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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL134766-04
Application #
9709312
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Lin, Sara
Project Start
2016-09-21
Project End
2023-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
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