IPF Fibroblast Phenotype

Summary

Principal Investigator: Craig A Henke
Abstract: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease refractory to pharmacological therapy. It afflicts 1/10,000 individuals leading to death within 3-5 years of diagnosis unless treated by lung transplantation. In attempt to arrest this lethal disease, this Program Project focuses on the fibroproliferative process and its key cellular constituent- the myofibroblast. Despite studies indicating that IPF fibroblasts display a distinct pathological phenotype, large gaps in knowledge remain regarding differences between the pathological nature of IPF myofibroblasts responsible for progressive fibrosis and the physiological function of myofibroblasts essential for normal tissue repair. Considering this, the individual projects comprising this PPG promote a unified theme: provide direct mechanistic insight into the molecular processes that make an IPF fibroblast abnormal by uncovering components of the myofibroblast cellular machinery that result in unrelenting fibrosis in IPF, and in proper tissue healing under normal circumstances. It is our theory that a malicious alliance of cytokines and matrix macromolecules modulates the fibroblast phenotype resulting in stable pathological changes in the basic fibroblast cellular machinery that can be discerned at the level of transcription, translation and signal transduction. Within this framework, Project 1 (Henke) examines the role of integrin-matrix in regulating IPF fibroblast proliferation;Project 2 (Bitterman) investigates translational control of the fibroblast phenotype in IPF;and Project 3 (Phan) assesses transcriptional control of myofibroblast differentiation. The scientific sections are supported by an Administrative Core (Henke) and a Biospecimen and Histopathology Core (Ingbar). The Biospecimen Core functions to provide standardized tissue specimens and cell lines to be used by each investigator in order to reduce uncontrolled alterations in fibroblast phenotype possible during cell isolation and cultivation. Thus, this Program Project has gathered a group of scientists with diverse areas of expertise to work together on a common theme. A major objective of this Program Project is to inform decisions of the IPF Clinical Network by providing information that can be translated into novel therapeutic strategies for IPF.
Funding Period: 2009-04-01 - 2015-03-31
more information: NIH RePORT

Top Publications

  1. pmc Pathologic caveolin-1 regulation of PTEN in idiopathic pulmonary fibrosis
    Hong Xia
    Department of Medicine, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455, USA
    Am J Pathol 176:2626-37. 2010
  2. pmc The in vivo fibrotic role of FIZZ1 in pulmonary fibrosis
    Tianju Liu
    Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
    PLoS ONE 9:e88362. 2014
  3. pmc Lung bone marrow-derived hematopoietic progenitor cells enhance pulmonary fibrosis
    Taku Nakashima
    1 Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan and
    Am J Respir Crit Care Med 188:976-84. 2013
  4. pmc FoxO3a (Forkhead Box O3a) deficiency protects Idiopathic Pulmonary Fibrosis (IPF) fibroblasts from type I polymerized collagen matrix-induced apoptosis via caveolin-1 (cav-1) and Fas
    Richard Seonghun Nho
    Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America
    PLoS ONE 8:e61017. 2013
  5. pmc Telomerase and telomere length in pulmonary fibrosis
    Tianju Liu
    Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109 2200, USA
    Am J Respir Cell Mol Biol 49:260-8. 2013
  6. ncbi Essential role of stem cell factor-c-Kit signalling pathway in bleomycin-induced pulmonary fibrosis
    Lin Ding
    Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109 2200, USA
    J Pathol 230:205-14. 2013
  7. pmc Regulation of myofibroblast differentiation by poly(ADP-ribose) polymerase 1
    Biao Hu
    Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109 2200, USA
    Am J Pathol 182:71-83. 2013
  8. pmc Myofibroblasts
    Biao Hu
    Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109 2200, USA
    Curr Opin Rheumatol 25:71-7. 2013
  9. pmc Low α(2)β(1) integrin function enhances the proliferation of fibroblasts from patients with idiopathic pulmonary fibrosis by activation of the β-catenin pathway
    Hong Xia
    Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
    Am J Pathol 181:222-33. 2012
  10. pmc Attacking a nexus of the oncogenic circuitry by reversing aberrant eIF4F-mediated translation
    Peter B Bitterman
    Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
    Mol Cancer Ther 11:1051-61. 2012

Research Grants

  1. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
  2. Blood Pressure Regulation: Novel Roles for the Kidney
    Pablo A Ortiz; Fiscal Year: 2013

Detail Information

Publications19

  1. pmc Pathologic caveolin-1 regulation of PTEN in idiopathic pulmonary fibrosis
    Hong Xia
    Department of Medicine, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455, USA
    Am J Pathol 176:2626-37. 2010
    ..This creates a membrane microenvironment depleted of inhibitory phosphatase activity, facilitating the aberrant activation PI3K/Akt and pathological proliferation...
  2. pmc The in vivo fibrotic role of FIZZ1 in pulmonary fibrosis
    Tianju Liu
    Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
    PLoS ONE 9:e88362. 2014
    ..These findings suggested that FIZZ1 exhibited profibrogenic properties essential for bleomycin induced pulmonary fibrosis, as reflected by its ability to induce myofibroblast differentiation and recruit bone marrow-derived cells. ..
  3. pmc Lung bone marrow-derived hematopoietic progenitor cells enhance pulmonary fibrosis
    Taku Nakashima
    1 Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan and
    Am J Respir Crit Care Med 188:976-84. 2013
    ..Bone marrow (BM)-derived cells have been implicated in pulmonary fibrosis. However, their precise role in pathogenesis is incompletely understood...
  4. pmc FoxO3a (Forkhead Box O3a) deficiency protects Idiopathic Pulmonary Fibrosis (IPF) fibroblasts from type I polymerized collagen matrix-induced apoptosis via caveolin-1 (cav-1) and Fas
    Richard Seonghun Nho
    Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America
    PLoS ONE 8:e61017. 2013
    ..Our data indicate that the pathologically altered PTEN/Akt axis inactivates FoxO3a down-regulating cav-1 and Fas expression. This confers IPF fibroblasts with an apoptosis-resistant phenotype and may be responsible for IPF progression...
  5. pmc Telomerase and telomere length in pulmonary fibrosis
    Tianju Liu
    Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109 2200, USA
    Am J Respir Cell Mol Biol 49:260-8. 2013
    ..Notably, the animal studies indicated that the pathogenesis of pulmonary fibrosis was independent of telomere length. ..
  6. ncbi Essential role of stem cell factor-c-Kit signalling pathway in bleomycin-induced pulmonary fibrosis
    Lin Ding
    Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109 2200, USA
    J Pathol 230:205-14. 2013
    ..Taken together, the SCF-c-Kit pathway was activated in BLM-injured lung and might play a direct role in pulmonary fibrosis by the recruitment of bone marrow progenitor cells capable of promoting lung myofibroblast differentiation...
  7. pmc Regulation of myofibroblast differentiation by poly(ADP-ribose) polymerase 1
    Biao Hu
    Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109 2200, USA
    Am J Pathol 182:71-83. 2013
    ..These results suggest that PARylation is important for myofibroblast differentiation and the pathogenesis of pulmonary fibrosis...
  8. pmc Myofibroblasts
    Biao Hu
    Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109 2200, USA
    Curr Opin Rheumatol 25:71-7. 2013
    ..The objective of the review is to highlight this recent progress...
  9. pmc Low α(2)β(1) integrin function enhances the proliferation of fibroblasts from patients with idiopathic pulmonary fibrosis by activation of the β-catenin pathway
    Hong Xia
    Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
    Am J Pathol 181:222-33. 2012
    ..Our findings indicate that the IPF fibroblast phenotype is characterized by low α(2)β(1) integrin expression, resulting in a failure of integrin to activate ..
  10. pmc Attacking a nexus of the oncogenic circuitry by reversing aberrant eIF4F-mediated translation
    Peter B Bitterman
    Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
    Mol Cancer Ther 11:1051-61. 2012
    ..A genome-wide, systems-level means to objectively evaluate the pharmacologic response to therapeutics targeting eIF4F remains an unmet challenge...
  11. pmc Mesenchymal-specific deletion of C/EBPβ suppresses pulmonary fibrosis
    Biao Hu
    Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
    Am J Pathol 180:2257-67. 2012
    ..Thus, these findings indicate an essential role for C/EBPβ in the mesenchymal compartment in pulmonary fibrosis that is independent of its effects on inflammation or immune cell infiltration...
  12. pmc Recent developments in myofibroblast biology: paradigms for connective tissue remodeling
    Boris Hinz
    Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada
    Am J Pathol 180:1340-55. 2012
    ..Finally, we summarize the emerging strategies for influencing myofibroblast behavior in vitro and in vivo, with the ultimate goal of an effective therapeutic approach for myofibroblast-dependent diseases...
  13. pmc A novel zebrafish embryo xenotransplantation model to study primary human fibroblast motility in health and disease
    Alexey O Benyumov
    Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
    Zebrafish 9:38-43. 2012
    ..IPF fibroblasts displayed a significantly higher level of motility than did fibroblasts from nonfibrotic lungs. This is the first in vivo examination of primary human lung fibroblast motility in health and disease using zebrafish models...
  14. pmc Pathological alteration of FoxO3a activity promotes idiopathic pulmonary fibrosis fibroblast proliferation on type i collagen matrix
    Richard Seonghun Nho
    Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
    Am J Pathol 179:2420-30. 2011
    ..These data indicate that the ability of IPF fibroblasts to circumvent the proliferation-suppressive properties of polymerized collagen involves inactivation of FoxO3a by high Akt activity, resulting in down-regulation of p27...
  15. pmc FIZZ2/RELM-β induction and role in pulmonary fibrosis
    Tianju Liu
    Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
    J Immunol 187:450-61. 2011
    ..These findings suggest that FIZZ2 is a Th2-associated multifunctional mediator with potentially important roles in the pathogenesis of fibrotic lung diseases...
  16. pmc Essential role of MeCP2 in the regulation of myofibroblast differentiation during pulmonary fibrosis
    Biao Hu
    Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109 2200, USA
    Am J Pathol 178:1500-8. 2011
    ..Thus, MeCP2 is essential for myofibroblast differentiation and pulmonary fibrosis...
  17. pmc Epigenetic regulation of myofibroblast differentiation by DNA methylation
    Biao Hu
    Department of Pathology, University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109 2200, USA
    Am J Pathol 177:21-8. 2010
    ..These findings suggest that DNA methylation mediated by DNA methyltransferase is an important mechanism regulating the alpha-SMA gene expression during myofibroblast differentiation...
  18. pmc Identification of a cell-of-origin for fibroblasts comprising the fibrotic reticulum in idiopathic pulmonary fibrosis
    Hong Xia
    Department of Medicine, University of Minnesota, Minneapolis, Minnesota
    Am J Pathol 184:1369-83. 2014
    ..These fibrogenic mesenchymal progenitors and their progeny represent an unexplored target for novel therapies to interdict fibrosis. ..

Research Grants30

  1. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
    ..Through all of its activities, the Center improves communication, promotes collaboration, develops careers and generally enriches the intellectual climate for digestive disease research. ..
  2. Blood Pressure Regulation: Novel Roles for the Kidney
    Pablo A Ortiz; Fiscal Year: 2013
    ..Thus it will accelerate acquisition of knowledge of the novel mechanisms by which the kidney regulates blood pressure, and may provide new targets for anti-hypertensive drugs. ..