1 Department of Pediatric Pneumology, Allergology and Neonatology.
2 Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), Member of the German Center for Lung Research (DZL).
Am J Respir Crit Care Med. 2018 Aug 1;198(3):350-360. doi: 10.1164/rccm.201708-1562OC.
Although 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 are missing.
We have tested the therapeutic potential of iPSC-derived macrophages in a humanized disease model of hereditary pulmonary alveolar proteinosis (PAP). Hereditary PAP is caused by a genetic defect of the GM-CSF (granulocyte-macrophage colony-stimulating factor) receptor, which leads to disturbed macrophage differentiation and protein/surfactant degradation in the lungs, subsequently resulting in severe respiratory insufficiency.
Macrophages derived from human iPSCs underwent intrapulmonary transplantation into humanized PAP mice, and engraftment, in vivo differentiation, and therapeutic efficacy of the transplanted cells were analyzed.
On intratracheal application, iPSC-derived macrophages engrafted in the lungs of humanized PAP mice. After 2 months, transplanted cells displayed the typical morphology, surface markers, functionality, and transcription profile of primary human alveolar macrophages. Alveolar proteinosis was significantly reduced as demonstrated by diminished protein content and surfactant protein D levels, decreased turbidity of the BAL fluid, and reduced surfactant deposition in the lungs of transplanted mice.
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 alveolar macrophage 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 human iPSC-derived cells in a pulmonary disease and may have profound implications beyond the rare disease of PAP.
尽管诱导多能干细胞（iPSC）衍生细胞的移植在治疗肺部疾病方面具有巨大的潜力，但缺乏体内数据证明人类 iPSC 衍生细胞在肺部疾病模型中具有明确的治疗益处。
我们在遗传性肺泡蛋白沉积症（PAP）的人源化疾病模型中测试了 iPSC 衍生巨噬细胞的治疗潜力。遗传性 PAP 是由 GM-CSF（粒细胞-巨噬细胞集落刺激因子）受体的遗传缺陷引起的，导致肺部巨噬细胞分化障碍和蛋白质/表面活性剂降解，随后导致严重的呼吸功能不全。
将源自人类 iPSC 的巨噬细胞进行肺内移植到人源化 PAP 小鼠中，并分析移植细胞的植入、体内分化和治疗效果。
在气管内应用时，iPSC 衍生的巨噬细胞在人源化 PAP 小鼠的肺部中植入。2 个月后，移植的细胞表现出典型的形态、表面标志物、功能和原发性人类肺泡巨噬细胞的转录谱。肺泡蛋白沉积症显著减少，表现为蛋白质含量和表面活性剂蛋白 D 水平降低、BAL 液混浊度降低以及移植小鼠肺部表面活性剂沉积减少。
我们首次证明，肺内移植人类 iPSC 衍生的巨噬细胞可导致肺部植入、原位分化为肺泡巨噬细胞表型，并减少人源化 PAP 模型中的肺泡蛋白沉积症。据我们所知，这一发现首次证明了人类 iPSC 衍生细胞在肺部疾病中的治疗潜力，并可能超越 PAP 这种罕见疾病产生深远影响。
