© 2003 American Thoracic Society
Cellular AlchemyPulmonary and Critical Care Medicine Carl T. Hayden VA Medical Center, Phoenix, Arizona and Arizona Respiratory Center University of Arizona Tucson, Arizona Alchemy, the art of transmuting base metals into gold, has been contrary to accepted belief for some time. Only a few years ago, the concept of blood cells transmuting into lung cells would have been no less heretical because it was widely accepted that the human lung had a limited capacity to grow and regenerate. In this issue of AJRCCM (pp. 318–322), Suratt and coworkers (1) challenge this maxim by providing further evidence in support of the capacity of hematopoietic stem cells to replenish lung cells. The authors examined lung biopsies after male-to-female stem cell bone marrow transplantation in three subjects and three control subjects. Their approach was immunohistochemical staining of the cells for cytokeratin to identify epithelial cells, platelet endothelial cell adhesion molecule to identify endothelial cells, and fluorescent in situ hybridization analysis to identify male cells. The results demonstrate that 2.5 to 8.0% of lung epithelial cells and 37.5 to 42.3% of lung endothelial cells were male, indicating the lung contained cells derived from the transplanted stem cells forming a chimera. The cellular source of multipotential stem cells may differ in the lung, depending on their location within the bronchopulmonary tree. In the proximal airways (trachea and bronchi), the basal cells appear to be the major source of proliferative cells. Further down in the terminal and respiratory bronchioles, Clara cells increase their proliferative rate in response to injury (2). The type II pneumocyte appears to be the stem cell in the alveoli and is able to generate daughter cells that can differentiate into type I pneumocytes. Studies by Krause and coworkers (3) and Kotton and coworkers (4) in murine lung support the concept of hematopoietic stem cells as a source of lung cells. In the former study, a single stem cell derived from male bone marrow was injected it into a female recipient. After 11 months, 20% of the cytokeratin expressing alveolar pneumocytes were Y-chromosome positive (many being type II cells). This surprisingly high number was attributed to a viral infection and/or the pretreatment of the animals with a dose of potentially lethal irradiation. The latter article describes a study of murine lungs after cultured bone marrow infusion in response to bleomycin-induced lung injury. Marrow-derived cells engrafted in recipient lung parenchyma were detected as cells with the morphologic and molecular phenotype of type I pneumocytes of the alveolar epithelium. The studies by Suratt and coworkers (1) expand these concepts by demonstrating that human studies generate similar results. An extension of the study of Suratt and coworkers (1) is that these hematopoietic stem cells could potentially be used therapeutically. The studies of hematopoietic stem cells grew from the discovery that pluripotent stem cells can be cultured from human fetal tissue and retain their ability to give rise to a variety of differentiated cell types found in all three embryonic germ layers (5). These embryonic stem cells are derived from blastocysts and fetal gonadal tissue. The use of embryonic stem cells, however, is clouded by the ethical issues that surround the use of cells harvested from early human embryos (6). Those who believe therapeutic cloning to be immoral have championed the use of adult hematopoietic stem cells. Some have claimed that because adult hematopoietic stem cells can be induced to differentiate into multiple cell lineages, embryonal cells will no longer be needed. The concept that autologous bone marrow stem cells target a specific organ and replace diseased cells is particularly attractive. Hematopoietic stem cells could potentially be used not only to repopulate damaged lung, but also to deliver genes as therapy in disorders with single gene defects such as cystic fibrosis or surfactant deficiencies. Hematopoietic stem cells could be taken from the blood, transfected with the potential therapeutic gene, and reinfused, correcting the genetic defect. Grove and coworkers (7) used bone marrow–derived stem cells to deliver gene therapy to murine lung epithelium. Irradiated female mice were transplanted with male marrow that had been transfected with a retrovirus encoding for enhanced green fluorescent protein. Lung epithelial cells expressing the green fluorescent marker protein were present in all recipients analyzed at 2, 5, or 11 months after transplantation, suggesting the feasibility of such an approach in humans. Although therapeutic stem cell transplantation has been shown to be possible in a mouse model, there is a long way to go before this technology can be applied to humans. A better understanding of how stem cells are targeted and migrate into the lung and the influence of microenvironmental factors in which a stem cell is placed must be obtained (8). Interaction with other cell types, components of the extracellular matrix, and a variety of cytokines and growth factors that influence transcription factors determines whether the cell remains in the undifferentiated state, proliferates, or differentiates. This is not to mention the myriad of problems with gene and protein expression, microenvironemental factors, angiogenesis, aging, and oncogenicity that need to be resolved before targeting cells and genes to the lung in humans (9). Suratt and coworkers (1) have taken the next logical step in demonstrating that lung cells can be derived from hematopoietic stem cells, extending the murine studies to humans and obtaining a better understanding of how lungs might be repaired. Moreover, these investigations provide the proof of concept that is necessary to further study the use of hematopoietic stem cells as therapies in a variety of pulmonary disorders. It now seems that repopulating the lung with hematopoietic cells, a concept that once seemed as far-fetched as turning lead into gold, might be possible. REFERENCES
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