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Gene delivery by the hSP-B promoter to lung alveolar type II epithelial cells in LAL-knockout mice through bone marrow mesenchymal stem cells

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Abstract

Tissue damage and inflammation promote bone marrow stem cells (BMSCs) to differentiate into a variety of cell types in residing tissues. BMSCs can stably maintain their plasticity and are an ideal cell population for delivery of therapeutic genes to non-hematopoietic tissues. Using lacZ as a reporter gene, we demonstrated that the lung-specific human surfactant protein B (hSP-B) 1.5-kb promoter is able to deliver the lacZ gene into the lung of lysosomal acid lipase (LAL) gene-knockout (lal−/−) mice by β-galactosidase staining, flow cytometry and double immunofluorescence staining. Around 10–18% alveolar type II epithelial cells (AT II cells) exhibited positive lacZ gene expression after 8 weeks of BMSC injection in recipient lal−/− mice. The wild-type mice exhibited no expression after the same treatment. BMSCs from hSP-B 1.5-kb lacZ transgenic mice entered and repopulated in lal−/− bone marrow. The study supports a concept that pulmonary inflammation caused by LAL deficiency can trigger BMSC residing in lal−/− bone marrow, migrating into the lung and converting into residential AT II cells. The hSP-B 1.5 kb promoter is an ideal tool to deliver therapeutic genes into AT II cells through BMSCs to cure pulmonary inflammation-triggered diseases.

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References

  1. Aliotta JM, Passero M, Meharg J, Klinger J, Dooner MS, Pimentel J et al. Stem cells and pulmonary metamorphosis: new concepts in repair and regeneration. J Cell Physiol 2005; 204: 725–741.

    Article  CAS  Google Scholar 

  2. Yan C, Du H . Alveolus formation: what have we learned from genetic studies? J Appl Physiol 2004; 97: 1543–1548.

    Article  CAS  Google Scholar 

  3. Yan C, Lian X, Li Y, Dai Y, White A, Qin Y et al. Macrophage-specific expression of human lysosomal acid lipase corrects inflammation and pathogenic phenotypes in lal−/− mice. Am J Pathol 2006; 169: 916–926.

    Article  CAS  Google Scholar 

  4. Lian X, Yan C, Yang L, Xu Y, Du H . Lysosomal acid lipase deficiency causes respiratory inflammation and destruction in the lung. Am J Physiol Lung Cell Mol Physiol 2004; 286: L801–L807.

    Article  CAS  Google Scholar 

  5. Lian X, Yan C, Qin Y, Knox L, Li T, Du H . Neutral lipids and peroxisome proliferator-activated receptor-{gamma} control pulmonary gene expression and inflammation-triggered pathogenesis in lysosomal acid lipase knockout mice. Am J Pathol 2005; 167: 813–821.

    Article  CAS  Google Scholar 

  6. Whitsett JA, Nogee LM, Weaver TE, Horowitz AD . Human surfactant protein B: structure, function, regulation, and genetic disease. Physiol Rev 1995; 75: 749–757.

    Article  CAS  Google Scholar 

  7. Yang L, Naltner A, Kreiner A, Yan D, Cowen A, Du H et al. An enhancer region determines hSP-B gene expression in bronchiolar and ATII epithelial cells in transgenic mice. Am J Physiol Lung Cell Mol Physiol 2003; 284: L481–L488.

    Article  CAS  Google Scholar 

  8. Rehli M, Niller HH, Ammon C, Langmann S, Schwarzfischer L, Andreesen R et al. Transcriptional regulation of CHI3L1, a marker gene for late stages of macrophage differentiation. J Biol Chem 2003; 278: 44058–44067.

    Article  CAS  Google Scholar 

  9. Kim CF, Jackson EL, Woolfenden AE, Lawrence S, Babar I, Vogel S et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 2005; 121: 823–835.

    Article  CAS  Google Scholar 

  10. Glasser SW, Burhans MS, Korfhagen TR, Na CL, Sly PD, Ross GF et al. Altered stability of pulmonary surfactant in SP-C-deficient mice. Proc Natl Acad Sci USA 2001; 98: 6366–6371.

    Article  CAS  Google Scholar 

  11. Glasser SW, Detmer EA, Ikegami M, Na CL, Stahlman MT, Whitsett JA . Pneumonitis and emphysema in sp-C gene targeted mice. J Biol Chem 2003; 278: 14291–14298.

    Article  CAS  Google Scholar 

  12. Hawgood S, Ochs M, Jung A, Akiyama J, Allen L, Brown C et al. Sequential targeted deficiency of SP-A and -D leads to progressive alveolar lipoproteinosis and emphysema. Am J Physiol Lung Cell Mol Physiol 2002; 283: L1002–L1010.

    Article  CAS  Google Scholar 

  13. Korfhagen TR, Bruno MD, Ross GF, Huelsman KM, Ikegami M, Jobe AH et al. Altered surfactant function and structure in SP-A gene targeted mice. Proc Natl Acad Sci USA 1996; 93: 9594–9599.

    Article  CAS  Google Scholar 

  14. Wert SE, Yoshida M, LeVine AM, Ikegami M, Jones T, Ross GF et al. Increased metalloproteinase activity, oxidant production, and emphysema in surfactant protein D gene-inactivated mice. Proc Natl Acad Sci USA 2000; 97: 5972–5977.

    Article  CAS  Google Scholar 

  15. Rice WR, Conkright JJ, Na CL, Ikegami M, Shannon JM, Weaver TE . Maintenance of the mouse type II cell phenotype in vitro. Am J Physiol Lung Cell Mol Physiol 2002; 283: L256–L264.

    Article  CAS  Google Scholar 

  16. Yang L, Lian X, Cowen A, Xu H, Du H, Yan C . Synergy between signal transducer and activator of transcription 3 and retinoic acid receptor-alpha in regulation of the surfactant protein B gene in the lung. Mol Endocrinol 2004; 18: 1520–1532.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by National Institute of Health Grants HL-061803 and HL-067862 (C Yan and H Du). We thank Ms Marjorie Albrecht for critical reading of this manuscript.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, The Center for Immunobiology, Indiana University School of Medicine, Indianapolis, IN, USA

    C Yan, Y Dai, X Wang & P Qu

  2. Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

    X Lian, A White, Y Qin & H Du

  3. Department of Pathology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    C Yan & X Wang

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  1. C Yan
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  2. X Lian
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  3. Y Dai
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  4. X Wang
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  5. P Qu
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  6. A White
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  7. Y Qin
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  8. H Du
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Correspondence to C Yan or H Du.

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Supplementary Information accompanies the paper on Gene Therapy website (http://www.nature.com/gt)

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Yan, C., Lian, X., Dai, Y. et al. Gene delivery by the hSP-B promoter to lung alveolar type II epithelial cells in LAL-knockout mice through bone marrow mesenchymal stem cells. Gene Ther 14, 1461–1470 (2007). https://doi.org/10.1038/sj.gt.3303006

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  • DOI: https://doi.org/10.1038/sj.gt.3303006

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