Role and Regulation of PDGFRα Signaling in Liver Development and Regeneration

Aberrant platelet-derived growth factor receptor-α (PDGFRα) signaling is evident in a subset of hepatocellular cancers (HCCs). However, its role and regulation in hepatic physiology remains elusive. In the current study, we examined PDGFRα signaling in liver development and regeneration. We identified notable PDGFRα activation in hepatic morphogenesis that, when interrupted by PDGFRα-blocking antibody, led to decreased hepatoblast proliferation and survival in embryonic liver cultures. We also identified temporal PDGFRα overexpression, which is regulated by epidermal growth factor (EGF) and tumor necrosis factor α, and its activation at 3 to 24 hours after partial hepatectomy. Through generation of hepatocyte-specific PDGFRA knockout (KO) mice that lack an overt phenotype, we show that absent PDGFRα compromises extracelluar signal-regulated kinases and AKT activation 3 hours after partial hepatectomy, which, however, is alleviated by temporal compensatory increases in the EGF receptor (EGFR) and the hepatocyte growth factor receptor (Met) expression and activation along with rebound activation of extracellular signal-regulated kinases and AKT at 24 hours. These untimely increases in EGFR and Met allow for normal hepatocyte proliferation at 48 hours in KO, which, however, are aberrantly prolonged up to 72 hours. Intriguingly, such compensation also was visible in primary KO hepatocyte cultures but not in HCC cells after siRNA-mediated PDGFRα knockdown. Thus, temporal activation of PDGFRα in liver development is important in hepatic morphogenesis. In liver regeneration, despite increased signaling, PDGFRα is dispensable owing to EGFR and Met compensation, which is unique to normal hepatocytes but not HCC cells. Aberrant platelet-derived growth factor receptor-α (PDGFRα) signaling is evident in a subset of hepatocellular cancers (HCCs). However, its role and regulation in hepatic physiology remains elusive. In the current study, we examined PDGFRα signaling in liver development and regeneration. We identified notable PDGFRα activation in hepatic morphogenesis that, when interrupted by PDGFRα-blocking antibody, led to decreased hepatoblast proliferation and survival in embryonic liver cultures. We also identified temporal PDGFRα overexpression, which is regulated by epidermal growth factor (EGF) and tumor necrosis factor α, and its activation at 3 to 24 hours after partial hepatectomy. Through generation of hepatocyte-specific PDGFRA knockout (KO) mice that lack an overt phenotype, we show that absent PDGFRα compromises extracelluar signal-regulated kinases and AKT activation 3 hours after partial hepatectomy, which, however, is alleviated by temporal compensatory increases in the EGF receptor (EGFR) and the hepatocyte growth factor receptor (Met) expression and activation along with rebound activation of extracellular signal-regulated kinases and AKT at 24 hours. These untimely increases in EGFR and Met allow for normal hepatocyte proliferation at 48 hours in KO, which, however, are aberrantly prolonged up to 72 hours. Intriguingly, such compensation also was visible in primary KO hepatocyte cultures but not in HCC cells after siRNA-mediated PDGFRα knockdown. Thus, temporal activation of PDGFRα in liver development is important in hepatic morphogenesis. In liver regeneration, despite increased signaling, PDGFRα is dispensable owing to EGFR and Met compensation, which is unique to normal hepatocytes but not HCC cells. Platelet-derived growth factor receptor-α (PDGFRα) is a receptor tyrosine kinase (RTK) expressed chiefly on mesenchymal cells including fibroblasts and smooth muscle cells.1Andrae J. Gallini R. Betsholtz C. Role of platelet-derived growth factors in physiology and medicine.Genes Dev. 2008; 22: 1276-1312Crossref PubMed Scopus (1739) Google Scholar, 2Claesson-Welsh L. Platelet-derived growth factor receptor signals.J Biol Chem. 1994; 269: 32023-32026Abstract Full Text PDF PubMed Google Scholar, 3Hoch R.V. Soriano P. Roles of PDGF in animal development.Development. 2003; 130: 4769-4784Crossref PubMed Scopus (458) Google Scholar In addition, it also is expressed on other cell types including neurons and endothelial cells. Its activation is elicited by PDGFs, especially AA and CC, which induce effects on growth, motility, and survival, thus regulating the function of these cells.4Heldin C.H. Ostman A. Ronnstrand L. Signal transduction via platelet-derived growth factor receptors.Biochim Biophys Acta. 1998; 1378: F79-F113PubMed Google Scholar After engagement, PDGFRα tyrosine phosphorylation can occur at diverse residues to elicit activation of distinct downstream effectors. Specifically relevant are downstream activation of phosphatidylinositide 3-kinases and AKT, as well as ERK signaling.5Franke T.F. Yang S.I. Chan T.O. Datta K. Kazlauskas A. Morrison D.K. Kaplan D.R. Tsichlis P.N. The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase.Cell. 1995; 81: 727-736Abstract Full Text PDF PubMed Scopus (1829) Google Scholar, 6Heldin C.H. Westermark B. Mechanism of action and in vivo role of platelet-derived growth factor.Physiol Rev. 1999; 79: 1283-1316Crossref PubMed Scopus (1996) Google Scholar, 7Wu E. Palmer N. Tian Z. Moseman A.P. Galdzicki M. Wang X. Berger B. Zhang H. Kohane I.S. Comprehensive dissection of PDGF-PDGFR signaling pathways in PDGFR genetically defined cells.PLoS One. 2008; 3: e3794Crossref PubMed Scopus (93) Google Scholar Based on gene array studies using RNA from livers at different stages of gestational development in mice, our laboratory previously reported that PDGFRα expression was at its highest during early stages, especially around embryonic day 10 (E10) to E12. This coincided with the time of peak hepatoblast proliferation, after which the PDGFRα levels gradually decreased to low levels.8Stock P. Monga D. Tan X. Micsenyi A. Loizos N. Monga S.P. Platelet-derived growth factor receptor-alpha: a novel therapeutic target in human hepatocellular cancer.Mol Cancer Ther. 2007; 6: 1932-1941Crossref PubMed Scopus (95) Google Scholar In an adult liver, only low PDGFRα expression is evident, however, its expression is increased dramatically in a significant subset of hepatocellular carcinomas (HCCs) and its inhibition in human HCC cells leads to reduced tumor cell proliferation and viability.8Stock P. Monga D. Tan X. Micsenyi A. Loizos N. Monga S.P. Platelet-derived growth factor receptor-alpha: a novel therapeutic target in human hepatocellular cancer.Mol Cancer Ther. 2007; 6: 1932-1941Crossref PubMed Scopus (95) Google Scholar, 9Oseini A.M. Roberts L.R. PDGFRalpha: a new therapeutic target in the treatment of hepatocellular carcinoma?.Expert Opin Ther Targets. 2009; 13: 443-454Crossref PubMed Scopus (39) Google Scholar It is thus pertinent to investigate further the role and regulation of PDGFRα in liver growth. In the current study, we investigated the role of this RTK in two major models of hepatic growth. Liver development was characterized by regulated hepatic growth and differentiation of bipotential progenitors or hepatoblasts that compose the early hepatic bud at approximately E9.5 in mice showed temporal proliferation and resistance to apoptosis, eventually leading to expansion of the primitive liver bud.10Si-Tayeb K. Lemaigre F.P. Duncan S.A. Organogenesis and development of the liver.Dev Cell. 2010; 18: 175-189Abstract Full Text Full Text PDF PubMed Scopus (566) Google Scholar During the later stages of hepatic morphogenesis, additional molecular cues direct the differentiation of hepatic progenitors to either hepatocytes or cholangiocytes. Similarly, liver regeneration (LR) after partial hepatectomy (PHx) is a widely used model to study the importance of signaling molecules in hepatic growth. The process of an cell types and signaling N. Liver PubMed Scopus Google Scholar, Liver 2007; PubMed Scopus Google Scholar The and molecular for show significant to allow of the process as by studies in models or after In the current study, we used livers from gestational stages to the expression of PDGFRα in hepatoblasts and show its activation during early hepatic development owing to the of its using previously characterized embryonic liver S.P. Monga Tan X. K. P. studies in embryonic liver role in proliferation, apoptosis, and 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, S.P. A. B. L. of hepatic and cells embryonic liver Google Scholar we with PDGFRα signaling the of a characterized PDGFRα P. M. J. C. Loizos N. platelet-derived growth factor receptor a therapeutic target of tumor cell expression in Cancer Ther. PubMed Scopus Google Scholar to its role in hepatoblast proliferation and We also show that adult hepatocytes at low However, after we temporal and activation of PDGFRα and we its regulation during this Through generation of hepatocyte-specific PDGFRα knockout mice by Soriano P. for in of and 2003; 130: PubMed Scopus Google Scholar and C. in liver by an with PubMed Scopus Google Scholar we show that its from hepatocytes is well to as a of compensatory increases in the expression and activation of epidermal growth factor receptor (EGFR) and the hepatocyte growth factor is unique to but not growth, PDGFRα an therapeutic Thus, we show an important role of PDGFRα in of liver growth and to and mice on a from mice to mice and the a and to the The mice with the and of are to as or KO mice and other including and or are to as on mice the of the and the and at the of mice used to from the of gestational liver from was by dissection using an and as an as S.P. Monga Tan X. K. P. studies in embryonic liver role in proliferation, apoptosis, and 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, S.P. A. B. L. of hepatic and cells embryonic liver Google Scholar livers in and livers in the of a PDGFRα-blocking antibody, which was a from Loizos and reported to signaling at this P. M. J. C. Loizos N. platelet-derived growth factor receptor a therapeutic target of tumor cell expression in Cancer Ther. PubMed Scopus Google Scholar for 72 hours with or the 24 hours. in for and mice also used to from the and for in for to KO and to as J. C. Monga S.P. liver regeneration and in mice 2010; PubMed Scopus Google Scholar, X. J. B. Monga S.P. of its role in liver growth and Full Text Full Text PDF PubMed Scopus Google Scholar 3 at time after as in the and in and from or KO mice along with and was at 3 to 10 for from these mice for from KO and with in a new and livers and at also in to used for or in for livers from from to day and and 10 for to 3 for to for in from liver and from cell cultures and from or livers in for by as J. C. Monga S.P. liver regeneration and in mice 2010; PubMed Scopus Google Scholar After the to using The for a protein was the KO and and for by the and a was used for the EGFR PDGFRα Met and from and from from and and of or of and and from RNA was from livers using as the RNA from was with the for with an treatment In addition, of RNA from and KO livers to of along with and the used for The for in to The was used for the with was used for and the The was with a gene for and only used for The using from to for hepatocyte cell or as J. C. Monga S.P. liver regeneration and in mice 2010; PubMed Scopus Google Scholar hepatocytes using an in at a of and KO livers after for by the with a of for 10 in in and in for PDGFRα and in for by in and at and in for in in and in for in and a a hepatoblast cell was a from of and was differentiation for as bipotential differentiation of embryonic hepatoblasts in Google Scholar cells in with EGF hepatocyte growth factor tumor necrosis factor and 3 EGFR for 24 hours. and in and by cells also used for of in in with for and with PDGFRA or for by the of with at 24 hours and 48 hours for was used to hepatocytes from and KO mice for hepatocyte as J. C. Monga S.P. liver regeneration and in mice 2010; PubMed Scopus Google Scholar hepatocytes from KO and mice for hours in by hepatocyte growth and epidermal growth factor for 24 and for in for P. Monga D. Tan X. Micsenyi A. Loizos N. Monga S.P. Platelet-derived growth factor receptor-alpha: a novel therapeutic target in human hepatocellular cancer.Mol Cancer Ther. 2007; 6: 1932-1941Crossref PubMed Scopus (95) Google Scholar we used from livers from stages in mice to for PDGFRα and PDGFRα is expressed at levels in and with a in protein expression also was expressed PDGFRα was expressed in the cell of liver, we for PDGFRα and a for hepatoblasts and and of PDGFRα was evident in cells at the we examined its with but not at further the expression of PDGFRα in we a hepatoblast cell which showed PDGFRα expression with livers we for the of that for PDGFRα during early was the at early stages, at and however, levels to expressed liver PDGFRα signaling is during hepatic we cell for phosphorylation of PDGFRα at We identified to in at and at the to stages, showed only phosphorylation at the of the downstream signaling at the we examined the of phosphatidylinositide and AKT signaling these to regulated by especially when are at and other as T.F. Yang S.I. Chan T.O. Datta K. Kazlauskas A. Morrison D.K. Kaplan D.R. Tsichlis P.N. The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase.Cell. 1995; 81: 727-736Abstract Full Text PDF PubMed Scopus (1829) Google Scholar phosphatidylinositide and AKT levels during hepatic development after and levels in the liver at the to stages, by a at later stages with the of PDGFRα and its that PDGFRα and expression activation of this RTK to to hepatic morphogenesis. further investigate the role of PDGFRα signaling during early liver we used embryonic liver cultures and PDGFRα-blocking by and P. M. J. C. Loizos N. platelet-derived growth factor receptor a therapeutic target of tumor cell expression in Cancer Ther. PubMed Scopus Google Scholar from and in the of and as with for 72 hours showed hepatoblasts when examined by for the of reduced we the cultures for proliferation and in cell The embryonic livers showed dramatically cells in the as by for decreased cell proliferation after 72 hours of PDGFRα these livers showed a in the of which is of Thus, on the expression of PDGFRα in it is that PDGFRα signaling is of the molecular pathways in hepatoblast proliferation and and in liver growth during vivo hepatic morphogenesis. PDGFRα a role in model of regulated hepatic growth, we its expression during the process of after especially hepatocytes are to during this M. Liver Google Scholar We examined from livers at different after in the PDGFRα protein was evident at 24 hours during in its expression was in from this PDGFRα expression was examined in livers from mice at 24 hours after showed a in PDGFRα expression at this time during other of PDGFRα not increased phosphorylation at was in livers from 3 to the such an to an early in was a notable in and which the role of PDGFRα in regulating the of these important of the of protein expression of we examined expression and identified a in in livers as with the molecular of increased PDGFRα expression after we examined the effects of growth factors and that are to of Liver 2007; PubMed Scopus Google Scholar human cell was for 24 hours with hepatocyte growth and as in and and cells for in PDGFRα protein expression by EGF treatment increases in PDGFRα which was by treatment of cells with an EGFR treatment also led to a notable in Thus, EGF and induce PDGFRα expression during early the function of PDGFRα during we hepatocyte-specific KO in a normal and not show was by the of a PDGFRα and by The livers from KO and livers showed in liver to KO and mice and showed and KO KO livers used for and in PDGFRα was evident in KO by as with the livers in or PDGFRα such as or in the KO in the livers from and was significant expression of PDGFRα in KO we PDGFRα by in KO and PDGFRα to expressed in cells in the KO livers as with the gene from hepatocytes also showed an in PDGFRA expression in KO which was in or KO and mice to peak PDGFRα expression was at 24 we these levels at this time in KO KO livers lack in PDGFRα at 24 hours after as with which that the in PDGFRα protein is in the cell at 24 hours during PDGFRα expression is dramatically in KO mice and is evident in show in hepatocytes The KO mice up after for to a in the KO at approximately 24 hours after however, KO mice from and from at later time Based on the role of PDGFRα in liver development and in P. Monga D. Tan X. Micsenyi A. Loizos N. Monga S.P. Platelet-derived growth factor receptor-alpha: a novel therapeutic target in human hepatocellular cancer.Mol Cancer Ther. 2007; 6: 1932-1941Crossref PubMed Scopus (95) Google Scholar we hepatocyte proliferation the two of during We that PDGFRα and activation at 24 hours of the signaling regulating hepatocyte proliferation during which approximately 48 hours after in mice, However, we and of hepatocytes in the as by for at 48 hours in KO and livers and Intriguingly, at 72 was in KO mice to hepatocytes in the and However, further growth was evident at later stages and KO and mice a in hepatic at after of a lack of in cell proliferation in KO mice at 48 hours and in a proliferation at normal levels at 72 we compensatory for this We on 24 to 72 which the activation of the cell and of cell proliferation during the liver for PDGF signaling, which was for in and which to for PDGFRα in E. Palmer N. Tian Z. Moseman A.P. Galdzicki M. Wang X. Berger B. Zhang H. Kohane I.S. Comprehensive dissection of PDGF-PDGFR signaling pathways in PDGFR genetically defined cells.PLoS One. 2008; 3: e3794Crossref PubMed Scopus (93) Google Scholar We investigated expression for such as EGFR and which are major of and also are with hepatocyte Liver 2007; PubMed Scopus Google Scholar showed increased levels of EGFR and Met protein at 24 hours in the KO livers after to an approximately in EGFR and a in Met the levels at 24 hours and the of RTK signaling, we for phosphorylation of EGFR and levels of and in of PDGFRα activation at 24 hours after in KO livers Thus, the increases in EGFR and Met expression and at 24 hours hepatocyte proliferation at 48 hours in PDGFRα KO that is with but the eventually at 72 hours when proliferation in KO hepatocytes to and EGFR and Met are on PDGFRα we the of PDGFRα in primary which by from and KO mice and for 24 hours as in and notable in EGFR and Met expression was evident in KO hepatocytes as with hepatocytes after 24 hours in we the of PDGFRα in cells on EGFR and Met After of PDGFRα but not for either 24 hours or 48 a PDGFRα in cells However, in either EGFR or Met protein levels at the that only primary hepatocytes but not HCC cells the to the expression of the two on PDGFRα a growth factor receptor for mesenchymal is expressed in human HCC cells and is to induce cell J. Gallini R. Betsholtz C. Role of platelet-derived growth factors in physiology and medicine.Genes Dev. 2008; 22: 1276-1312Crossref PubMed Scopus (1739) Google Scholar, 3Hoch R.V. Soriano P. Roles of PDGF in animal development.Development. 2003; 130: 4769-4784Crossref PubMed Scopus (458) Google Scholar, C.H. Ostman A. Ronnstrand L. Signal transduction via platelet-derived growth factor receptors.Biochim Biophys Acta. 1998; 1378: F79-F113PubMed Google Scholar, 6Heldin C.H. Westermark B. Mechanism of action and in vivo role of platelet-derived growth factor.Physiol Rev. 1999; 79: 1283-1316Crossref PubMed Scopus (1996) Google Scholar, P. Monga D. Tan X. Micsenyi A. Loizos N. Monga S.P. Platelet-derived growth factor receptor-alpha: a novel therapeutic target in human hepatocellular cancer.Mol Cancer Ther. 2007; 6: 1932-1941Crossref PubMed Scopus (95) Google Scholar, 9Oseini A.M. Roberts L.R. PDGFRalpha: a new therapeutic target in the treatment of hepatocellular carcinoma?.Expert Opin Ther Targets. 2009; 13: 443-454Crossref PubMed Scopus (39) Google Scholar the role and regulation of PDGFRα in normal liver growth, especially in cells of the liver, we investigated its in liver development and in a model of we reported the highest expression of the PDGFRα gene in the stages of hepatic which was identified by P. Monga D. Tan X. Micsenyi A. Loizos N. Monga S.P. Platelet-derived growth factor receptor-alpha: a novel therapeutic target in human hepatocellular cancer.Mol Cancer Ther. 2007; 6: 1932-1941Crossref PubMed Scopus (95) Google Scholar In the current study, we that hepatoblasts and is a of hepatoblasts and hepatocytes during hepatic C. L. 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The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase.Cell. 1995; 81: 727-736Abstract Full Text PDF PubMed Scopus (1829) Google Scholar However, of PDGFRα in hepatocytes during was with PDGFRα expression and signaling during liver development is temporal and is to the early stages of hepatic development Based on the in it is that of PDGFRα at this time remains and decreased proliferation and increased in embryonic liver cultures. The levels of PDGFRα with hepatic development such that adult livers low expression of The lack of overt in hepatocyte-specific PDGFRα in at to after C. in liver by an with PubMed Scopus Google Scholar a time when PDGFRα is expressed at low levels and is not The in PDGFRα activation and expression at 3 to 24 hours after is novel was an in AKT and ERK signaling that is to important in and also to downstream of PDGFRα E. Palmer N. Tian Z. Moseman A.P. Galdzicki M. Wang X. Berger B. Zhang H. 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