There were more than 150 references to “stem cells and cystic fibrosis” by 2013. As their use in treating people with CF some way off only a few are mentioned here.
2005 Wang G, Bunnell BA, Painter RG, Quiniones BC, Tom S, Lanson NA Jr, Spees JL Bertucci D, Peister A, Weiss DJ, Valentine VG, Prockop DJ Kolls JK. Adult stem cells from bone marrow stroma differentiate into airway epithelial cells: potential therapy for cystic fibrosis. Proc Nat Acad Sci 2005; 102:186- 191. [PubMed]
The authors 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. They 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 vivococulture system established in this report offers an invaluable approach for selection of stem-cell populations that may have greater potency in lung differentiation.
So stem cells from the marrow of people with CF could be treated with gene therapy and still develop into airway epithelia and function as chloride channels when they reached the lungs. Another attractive potential method of correcting the basic defect in respiratory epithelium.
2005 Spencer H, Rampling D, Aurora P, Bonnet D, Hart SL, Jaffe A. Transbronchial biopsies provide longitudinal evidence for epithelial chimerism in children following sex mismatched lung transplantation. Thorax 2005; 60:60-62. [PubMed]
The aim of this study was to assess whether transbronchial biopsies could be used to study the time course of chimerism following lung transplantation (chimerism = the presence in an individual cells of different origins). Specimens of transbronchial lung biopsies from five time points taken for clinical purposes from two boys, who had received a sex mismatched heart-lung transplant for end stage CF, were examined. Evidence of chimerism was found in up to 6.6% of epithelial cells in bronchial tissue without apparent evidence of fusion. This engraftment was seen as early as 3 weeks and remained relatively constant up to 37 months.
This study has demonstrated proof of principle for long term chimerism in lung epithelium. Transbronchial biopsies may provide a new method for studying the kinetics of stem cell engraftment in the lung.
2005 Coraux C. Nawrocki-Raby B. Hinnrasky J. Kileztky C. Gaillard D. Dani C. Puchelle E. Embryonic stem cells generate airway epithelial tissue. Am J Resp Cell Mol Biol 2005; 32:87-92. [PubMed]
Embryonic stem (ES) cells are self-renewable and pluripotent cells derived from the inner cell mass of a blastocyst-stage embryo. ES cell pluripotency is being investigated increasingly to obtain specific cell lineages for therapeutic treatments and tissue engineering. Type II alveolar epithelial cells have been derived from murine ES cells, but the capacity of the latter to generate differentiated airway epithelial tissue has never been reported. Herein, we show by RT-PCR and immunocytochemistry that murine ES cells are able to differentiate into nonciliated secretory Clara cells, and that type I collagen induces this commitment. Moreover, when cultured at the air-liquid interface, ES cells give rise to a fully differentiated airway epithelium. By quantitative histologic examination, immunohistochemistry, and scanning electron microscopy, we show that the bioengineered epithelium is composed of basal, ciliated, intermediate, and Clara cells, similar to those of native tracheobronchial airway epithelium. Transmission electron microscopy and Western blotting reveal that the generated epithelium also exhibits the ultrastructural features and secretory functions characteristic of airway epithelial tissue. These results open new perspectives for cell therapy of injured epithelium in airway diseases, such as bronchopulmonary dysplasia, cystic fibrosis, or bronchiolitis obliterans.
2005 Wang G. Bunnell BA. Painter RG. Quiniones BC. Tom S. Lanson NA Jr. Spees JL. Bertucci D. Peister A. Weiss DJ. Valentine VG. Prockop DJ. Kolls JK. Adult stem cells from bone marrow stroma differentiate into airway epithelial cells: potential therapy for cystic fibrosis. Proc Nat Acad Sci 2005; 102:186-191. [PubMed]
Marrow stromal stem cells (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.
2008 Sueblinvong V, Loi R, Eisenhauer PL, Bernstein IM, Suratt BT, Spees JL, Weiss DJ. Derivation of lung epithelium from human cord blood-derived mesenchymal stem cells. Am J Resp Crit Care 2008; 177:701-711. [PubMed]
Both embryonic stem cells and adult bone marrow stem cells can participate in the regeneration and repair of diseased adult organs, including the lungs. However, there are no available in vivo data with embryonic stem cells. Human umbilical cord blood contains both hematopoietic and non-hematopoietic stem cells, which have been used clinically as an alternative to bone marrow transplantation for hematologic malignancies and other diseases.
Human cord blood was obtained from normal deliveries at the University of Vermont. Cord blood-derived mesenchymal stem cells (MSCs) were cultured in specialized airway growth media or with specific growth factors. mRNA and protein expression were analyzed with PCR and immunofluorescent staining. The MSCs were systematically administered to immunotolerant, non-obese diabetic/severe combined immunodeficiency (NOD-SCID) mice and their lungs were analyzed for the presence of human cells. When cultured in specialized airway growth media or with specific growth factors, CB-MSCs differentially expressed a variety of protein including CFTR. Furthermore, CB-MSCs were easily transduced with recombinant lentiviral vectors to express human CFTR. After systemic administration to immunotolerant, NOD-SCID, mice, rare cells were found in the airway epithelium that had acquired cytokeratin and human CFTR expression. The authors concluded that cord blood stem cells appear to be comparable to marrow-derived stem cells in their ability to express phenotypic markers of airway epithelium and to participate in airway remodelling in vivo.
There is no way to describe this study briefly and it appears to be potentially important providing as it does further evidence that stem cell therapy may be a possibility for cystic fibrosis. Cord blood-derived mesenchymal stem cells appear to be comparable to mesenchymal stem cells obtained from adult bone marrow in their ability to express phenotypic markers of airway epithelium and to participate in airway remodeling in vivo. This is relevant particularly for those CF families that have already arranged to store umbilical cord blood from any subsequent pregnancies in the hope that it may prove to be a source of stem cells which could be used to treat their previous child with CF.
2012 Wong AP, Bear CE, Chin S, Pasceri P, Thompson TO, Huan LJ, Ratjen F, Ellis J, Rossant J.Directed differentiation of human pluripotent stem cells into mature airway epithelia expressing functional CFTR protein. Nat Biotechnol. 2012; 30(9):876-82. [PubMed]
The authors describe an in vitro directed differentiation protocol for generating functional CFTR-expressing airway epithelia from human embryonic stem cells. Carefully timed treatment by exogenous growth factors that mimic endoderm developmental pathways in vivo followed by air-liquid interface culture results in maturation of patches of tight junction–coupled differentiated airway epithelial cells that demonstrate active CFTR transport function. As a proof of concept, treatment of CF patient induced pluripotent stem cell–derived epithelial cells with a small-molecule compound to correct for the common CF processing mutation resulted in enhanced plasma membrane localization of mature CFTR protein.
The study provides a much needed method for generating patient-specific airway epithelial cells for disease modeling and in vitro drug testing.
2014 Firth AL. Dargitz CT. Qualls SJ. Menon T. Wright R. Singer O. Gage FH. Khanna A. Verma IM. Generation of multiciliated cells in functional airway epithelia from human induced pluripotent stem cells. Proc Natl Acad Sci USA 2014; 111(17):E1723-30. (free full text) [PubMed]
Using induced pluripotent stem cells (iPSCs), the authors generated mature multi-ciliated cells in a functional airway epithelium.
Their report demonstrating the generation of mature multi-ciliated cells in respiratory epithelium from iPSCs is a significant advance toward modelling a number of human respiratory diseases in vitro.
Boruczkowski D; Gladysz D; Demkow U; Pawelec K. The Potential of Wharton’s Jelly Derived Mesenchymal Stem Cells in Treating Patients with Cystic Fibrosis. Adv Exp Med Biol 2015; 833:23-9. [PubMed]
Even though CF is monogenic, the trials of topical gene transfer into airway epithelial cells have so far been disappointing. It is proven that stem cells can be differentiated into type II alveolar epithelial cells. Wharton’s jelly-derived mesenchymal stem cells (MSC) from non-CF carrier third-party donors could be an effective alternative to bone marrow or embryonic stem cells. This review discusses the clinical potential of mesenchymal stem cell in CF patients.