title: 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.
authors.affiliation: Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe-University, 60590 Frankfurt, Germany.|German Center for Cardiovascular Research (DZHK), Partner Site RheinMain, 60590 Frankfurt, Germany.
authors.forename: Yosif
authors.initials: Y
authors.lastname: Manavski
authors.affiliation: Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225 Langen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Abel
authors.affiliation: Department of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), 69120 Heidelberg, Germany.|Interdisciplinary Research Center on Biology and Chemistry, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Junhao
authors.initials: J
authors.lastname: Hu
authors.affiliation: Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225 Langen, Germany.
authors.forename: Dina
authors.initials: D
authors.lastname: Kleinlützum
authors.affiliation: Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225 Langen, Germany.
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Buchholz
authors.affiliation: Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe-University, 60590 Frankfurt, Germany.|German Center for Cardiovascular Research (DZHK), Partner Site RheinMain, 60590 Frankfurt, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Belz
authors.affiliation: Department of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), 69120 Heidelberg, Germany.|Department of Vascular Biology and Tumor Angiogenesis, Medical Faculty Mannheim (CBTM), Heidelberg University, 68167 Mannheim, Germany.
authors.forename: Hellmut G
authors.initials: HG
authors.lastname: Augustin
authors.affiliation: Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe-University, 60590 Frankfurt, Germany.|German Center for Cardiovascular Research (DZHK), Partner Site RheinMain, 60590 Frankfurt, Germany.
authors.forename: Reinier A
authors.identifier: 0000-0001-7944-9748
authors.initials: RA
authors.lastname: Boon
authors.affiliation: Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe-University, 60590 Frankfurt, Germany; dimmeler@em.uni-frankfurt.de.|German Center for Cardiovascular Research (DZHK), Partner Site RheinMain, 60590 Frankfurt, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dimmeler
mesh_terms: D028341:Activins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D049109:Cell Proliferation; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics / Q000473:pathology; D008115:Liver Regeneration / Q000502:physiology*; D008822:Mice, Transgenic
chemical_list: C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; C422405:activin A; D028341:Activins; D002251:Carbon Tetrachloride
keywords: KLF2; activin A; vascular niche