Evidence of a single type of epithelial stem cell in the airway and its implication for the future therapeutic strategy

Aims: Epithelial stem cells of the respiratory tract have been under intense investigation for their detection and characterization. However, no definite conclusion has yet been reached. This is partly because the respiratory tract is complex, consisting of several functionally and structurally different segments. This special situation has provided a general understanding that each of these segments possesses a specifically differentiated cell type that can also play a role as a precursor for epithelial regeneration. For this reason, investigators have primarily been concerned with detection of solid molecular markers which define only conspicuous phenotypes. This a priori tends to exclude the observation that phenotypic traits of stem cells are changeable depending on the environment (niche) in which they reside. This paper presents a new line of evidence that the airway stem cell is essentially of a single type which yet assumes partial differentiation to various phenotypes depending on where it is present.

Material and Methods: Undifferentiated cells of a cloned epithelial cell line obtained from the lung of a near-term hamster fetus were exposed to six different model environments constructed in culture vessels and the exposure continued over variously prescribed periods of time. The thus constructed environments consisted of collagen gel, semi-solid agar, airway submucosal fibroblasts, growth factors, vitamin A, hydrocortisone, high Ca2⁺ with low serum in medium, hypoxia, and long term (150 passages) culture. Differentiated cell characteristics were mainly identified by lipid analysis, immunochemical techniques, and light and electron microscopy.

Results: Responding to the specific nature of the model environment introduced in culture, the cells underwent differentiation along six distinctly recognizable lineages, which can be observed in physiological or pathological conditions of the airway. These lineages include Clara cells, type II pneumocytes, neuroendocrine cells, ciliated cells in pseudostratified epithelium, specific keratin positive cells, and cornified cells with cross-linking envelope.

Conclusion:

• The above described observation strongly suggests that the airway stem cell is of a single type, undifferentiated and multipotential, capable of regenerating all types of functional cells to be found in the airway epithelium.

• Although exact mechanisms of this multi-lineage differentiation and both internal and external factors involved in these mechanisms are yet to be investigated, studies to see whether similar in vitro observations hold true in the human stem cells seem worthy of undertaking.

• One of the goals of adult or fetal stem cell research is to establish inexhaustible sources of cells or tissues, with which impaired organs, tissues or cells can be supplemented or replaced. Provided that there is also a similar type of stem cell in human airways, it is desirable to explore the way which enables us to raise adult/fetal human stem cell lines with the least genetic alterations. Further, submucosal glands may be the most appropriate part of the respiratory tract from which such stem cells are surgically obtained without severe damage to the organ.