Injuries to the lung alveolar epithelium can lead to the adult respiratory distress syndrome, a disease responsible for considerable morbidity and mortality in the United States. To date treatment for this condition is merely supportive and no direct therapy able to reconstitute the injured lung epithelium has been feasible. The long-term goal of this project is to develop an autologous cell-based therapy to reconstitute the injured lung epithelium utilizing induced pluripotent stem (iPS) cells, a novel cell population generated by reprogramming fibroblasts into cells virtually indistinguishable from embryonic stem (ES) cells. The remarkable developmental and differentiation potential of iPS cells makes them attractive candidates for cell-based therapies. Before the full potential of iPS cells can be realized, however, it is first necessary to precisely direct their differentiation in culture and to understand the complex signals and genetic mechanisms that control this differentiation. This proposal presents three specific aims designed to further advance iPS modeling of lung development and to develop a novel iPS cell-based therapy for lung disease.
Aim 1 directly compares the in vitro capacity of mouse iPS and ES cells to form definitive endoderm, the immediate developmental precursor of lung epithelial progenitors.
Aim 2 develops novel methods, using reporter genes, for the purification of lung epithelial progenitors from iPS- and ES-derived definitive endodermal cells.
Aim 3 begins in vivo application of the iPS-derived endodermal and lung epithelial progenitor populations by using mouse transplant models to test the ability of these cells to survive and proliferate without tumor formation in vivo. Finally the capacity of these cells to reconstitute the lung epithelium after bleomycin or hyperoxia- induced lung injury is evaluated.
Injury to the thin layer of cells lining lung alveoli (epithelial cells) is responsible for considerable morbidity and mortality, and incomplete or ineffective repair of these cells is characteristic of diseases such as the adult respiratory distress syndrome or respiratory distress of the newborn. This proposal develops novel therapies, based on infusions of lung progenitors derived from induced pluripotent stem (iPS) cells, designed to rescue and repair the injured lining of lung alveoli.
|Wilson, Andrew A; Ying, Lei; Liesa, Marc et al. (2015) Emergence of a stage-dependent human liver disease signature with directed differentiation of alpha-1 antitrypsin-deficient iPS cells. Stem Cell Reports 4:873-85|
|Kurmann, Anita A; Serra, Maria; Hawkins, Finn et al. (2015) Regeneration of Thyroid Function by Transplantation of Differentiated Pluripotent Stem Cells. Cell Stem Cell 17:527-42|
|Sommer, Cesar A; Christodoulou, Constantina; Gianotti-Sommer, Andreia et al. (2012) Residual expression of reprogramming factors affects the transcriptional program and epigenetic signatures of induced pluripotent stem cells. PLoS One 7:e51711|
|Longmire, Tyler A; Ikonomou, Laertis; Hawkins, Finn et al. (2012) Efficient derivation of purified lung and thyroid progenitors from embryonic stem cells. Cell Stem Cell 10:398-411|
|Longmire, Tyler A; Ikonomou, Laertis; Kotton, Darrell N (2012) Mouse ESC Differentiation to Nkx2.1+ Lung and Thyroid Progenitors. Bio Protoc 2:|
|Christodoulou, Constantina; Longmire, Tyler A; Shen, Steven S et al. (2011) Mouse ES and iPS cells can form similar definitive endoderm despite differences in imprinted genes. J Clin Invest 121:2313-25|
|Somers, Aba; Jean, Jyh-Chang; Sommer, Cesar A et al. (2010) Generation of transgene-free lung disease-specific human induced pluripotent stem cells using a single excisable lentiviral stem cell cassette. Stem Cells 28:1728-40|