Use of alveolar or airway organoids for the treatment of lung diseases and disorders
Various aspects described herein provide methods of generating alveolar or alveolar/airway organoids from a population of lung cells to differentiate into alveolar or alveolar/airway organoids. Also provided herein are methods and compositions for treating lung disease comprising transplantation of the alveolar or alveolar/airway organoids, or a cell isolated therefrom to a subject.
1. A method for treating a lung disease or disorder, or a lung injury, in a subject in need thereof, the method comprising administering to a subject, intratracheally, a therapeutically effective amount of a composition comprising an alveolar organoid or an isolated cell thereof,
wherein the alveolar organoid is provided or produced in vitro or ex vivo from a lung cell by culturing the lung cell in a 3-dimensional culture for a time and under conditions sufficient to produce the alveolar organoid,
wherein administering is transplanting, and
wherein the alveolar organoid or cell thereof functionally engrafts into the lung after transplanting thereby treating the lung disease or disorder or lung injury in the subject.
2. The method of claim 1 , wherein the alveolar organoid or cell thereof is CD31/CD45−, Epcam+ and Sca1− in murine cells, or CD31−/CD45−, Epcam+, and HTII-280+ in human cells.
3. The method of claim 1 , wherein the alveolar organoid or cell thereof are autologous to the subject to be treated; or wherein the alveolar organoid or cell thereof are heterologous to the subject to be treated.
4. The method of claim 1 , wherein the alveolar organoid further comprises a lung epithelial cell, or a stromal cell.
5. The method of claim 1 , wherein the lung cell is isolated from a donor or is derived in vitro from a stem cell.
6. The method of claim 5 , wherein the stem cell is an induced pluripotent stem cell (iPSC), an embryonic stem cell, or a lung progenitor cell.
7. The method of claim 1 , wherein the alveolar organoid is a human primary alveolar (hPAL) cell-derived organoid, a human iPSC-derived organoid or a human primary airway (hPAR) cell-derived organoid.
8. The method of claim 1 , wherein the lung cell is CD31/CD45− and Epcam+.
9. The method of claim 8 , wherein the lung cell is Sca1+; or wherein the lung cell is Sca1−.
10. The method of claim 1 , wherein the Sca1+organoids engraft and populate in the alveolar space.
11. The method of claim 1 , wherein the Sca1−organoids engraft into regions of the lung having damaged alveolar cells.
12. The method of claim 10 , wherein the engrafted cells are Keratin 8+ and/or Keratin 17+.
13. The method of claim 1 , wherein the transplanted or engrafted cells retain progenitor function as assessed by (i) their ability to give rise to organoids when returned to in vitro culture and/or (ii) their ability to respond to a second lung injury.
14. The method of claim 1 , further comprising, prior to transplanting, the step of diagnosing a subject as having a lung disease or disorder, and/or being immunocompromised.
15. The method of claim 1 , further comprising, prior to transplanting, receiving the results of an assay that diagnoses a subject as having a lung disease or disorder, and/or being immunocompromised.
16. The method of claim 1 , further comprising the step of genetically modifying the lung cell, and/or the alveolar cell.
17. The method of claim 1 , further comprising administering an immunosuppressive agent prior to, or substantially at the same time as the transplantation.