Stem Cell-Derived Exosomes May Prevent Lung Disease in Babies

Now there’s a word you don’t see everyday: Exosome. What on earth is an exosome? They are small, membrane-enclosed vesicles that are released by cells. Exosomes contain proteins and nucleic acids, and they are have surfaces that are decorated with various types of proteins. Exosomes are 40-100 nm in diameter and there are several different cell types that are known to secrete exosomes. Cancer cells use exosomes to mold surrounding cell into structures that the cancer needs (see Huang et al., (2011). Cancer Lett 315, 28-37 and Cho et al., (2012). Int J Oncol. 40(1):130-138). Likewise, exosomes from mesenchymal stem cells seem to delivery proteins and RNA to heart muscle cells that help them heal after a heart attack (Lai et al., Regen. Med. (2011) 6(4), 481–492). Finally, there have been reports that exosomes can protect against tissue injury such as acute kidney damage (see Bruno S, et al. (2009). J. Am. Soc. Nephrol. 20, 1053–1067.

New work from Harvard University’s Boston Children’s Newborn Medicine division in Massachusetts suggests that exosomes from stem cells can protect the fragile lungs of premature babies from serious lung diseases and chronic lung injury. Mesenchymal stem cells (MSCs) can decrease inflammation under several different conditions. They seem to do so by secreting exosomes that hold inflammatory cells at bay. In a mouse model of lung inflammation, infused MSCs can quell inflammation, but the culture medium in which the MSCs were grown can do as good a job and decreasing inflammation as the whole cells. This suggest that the MSCs are making something that assuages inflammation (see Ionescu, L. et al., (2012). Am J Physiol Lung Cell Mol Physiol. doi: 10.​1152/​ajplung.​00144.​2011).

Babies born prematurely have to struggle to get sufficient oxygen into their small, incipient lungs. This causes these poor babies to suffer from chronic oxygen insufficiencies (hypoxia) and they usually need artificial respirators to breathe. The lungs of these babies are susceptible to inflammation and this can lead to chronic lung disease and poor lung function.

Lung inflammation also causes pulmonary hypertension, which simply means that the blood pressure in the artery that carries blood from the heart to the lungs (pulmonary artery) is abnormally high. This causes foaming in the lungs, which reduces gas exchange in the lungs, but the lungs also start to thicken and scar over and that also permanently decreases gas exchange.

Stella Kourembanas is the chair of Boston Medical’s Newborn Medicine Division, and she is heading up investigations into the efficacy of MSC-derived exosomes to stave off inflammation in the lungs of premature babies.

Kourembanas explained, “PH (pulmonary hypertension) is a complex disease fueled by diverse, intertwined cellular and molecular pathways. We have treatments that improve symptoms but no cure, largely because of this complexity. We need to be able to target more than one pathway at a time.”

In 2009, Kourembanas and her colleagues showed that injections of MSCs could prevent PH and chronic lung injury in a newborn mouse model of the disease (Bone marrow stromal cells attenuate lung injury in a murine model of neonatal chronic lung disease (Aslam M, et al., (2009). Am J Respir Crit Care Med. 180(11):1122-30). They also showed that they could achieve the same results by injecting the growth medium that had previously fed the cells.

According to Kourembanas, “We knew, then, that the significant anti-inflammatory and protective effects we saw had to e caused by something released by he MSCs.”

To further their search for factors that heal damaged lungs, Kourembanas and co-workers searched the growth medium of MSCs and they came upon exosomes. By purifying exosomes from the growth medium, Kourembanas’ team showed that the anti-inflammatory effects of the MSCs could be completely recapitulated by simply applying isolated exosomes to the lungs of newborn mice.

Kourembanas said, “We are working to figure out what exactly within the MSC-produced exosomes causes these anti-inflammatory and protective effects. But we know that these exosomes contain microRNAs as well as other nucleic acids. They also induce expression of specific microRNAs in the recipient lung.”

MicroRNAs a small RNA molecules that regulate gene expression. Thousands of microRNAs have been discovered and they are also found in many different biological organisms ranging from plants to worms, to fish, frogs and people.

Kourembanas noted that, “What we may be seeing is the effect of these microRNAs on the expression of multiple genes and the activity of multiple genes and the activity of multiple pathways within the lungs and the immune system all at once.”

Kourembanas hopes that exosome research will someday act alongside stem cell-based therapies. MSC-based exosomes could potentially be used as treatments for premature babies at risk of suffering from chronic lung disease and PH. Also, MSCs are not the only cells that make useful exosomes. Umbilical cord stem cells also secrete exosomes with therapeutic value. Even though many different types of stem cells are recognized by the immune system as foreign, exosomes are not, which gives them an added advantage as therapeutic agents. Kourembanas notes, “they could potentially be collected, banked and given like a drug without the risks of rejection or tumor development that can theoretically come with donor cell or stem cell transplantation.”