Chen, Lu et al, 2014, Manavski, Abel et al, 2017, so other therapeutic approaches need to be identified. microRNAs (miRNAs) are small (~22 nucleotide long) non-coding RNAs that negatively regulate gene expression at the posttranscriptional level (Small & Olson, 2011).…”