We read with interest the Community Corner that appeared in Nature Medicine1 on the topic of our recent work on human lung stem cells (hLSCs) 2. In their comments, Brigid Hogan and Barry Stripp have made a number of rather strong remarks concerning the actual validity of our results, some of which clearly lack acceptable scientific objectivity and border on personal attacks. Putting aside the healthy skepticism that confronts new findings, we are at a loss to explain the negative tone with which these comments were written. There is an important philosophical principle in medicine that has apparently been overlooked in these comments. Human studies constitute the foundation for animal work, not the reverse; this is also the policy of the US National Institutes of Health. The fact that new information does not coincide with established views should create excitement rather than unqualified criticisms. Contrary to the opinions expressed in the Community Corner, we think that the impossibility of performing lineage-tracing studies in humans does not diminish in any way the validity of our data.

Fate-mapping strategies using fluorescent reporter genes are commonly used to track the origin of cells and their destiny in animals in which genetic manipulations are easily introduced. This approach would represent the ideal retrospective assay for the detection of lung-cell formation, as the expression of the fluorescent label can be placed under the control of promoters of genes coding for epithelial and vascular proteins. However, with lineage-tracing studies, it is impossible to determine whether stem cells divide asymmetrically (that is, they self-renew), or whether the cell types of the tagged progeny derive from activation of an individual or several resident stem cells (that is, they are unipotent or multipotent). To obtain indisputable evidence in favor of the ability of hLSCs to self-renew and create lung parenchyma in vivo, we injected single-cell–derived clonal hLSCs (Fig. 1a) into damaged lungs of immunosuppressed mice. Clonal hLSCs divided asymmetrically2 and generated bronchioles, alveoli (Fig. 1b) and pulmonary vessels (Fig. 1c). Thus, hLSCs have the ability in vivoto form new stem cells and cells destined to acquire specialized function—these are the fundamental characteristics of tissue-specific adult stem cells3, 4. In contrast to these observations, Hogan’s view that basal cells are adult airway stem cells is incorrect5–7. These cells express the transcription factor p63 and the epithelial cell cytoplasmic proteins cytokeratin-5, cytokeratin-8, cytokeratin-14 and cytokeratin-18 (ref. 6). The lack of stem cell antigens and the presence of specific nuclear and cytoplasmic markers make this cell, at most, an amplifying cell; it is simply not a progenitor or a precursor cell8. By definition, stem cells are lineage-negative cells9, 10. The lineage-tracing studies performed using a Clara cell promoter5 further disproves the purported stemness of basal cells. The identification and characterization of tissue-specific adult stem cells is a complex, demanding process. After nearly 50 years since the discovery of hematopoietic stem cells, the search for the long-term multilineage repopulating cells continues and has not been resolved yet10.