Stem cells are found in all multi-cellular organisms and are characterised by both self-renewal – the ability to go through multiple cycles of cell division in an undifferentiated state – and the ability to differentiate into multiple cell types. Humans and other mammals have two types of stem cells. Embryonic stem cells can differentiate into all cell types (they are omnipotent); adult stem cells are found in small numbers in many organs and most have restricted differentiation potential, with, for example, haematopoieticstem cells being only able to differentiate into blood cell types. Stem cells share some of the characteristics of cancer cells, and several types of cancer are known to arise from a smaller population of "cancer stem cells". They also have potential uses in the treatment of degenerative and other diseases through promoting tissue restoration.

Cells with all the characteristics of adult stem cells have not previously been observed in the human lung, although both lung basal epithelial cells and Clara cells in the tracheal epithelium have some capacity to differentiate further. Piero Anversa of Harvard Medical School, Boston, Massachusetts, USA and his colleagues have now undertaken a study of human lung tissue to establish the identity and location of any pool of stem cells in this organ. Only cells established as being capable of self-renewal, differentiation into distinct lung cell types (multipotency) and generation of a clonal cell population in vivo and in vitro were to be classified as stem cells.

Anversa and his colleagues obtained samples of normal adult human lung tissue from unused donor organs, and fetal lung tissue from cases where a fetus had died in utero. Tissue and cell suspensions were analysed using a variety of biochemical techniques including cell sorting, immunocytochemistry, Western blotting, and immunoprecipitation using the stem cell antigen c-kit as a marker. Cells found to be positive for c-kit were identified as possible lung stem cells and sorted for further investigation. These c-kit positive cells were found to be negative for markers of other cell types, including those for haematopoietic and mesenchymal stem cells and epithelial and endothelial cells. They were able to generate clones of identical cells within three to four weeks. They were also seen in vitro to be able to differentiate into both epithelial and vessel-forming cells, but not into the cell types generated from cardiac stem cells. This suggested that these cells could indeed be classified as adult lung stem cells.

All stem cells may divide symmetrically into two identical stem cells or asymmetrically into one stem and one more differentiated cell. Both these modes of differentiation were observed in the harvested lung stem cells, although symmetric differentiation pre-dominated. The researchers then investigated the behaviour of these cells in vivo by transplanting them into the lungs of immunosuppressed mice with previously damaged lung tissue. The cells began both symmetric and non-symmetric division within two days of transplantation. Within 14 days, they were seen to have formed human bronchioles, alveoli and pulmonary vessels within the damaged mouse lungs. Stem cells were identified and harvested from this tissue and immediately transplanted into another mouse lung; these were also found able to generate human lung tissues, proving further that the cells were capable of self-renewal and long term proliferation in vivo.

Adult stem cells are typically located in distinct anatomical niches, connected to neighbouring cells by transmembrane proteins known as connexins and cadherins. Anversa and his group examined their original samples of adult and fetal lung tissue and found structures resembling stem cell niches in the alveolar wall and in the bronchioles. From cell counts, the group estimated that 79% of adult lung stem cells were likely to be found in bronchiole niches and 21% associated with alveoli.

Taken together, these findings suggest that multipotent cells with all the characteristics of adult stem cells are found in the human lung, and that these have more differentiation potential than, for example, basal epithelial and Clara cells. These cells have been shown to be capable of tissue regeneration in an animal model and may have potential in the treatment of lung disease.

Article: Kajstura, J., Rota, M., Hall, S.R. and 19 others (2011). Evidence for Human Lung Stem Cells. New Engl J Med 364(19): 1795-806