The overall goal of this application is to develop a compelling rationale and workable methodology for the treatment of diffuse alveolar damage with transplanted human epithelial stem/progenitor cells capable of long term engraftment and improved organ function. Stem/progenitor replacement therapy is envisioned as a meaningful therapeutic adjunct in several clinical situations dominated by diffuse alveolar damage with epithelial loss: severe, acute lung injury, e.g. due to influenza or other causes of ARDS, as well as acute exacerbations of chronic fibrotic lung disease. Recent studies discussed in the application indicate effective alveolar regeneration, and thus improved lung function, requires both a first phase of expansion and migration of stem/progenitor cells to re-establish alveolar barriers followed by a second phase of differentiation of new barrier cells into mature type II (AEC2s) and type I alveolar cells. To develop a translational program for alveolar regeneration by transplantation of healthy lung epithelial stem/progenitor cells, three basic objectives are advanced: (1) Further delineation of the signaling programs by which endogenous human distal lung epithelial stem cells can be activated following major injury to establish new alveolar barriers and then differentiate to AEC2s. (2) In vitro development of pools of human distal (small airway and alveolar) epithelial stem cells, both endogenous and iPSC-derived, suitable for transplantation and directed differentiation in mice. Distal basal-like cells from human iPS cells using gene edited cells reporting surfactant protein C, cytokeratin 17 (Krt17), and NKX2.1 will be used to develop a workable protocol for directed differentiation after transplant. (3) Employ models of lung repair/regeneration approachable by transplantation as tools to assess the regenerative potential of human epithelial stem/progenitor cells. Macaque iPS cells suitable for transplantation into influenza-infected monkeys will be used as a primate model for therapy. It is anticipated that functional improvement in gas exchange and alveolar histology can be achieved in primates, providing both a rationale and methodology for stem/progenitor cells as adjunctive therapy after severe acute lung injury in humans.

Public Health Relevance

This application describes a new therapeutic approach to lung repair that extends recent results in mice demonstrating that lung stem/progenitor cells can transplant and engraft in damaged lungs. The application is driven by the frustrating current state of pulmonary medicine that offers little more than supportive care in the management of acute respiratory failure and progressive fibrotic lung diseases. A group of investigators have come together to overcome the hurdles of stem/progenitor cell replacement therapy in humans.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZHL1-CSR-O (S1))
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Lin, Sara
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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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
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
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
Lechner, Andrew J; Driver, Ian H; Lee, Jinwoo et al. (2017) Recruited Monocytes and Type 2 Immunity Promote Lung Regeneration following Pneumonectomy. Cell Stem Cell 21:120-134.e7
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
Xi, Ying; Kim, Thomas; Brumwell, Alexis N et al. (2017) Local lung hypoxia determines epithelial fate decisions during alveolar regeneration. Nat Cell Biol 19:904-914
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