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

Abstract

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 CFTRcorrected 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.

Assessment of cystic fibrosis transmembrane conductance regulator (CFTR) activity in CFTR-null mice after bone marrow transplantation

“…Because unfractionated BM was used for transplantation, the identity of the cells that differentiate into mature GI epithelial cells cannot be determined. Recent in vitro studies suggest that marrow stromal stem cells can contribute to the airway epithelium (4). Also, a recent in vivo study suggests that freshly isolated BM cells can contribute to the respiratory tract (23).…”

“…CF would be a good candidate for this approach because (i) CF is a multiorgan disease characterized by epithelial dysfunction, (ii) replacement of just 10% of epithelial cells could be sufficient to correct the phenotype (2), and (iii) cell therapy may be combined with gene therapy, as suggested by data demonstrating that BMDCs can be stably transduced in vitro and retain their ability to differentiate into lung epithelium while maintaining long-term transgene expression (3). Furthermore, BMDCs can differentiate into epithelial cells in vitro and express functional CFTR (4).…”

Mesenchymal stem cells inhibit proliferation and apoptosis of tumor cells: impact on in vivo tumor growth

“…This might account for the observation that, in some circumstances, tumor cells metastasizing to the BM remain dormant and can only be detected by sensitive methods. 34 We suggest that MSC have the ability to form a cancer stem cell niche in which tumor cells preserve their self-renewal ability and thus the potential to proliferate and sustain the malignant process. Therefore, much caution should be used in the therapeutic exploitation of MSC in the context of malignant conditions.…”

Derivation and immunological characterization of mesenchymal stromal cells from human embryonic stem cells

“…Over the last several years MSCs have been derived from a variety of other tissues of adult [5][6][7] or fetal origin [8,9]. Interestingly, these MSCs have also been shown to have a wider differentiation capability in vitro and in vivo than previously appreciated, at least in some experimental models, [10][11][12] and thus have attracted attention as very desirable cells for regenerative medicine. Furthermore, MSCs from BM and other tissues possess unique immunological characteristics that make them even more attractive for potential clinical applications [13][14][15][16].…”