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Paracrine soluble factors released by induced pluripotent stem cells in lung regeneration and repair

English title Paracrine soluble factors released by induced pluripotent stem cells in lung regeneration and repair
Applicant Geiser Thomas
Number 141102
Funding scheme Project funding
Research institution Universitätsklinik für Pneumologie Inselspital
Institution of higher education University of Berne - BE
Main discipline Pathophysiology
Start/End 01.11.2012 - 31.03.2016
Approved amount 315'000.00
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All Disciplines (2)

Discipline
Pathophysiology
Physiology : other topics

Keywords (5)

hepatocyte growth factor HGF; pulmonary fibrosis; regeneration; paracrine factors; induced pluripotent stem cells iPSC

Lay Summary (English)

Lead
Lay summary

Paracrine soluble factors released by induced pluripotent stem cells in lung regeneration and repair

Background Recent evidence suggest that idiopathic pulmonary fibrosis (IPF) is a disease of inefficient alveolar repair after repeated microinjuries. Mesenchymal bone-marrow derived stem cells (BMSC) have promising regenerative properties, mainly by release of paracrine factors that support regeneration and repair. Hepatocyte growth factor (HGF) is one of the major soluble factors inducing lung repair regeneration, thereby reducing pulmonary fibrosis. The regenerative effect of induced pluripotent stem cells (iPSC) on lung injury and fibrosis is not known.

Hypothesis iPSC, HGF-modified iPSC or iPS-derived alveolar epithelial cells (iPS-AEC) and their paracrine soluble factors induce alveolar epithelial repair in vitro and improve lung injury and fibrosis in vivo.

Specific Aims We will study the potential of a cell-based, but cell-free strategy in lung repair and fibrosis by using paracrine secreted factors from iPSC and modified iPSC. We will generate and characterize iPS cells in vitro regarding their proliferative, secretory and differentiation capacities to AEC and will study the effect of iPSC, HGF-modified iPSC and iPSC-AEC and their paracrine soluble factors on lung epithelail repair in vitro and pulmonary fibrosis in vivo.

Methods iPS cells will be generated by transfection of the transcription factors SOX2, OCT4, KLF4, and c-MYC and further modified by transfection of HGF or differentiation to iPS-AEC using specific culture conditions. iPSC will be characterized by FACS analysis, immunhistology and electron microscopy. The regenerative properties of iPSC, modified iPSC and their conditioned medium containing paracrine factors will be studied using our in vitro co-culture alveolar epithelial wound repair model. The effect of iPSC and their paracrine factors on lung injury and repair in vivo will be studied using a bleomycin induced lung injury and fibrosis model in the rat. Immunohistochemistry and electron microscopy in combination with morphometric, biochemical and functional analysis of the lung will be performed. Finally, paracrine soluble factors released by iPSC and modified iPSC will be identified and analyzed by proteomics followed by specific in vitro and in vivo inhibition experiments.

Expected values of the project  Although stem cells offer very promising possibilities in regenerative medicine, BMSC or embryonic stem cells are difficult to obtain and have biological and ethical limitations. iPSC offer the advantage of generating pluripotent stem cells from individual patients that can be multiplied in culture, modified and differentiated before giving them back to the patients as specific treatment. Alternatively, paracrine soluble factors released from iPSC may be as efficient as iPSC alone and therefore represent another promising therapeutic strategy. We hope to contribute to the understanding of the therapeutic potential of iPSC and their paracrine factors in lung regeneration and repair, hoping to develop a novel theurapeutic approach in patients with pulmonary fibrosis.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Toll-like receptor 4 activation attenuates profibrotic response in control lung fibroblasts but not in fibroblasts from patients with IPF
Ebener S, Barnowski S, Wotzkow C, Marti TM, Lopez-Rodriguez E, Crestani B, Blank F, Schmid RA, Geiser T, Funke M (2017), Toll-like receptor 4 activation attenuates profibrotic response in control lung fibroblasts but not in fibroblasts from patients with IPF, in Am J Physiol Lung Cell Mol Physiol, 312(1), L42-L55.
Alveolar derecruitment and collapse induration as crucial mechanisms in lung injury and fibrosis
Lutz D, Gazdhar A, Lopez-Rodriguez E, Ruppert C, Mahavadi P, Günther P, Klepetko W, Bates JH, Smith B, Geiser T, Ochs M, Knudsen L (2015), Alveolar derecruitment and collapse induration as crucial mechanisms in lung injury and fibrosis, in Am J Respir Cell Mol Biol, 52(2), 232-243.
The secretome of induced pluripotent stem cells reduces lung fibrosis in part by hepatocyte growth factor
Gazdhar A, Grad I, Tamò L, Gugger M, Feki A, Geiser T (2014), The secretome of induced pluripotent stem cells reduces lung fibrosis in part by hepatocyte growth factor, in Stem Cell Res Ther 2014 Nov 10, 5(6), 123-123.
Time-dependent and somatically acquired mitochondrial DNA mutagenesis and respiratory chain dysfunction in a scleroderma model of lung fibrosis
Gazdhar A, Lebrecht D, Roth M, Tamm M, Venhoff N, Foocharoen C, Geiser T, Walker UA (2014), Time-dependent and somatically acquired mitochondrial DNA mutagenesis and respiratory chain dysfunction in a scleroderma model of lung fibrosis, in Sci Rep, 4(5336), 000-000.
HGF expressing stem cells in usual interstitial pneumonia originate from the bone marrow and are antifibrotic
Gazdhar A, Susuri N, Hostettler K, Gugger M, Knudsen L, Roth M, Ochs M, Geiser T (2013), HGF expressing stem cells in usual interstitial pneumonia originate from the bone marrow and are antifibrotic, in PLoS One, 8(6), 0000-0000.
Hepatocyte growth factor secreted by bone marrow stem cell reduces ER stress and improves repair in alveolar epithelial type II cells in vitro
Nita I, Hostettler K, Tamò L, Medová M, Zhong J, Zimmer Y, Roth M, Geiser T, Gazdhar A, Hepatocyte growth factor secreted by bone marrow stem cell reduces ER stress and improves repair in alveolar epithelial type II cells in vitro, in Scient Reports.

Collaboration

Group / person Country
Types of collaboration
Prof. Michael Roth, Lung Cell Laboratoy, University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
PD Dr Carlo Largiader, Institute of Clinical Chemistry, University Hospital Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Prof. Bruno Crestani, INSERM 700, Paris France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
PD Dr Manfred Heller, Department of Clinical Research, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof Matthias Ochs, Anatomie, Medizinische Hochschule Hannover Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
European Lung Science Research Seminar Talk given at a conference Protein net works in the lung 03.12.2016 Barcelona, Spain Geiser Thomas;
European Respiratory Society ERS Annual Conference Talk given at a conference Alveolar type II cell line generated from iPSC 02.09.2016 London, Great Britain and Northern Ireland Tamò Luca; Geiser Thomas;
International Conference on Lung and Airway Fibrosis ICLAF Talk given at a conference Lung alveolar epithelials cell line generated from iPSC cells 02.09.2016 Dublin, Ireland Geiser Thomas;
European REspiratory Society ERS Annual Conference Poster Stem cells and lung fibrosis 15.09.2015 München, Germany Tamò Luca; Geiser Thomas;
European Respiratory Society ERS Annual Conference Talk given at a conference Mesenchymal stem cells in IPF 02.09.2014 Amsterdam, Netherlands Tamò Luca; Geiser Thomas;


Self-organised

Title Date Place
Jahresvesammlung Schweizerische Gesellschaft für Pneumologie SGP 15.06.2015 Bern, Switzerland

Communication with the public

Communication Title Media Place Year
Media relations: radio, television Lungenfibrose SRF 1 Gesundheitssprechstunde German-speaking Switzerland 2016
Media relations: print media, online media Lung-on-chip Technologie Bund Tagesanzeiger German-speaking Switzerland 2016

Use-inspired outputs


Start-ups

Name Year
Alveolix AG 2015

Associated projects

Number Title Start Funding scheme
120408 Cell-specific gene transfer of hepatocyte growth factor in lung injury, inflammation and repair 01.02.2009 Project funding
157748 Microscopy Equipment for Organ-on-Chips and Perfused Microfluidic Systems with High Speed Camera 01.12.2014 R'EQUIP
160704 Lung resident stem cells for treatment of pulmonary fibrosis 01.11.2015 Sinergia
145003 A new Zeiss LSM 710 laser scanning microscope for the DCR LCI Core Facility 01.12.2012 R'EQUIP
135784 Somatisch erworbene Mitochondrienläsionen bei idiopathischer und Sklerodermie-assoziierter Lungenfibrose 01.07.2011 Project funding
120408 Cell-specific gene transfer of hepatocyte growth factor in lung injury, inflammation and repair 01.02.2009 Project funding

Abstract

Background: Recent evidence suggest that idiopathic pulmonary fibrosis (IPF) is a disease of inefficient alveolar repair after repeated microinjuries. Mesenchymal bone-marrow derived stem cells (BMSC) have promising regenerative properties, mainly by release of paracrine factors that support regeneration and repair. Hepatocyte growth factor (HGF) is one of the major soluble factors inducing lung repair regeneration, thereby reducing pulmonary fibrosis. The regenerative effect of induced pluripotent stem cells (iPSC) on lung injury and fibrosis is not known.Hypothesis: iPSC, HGF-modified iPSC or iPS-derived alveolar epithelial cells (iPS-AEC) and their paracrine soluble factors induce alveolar epithelial repair in vitro and improve lung injury and fibrosis in vivo. Specific Aims: We will study the potential of a cell-based, but cell-free strategy in lung repair and fibrosis by using paracrine secreted factors from iPSC and modified iPSC. We will generate and characterize iPS cells in vitro regarding their proliferative, secretory and differentiation capacities to AEC and will study the effect of iPSC, HGF-modified iPSC and iPSC-AEC and their paracrine soluble factors on lung epithelail repair in vitro and pulmonary fibrosis in vivo.Methods: iPS cells will be generated by transfection of the transcription factors SOX2, OCT4, KLF4, and c-MYC and further modified by transfection of HGF or differentiation to iPS-AEC using specific culture conditions. iPSC will be characterized by FACS analysis, immunhistology and electron microscopy. The regenerative properties of iPSC, modified iPSC and their conditioned medium containing paracrine factors will be studied using our in vitro co-culture alveolar epithelial wound repair model. The effect of iPSC and their paracrine factors on lung injury and repair in vivo will be studied using a bleomycin induced lung injury and fibrosis model in the rat. Immunohistochemistry and electron microscopy in combination with morphometric, biochemical and functional analysis of the lung will be performed. Finally, paracrine soluble factors released by iPSC and modified iPSC will be identified and analyzed by proteomics followed by specific in vitro and in vivo inhibition experiments.Expected values of the project: Although stem cells offer very promising possibilities in regenerative medicine, BMSC or embryonic stem cells are difficult to obtain and have biological and ethical limitations. iPSC offer the advantage of generating pluripotent stem cells from individual patients that can be multiplied in culture, modified and differentiated before giving them back to the patients as specific treatment. Alternatively, paracrine soluble factors released from iPSC may be as efficient as iPSC alone and therefore represent another promising therapeutic strategy. We hope to contribute to the understanding of the therapeutic potential of iPSC and their paracrine factors in lung regeneration and repair, hoping to develop a novel theurapeutic approach in patients with pulmonary fibrosis.
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