Understanding how circulating stem cells released from the haematopoietic compartment accumulate and differentiate into the parenchymal cells of organs has become an exciting, thought provoking, and intriguing forefront of medical science. Many investigators have begun to address the ability of various populations of stem cells to aid in the repair of nearly every organ including the lungs,^1–19 either through recruitment and differentiation into parenchymal cells or through facilitating proliferation and differentiation of cells already present to mediate the repair. Numerous questions remain about if and how stem cells can facilitate organ repair.

ROLE OF ENDOTHELIAL PROGENITOR CELLS IN LUNG REPAIR

The studies presented by Yamada and colleagues¹ in this issue of Thorax address an important aspect about endothelial progenitor cells (EPC) in lung repair. They show that patients with pneumonia confined to one lobe and no other illnesses have circulating EPC in their blood within the first day of illness, and that this number is decreased 8 weeks after treatment and recovery. Their data provide strong evidence that inflammation in the lungs induces release of progenitor cells from the bone marrow that are capable of differentiating toward endothelial cell phenotypes upon culturing in appropriate growth media. Most curiously, the patients who had fibrotic changes persisting at 8 weeks were the ones with low numbers of circulating EPC within the first 28 hours of pneumonia. These data raise the possibility that circulating EPC may contribute to normal lung repair.

As with all good clinical studies, these results raise more questions than they answer. Are these circulating EPC retained within the lungs and what is their fate? Do they participate in the repair of the lungs and, if so, what role do they play? Studies examining the lungs of patients with transplanted haematopoietic stem cells from a donor of a different sex than the recipient have proved to be helpful in showing that donor-derived endothelial and epithelial cells are present within the lungs, and many studies in other species have also supported this concept.^20,21 In healthy lungs there may be little need for stem cells to contribute to the turnover rates of parenchymal cells, as this turnover is quite slow and may occur through relatively undifferentiated cells within the lung tissue. In mice the incorporation and differentiation of marrow-derived stem cells into lung parenchymal cells is also, at best, very slow. However, when the lung is injured, the role of circulating stem cells probably becomes quite different. Yamada and other investigators have previously shown in mice that stem cells are required for the normal repair of lung tissue following pneumonia induced by lipopolysaccharide.² Intra-airway lipopolysaccharide induced release of bone marrow-derived progenitor stem cells and their accumulation within the lungs, where they develop features of an endothelial cell phenotype. In elastase-induced emphysema, cells derived from the bone marrow develop characteristics of endothelial cells and contribute to repair of the alveolar capillary wall.^3,4 Differentiation of marrow-derived stem cells toward epithelial cell phenotypes also occurs in this region.^2–4 Studies focused on vascular repair in other organs suggest that stem cells have a role in the repair through inducing endogenous vascular proliferation and are not the only cells contributing to the new vasculature. Thus, there appear to be several roles for progenitor cells in repair of the lungs and other tissues.

Important questions remain unsolved regarding the environment and the mechanisms through which progenitor cells accumulate, differentiate, and participate in lung repair. The lungs are ideally positioned to trap the progenitor cells, since the bone marrow sinusoids empty into the venous circulation and the pulmonary microvasculature is the first capillary bed through which these cells must pass. The narrow diameter of the capillaries compared with the size of most leucocytes and stem cells suggests that their trafficking through the pulmonary capillary bed will require considerable time and deformation.^22,23 Long transit times through the pulmonary capillaries may allow stem cells to sample the microenvironment and determine whether pneumonia or other lung injuries are present and repair is needed. Adhesion molecules may also play a role in the retention of these cells, and complex signalling mechanisms between chemokines and adhesion molecules are probably required, similar to the paradigms for retention of leucocytes in the lungs. Interactions between SDF-1 and CXCR4 as well as integrins, immunoglobulin-like adhesion molecules, and selectins may be required.

Once the cells are retained at the site of pulmonary inflammation, questions focus on how they differentiate toward parenchymal cell phenotypes. Studies by Ishizawa et al⁴ have suggested that hepatocyte growth factor plays an important role in the proliferation of endothelial cells in the lungs of mice with elastase-induced emphysema, suggesting that this growth factor is important in the process of lung repair. Other traditional and novel growth factors are also likely to contribute, and understanding the signalling pathways underlying differentiation and the features of the microenvironment that enhance differentiation and lung repair would be valuable and provide potential therapeutic options. Furthermore, if these progenitor cells are not themselves differentiating and contributing to repair, then understanding how they alter the microenvironment and regulate repair would also be critical to our understanding of lung disease.

Another interesting question raised by the work of Yamada et al is which parenchymal cells need to be replaced by circulating progenitor cells and whether replacing only the endothelial cells can enhance the repair and resolution of inflammation. One might hypothesise that differentiation of the progenitor cells towards an endothelial cell phenotype might be sufficient for providing the structure necessary for repair of the alveolar walls. The spotty and focal differentiation of progenitor cells in recovering inflammatory lesions^2,3 suggests that replacement of damaged endothelial cells may be sufficient to help with the repair. Other critical questions include the degree of differentiation that is necessary for functional repair; how similar must EPCs become to endogenous lung capillary endothelial cells to facilitate repair?

Finally, questions remain regarding the mechanisms through which progenitor cells are released from the bone marrow during the inflammatory process. The authors found an association between the numbers of circulating monocytes and lymphocytes and the numbers of circulating EPC, leading them to suggest that EPC are released through similar mechanisms as these leucocytes. Questions about the molecules that mediate release of EPC and whether these mechanisms are, in fact, common to other leucocytes beg further study. Our understanding of the mechanisms through which cells are released from the bone marrow is minimal, despite contributions from many outstanding scientists. How mechanisms thought to retain cells within the bone marrow work and how these mechanisms of retention are balanced by stimuli for release are unclear. While many commonalities are likely to exist, specific features that may be responsible for the release of one population over another might prove very beneficial and form the basis of a therapeutic intervention. Surprising effects of vascular endothelial growth factor 1 and of inhibitors of HMG-CoA reductase in inducing marrow release of EPCs are harbingers of observations likely to appear.^24–26

IMPLICATIONS FOR THE FUTURE

The critical question put forward by this paper and others is therefore—what role do circulating EPCs and other progenitor cells play in the resolution of pneumonia and other pulmonary inflammatory events? Yamada et al¹ have successfully translated their initial studies in mice to provide data showing that pneumonia increases the number of circulating EPC and tantalising observations that these EPC are important in effective lung repair. If a role for progenitor cells can be demonstrated in the repopulation of lung parenchymal cells themselves or in regulating the differentiation of other cells and the resolution of injury, then efforts to understand these mechanisms become critical. Differential release of progenitor cells from the bone marrow without enhancing the release of neutrophils and monocytes—which may act to damage the lung once host defence mechanisms have destroyed the offending organism—have an extraordinary therapeutic potential. Ways to manipulate the microenvironment to enhance lung repair, particularly in patients who are immunocompromised and have inadequate bone marrow responses, would have obvious therapeutic benefits. Determining which of the myriad of progenitor cells are critical in repairing lung injuries could lead to important approaches of cell based treatments where effective progenitor cells were infused in patients with acute and chronic inflammatory diseases, pulmonary hypertension, or other lung diseases. Modifying the function of these progenitor cells through gene therapy may expand their potential uses. Furthermore, understanding how to modify differentiation might also prove beneficial in diseases such as interstitial fibrosis where preventing abnormal fibrotic tissue and enhancing formation of gas exchanging tissue with normal compliance might benefit patients. Finally, one could even envisage growth of new normal lung tissue in patients with a number of lung diseases. All of us would no doubt welcome the day when our biggest problem in pulmonary disease is abuse of lung regeneration therapy by athletes who want to run, skate, jump, swim, bicycle, or ski better without limitations of gas exchange!