Within the tiny alveolar sacs of our lungs is an immune cell that surveys and directs the immune response within the lung. This immune cell is called an “alveolar macrophage,” and this cell is an actively phagocytic cell. It gobbles up invading bacteria and foreign material in order to keep the lungs clean. When these cells work normally, they help our lungs function properly. When, however, they go rogue, they can fill the lungs with cells that clog the lungs and prevent you from breathing.
Certain diseases like chronic obstructive pulmonary disease, asthma, and lung fibrosis, have abnormal alveolar macrophages and no specific treatments can appropriately compensate for these abnormalities.
Since alveolar macrophages (AMs) can be made from pluripotent stem cells, perhaps transplanting exogenous AMs derived from pluripotent stem cells can clean up messy lungs.
Martin Post, from the University of Toronto, in Ontario, Canada, and his colleagues tested this very hypothesis in mice. Post and his coworkers differentiated mouse embryonic stem cells by using factor-defined media in order to generate embryonic macrophages that could be grown in culture. Then they conditioned their cells into an alveolar-like phenotype by treating them with the cytokine GM-CSF. The cells were surprisingly like normal AMs, at least in culture.
To test these cells in mice, Post and his group created mice that lacked the ADA (adenine deaminase) gene and these mice lacked proper AM activity and suffered chronic lung damage.
Next, Post’s team transplanted their embryonic stem cell-derived alveolar-like macrophages into the tracheas (windpipes) of these injured animals in order to view their therapeutic potential.
What Post and others saw truly amazed them. Not only was their differentiation protocol wonderfully efficient and adaptable to human pluripotent stem cells, but their PSC-derived macrophages essentially “walked and talked” like regular, normal AMs. These cells made all the right cell surface proteins to be identified as AMs and they engulfed bacteria and dying cells. In fact, they were better phagocytes than bone marrow-derived macrophages.
The implanted macrophages stayed in the airways of the recipient mice for at least 4 weeks, and were able to gobble up other types of rogue white blood cells (i.e., neutrophils) during acute lung injury. Thus, the implanted cells were able to protect the lung from further damage under conditions of lung injury. Additionally, the implanted AMs enhanced tissue repair in the lungs and promoted survival of these mice. Interestingly, the mice did not develop abnormal pathology or teratomas as a result of the implanted macrophages.
Thus, this work from Post and his colleagues shows that pluripotent stem cells are a viable source of therapeutically effective alveolar-like macrophages that can be implanted into the lungs and treat airway diseases. Further experiments in larger animals should prepare this strategy for clinical trials.
This study was published in the American Journal of Respiratory and Critical Care Medicine. published online 05 Jan 2016 as DOI: 10.1164/rccm.201509-1838OC.