Fig. 4 Prenatal gene editing in SftpcI73Tmice decreases mutant SP-CI73Tproprotein and improves lung alveolarization. Prenatal gene editing in SftpcI73Tmice.

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Volume 25, Issue 2, Pages (February 2017)

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Fig. 4 Prenatal gene editing in SftpcI73Tmice decreases mutant SP-CI73Tproprotein and improves lung alveolarization. Prenatal gene editing in SftpcI73Tmice decreases mutant SP-CI73Tproprotein and improves lung alveolarization. (A) Schematic representation of SftpcI73T mutation causing intracellular accumulation of SP-CI73T proprotein resulting in AT2 cell injury and potential cell rescue with CRISPR-Cas9–mediated excision of SftpcI73T. (B) Fluorescent stereomicroscopy, using a filter to detect EGFP, of an E19 fetus (outlined by white dashed line) after intra-amniotic injection of Ad.Sftpc.GFP at E16 shows green fluorescence in the chest region. (C) Fluorescent stereomicroscopy, using a filter to detect EGFP, of lungs at E19 after E16 intra-amniotic injection of Ad.Sftpc.GFP. (D) IHC for EGFP of lung parenchyma at E19 after E16 intra-amniotic injection of Ad.Sftpc.GFP. (E) FACS analysis to assess EGFP expression in all pulmonary cells and pulmonary epithelial cells (EPCAM+ cells) from E19 fetuses after E16 intra-amniotic injection of Ad.Sftpc.GFP. n = 10 to 11 per group. (F) PCR analysis of DNA from E19 lung epithelial cells (EPCAM+-sorted cells) of E16 Ad.Sftpc.GFP intra-amniotic injected fetuses. Edited Sftpc band, 605 bp; −C and +C, negative and positive controls consisting of nontransfected mouse neuro-2a cells and mouse N2a cells cotransfected with plasmids containing spyCas9 or sgRNA1-A and sgRNA5-B, respectively. (G) Schematic of SftpcI73T experimental design. (H) Excision of the mutant Sftpc allele in AT2 cells was assessed by IHC. Lungs of E19 SftpcI73T/WT mice were assessed for expression of surfactant protein B (SFTPB) and hemagglutinin (HA) after E16 intra-amniotic injection of Ad.Null.GFP or Ad.Sftpc.GFP. SFTPB+HA− (yellow arrowheads indicate representative cells), excision; SFTPB+HA+ (white arrowheads indicate representative cells), no excision; control, uninjected WT E19 lungs. (I) The percentage of SFTPB+HA− cells on IHC was quantified. (J) Lung IHC for homeodomain only protein X (HOPX) at E19 to assess AT1 cell morphology and spreading in SftpcI73T/WT mice injected with Ad.Null.GFP or Ad.Sftpc.GFP at E16. (K) The internuclear distance was measured to quantify AT1 spreading. (L) Hematoxylin and eosin (H&E) staining of lungs from E19 SftpcI73T/WT mice injected at E16 with Ad.Null.GFP or Ad.Sftpc.GFP to assess alveolarization and sacculation. (M) The MLI was calculated to assess alveolarization. n = 3 to 4 per group; ##P < 0.0001, **P < 0.01, and *P < 0.05 by one-way ANOVA followed by Tukey’s multiple comparison test. WT, wild-type. Scale bars, 50 μm. Deepthi Alapati et al., Sci Transl Med 2019;11:eaav8375 Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works