Stem cells are special cells that can self-renew and give rise to many different cell types. Certain body parts, like the blood and intestine, are known to regenerate in adults from multipotent stem cell populations. Other organs, like the lungs, traditionally have not been thought to possess such cells.
In a paper published this week in NEJM, Kajstura et al. challenge this paradigm. They claim to have found human lung stem cells: self-renewing cells with the potential to form a range of lung cell types and structures, from bronchioles to alveoli to blood vessels.
IDENTIFYING LUNG STEM CELLS
To identify a population of putative lung stem cells, the authors used molecular cell-sorting techniques to isolate cells bearing stem cell markers from samples of normal lung tissue. These cells, when implanted in mice with lung injuries, appeared to drive the regeneration of entire respiratory units: human DNA was detected in regenerated bronchioles, alveoli, and vessels perfusing those alveoli. What’s more, these human structures successfully integrated with existing mouse structures. For example, direct connections were found between mouse and human pulmonary vessels.
In addition to evidence of multipotency, the authors report evidence of self-renewal. When clonal human lung stem cells were harvested from the treated mice and reimplanted in other injured mice, the second set of mice demonstrated evidence of lung repair as well. The authors also confirmed that stem cells from other organs, like the heart, were not able to regenerate lung tissue when introduced into injured lung. This supported the interpretation that a lung-specific stem cell, rather than the general lung milieu, drives regeneration.
While the proposal of a lung stem cell represents a radical shift in thinking, it does not entirely negate the current paradigm. The authors propose that in vivo, both stem cells and unipotent progenitor cells like Clara cells and Type II pneumocytes are involved in the regenerative response to injury. The lung stem cell may serve as a “reservoir” for regenerating various epithelial and mesenchymal progenitors, offering the benefits of multipotency to complement the relatively greater regenerative potential of the unipotent progenitors.
That being said, why does the existence of a lung stem cell matter?
In an accompanying editorial, Harold Chapman, M.D., of the division of Pulmonary and Critical Care Medicine at the University of California, San Francisco (USCF) School of Medicine describes the potential impact of this discovery on the field of bioengineering. It may be possible to bioengineer lung tissue that can help treat patients with lung injury. Using lung stem cells would avoid the many potential complications associated with allogeneic transplantation.
Still, significant additional evidence is needed to demonstrate the functional viability of any regenerated lung tissue. As Chapman writes, “Kajstura et al report no evidence that the observed respiratory units integrate sufficiently with the host vasculature or airways to support perfusion or ventilation. There are reasons to anticipate such connections will develop, but can these stem cells efficiently assemble into a permanent, fully functional unit?”
NEJM Deputy Editor Dan L. Longo, M.D., states, “The findings are intriguing and open new avenues of investigation. How do [stem] cells from the heart and marrow differ from those in the lung? What local factors act to promote the differentiation of such cells into tissues that are thought to be derived from distinct germ cell layers, for example, endoderm-derived epithelial cells and mesoderm-derived blood vessels? Can these cells be applied to the treatment of human lung diseases? Future work will no doubt shed light on these important questions.”
How do currently available bioengineering-based treatment options factor into your clinical practice? How does the putative existence of lung stem cells influence your approach to treating lung injury?