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      Gene-edited MLE-15 Cells as a Model for the Hermansky-Pudlak Syndromes.

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          Abstract

          Defining the mechanisms of cellular pathogenesis in rare lung diseases such as Hermansky-Pudlak syndrome (HPS) is often complicated by loss of the differentiated phenotype of cultured primary alveolar type 2 (AT2) cells, as well as by a lack of durable cell lines that are faithful to both AT2-cell and rare disease phenotypes. We used CRISPR/Cas9 gene editing to generate a series of HPS-specific mutations in the MLE-15 cell line. The resulting MLE-15/HPS cell lines exhibit preservation of AT2 cellular functions, including formation of lamellar body-like organelles, complete processing of surfactant protein B, and known features of HPS specific to each trafficking complex, including loss of protein targeting to lamellar bodies. MLE-15/HPS1 and MLE-15/HPS2 (with a mutation in Ap3β1) express increased macrophage chemotactic protein-1, a well-described mediator of alveolitis in patients with HPS and in mouse models. We show that MLE-15/HPS9 and pallid AT2 cells (with a mutation in Bloc1s6) also express increased macrophage chemotactic protein-1, suggesting that mice and humans with BLOC-1 mutations may also be susceptible to alveolitis. In addition to providing a flexible platform to examine the role of HPS-specific mutations in trafficking AT2 cells, MLE-15/HPS cell lines provide a durable resource for high-throughput screening and studies of cellular pathophysiology that are likely to accelerate progress toward developing novel therapies for this rare lung disease.

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          Author and article information

          Journal
          Am. J. Respir. Cell Mol. Biol.
          American journal of respiratory cell and molecular biology
          American Thoracic Society
          1535-4989
          1044-1549
          May 2018
          : 58
          : 5
          Affiliations
          [1 ] 1 Division of Neonatology and.
          [2 ] 2 Division of Pediatric Pulmonary Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee.
          Article
          10.1165/rcmb.2017-0324MA
          29190429

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