Injuries to the lung epithelium can be triggered by several diseases, including COVID-19, COPD, and chronic lung diseases, and they represent one of the main causes of worldwide mortality.
Treatment options are currently limited, and frequently involve lung transplantation as the last resort. However, the availability of donor organs and the risk of immune rejection remain significant challenges.
Recently, Dr. Darrel Kotton's team at Boston University published two consecutive research papers in Cell Stem Cell, describing the application of iPSC-derived lung cells to regenerate tracheal and alveolar tissue in immunocompetent mice, utilizing both mouse and human iPSCs.
One of the published studies involved the differentiation of mouse and human iPSCs into basal cells, which have the remarkable capacity to reconstitute all cell types found in the lung airways, including goblet, ciliated, secretory, and club cells. Following chemical treatment to remove the endogenous cells, mice were transplanted with iPSC-derived cells containing a green fluorescent protein (GFP) tag.
The researchers successfully detected these cells in the majority of the recovered mouse tissues up to 2 years after transplantation. Furthermore, they demonstrated the ability to retransplant these cells into new generations of mice, with no signs of rejection.
These findings demonstrate the capacity of iPSC-derived basal cells to engraft into recipient mice. Additionally, functionality of the cells was proven by their capacity to differentiate into the various cell types present in the airways.
A second study involved the transplantation of iPSC-derived alveolar progenitors. The alveolar epithelium comprises two primary cell types: alveolar type I and alveolar type II cells. Type I cells line the alveolar surface and are responsible for gas exchange, while type II cells secrete surfactant proteins to reduce surface tension. When transplanted into mice, the iPSC-derived cells persisted for at least 6 months and demonstrated the ability to produce both alveolar AT2 and AT1 cells, which exhibited transcriptomic and functional similarities to endogenous alveolar epithelial cells, including characteristic organelles such as lamellar bodies.
While the field of lung regenerative medicine is still in its early stages, and more studies are necessary to establish the long-term effectiveness of these treatments, these findings signify the successful engraftment of iPSC-derived cells into an immunocompetent host. This breakthrough holds significant promise for the development of clinically relevant iPSC-derived pulmonary cell therapy without the need for immunosuppression.
Key points
iPSC-derived lung transplantation effectively regenerates the mouse airway and alveolar compartments.
Transplanted cells can persist for 6-24 months while maintaining their cellular functions.
iPSC-derived transplanted cells contribute to major epithelial lineages, displaying a high degree of similarity with endogenous cell types.
References
[1] Liang Ma, et al. Airway stem cell reconstitution by the transplantation of primary or pluripotent stem cell-derived basal cells. Cell Stem Cell, Volume 30, Issue 9, 2023, https://doi.org/10.1016/j.stem.2023.07.014.
[2]Michael J. Herriges, et al. Durable alveolar engraftment of PSC-derived lung epithelial cells into immunocompetent mice. Cell Stem Cell, Volume 30, Issue 9, 2023, https://doi.org/10.1016/j.stem.2023.07.016.