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Lung stem cells in health, repair and disease

Lung diseases – including chronic obstructive pulmonary disease (COPD), cancer, lung fibrosis and pneumonia – are among the most common diseases in Europe. Chronic lung diseases can cause severe, protracted illness and ultimately death. This means that patients suffer long hospitalisation times and healthcare systems incur high costs. Research on lung stem cells helps to understand how tissue is maintained, and how the disruption and failure in mechanisms of repair after injury (for example, caused by smoking or air pollution) contribute to the development of these diseases. Understanding how lung stem cells achieve tissue regeneration is helping to develop new treatments to restore functional lung tissue. 

Stem cells in the lung

Our lungs work hard. Someone who lives to 80 years of age will have taken approximately 600 million breaths and experienced a daily airflow of over 10,000 litres. Mammalian lungs are made up of two distinct regions: 

1.     The conducting airway tubes, including the trachea, bronchi, and bronchioles. 

2.     The gas exchange regions, or alveolar spaces. 

Some stem cells contribute to initial lung development. Others help to repair and regenerate the lung throughout life. In adult lungs, scientists have discovered that the regions of the lung each contain unique types of stem cells located in specific niches. Normally, many stem cells are present throughout each region. These cells divide to replace old or damaged lung cells, which maintains the healthy structure and function of lung tissue. 

Diagram of a healthy lung, showing large airways, alveoli, and cell composition

In diseased lungs, the stem cells and the surrounding environment (stem cell niche), can become altered. Consequently, normal lung structure and main functions - filtering the air we breathe and gas exchange - often cannot be well maintained. The causes of these changes are not completely known but can include smoking, air pollution, severe infections and genetic factors. 

In the alveoli of COPD lungs there are fewer alveolar type I cells (the cells responsible for gas exchange). In healthy lungs, alveolar type II cells can make type I cells. While this process still happens in COPD lungs, it is less efficient which explains the reduced numbers of alveolar type 1 cells.  Importantly, the environment surrounding stem cells also changes in disease. There are more macrophages and fibroblasts found in the alveoli of COPD lungs. These surrounding cells can provide signals which change normal stem cell behaviour. 

The stem cell populations in the lung include: 

  • tracheal basal cells 
  • bronchiolar secretory cells (known as club cells) 
  • alveolar type 2 cells 

Division of these stem cells is thought to be sufficient to maintain the lung's structure throughout normal adult life. In response to specific type of injuries distinct progenitor cell populations may respond to enable tissue repair, depending on the region and severity of the injury. 

Approximately 300 million people currently have asthma, being the most common chronic disease in children affecting 14% of children worldwide. 

The lung can roughly be divided into the airways and the alveoli. The air that we breathe is filtered in the airways and oxygen is transferred to the bloodstream in the alveoli. 

In a healthy lung, the different types of stem cells slowly produce new lung cells at the same rate as cells are lost in order to maintain a normal lung structure. Lung stem cells can also rapidly respond to lung injury by making new cells more quickly. In lung diseases these maintenance and repair processes are affected, meaning that fewer functional cells are produced than are required. This means that the lung’s ability to supply the body with oxygen is reduced. This can lead to the symptoms we associate with illness, and in extreme cases, to death.Differences in the composition and behaviour of lung cells have been confirmed in various lung conditions. The lungs of patients with chronic lung diseases show alterations in the airways and in the alveoli, especially after exposure to cigarette smoke. 

For example, the large airways of patients with COPD show: 

  • an increased number of basal cells (basal cell hyperplasia)  
  • loss of ciliated cells 
  • an increased number of mucous-secreting goblet cells. 

Diagram of lung affected by COPD

In diseased lungs, the stem cells and the surrounding environment (stem cell niche), can become altered. Consequently, normal lung structure and main functions - filtering the air we breathe and gas exchange - often cannot be well maintained. The causes of these changes are not completely known but can include smoking, air pollution, severe infections and genetic factors. 

In the alveoli of COPD lungs there are fewer alveolar type I cells (the cells responsible for gas exchange). In healthy lungs, alveolar type II cells can make type I cells. While this process still happens in COPD lungs, it is less efficient which explains the reduced numbers of alveolar type 1 cells.  Importantly, the environment surrounding stem cells also changes in disease. There are more macrophages and fibroblasts found in the alveoli of COPD lungs. These surrounding cells can provide signals which change normal stem cell behaviour. 

 

How might gene and cell therapy help?

250 million people suffer chronic obstructive pulmonary disease (COPD) and 3 million die from it every year, being the third cause of death worldwide. 

Several lung diseases are caused by alterations in one particular gene, including cystic fibrosis, primary ciliary dyskinesia and congenital alveolar proteinosis. 

As an example, cystic fibrosis (CF) is caused by changes in the gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR). This protein is important for regulating the balance of water and salts in tissues. When the protein doesn’t function properly there is a build-up of thick mucus in the lungs, which impairs their function and makes patients susceptible to infection. The goal of gene therapy to treat diseases like CF by restoring the normal function of the affected protein by modifying the DNA in lung cells. Since lung cells are continuously renewing, it might be possible to avoid the need for repeated doses of gene therapy by targeting lung stem cells. 

Gene therapy and lung disease

Gene therapy involves transferring genetic sequences into cells. This is challenging as DNA does not readily pass through cell membranes. Gene therapy therefore requires a vector to transport the genetic material into the cell. 

Replication-deficient viruses (those which cannot multiply within cells and infect other surrounding cells) are used as vectors, as these can carry DNA into cells. The delivery of these viral vectors directly to the lungs might allow DNA modification within patients. This could involve: 

  • the addition of a functional copy of the gene to the genome 
  • gene editing (where the patients’ dysfunctional gene is corrected).  

An alternative approach is to combine cell and gene therapies. We can grow large numbers (expand) of lung stem cells from human lungs in the laboratory. It is therefore possible to grow cells from patient biopsies, infect them with a virus to allow expression of healthy CFTR and then return these corrected cells as a transplant. Current methods to expand cells could, theoretically allow for this to be done on an individual, ‘per-patient’ basis. This would avoid problems associated with the rejection of donor tissue. Most challenging, though, is establishing how to deliver these cells to the injured site, and whether they will be able to integrate into the tissue (engraft) and regenerate the tissue. 

Next steps

91% of the world population lives in places where air quality exceeds the limits suggested by the WHO. This significantly influences the development or worsen of chronic obstructive pulmonary disease (COPD), asthma, interstitial pulmonary disease, pulmonary hypertension or acute respiratory infections 

As scientists improve their knowledge of how human lung stem cells contribute to lung development, maintenance and regeneration our ability to direct these processes with new therapeutics will improve.  

The development of new models is particularly necessary. This will allow scientists to investigate the mechanisms involved in repair and regeneration, and to find out how to promote lung regeneration to treat human lung disease. Novel animal models and ex vivo platforms can provide a basis for a deeper understanding of lung physiology and pathology in humans, and allow the investigation and design of more curative therapies. 

Clinical trials are currently being conducted for treatment of cystic fibrosis. These trials aim to overcome some of the challenges of delivering a functional CFTR gene to patient (stem) cells. 

However, there are still significant hurdles to overcome before cell and gene therapies are routinely used within the context of respiratory disease. More pre-clinical research is still required. However, significant progress is being made in terms of our ability to safely edit the DNA sequence of lung stem cells. This provides hope that this approach might prove a viable route for treating respiratory genetic diseases in the long term.  

Research is still needed to develop strategies for using cell therapies in lungs already damaged by disease. Scientists are investigating the potential of these therapies, in combination with other approaches, to restore damaged structures, and regenerate tissue to improve patients’ breathing once more.in combination with other therapeutic approaches targeting pathological events and addressed towards restoring lung architecture and regenerate functional alveolar units for breathing. 

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