Matrix Modulation of Compensatory Lung Regrownth and Progenitor Cell Proliferation in Mice

Hoffman et al. Am J Physiol Lung Cell Mol Physiol., November 9, 2009

Originally the liver was the only major organ which was described as having regenerative potential. However in the last 2 decades studies have been showing that organs such as the heart, brain and kidney have "endogenous stem cells" that are capable of creating a certain, albeit small, degree of regeneration after injury. Generally speaking, the cells associated with regeneration seem to have common properties such as expression of various drug efflux pumps, proteins such as CD133, and to reside in areas of relatively lower oxygen concentration.

The current study examined stem cells that reside in lungs during conditions of stress. Instead of using a fibrosis model, such as bleomycin induced injury, the current study used a unique system in which one of the lungs was removed from the animal. This results in increased demand and pressure in the remaining lung. It was observed that cells possessing the "stem cell" phenotype, CCSP+/SP-C+, as well as type II alveolar epithelial cells, started to multiply in response to the stress of having only one lung. In order to demonstrate that it was the mechanical pressure that was causative of the stem cell proliferation and not other factors, the investigators relieved the pressure by inserting a small catheter, which resulted in decreased proliferation of the pulmonary progenitor cells.

In conditions such as COPD there is a deficient content of the protein elastin, which as the name implies, is associated with maintaining pulmonary elasticity. To mimic this clinical condition, mice that expressed suboptimal levels of elastin were used in some experiments, as well, in some groups mice were treated with the enzyme elastase in order to cause degradation of elastin.

Strikingly, in mice with insufficient elastin the proliferation of stem cells after mechanical stress was completely absent, however some degree of lung regrowth was observed. In other experiments, when the enzyme elastase was administered to mice, the population of endogenous stem cells was found to be lacking from their usual anatomical location, in the bronchioalveolar duct junction.

This study demonstrates that proteins such as elastin play a role in controlling the activity of tissue-resident stem cells. The modification of extracellular matrix by various nutrients or supplements may be a useful method of enhancing the efficacy of cellular therapy. It is known that certain conditions, for example, chronic inflammation, reduces stem cell activity. This study demonstrates that the actual content of the extracellular matrix plays an important role in stem cell effects and should be considered as part of therapeutics development.