It’s not the stem cells but what’s inside them that matters for babies with lung disease

The molecular equivalent of a message in a bottle could open up the possibility of stem cell-based therapies for newborn lung disease — but without the cells. (aturkus/Flickr)

Three years ago, Stella Kourembanas, MD, and S. Alex Mitsialis, PhD, thought they had a major breakthrough in treating pulmonary hypertension (PH) — dangerously high blood pressure in the pulmonary artery (the vessel that carries blood from the heart to the lungs) — and bronchopulmonary dysplasia (BPD) — a chronic lung disease that can affect babies born prematurely or who were put on a ventilator.

The two diseases are complex and serious, often occur together and are currently incurable.

The solution for PH and BPD, the two researchers from Boston Children’s Division of Newborn Medicine thought, was to protect the babies’ fragile lungs with a kind of stem cell called mesenchymal stem cells (MCSs), which can develop into lung tissue.

Their preclinical studies were pretty conclusive. If they transplanted MSCs in mouse models of BPD and PH, the mice didn’t develop the lung inflammation that triggers the disease.

But the results were a little confusing. Even though the mice benefitted from the treatment, few of the transplanted cells were actually incorporated into their injured lungs. And it seemed that the liquid that the cells had been grown in prior to transplantation, called conditioned media, was in some cases even more effective than the cells themselves. Why?

The pair now has an answer, one that could cause doctors and researchers to rethink some of their ideas about stem cell-based therapies.

“We knew that the significant anti-inflammatory and protective effects we saw had to be caused by something released by the MSCs,” explains Kourembanas, who chairs the division. “The question was, what?”

To find out, she and Mitsialis, along with postdoctoral fellow Changjin Lee, PhD, grew MSCs in culture, siphoned off the conditioned media and separated its components to unearth its active ingredient.

That’s when they found the exosomes.

Exosomes are little microscopic packets of proteins, nucleic acids and other materials that cells produce as a kind of a molecular message in a bottle. They’re similar in some ways to the artificial liposomes I wrote about a few weeks ago.

In the case of exosomes from MSCs, that bottle carries messages that stop the cascade of molecular and cellular events that result in PH. And quite effectively at that: in their model, injecting just purified exosomes from MSCs without any cells was enough to prevent the disease.

In contrast, conditioned media depleted of exosomes had no effect on inflammation or PH, nor did exosomes produced by other types of cells, suggesting something unique within the MSC-produced exosomes.

Kourembanas and Mitsialis are now trying to figure out what that something is.

“We know that these exosomes contain certain microRNAs as well as other nucleic acids,” Kourembanas says. “They also induce expression of specific microRNAs in the recipient lung.”

MicroRNAs are small pieces of RNA that regulate gene activity much like the volume knob on a stereo, turning the expression of particular genes up and down. In the two decades since they were first noticed in worms, thousands of microRNAs have been identified in species up and down the evolutionary tree, suggesting they play a fundamental role in the cell’s regulatory machinery.

microRNAs exosomes  newborn lung disease
MicroRNAs packaged in exosomes (the doughnut-like structures above) might regulate gene activity much like the volume knob on a stereo. (Credit: the Kourembanas laboratory)

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

With further study, Kourembanas thinks exosomes could be developed into a direct therapy for premature infants at risk of or suffering from chronic lung disease and PH. They may also hold promise for other diseases fueled by inflammation.

They could also open up new avenues for stem cell-based therapies that don’t rely on the cells themselves.

“Exosomes can be isolated from MSCs from several sources, including the umbilical cord,” she says. “And they can 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.”