Fibrotic myofibroblasts manifest genome-wide derangements of translational control.
BACKGROUND
As a group, fibroproliferative disorders of the lung, liver, kidney, heart, vasculature and integument are common, progressive and refractory to therapy. They can emerge following toxic insults, but are frequently idiopathic. Their enigmatic propensity to resist therapy and progress to organ failure has focused attention on the myofibroblast-the primary effector of the fibroproliferative response. We have recently shown that aberrant beta 1 integrin signaling in fibrotic fibroblasts results in defective PTEN function, unrestrained Akt signaling and subsequent activation of the translation initiation machinery. How this pathological integrin signaling alters the gene expression pathway has not been elucidated.


RESULTS
Using a systems approach to study this question in a prototype fibrotic disease, Idiopathic Pulmonary Fibrosis (IPF); here we show organized changes in the gene expression pathway of primary lung myofibroblasts that persist for up to 9 sub-cultivations in vitro. When comparing IPF and control myofibroblasts in a 3-dimensional type I collagen matrix, more genes differed at the level of ribosome recruitment than at the level of transcript abundance, indicating pathological translational control as a major characteristic of IPF myofibroblasts. To determine the effect of matrix state on translational control, myofibroblasts were permitted to contract the matrix. Ribosome recruitment in control myofibroblasts was relatively stable. In contrast, IPF cells manifested large alterations in the ribosome recruitment pattern. Pathological studies suggest an epithelial origin for IPF myofibroblasts through the epithelial to mesenchymal transition (EMT). In accord with this, we found systems-level indications for TGF-beta -driven EMT as one source of IPF myofibroblasts.


CONCLUSIONS
These findings establish the power of systems level genome-wide analysis to provide mechanistic insights into fibrotic disorders such as IPF. Our data point to derangements of translational control downstream of aberrant beta 1 integrin signaling as a fundamental component of IPF pathobiology and indicates that TGF-beta -driven EMT is one source for IPF myofibroblasts.
Larsson
Ola
O
Pulmonary Division, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America. ola.larsson@mail.mcgill.ca
Diebold
Deanna
D
Fan
Danhua
D
Peterson
Mark
M
Nho
Richard Seonghun
RS
Bitterman
Peter B
PB
Henke
Craig A
CA
D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D015894:Genome, Human; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D014176:Protein Biosynthesis; D011658:Pulmonary Fibrosis / Q000235:genetics* / Q000378:metabolism*; D012270:Ribosomes / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
D019012:Integrin beta1; D016212:Transforming Growth Factor beta
Respir Res. 2006 Jun 30;7:95
16813649
J Cell Biol. 1994 Feb;124(4):401-4
8106541
Chest. 2006 Jul;130(1):22-9
16840378
Am J Respir Crit Care Med. 2005 Jun 1;171(11):1279-85
15735062
J Pathol. 2004 Apr;202(4):486-95
15095276
Am J Respir Crit Care Med. 2004 Aug 1;170(3):242-51
15117744
Mol Cell. 2003 Oct;12(4):889-901
14580340
Proc Am Thorac Soc. 2006 Jun;3(4):339-44
16738198
Am J Respir Cell Mol Biol. 2006 Jul;35(1):65-71
16498083
Am J Pathol. 2003 Jul;163(1):345-54
12819039
J Biol Chem. 2003 Jan 31;278(5):3015-22
12441348
J Biol Chem. 2006 Nov 3;281(44):33291-301
16963781
Electrophoresis. 1997 Mar-Apr;18(3-4):533-7
9150937
Cancer Res. 2007 Jul 15;67(14):6814-24
17638893
Am J Respir Crit Care Med. 2001 Sep 15;164(6):1025-32
11587991
Exp Nephrol. 1999 Mar-Apr;7(2):167-77
10213870
Am J Respir Crit Care Med. 2002 Jul 15;166(2):173-7
12119229
Mol Cell Biol. 2004 Sep;24(17):7469-82
15314157
Am J Respir Crit Care Med. 2004 Sep 1;170(5):508-15
15191918
J Clin Invest. 1994 Apr;93(4):1525-32
8163656
PLoS One. 2007 Feb 21;2(2):e242
17311107
Nucleic Acids Res. 2005 Nov 10;33(20):e175
16284200
Chest. 1991 Mar;99(3 Suppl):81S-84S
1997286
Pflugers Arch. 2003 Jun;446(3):387-93
12684791
BMC Bioinformatics. 2005 May 29;6:129
15921534
Bioinformatics. 2004 Dec 12;20(18):3710-5
15297299
Am J Respir Cell Mol Biol. 2006 Mar;34(3):293-304
16272460
J Invest Dermatol. 1998 Feb;110(2):153-7
9457911
BMC Bioinformatics. 2007 Feb 08;8:48
17288599
J Biol Chem. 2005 Jul 15;280(28):26630-9
15905178
J Exp Med. 2008 Jul 7;205(7):1659-72
18541712
Mol Cell Biol. 1999 Mar;19(3):1720-30
10022859
Exp Cell Res. 1965 Mar;37:614-36
14315085
J Biol Chem. 2007 Aug 10;282(32):23337-47
17562716
Leukemia. 1999 Apr;13(4):499-501
10214853
OMICS. 2006 Fall;10(3):381-97
17069515
J Cell Biol. 2007 Dec 17;179(6):1311-23
18086923
J Biol Chem. 2004 Jul 30;279(31):33024-34
15166238
Am J Pathol. 2005 May;166(5):1321-32
15855634
Genome Biol. 2005;6(13):R109
16420669
Arthritis Rheum. 2001 Jul;44(7):1667-76
11465719
Thorax. 1986 May;41(5):355-9
3750241
Am J Respir Cell Mol Biol. 2001 May;24(5):591-8
11350829
Nucleic Acids Res. 2006;34(16):4375-86
16936314
Am J Respir Crit Care Med. 2006 Jan 15;173(2):188-98
16166619
Ann Pharmacother. 2005 Oct;39(10):1678-86
16160001
Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5116-21
11309499
Nucleic Acids Res. 2006 Jan 1;34(Database issue):D322-6
16381878
Respir Res. 2004 Nov 30;5:24
15571627
Bioinformatics. 2005 Jul 1;21(13):2988-93
15840702
Proc Natl Acad Sci U S A. 2006 Aug 29;103(35):13180-5
16924102
J Biol Chem. 2002 Jul 5;277(27):24667-75
11986332
PLoS Med. 2005 Sep;2(9):e251
16128620
Nat Rev Immunol. 2004 Aug;4(8):583-94
15286725
In Vivo. 2005 Nov-Dec;19(6):959-63
16277007
Wound Repair Regen. 1998 Jan-Feb;6(1):28-37
9776848