Article Summary, from International Journal of COPD 2010:5 81-88. Tillie L Hackett, Darryl A Knight, Don D Sin, Heart and Lung Institute, St Paul’s Hospital, Vancouver, BC, Canada
Chronic obstructive pulmonary disease (COPD) is a worldwide epidemic affecting an estimated 210 million people and accounting for more than three million deaths annually. (1). Over the next 20 years, the World Health Organization expects total COPD mortality to more than double.
In China alone, three million men and women are expected to die from COPD by the year 2030 if current cigarette and biomass exposure trends continue. (2)
Unfortunately, aside from supplemental domiciliary oxygen for the small number of patients who demonstrate resting arterial hypoxemia and smoking cessation for continued smokers, there are no interventions that have been unequivocally shown to prolong survival in patients with COPD (3) and no therapies that can fully restore the lost lung function associated with COPD.
As COPD is characterized by loss of lung tissue and remodeling of the airways, there is growing enthusiasm for using stem and progenitor cells to regenerate healthy parenchymal and airway cells and restore lung function in patients with COPD.
Morphologically, COPD is characterized by two distinct but related pathologic features, ie, bronchiolitis involving predominantly the small airways (airways less than 2 mm in diameter) and emphysema. (4). Emphysema is characterized by dilatation and destruction of lung tissue beyond the terminal bronchioles. The centriacinar form of emphysema is characterized by tissue destruction of the respiratory bronchioles and occurs most frequently in cigarette smokers. Panacinar emphysema, on the other hand, is characterized by destruction of the entire acinar unit and occurs largely in the setting of alpha-1 antitrypsin deficiency. (4)
The key pathophysiologic changes underlying airflow limitation in COPD include the loss of elastic lung recoil pressure due to the destruction of alveolar septa and terminal bronchioles (emphysema), increased airflow resistance due to airway wall remodeling (ie, thickening of small airway wall) and mucoid impaction of the airway lumen. (4) In addition, there is growing evidence that endothelial dysfunction and vascular remodeling initiated by vascular endothelial growth factor-mediated apoptosis of endothelial cells may also contribute to disease progression in COPD. (5)
Although there have been tremendous advances in our understanding of COPD pathobiology over the past two decades, the exact pathologic mechanisms by which emphysema and airway remodeling occur in COPD remain largely a mystery. One of the leading theories is the “inflammatory hypothesis”. Proponents argue that in certain (genetically) susceptible individuals, lung inflammation, which occurs in response to environmental triggers such as air pollution and cigarette smoke, changes from a “normal” response to an abnormal one, characterized by excess innate and adaptive immunity, at some point during the exposure.
Interestingly, once the inflammatory changes are firmly established in the lungs, the removal of the environmental trigger such as cigarette smoke does not fully abrogate the abnormal inflammatory response observed in the airways. Indeed, smokers who discontinue smoking continue to demonstrate airway inflammation. (10)
Another emerging hypothesis relates to accelerated cellular aging, or senescence that results in a series of perturbations in cell morphology and function, ultimately culminating in cell cycle arrest. (11,12) Collectively, there appears to be sufficient evidence to suggest that resident structural cells within the lungs and lymphocytes within the systemic circulation of COPD patients exhibit markers of cellular senescence and accelerated aging, which is potentially detrimental to normal lung repair.
Mechanisms of lung repair
Theoretically, if the reparative and regenerative processes in the lungs can keep up with the destructive, inflammatory, or apoptotic processes, then lung homeostasis can be maintained, leading to the preservation of normal tissue and function. Following epithelial injury, the airway epithelium begins to repair almost immediately. At the wound edge, the (undamaged) epithelial cells de-differentiate and migrate to “cover up” the wounded area and release a variety of proinflammatory cytokines and growth factors to attract proteins and cells needed for restoration of the extracellular matrix, which is crucial for normal wound repair. Once this occurs, re-epithelialization can proceed.
The adult human lung comprises various trophic units which are each lined by specialized types of airway epithelia. (26) The ability of the lung to repair itself in the setting of injury is determined by the molecular events that mobilize the resident stem and progenitor cells within each of the trophic units. Stem cells and progenitors are similar in that they both proliferate and give rise to differentiated cells but only stem cells are capable of self-renewal. (27) The reader is referred to Figure 1 for the putative stem and progenitor cell niches within the human lung.
Resident stem cells within the lung
In contrast to dermal and intestinal epithelia, which are highly proliferative and rapidly renewing, the turnover of the airway epithelium is extremely slow unless injured. (28) Each of the tracheal, bronchial, and alveolar regions within the lung has a distinct resident stem or progenitor cell population which possesses unique cellular physiologic properties. To date, several cells within the trachea and bronchial tissue have been reported to be enriched for stem/progenitor cell activity including cytokeratin 5/14-expressing basal cells, secretory (Clara) cells, cells residing in submucosal glands, and neuroepithelial bodies (NEB). (29–33).
A more recent study indicates that cytokeratin 5/14 expressing basal cells can self-renew and also give rise to new ciliated Clara and secretory cells following epithelial injury. (34)
We have also demonstrated that within human airways the basal cell population contains a side population (SP) of cells, which are characterized by the ability to efflux actively the DNA binding dye, Hoescht 33342. (35)
As with other epithelial tissues such as in mammary glands, (36,37) the eye, (38) and the skin, (39) SP cells within the airways are rare, making up less than 0.1%of the total epithelial cell population.
Both embryonic and adult stem cells in vitro can be induced to differentiate into airway and alveolar epithelial cells.
MSCs isolated from amniotic fluid, umbilical cord blood, adipose tissue, or bone marrow have been used to generate tracheal cartilage using biosynthetic scaffolds in order to repair congenital tracheal defects in rodent models and more recently in human clinical trials. (56–58)
Macchiarini et al were able to use a patient’s epithelial cells and MSC-derived chondrocytes to generate a bioengineered trachea, which after engraftment provided a functional airway without the requirement for immunosuppressive drugs. (59)
Mesenchymal stem cells (MSCs) are nonhematopoietic stem cells of mesodermal origin, with the capacity to differentiate into both mesenchymal and nonmesenchymal lineages.
MSCs are found primarily in the bone marrow of adults and give rise to blood, skeletal muscle, vascular, and connective tissues throughout the body. Postnatally, bone marrow MSC can be isolated from adipose tissue, liver, synovial membrane, teeth, and tendons. In particular, MSCs are easily isolated from a small aspirate of bone marrow and can be expanded with high efficiency. MSCs have great potential in clinical therapy because they express intermediate to low levels of HLA Class I, low levels of HLA Class II, and low levels of costimulatory molecules to avoid self-recognition by the immune system. (69)
In immunocompetent patients, MSCs have also been demonstrated to suppress allogeneic T-cell proliferation and evade alloreactive recognition. (70)
The immunomodulatory properties of MSCs are thought to involve the secretion of soluble mediators and cell-cell contact inhibition; however, the exact mechanisms of action are unclear. (71).
Autologous and allogeneic MSCs are currently being tested in clinical trials for a variety of diseases including Crohn’s disease, multiple sclerosis, diabetes mellitus and end-stage liver disease, and to prevent transplant rejection and restore left ventricular function in patients with congestive heart failure. An open-label Phase II trial utilizing Prochymal ®, an allogenic MSC infusion in patients with severe Crohn’s disease, who were unresponsive to corticosteroids, infliximab (anti-TNF antibody), and other immunosuppressive therapies, has recently been completed. The study reported significant mprovements in symptoms as assessed by the Crohn’s disease activity index (CDAI). This has led to the approval by the Food and Drug Administration for a Phase III doubleblind, placebo-controlled trial of this therapy for the treatment of Crohn’s disease. (77)
Despite significant progress in our understanding of lung stem cells and their functional capacities over the past decade, much remains unknown about the processes involved in lung repair. Accumulating data from both animal models and clinical trials suggest that adult-derived stem cells may provide potential therapeutic strategies for lung repair in COPD.