This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 200502-309OCv1 173/2/171    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Loi, R. Articles by Weiss, D. J. Search for Related Content PubMed PubMed Citation Articles by Loi, R. Articles by Weiss, D. J.

Limited Restoration of Cystic Fibrosis Lung Epithelium In Vivo with Adult Bone Marrow–derived Cells

Pulmonary and Critical Care, University of Vermont College of Medicine, Burlington, Vermont

Correspondence and requests for reprints should be addressed to Daniel J. Weiss, M.D., Ph.D., 226 Health Sciences Research Facility, University of Vermont College of Medicine, Burlington, VT 05405. E-mail: dweiss{at}zoo.uvm.edu

Rationale: Recent literature suggests that adult bone marrow–derived cells can localize to lung and acquire immunophenotypic characteristics of lung epithelial cells. We speculated this might be a potential therapeutic approach for correcting defective lung epithelium in cystic fibrosis.

Objective: To determine whether adult bone marrow–derived cells containing normal cystic fibrosis transmembrane conductance regulator protein (CFTR) could repopulate lung epithelium in transgenic mice deficient in that protein.

Methods: Stromal marrow cells or total marrow obtained from adult male wild-type mice were transplanted into adult female Cftr knockout mice. To increase marrow cell recruitment naphthalene was used to induce airway epithelial injury in recipient mice.

Measurements and Main Results: At 1 wk, 1 mo, and 3 mo after transplantation, Cftr mRNA was detected in lung homogenates of recipient mice by reverse transcription–polymerase chain reaction. Cftr mRNA was not found in either donor marrow cells or mature circulating leukocytes. In situ examination of recipient mouse lungs demonstrated rare (0.025%) chimeric airway epithelial cells, some of which (0.01%) expressed CFTR protein. Naphthalene-induced airway remodeling nonsignificantly increased the number of chimeric airway epithelial cells expressing Cftr.

Conclusions: These results demonstrate that adult marrow cells can be recruited to airway epithelium and induced to express Cftr in mice otherwise lacking this protein. However, the number of observed chimeric epithelial cells is small and new strategies for enhancing airway epithelial remodeling by adult bone marrow–derived cells will be necessary for correction of defective CFTR-dependent chloride transport.

Key Words: cystic fibrosis • cystic fibrosis transmembrane conductance regulator protein • epithelium • lung • stem cell

This article has been cited by other articles:

				J. A. Fritzell Jr., Q. Mao, S. Gundavarapu, T. Pasquariello, J. M. Aliotta, A. Ayala, J. F. Padbury, and M. E. De Paepe Fate and Effects of Adult Bone Marrow Cells in Lungs of Normoxic and Hyperoxic Newborn Mice Am. J. Respir. Cell Mol. Biol., May 1, 2009; 40(5): 575 - 587. [Abstract] [Full Text] [PDF]

				F. Khan, T. S. Hallstrand, M. N. Geddes, W. R. Henderson Jr, and J. Storek Is allergic disease curable or transferable with allogeneic hematopoietic cell transplantation? Blood, January 8, 2009; 113(2): 279 - 290. [Abstract] [Full Text] [PDF]

				B. R. Stripp Hierarchical Organization of Lung Progenitor Cells: Is there An Adult Lung Tissue Stem Cell? Proceedings of the ATS, August 15, 2008; 5(6): 695 - 698. [Abstract] [Full Text] [PDF]

				J. E. Nichols and J. Cortiella Engineering of a Complex Organ: Progress Toward Development of a Tissue-engineered Lung Proceedings of the ATS, August 15, 2008; 5(6): 723 - 730. [Abstract] [Full Text] [PDF]

				J. M. Liebler, C. Lutzko, A. Banfalvi, D. Senadheera, N. Aghamohammadi, E. D. Crandall, and Z. Borok Retention of human bone marrow-derived cells in murine lungs following bleomycin-induced lung injury Am J Physiol Lung Cell Mol Physiol, August 1, 2008; 295(2): L285 - L292. [Abstract] [Full Text] [PDF]

				D. J. Weiss, J. K. Kolls, L. A. Ortiz, A. Panoskaltsis-Mortari, and D. J. Prockop Stem Cells and Cell Therapies in Lung Biology and Lung Diseases Proceedings of the ATS, July 15, 2008; 5(5): 637 - 667. [Full Text] [PDF]

				J. L. Spees, M. J. Whitney, D. E. Sullivan, J. A. Lasky, M. Laboy, J. Ylostalo, and D. J. Prockop Bone marrow progenitor cells contribute to repair and remodeling of the lung and heart in a rat model of progressive pulmonary hypertension FASEB J, April 1, 2008; 22(4): 1226 - 1236. [Abstract] [Full Text] [PDF]

				V. Sueblinvong, R. Loi, P. L. Eisenhauer, I. M. Bernstein, B. T. Suratt, J. L. Spees, and D. J. Weiss Derivation of Lung Epithelium from Human Cord Blood-derived Mesenchymal Stem Cells Am. J. Respir. Crit. Care Med., April 1, 2008; 177(7): 701 - 711. [Abstract] [Full Text] [PDF]

				A. P. Wong, A. E. Dutly, A. Sacher, H. Lee, D. M. Hwang, M. Liu, S. Keshavjee, J. Hu, and T. K. Waddell Targeted cell replacement with bone marrow cells for airway epithelial regeneration Am J Physiol Lung Cell Mol Physiol, September 1, 2007; 293(3): L740 - L752. [Abstract] [Full Text] [PDF]

				J. L. Spees, D. A. Pociask, D. E. Sullivan, M. J. Whitney, J. A. Lasky, D. J. Prockop, and A. R. Brody Engraftment of Bone Marrow Progenitor Cells in a Rat Model of Asbestos-Induced Pulmonary Fibrosis Am. J. Respir. Crit. Care Med., August 15, 2007; 176(4): 385 - 394. [Abstract] [Full Text] [PDF]

				E. L. Herzog, J. Van Arnam, B. Hu, J. Zhang, Q. Chen, A. M. Haberman, and D. S. Krause Lung-specific nuclear reprogramming is accompanied by heterokaryon formation and Y chromosome loss following bone marrow transplantation and secondary inflammation FASEB J, August 1, 2007; 21(10): 2592 - 2601. [Abstract] [Full Text] [PDF]

				M. R. Loebinger and S. M. Janes Stem Cells for Lung Disease Chest, July 1, 2007; 132(1): 279 - 285. [Abstract] [Full Text] [PDF]

				F. J. Accurso Update in Cystic Fibrosis 2006 Am. J. Respir. Crit. Care Med., April 15, 2007; 175(8): 754 - 757. [Full Text] [PDF]

				V. Brocker, F. Langer, T. G. Fellous, M. Mengel, M. Brittan, M. Bredt, S. Milde, T. Welte, M. Eder, A. Haverich, et al. Fibroblasts of Recipient Origin Contribute to Bronchiolitis Obliterans in Human Lung Transplants Am. J. Respir. Crit. Care Med., June 1, 2006; 173(11): 1276 - 1282. [Abstract] [Full Text] [PDF]

				B. R. Stripp and S. D. Shapiro Stem Cells in Lung Disease, Repair, and the Potential for Therapeutic Interventions: State-of-the-Art and Future Challenges. Am. J. Respir. Cell Mol. Biol., May 1, 2006; 34(5): 517 - 522. [Full Text] [PDF]

				D. J. Weiss, M. A. Berberich, Z. Borok, D. B. Gail, J. K. Kolls, C. Penland, and D. J. Prockop Adult Stem Cells, Lung Biology, and Lung Disease Proceedings of the ATS, May 1, 2006; 3(3): 193 - 207. [Full Text] [PDF]

				M. Selman and A. Pardo Role of epithelial cells in idiopathic pulmonary fibrosis: from innocent targets to serial killers. Proceedings of the ATS, January 1, 2006; 3(4): 364 - 372. [Abstract] [Full Text] [PDF]