Our ultimate goal is to rebuild the lung using decellularized lung as a natural 3-dimensional (3-D) matrix base for lung progenitor cells. Lung transplantation is usually the only option for patients with irreversible structural lung damage but is hindered by major obstacles such as lack of lung organ donors and chronic rejection. Artificial scaffolds cannot replicate the branching or the composition, arrangement and stretch of the extracellular matrix of the lung. We will focus on rebuilding the lung using ventilated, decellularized whole lungs as a natural 3-D matrix and repopulate it with cells having potential as lung epithelial and endothelial progenitors. We have data that rodent lungs can successfully be decellularized while maintaining extracellular matrix in the correct geospatial branching pattern even after prolonged ventilation. Adult and fetal lung cells can successfully be infused and cultured in decellularized, ventilated lungs. We hypothesize that, given the right growth conditions, putative progenitors will re-epithelialize and re-endothelialize the matrix and produce proteins characteristic of lung cells. We also expect that timing of cell input, growth factors and developmental stage-appropriate ventilatory stretch will be critical to this process.
In Aim 1, we will determine if putative lung progenitor cell populations such as induced pluripotent (iPS) cells, BM-derived cells and EpCAM+ lung-derived cells, will grow and differentiate in the setting of a ventilated, decellularized, whole lung matrix in our new """"""""lung bioreactor"""""""" system. We will compare culturing these cells, alone and in combination, in decellularized matrices prepared from adult and fetal lungs.
In Aim 2, we will determine if both epithelium and endothelium can be recellularized using blood outgrowth endothelial cells (BOECs) and the best cells from Aim 1. We are in a unique position to perform these studies. We have a unique model system and highly experienced collaborators who provide novel cells, critical expertise and advice for this grant application.

Public Health Relevance

Lung transplantation is usually the only option for patients with irreversible structural lung damage but is hindered by major obstacles such as lack of lung organ donors and chronic rejection. We will focus on rebuilding the lung using ventilated, decellularized whole rodent lungs as a natural 3-D matrix and repopulate it with cells having the potential to grow into lung tissue and produce proteins characteristic of lung cells.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL102570-01
Application #
7871715
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Blaisdell, Carol J
Project Start
2010-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
1
Fiscal Year
2010
Total Cost
$204,852
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pediatrics
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455