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Title: Integrin-linked kinase (ILK) modulates wound healing through regulation of hepatocyte growth factor (HGF)

Abstract

Integrin-linked kinase (ILK) is an intracellular effector of cell-matrix interactions and regulates many cellular processes, including growth, proliferation, survival, differentiation, migration, invasion and angiogenesis. The present work analyzes the role of ILK in wound healing in adult animals using a conditional knock-out of the ILK gene generated with the tamoxifen-inducible Cre-lox system (CRE-LOX mice). Results show that ILK deficiency leads to retarded wound closure in skin. Intracellular mechanisms involved in this process were analyzed in cultured mouse embryonic fibroblast (MEF) isolated from CRE-LOX mice and revealed that wounding promotes rapid activation of phosphatidylinositol 3-kinase (PI3K) and ILK. Knockdown of ILK resulted in a retarded wound closure due to a decrease in cellular proliferation and loss of HGF protein expression during the healing process, in vitro and in vivo. Alterations in cell proliferation and wound closure in ILK-deficient MEF or mice could be rescued by exogenous administration of human HGF. These data demonstrate, for the first time, that the activation of PI3K and ILK after skin wounding are critical for HGF-dependent tissue repair and wound healing. -- Highlights: Black-Right-Pointing-Pointer ILK deletion results in decreased HGF expression and delayed scratch wound repair. Black-Right-Pointing-Pointer PI3K/ILK/AKT pathway signals through HGF to regulate wound healing.more » Black-Right-Pointing-Pointer An ILK-dependent increase in HGF expression is responsible for wound healing in vivo. Black-Right-Pointing-Pointer ILK-KO mice are used to confirm the requirement for ILK function in wound healing. Black-Right-Pointing-Pointer Human HGF treatment restores delayed wound closure in vitro and in vivo.« less

Authors:
; ;  [1];  [2];  [3];  [2];  [4];  [2];  [5];  [2];  [6];  [2]
  1. Department of Physiology, University of Alcala, Alcala de Henares, Madrid (Spain)
  2. RedinRen; Spain
  3. Nephrology Unit, IDIBELL, Hospital de Bellvitge, Barcelona (Spain)
  4. Department of Pathology, University of Granada (Spain)
  5. Department of Integrative Oncology, BC Cancer Research Center, Vancouver, BC (Canada)
  6. Nephrology Unit, Hospital Universitario Principe de Asturias, Alcala de Henares, Madrid (Spain)
Publication Date:
OSTI Identifier:
22212617
Resource Type:
Journal Article
Journal Name:
Experimental Cell Research
Additional Journal Information:
Journal Volume: 318; Journal Issue: 19; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0014-4827
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANGIOGENESIS; ANIMAL TISSUES; CELL PROLIFERATION; ERRORS; FIBROBLASTS; GROWTH FACTORS; HEALING; IN VITRO; IN VIVO; MICE; RNA; SKIN; TAMOXIFEN; WOUNDS

Citation Formats

Serrano, Isabel, Diez-Marques, Maria L., Rodriguez-Puyol, Manuel, Investigacion Renal Cooperativa, Red de, Instituto Reina Sofia de Investigacion Nefrologica, Herrero-Fresneda, Inmaculada, Investigacion Renal Cooperativa, Red de, Garcia del Moral, Raimundo, Investigacion Renal Cooperativa, Red de, Dedhar, Shoukat, Ruiz-Torres, Maria P., E-mail: mpiedad.ruiz@uah.es, Investigacion Renal Cooperativa, Red de, Instituto Reina Sofia de Investigacion Nefrologica, Rodriguez-Puyol, Diego, Investigacion Renal Cooperativa, Red de, and Instituto Reina Sofia de Investigacion Nefrologica. Integrin-linked kinase (ILK) modulates wound healing through regulation of hepatocyte growth factor (HGF). United States: N. p., 2012. Web. doi:10.1016/J.YEXCR.2012.08.001.
Serrano, Isabel, Diez-Marques, Maria L., Rodriguez-Puyol, Manuel, Investigacion Renal Cooperativa, Red de, Instituto Reina Sofia de Investigacion Nefrologica, Herrero-Fresneda, Inmaculada, Investigacion Renal Cooperativa, Red de, Garcia del Moral, Raimundo, Investigacion Renal Cooperativa, Red de, Dedhar, Shoukat, Ruiz-Torres, Maria P., E-mail: mpiedad.ruiz@uah.es, Investigacion Renal Cooperativa, Red de, Instituto Reina Sofia de Investigacion Nefrologica, Rodriguez-Puyol, Diego, Investigacion Renal Cooperativa, Red de, & Instituto Reina Sofia de Investigacion Nefrologica. Integrin-linked kinase (ILK) modulates wound healing through regulation of hepatocyte growth factor (HGF). United States. doi:10.1016/J.YEXCR.2012.08.001.
Serrano, Isabel, Diez-Marques, Maria L., Rodriguez-Puyol, Manuel, Investigacion Renal Cooperativa, Red de, Instituto Reina Sofia de Investigacion Nefrologica, Herrero-Fresneda, Inmaculada, Investigacion Renal Cooperativa, Red de, Garcia del Moral, Raimundo, Investigacion Renal Cooperativa, Red de, Dedhar, Shoukat, Ruiz-Torres, Maria P., E-mail: mpiedad.ruiz@uah.es, Investigacion Renal Cooperativa, Red de, Instituto Reina Sofia de Investigacion Nefrologica, Rodriguez-Puyol, Diego, Investigacion Renal Cooperativa, Red de, and Instituto Reina Sofia de Investigacion Nefrologica. Thu . "Integrin-linked kinase (ILK) modulates wound healing through regulation of hepatocyte growth factor (HGF)". United States. doi:10.1016/J.YEXCR.2012.08.001.
@article{osti_22212617,
title = {Integrin-linked kinase (ILK) modulates wound healing through regulation of hepatocyte growth factor (HGF)},
author = {Serrano, Isabel and Diez-Marques, Maria L. and Rodriguez-Puyol, Manuel and Investigacion Renal Cooperativa, Red de and Instituto Reina Sofia de Investigacion Nefrologica and Herrero-Fresneda, Inmaculada and Investigacion Renal Cooperativa, Red de and Garcia del Moral, Raimundo and Investigacion Renal Cooperativa, Red de and Dedhar, Shoukat and Ruiz-Torres, Maria P., E-mail: mpiedad.ruiz@uah.es and Investigacion Renal Cooperativa, Red de and Instituto Reina Sofia de Investigacion Nefrologica and Rodriguez-Puyol, Diego and Investigacion Renal Cooperativa, Red de and Instituto Reina Sofia de Investigacion Nefrologica},
abstractNote = {Integrin-linked kinase (ILK) is an intracellular effector of cell-matrix interactions and regulates many cellular processes, including growth, proliferation, survival, differentiation, migration, invasion and angiogenesis. The present work analyzes the role of ILK in wound healing in adult animals using a conditional knock-out of the ILK gene generated with the tamoxifen-inducible Cre-lox system (CRE-LOX mice). Results show that ILK deficiency leads to retarded wound closure in skin. Intracellular mechanisms involved in this process were analyzed in cultured mouse embryonic fibroblast (MEF) isolated from CRE-LOX mice and revealed that wounding promotes rapid activation of phosphatidylinositol 3-kinase (PI3K) and ILK. Knockdown of ILK resulted in a retarded wound closure due to a decrease in cellular proliferation and loss of HGF protein expression during the healing process, in vitro and in vivo. Alterations in cell proliferation and wound closure in ILK-deficient MEF or mice could be rescued by exogenous administration of human HGF. These data demonstrate, for the first time, that the activation of PI3K and ILK after skin wounding are critical for HGF-dependent tissue repair and wound healing. -- Highlights: Black-Right-Pointing-Pointer ILK deletion results in decreased HGF expression and delayed scratch wound repair. Black-Right-Pointing-Pointer PI3K/ILK/AKT pathway signals through HGF to regulate wound healing. Black-Right-Pointing-Pointer An ILK-dependent increase in HGF expression is responsible for wound healing in vivo. Black-Right-Pointing-Pointer ILK-KO mice are used to confirm the requirement for ILK function in wound healing. Black-Right-Pointing-Pointer Human HGF treatment restores delayed wound closure in vitro and in vivo.},
doi = {10.1016/J.YEXCR.2012.08.001},
journal = {Experimental Cell Research},
issn = {0014-4827},
number = 19,
volume = 318,
place = {United States},
year = {2012},
month = {11}
}