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Published online on December 22, 2004, 10.1073/pnas.0406266102
PNAS | January 4, 2005 | vol. 102 | no. 1 | 186-191


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MEDICAL SCIENCES
Adult stem cells from bone marrow stroma differentiate into airway epithelial cells: Potential therapy for cystic fibrosis

Guoshun Wang * {dagger}, {ddagger}, Bruce A. Bunnell {dagger}, §, Richard G. Painter *, Blesilda C. Quiniones §, Susan Tom §, Nicholas A. Lanson, Jr *, Jeffrey L. Spees §, Donna Bertucci *, Alexandra Peister §, Daniel J. Weiss ¶, Vincent G. Valentine ||, Darwin J. Prockop §, and Jay K. Kolls **

*Departments of Medicine and Genetics, Gene Therapy Program, Louisiana State University Health Sciences Center, New Orleans, LA 70112; §Departments of Pharmacology and Medicine, Center for Gene Therapy, School of Medicine, Tulane University, New Orleans, LA 70112; ||Lung Transplantation Program, Ochsner Clinic Foundation, New Orleans, LA 70121; Pulmonary and Critical Care, Vermont Lung Center, University of Vermont College of Medicine, Burlington, VT 05405-0075; and **Department of Pediatrics, Division of Pulmonology, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213

Contributed by Darwin J. Prockop, November 19, 2004

Cystic fibrosis (CF), the most prevalent, fatal genetic disorder in the Caucasian population, is caused by mutations of CF transmembrane conductance regulator (CFTR). The mutations of this chloride channel alter the transport of chloride and associated liquid and thereby impair lung defenses. Patients typically succumb to chronic bacterial infections and respiratory failure. Restoration of the abnormal CFTR function to CF airway epithelium is considered the most direct way to treat the disease. In this report, we explore the potential of adult stem cells from bone marrow, referred to as mesenchymal or marrow stromal stem cells (MSCs), to provide a therapy for CF. We found that MSCs possess the capacity of differentiating into airway epithelia. MSCs from CF patients are amenable to CFTR gene correction, and expression of CFTR does not influence the pluripotency of MSCs. Moreover, the CFTR-corrected MSCs from CF patients are able to contribute to apical Cl- secretion in response to cAMP agonist stimulation, suggesting the possibility of developing cell-based therapy for CF. The ex vivo coculture system established in this report offers an invaluable approach for selection of stem-cell populations that may have greater potency in lung differentiation.

Abbreviations: CF, cystic fibrosis; CFTR, CF transmembrane conductance regulator; AEC, airway epithelial cell; MSCs, mesenchymal stem cells; CK-18, cytokeratin 18; TBP, TATA box-binding protein; IBMX, 3-isobutyl-1-methylxanthine; RFP, red fluorescent protein; FACS, fluorescence-activated cell sorter.

{dagger} G.W. and B.A.B. contributed equally to this work.

{ddagger} To whom correspondence should be addressed at: Louisiana State University Health Sciences Center, Gene Therapy Program, 642 CSRB, 533 Bolivar Street, New Orleans, LA 70112. E-mail: gwang{at}lsuhsc.edu.

© 2005 by The National Academy of Sciences of the USA


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