Pulmonary transplantation of macrophage progenitors as effective and long-lasting therapy for hereditary pulmonary alveolar proteinosis

Abstract

Hereditary pulmonary alveolar proteinosis (herPAP) is a rare lung disease caused by mutations in the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor genes, resulting in disturbed alveolar macrophage differentiation, massive alveolar proteinosis, and life-threatening respiratory insufficiency. So far, the only effective treatment for herPAP is repetitive whole-lung lavage, a merely symptomatic and highly invasive procedure. We introduce pulmonary transplantation of macrophage progenitors as effective and long-lasting therapy for herPAP. In a murine disease model, intrapulmonary transplanted macrophage progenitors displayed selective, long-term pulmonary engraftment and differentiation into functional alveolar macrophages. A single transplantation ameliorated the herPAP phenotype for at least 9 months, resulting in significantly reduced alveolar proteinosis, normalized lung densities in chest computed tomography, and improved lung function. A significant and sustained disease resolution was also observed in a second, humanized herPAP model after intrapulmonary transplantation of human macrophage progenitors. The therapeutic effect was mediated by long-lived, lung-resident macrophages, which displayed functional and phenotypical characteristics of primary human alveolar macrophages. Our findings present the concept of organotopic transplantation of macrophage progenitors as an effective and long-lasting therapy of herPAP and may also serve as a proof of principle for other diseases, expanding current stem cell-based strategies toward potent concepts using the transplantation of differentiated cells.

Ex vivo Generation of Genetically Modified Macrophages from Human Induced Pluripotent Stem Cells

“…Following up on recent reports highlighting the self-renewal and repopulating capacity of TRMs as well as their considerable tissue plasticity upon transplantation [9,10], we have recently demonstrated that a single intrapulmonary transplantation of healthy or genetically corrected bone marrow-derived macrophages can substantially improve the disease phenotype of pulmonary alveolar proteinosis in two relevant murine in vivo disease models [11,12]. Although our initial studies used HSPCs derived from murine bone marrow or human cord blood, also iPSC-derived macrophages represent a highly interesting source for cell therapy strategies in diseases related to macrophage dysfunction [13,14].…”

Tratamiento de la proteinosis alveolar primaria del adulto

“…Sin embargo, es un tratamiento aun en investigación y del que existe poca evidencia. Una nueva línea de investigación, que evitaría el tratamiento ablativo previo, podría ser el trasplante pulmonar de macrófagos alveolares 46 , que ha mostrado resultados prometedores en modelos murinos y que podría ser una opción de tratamiento en un futuro 47 .…”

Pulmonale Alveolarproteinose

“…Kürzlich wurde die Transplantation von Makrophagen als vielversprechende Perspektive für die Behandlung der hereditären AP vorgeschlagen [8,15,17].…”