Use of Induced Pluripotent Stem Cells to Recapitulate Pulmonary Alveolar Proteinosis Pathogenesis

Suzuki, Takuji; Mayhew, Christopher N.; Sallese, Anthony; Chalk, Claudia; Carey, Brenna; Malik, Punam; Wood, Robert E.; Trapnell, Bruce C.

doi:10.1164/rccm.201306-1039oc

Cited by 54 publications

(46 citation statements)

References 44 publications

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“…herPAP-specific, gene-corrected induced pluripotent stem cells (17,25) may also represent a future source for transplantable macrophage progenitors. Current gene therapy approaches primarily use the transplantation of HSCs, a strategy successfully applied in a variety of diseases (26)(27)(28)(29), and we previously described effective HSC-based gene therapy for herPAP in Csf2rb −/− mice (16).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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“…Shortly thereafter, patient-specific and disease-specific lines were used to model the intracellular protein misfolding of mutant α1 antitrypsin protein 131,132 and the aberrant intracellular trafficking of mutant cystic fibrosis transmembrane conductance regulator 113 in differentiated epithelial lineages derived from patient-specific iPSCs. In addition, the monogenic inherited form of pulmonary alveolar proteinosis was recently modeled in vitro using macrophages derived from iPSCs generated from pediatric patients with this rare disease 133,134 . iPSCs from individuals with α1 antitrypsin deficiency have even undergone successful gene correction in vitro followed by functional hepatic transplantation into rodents 132 .…”

Section: Figurementioning

confidence: 99%

Lung regeneration: mechanisms, applications and emerging stem cell populations

Kotton

Morrisey

2014

Nat Med

431

367

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Recent studies have shown that the respiratory system has an extensive ability to respond to injury and regenerate lost or damaged cells. The unperturbed adult lung is remarkably quiescent, but after insult or injury progenitor populations can be activated or remaining cells can re-enter the cell cycle. Techniques including cell-lineage tracing and transcriptome analysis have provided novel and exciting insights into how the lungs and trachea regenerate in response to injury and have allowed the identification of pathways important in lung development and regeneration. These studies are now informing approaches for modulating the pathways that may promote endogenous regeneration as well as the generation of exogenous lung cell lineages from pluripotent stem cells. The emerging advances, highlighted in this Review, are providing new techniques and assays for basic mechanistic studies as well as generating new model systems for human disease and strategies for cell replacement.

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“…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]. Here, the embryonic origin of the cells may even serve as an advantage [15], and the transplantation of iPSC-derived macrophages potentially may be superior to the transplantation of adult CD34+ HSC-derived macrophages.…”

Section: Discussionmentioning

confidence: 99%

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

Ackermann

Kuhn

Kunkiel

et al. 2017

Transfus Med Hemother

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Background: Pluripotent stem cells, including induced pluripotent stem cells (iPSCs), have the capacity to differentiate towards all three germ layers and have been highlighted as an attractive cell source for the field of regenerative medicine. Thus, stable expression of therapeutic transgenes in iPSCs, as well as thereof derived progeny of hematopoietic lineage, may lay the foundation for innovative cell replacement therapies. Methods: We have utilized human iPSC lines genetically modified by lentiviral vector technology or targeted integration of reporter genes to evaluate transgene expression during hematopoietic specification and differentiation towards macrophages. Results: Use of lentiviral vectors equipped with an ubiquitous chromatin opening element (CBX3-UCOE) as well as zinc finger nuclease-mediated targeting of an expression cassette into the human adeno-associated virus integration site 1 (AAVS1) safe harbor resulted in stable transgene expression in iPSCs. When iPSCs were differentiated along the myeloid pathway into macrophages, both strategies yielded sustained transgene expression during the hematopoietic specification process including mature CD14+ and CD11b+ macrophages. Conclusion: Combination of human iPSC technology with either lentiviral vector technology or designer nuclease-based genome editing allows for the generation of transgenic iPSC-derived macrophages with stable transgene expression which may be useful for novel cell and gene replacement therapies.

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Use of Induced Pluripotent Stem Cells to Recapitulate Pulmonary Alveolar Proteinosis Pathogenesis

Cited by 54 publications

References 44 publications

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

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

Lung regeneration: mechanisms, applications and emerging stem cell populations

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

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