Pulmonary Transplantation of Human Induced Pluripotent Stem Cell–derived Macrophages Ameliorates Pulmonary Alveolar Proteinosis

Abstract

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.

Generation and Functional Characterization of Monocytes and Macrophages Derived from Human Induced Pluripotent Stem Cells

“…The differentiation process is MYB‐independent and associated with HOXA expression (Buchrieser, James, & Moore, 2017; Dou et al., 2016; Ivanovs et al., 2017; Ng et al., 2016; Vanhee et al., 2015), indicating this recapitulates primitive hematopoiesis in vivo. Other studies found that hiPSC‐derived macrophages (iPSDMs) could acquire tissue‐specific characteristics in vitro (Takata et al., 2017) and in vivo (Happle et al., 2018; Takata et al., 2017) by coculture with other tissue‐resident cell types. All of these studies indicate that iPSDMs can be a unique source of patient‐specific, tissue‐resident macrophages given that they can be produced in unlimited cell numbers from a renewable donor source of choice and can adopt a tissue resident macrophage‐like identity.…”

Can animal models really teach us anything about pneumonia? Pro

“…Indeed, inhaled recombinant GM-CSF (Sargramostim, Leukine) improved oxygenation and outcome in patients with pneumonia-associated acute respiratory distress syndrome [59], demonstrating that preclinical animal models aid the development of adjuvant therapies against infectious lung diseases. Human pluripotent stem cell-derived macrophages prevent early Pseudomonas aeruginosa respiratory tract infections in mice [60]; this and other examples [61,62] may help develop antibiotic-independent cellular immunotherapies for use in humans. Antibiotic compound screening in animal models can identify novel Demonstration that cellular senescence increases expression of host ligands for bacterial adhesins in the lungs [40] Characterising effects of environmental exposures…”

Rare Lung Disease Research

“…23 Subsequently, the same group transplanted macrophages derived from human inducible pluripotent stem cells into the lungs of humanized PAP mice, where they functioned as primary human alveolar macrophages, leading to reduced alveolar fluid turbidity and improved lung histopathology. 24 Using a combination of strategies to deliver gene-corrected macrophages to the lungs may eventually lead to a cure for hereditary PAP.…”