Durable alveolar engraftment of PSC-derived lung epithelial cells into immunocompetent mice

Durable reconstitution of the distal lung epithelium with pluripotent stem cell (PSC) derivatives, if realized, would represent a promising therapy for diseases that result from alveolar damage. Here, we differentiate murine PSCs into self-renewing lung epithelial progenitors able to engraft into the injured distal lung epithelium of immunocompetent, syngeneic mouse recipients. After transplantation, these progenitors mature in the distal lung, assuming the molecular phenotypes of alveolar type 2 (AT2) and type 1 (AT1) cells. After months in vivo, donor-derived cells retain their mature phenotypes, as characterized by single-cell RNA sequencing (scRNA-seq), histologic profiling, and functional assessment that demonstrates continued capacity of the engrafted cells to proliferate and differentiate. These results indicate durable reconstitution of the distal lung’s facultative progenitor and differentiated epithelial cell compartments with PSC-derived cells, thus establishing a novel model for pulmonary cell therapy that can be utilized to better understand the mechanisms and utility of engraftment. [Display omitted] •Directed differentiation of mouse ESCs into tip-like lung epithelial progenitors•Primary and ESC-derived transplants produce similar AT1-like and AT2-like cells•ESC-derived tip-like cells persist for at least 6 months in immunocompetent mice•Donor-derived cells have the lamellar bodies and progenitor capacity of AT2 cells Kotton and colleagues differentiate embryonic stem cells (ESCs) into lung epithelial progenitors that can be transplanted into immunocompetent mouse lungs. These cells durably engraft into the recipient’s lung, giving rise to mature alveolar type 1 (AT1)-like and AT2-like cells that are transcriptomically and functionally similar to endogenous lineages.