Stem Cell Vesicles May Ease Infant Chronic Lung Disease, Rat Study Says

Bronchopulmonary dysplasia is a common complication in premature babies

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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Extracellular vesicles derived from mesenchymal stem cells eased the signs and symptoms of pulmonary hypertension (PH) in a rat model of bronchopulmonary dysplasia (BPD), a study shows.

BPD is one of the most common complications in prematurely born infants who need supplemental oxygen and is marked by airway damage and an increased risk of pulmonary hypertension.

This study was the first to provide guidance about the source of mesenchymal stem cells, dosing, route of administration, and long-term effects, according to the researchers.

“Our findings have significant translational implications for MSC [extracellular vesicle] therapies in preterm infants at high risk for BPD and PH as they provide a fundamental foundation for future clinical trials,” they wrote.

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The study, “Mesenchymal Stem Cell-derived Extracellular Vesicles Prevent Experimental Bronchopulmonary Dysplasia Complicated By Pulmonary Hypertension,” was published in the journal STEM CELLS Translational Medicine.

In BPD, the lungs, airways, and tiny air sacs of the lung (alveoli) are damaged. Up to 25% of infants with the disorder develop PH, characterized by high blood pressure in the blood vessels that supply the lungs, which contributes to worse outcomes.

However, there are limited therapeutic options to prevent PH in infants with the disorder.

What are mesenchymal stem cells?

Mesenchymal stem cells (MSCs) give rise to bone, cartilage, muscle, and fat cells, and have anti-inflammatory and anti-fibrotic (anti-scarring) properties, prevent cell death, and stimulate the growth of new blood vessels.

Extracellular vesicles (EVs) are tiny sacs released by all cells, including MSCs, that contain protein, fat-like lipids, and various RNA molecules that play various essential roles in cell-to-cell communication. Studies indicate that extracellular vesicles derived from MSCs restored alveolar structure and alleviated PH in experimental BPD models.

To confirm these findings and support the transition of MSC EVs from the laboratory to the clinic, researchers at the University of Miami Miller School of Medicine in Florida tested the efficacy of high-quality (GMP-grade) MSC EVs to preserve lung structure and prevent PH in a severe model of BPD.

They also investigated the source of MSCs (bone marrow or umbilical cord), dosing, route of administration, their impact on gene activity, and long-term effects.

The BPD model was created by exposing rats to high oxygen levels (85%), or hyperoxia, up to 14 days after birth. Control rats were exposed to room air oxygen (21%).

Hyperoxia-exposed rats developed PH as shown by significantly elevated blood pressure in the right ventricle (right ventricular systolic pressure or RVSP), part of the heart that pumps blood through the lungs, and right ventricle enlargement due to the increased work caused by high blood pressure.

After administration directly into the windpipe (trachea), EVs from both bone marrow and umbilical cord MSCs significantly reduced right ventricle pressure in PH rats. Although both sources of EVs reduced the degree of right ventricle enlargement, it was most pronounced in the rats treated with MSCs derived from the umbilical cord.

Similarly, both sources of EVs improved the density of blood vessels in the lungs, which had been significantly decreased after hyperoxia exposure, and significantly reduced the thickness of pulmonary vessels, which had increased in PH rats. Moreover, EVs from bone marrow and umbilical cord stem cells prevented the stoppage of alveolar growth, which is seen in infants with severe BPD and pulmonary hypertension.

The team tested low, medium, and high doses of umbilical cord stem cell EVs. Lung blood vessel density and structure, and lung alveolar structure significantly improved following all three doses with no dose-response relationship observed. All doses also showed a similar reduction in markers related to inflammation.

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Injecting EVs directly into the bloodstream showed no significant differences in treatment outcomes compared to the local intratracheal administration.

Examination of gene activity in lung tissue from PH rats with and without EV treatment identified 46 genes with increased activity and 31 genes with reduced activity following treatment. Changes in gene activity were mostly associated with pathways involved in the growth of new blood vessels.

Preterm infants with BPD and PH can experience ongoing lung disease into adulthood. To model this and the effects of the treatment in rats, the researchers administered a single intratracheal dose of umbilical cord MSC EVs to hyperoxia rats three days after birth and monitored them for three months.

After three months, the early induced PH persisted in untreated rats, as shown by elevated RVSP. In comparison, treatment with the single dose maintained significant easing of PH signs, preserved blood vessel growth, and improved alveolar structure.

“Our study is one of the first to provide comprehensive insight into the ideal source, dosing, route, and long-term effects of GMP-grade MSC EVs for BPD and PH,” the researchers concluded.