Am J Respir Crit Care Med. 2018 Apr 13. doi: 10.1164/rccm.201708-1562OC. [Epub ahead of print]

Pulmonary Transplantation of Human iPSC-derived Macrophages Ameliorates Pulmonary Alveolar Proteinosis.

Happle C^1,2, Lachmann N³, Ackermann M⁴, Mirenska A⁵, Göhring G⁶, Thomay K⁶, Mucci A⁴, Hetzel M^7,8, Glomb T⁹, Suzuki T¹⁰, Chalk C¹¹, Glage S¹², Dittrich-Breiholz O¹³, Trapnell B¹⁴, Moritz T⁴, Hansen G^15,16.

Abstract

Rationale While the transplantation of induced pluripotent stem cell (iPSC)-derived cells harbors enormous potential for the treatment of pulmonary diseases, in vivo data demonstrating clear therapeutic benefits of human iPSC-derived cells in lung disease models is missing. Objective We here tested the therapeutic potential of iPSC-derived macrophages in a humanized disease model of hereditary pulmonary alveolar proteinosis (herPAP). herPAP is caused by a genetic defect of the GM-CSF-receptor, which leads to disturbed macrophage differentiation and protein/surfactant degradation in the lungs subsequently resulting in severe respiratory insufficiency. Methods Macrophages derived from human iPSCs, were transplanted intrapulmonary into humanized PAP mice and engraftment, in vivo differentiation, and therapeutic efficacy of transplanted cells were analyzed. Main Results Upon intratracheal application, iPSC-derived macrophages engrafted in the lungs of humanized PAP mice. After two months, transplanted cells displayed the typical morphology, surface markers, functionality, and transcription profile of primary human AMs. Alveolar proteinosis was significantly reduced as demonstrated by diminished protein content, surfactant protein D levels and turbidity of the bronchoalveolar lavage fluid (BALF) and reduced surfactant deposition in the lungs of transplanted mice. Conclusions We here demonstrate for the first time that pulmonary transplantation of human iPSC-derived macrophages leads to pulmonary engraftment, their in situ differentiation to an AM phenotype and a reduction of alveolar proteinosis in a humanized PAP model. To our knowledge, this finding presents the first proof-of-concept for the therapeutic potential of iPSC-derived cells in a pulmonary disease and may have profound implications beyond the rare disease of PAP.