Harold A. Chapman, M.D.
N Engl J Med 2011; 364:1867-1868May 12, 2011
Article
During the fifth gestational week, the human lung begins to develop from epithelial buds of a primordial endodermal tube that is destined to give rise not only to the lung but also to most abdominal organs.1 Using tools to trace individual cells, biologists have determined that virtually all of the many epithelial cell types in the fully developed lung are progeny of these earliest lung-committed buds.2 Orderly lung development involves intricate crosstalk between the epithelium and the embryonic mesenchyme into which the epithelium grows and organizes, culminating in a complicated architecture involving many epithelial cell types as well as mesoderm-derived vessels and supporting stroma. But there is no known interconversion of endodermal and mesodermal cells during lung development. Given these principles, there has been no reason to suspect that a single cell — during development or in adulthood — has the capacity to program epithelial and mesenchymal elements of the lung. Rather, it is believed that the adult lung is maintained by regional domains of stem cells — for example, those supporting the epithelial glands, upper or lower airways, and alveoli.3,4
The findings of Kajstura et al. reported in this issue of the Journal challenge the current paradigms.5 These investigators report the isolation of a distinct stem-cell population from normal adult human lungs that, after clonal expansion, is capable of regenerating virtually all elements of an injured mouse lung and, astonishingly, of organizing apparently complete respiratory units in vivo within 14 days, including conducting airways and vessels. The authors used cell-surface c-kit receptors, known to mark hematopoietic and cardiac stem cells,6 to isolate and analyze these cells from adult lungs. They propose that c-kit–positive lung stem cells preferentially contribute to lung repair after injury because they are capable of differentiating into whatever element is needed to form a functional lung unit. If this is true, the identification of these stem cells promises to overcome one of the major hurdles in human lung regeneration: the identification and isolation of a native lung cell that could be used to replenish functioning lung tissue in a patient with lung disease, averting the hazards of allogeneic transplantation or reprogramming.
To assess whether this is fantasy, it is important to consider how the experiments reported by Kajstura et al. were conducted and what the investigators have and have not shown. Regeneration of lung tissue in vivo required ex vivo expansion of single c-kit–positive clones by a factor of more than 100,000 before implantation in an area of extremely severe injury. Yet in the normal lung, these cells are found mostly as isolated cells and the injury is usually not so severe. There is no evidence as yet that endogenous c-kit–positive lung stem cells contribute meaningfully to the development or repair of the lung. Indeed, if virtually all the epithelial cells during development and airway repair can be accounted for by amplification and differentiation of already lung-committed cells,2 then why do these cells exist? The authors offer the plausible possibility that there is a hierarchy of lung stem cells, with the c-kit–positive stem cells constituting the ultimate reservoir for self-renewal of epithelial and mesenchymal progenitors: cells with stemlike properties but more restricted regenerative potential. Clearly, studies that track the fate of c-kit–positive lung stem cells in vivo will be needed to clarify the functional effect of these cells on the development and maintenance of the lung.
The most provocative implication of the discovery of these cells concerns bioengineering. The field of bioengineered lung tissue sees clinical medicine on the distant horizon. But patients are living with airway transplants of devitalized tracheal matrix repopulated with their own epithelial cells.7 It is possible to grow well-organized rodent lung tissue beginning with an intact, devitalized lung matrix and embryonic lung cells and to observe a functional effect, if only briefly, when this tissue is implanted in live animals.8 Expanded, c-kit–positive lung stem cells from a patient are an appealing parent for bioengineered tissue, but 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 that such connections will develop,9 but can these stem cells efficiently assemble into a permanent, fully functional unit? What are the limits of expansion of lung stem cells that can be reasonably achieved while maintaining genomic integrity and avoiding senescence? In spite of the many major uncertainties that presage translation of the current results into applications in the clinical arena, these new findings should energize the field.
Elements of the extensive experiments reported here are sure to be controversial, and some may even prove to be incorrect. But the essential finding that undifferentiated human cells endowed with multilineage regenerative potential exist in normal lungs and, after expansion, can self-organize into integrated respiratory units in vivo is convincing. This finding alone raises not only bioengineering possibilities but also many questions about the role of such cells in disease. For example, telomerase deficiency, a known cause of familial adult pulmonary fibrosis, is also manifested in children as hematopoietic stem-cell failure.10 Might the c-kit–positive cells described here be key targets of telomerase deficiency in the lungs? The body of work reported by Kajstura et al. resets the starting point for clinical investigation into the role of stem cells and progenitor cells in lung disease.
Disclosure forms provided by the author are available with the full text of this article at NEJM.org.
Source Information
From the Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, School of Medicine, San Francisco.
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The New England Journal of Medicine: Research & Review Articles on Disease & Clinical Practice
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