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.
|McCauley, Katherine B; Alysandratos, Konstantinos-Dionysios; Jacob, Anjali et al. (2018) Single-Cell Transcriptomic Profiling of Pluripotent Stem Cell-Derived SCGB3A2+ Airway Epithelium. Stem Cell Reports 10:1579-1595|
|Kotton, Darrell N (2018) Claudin-18: unexpected regulator of lung alveolar epithelial cell proliferation. J Clin Invest 128:903-905|
|McCauley, Katherine B; Hawkins, Finn; Kotton, Darrell N (2018) Derivation of Epithelial-Only Airway Organoids from Human Pluripotent Stem Cells. Curr Protoc Stem Cell Biol 45:e51|
|Serra, Maria; Alysandratos, Konstantinos-Dionysios; Hawkins, Finn et al. (2017) Pluripotent stem cell differentiation reveals distinct developmental pathways regulating lung- versus thyroid-lineage specification. Development 144:3879-3893|
|Hawkins, Finn; Kramer, Philipp; Jacob, Anjali et al. (2017) Prospective isolation of NKX2-1-expressing human lung progenitors derived from pluripotent stem cells. J Clin Invest 127:2277-2294|
|Dame, Keri; Cincotta, Steven; Lang, Alex H et al. (2017) Thyroid Progenitors Are Robustly Derived from Embryonic Stem Cells through Transient, Developmental Stage-Specific Overexpression of Nkx2-1. Stem Cell Reports 8:216-225|
|McCauley, Katherine B; Hawkins, Finn; Serra, Maria et al. (2017) Efficient Derivation of Functional Human Airway Epithelium from Pluripotent Stem Cells via Temporal Regulation of Wnt Signaling. Cell Stem Cell 20:844-857.e6|
|Jacob, Anjali; Morley, Michael; Hawkins, Finn et al. (2017) Differentiation of Human Pluripotent Stem Cells into Functional Lung Alveolar Epithelial Cells. Cell Stem Cell 21:472-488.e10|
|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|
|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|
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